Eccentric punching shear can occur in concrete slab-column connections when the connection is subjected to shear and unbalanced moments. Typically, this situation results in edge and corner columns and is thus a common practical case. However, most punching experiments in the literature are concentric punching shear. This paper presents a developed database of eighty-eight experiments of flat slabs under eccentric punching shear, including a summary of the testing procedure of each reference and a description of the slab specimens. Additionally, a linear finite element analysis of all the specimens is included to determine the relevant sectional shear forces and moments. Finally, the ultimate shear stresses from the database experiments are compared to the shear capacities determined with ACI 318-19, Eurocode 2 NEN-EN 1992-1-1:2005, and the Model Code 2010. The comparison shows that the Model Code 2010 is the most precise in the predictions with an average tested over predicted ratio of 0.96 and a coefficient of variation of 27.96%. It can be concluded that this study represents the inconsistencies of the currently used design methods and the lack of experimental information.

In this study, we evaluated and compared several major carbon sequestration methods based on the first principles, namely, energy use efficiency and elemental stoichiometry. This study suggested that, at present, wood burial is the only feasible carbon sequestration method because it can be implemented immediately on a large scale, is cost-effective and efficient, has a long sequestration time, has low technical requirements, and has a relatively low impact on agriculture.

Up to 25% of early human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) patients will relapse despite the improvement achieved by the introduction of HER2-targeted therapy. Beyond trastuzumab, other agents approved for early HER2+ BC include the monoclonal antibody pertuzumab, the antibody-drug conjugate (ADC) trastuzumab-emtansine (T-DM1) and the reversible HER2 inhibitor lapatinib. New agents, such as trastuzumab-deruxtecan or tucatinib in combination with capecitabine and trastuzumab, have also shown an improvement in the metastatic setting. Other therapeutic strategies to overcome treatment resistance have been explored in HER2+ BC, mainly in HER2+ that also overexpress estrogen receptors (ER+). One strategy has been to target the cyclin-dependent kinases 4/6 (CDK4/6) as they are downstream of HER2 and many of the cellular pathways associated with resistance to HER2-targeted therapies play a key role in cell cycle and proliferation. Different trials have explored these strategies with encouraging results, but definitive results are needed. In addition, HER2+ BC is known to be more immunogenic than other BC subgroups, with high variability between tumors. Different immunotherapeutic agents have been investigated in this setting, with promising but controversial results obtained to date.

On a bleak therapeutic landscape unchanged since the 1980’s, IVF with egg donation still stand as the lone medical answer to diminished reserve and premature ovarian insufficiency. Intraovarian platelet-rich plasma (PRP) crossed the horizon in 2016 as hopeful answer to these intertwined problems. The once remote mirage of platelet cytokine effects on gene regulation or telomere stabilization is now in sharper focus, and current work is clarifying how PRP corrects oxidative stress, rectifies tissue hypoxia, downregulates apoptosis, and enhances cellular metabolism. Not yet ready for routine use, this investigational treatment does offer one point of general agreement: How intraovarian PRP results should be classified—Patients are either responders or non-responders. From this, it is intriguing that no published PRP protocol has reported a supranormal ovarian rebound or hyperstimulation effect. This could be explained by baseline age-related ovarian conditions prevalent among poor responders, but since dysregulated or malignant transformations are also absent in other tissue contexts following autologous PRP treatment, the contribution of some platelet product which intrinsically delimits regenerative action cannot be discounted. Here we summarize results with recent experimental and clinical platelet research, framing those most likely to help advance reproductive endocrinology practice.

Existing research has focused on discussing various issues in isolation, e.g., climate change or deglobalisation, without capturing the geo-political, legal, socio-economic, and technological implications in a holistic manner, especially in China and Southeast Asia. This has hindered the derivation of clear guidelines to navigate the business environment in the next decade, thus leaving the business world with fragmented theories and concepts that are hard to amalgamate and turn into tangible business strategies. Thus, this study illustrates the key challenges that are likely to influence the stability and sustainability of the global business environment by 2030, as well as suggests the main business strategies to leverage to mitigate them. This contribution, for the first time, proposes an alternative holistic approach by highlighting the key threats to global business in the next decade, as well as suggesting clear action points to account for the main ones from geo-political, legal, socio-economic, and technological standpoints in a unified theory. Local and more tailored strategies are described and discussed as referred to various industries to help in navigating a deglobalised and more competitive market by 2030.

Solid tumours are characterized by an altered microenvironment (TME) from the physi-cochemical point of view, displaying a highly hypoxic and acidic interstitial fluid. Hy-poxia results from uncontrolled proliferation, aberrant vascularization and altered can-cer cell metabolism. Tumour cellular apparatus adapt to hypoxia by altering its metab-olism and behaviour, increasing its migratory and metastatic abilities by acquisition of a mesenchymal phenotype and selection of aggressive tumour cell clones. Extracellular acidosis is considered a cancer hallmark, acting as a driver of cancer aggressiveness by promoting tumour metastasis and chemoresistance by selecting for more aggressive cell phenotypes, although the underlying mechanism is still not clear. In this context, Ca2+ channels represent good target candidates due to their ability to integrate signals from the TME. Ca2+ channels are pH and hypoxia sensors and alterations in Ca2+ homeostasis in cancer progression and vascularization have been extensively reported. The present review will focus on Ca2+ permeable ion channels, with a major focus on TRP, SOC and PIEZO channels, that are modulated by tumour hypoxia and acidosis as well as the role of the resulted altered Ca2+ signals on cancer progression hallmarks. A deeper compre-hension of the Ca2+ signaling and acidic pH/hypoxia interplay will break new ground for the discovery of alternative and attractive therapeutics targets.

Two extensions of the generalized double Lomax distribution are introduced - the spliced-scale generalized double Lomax distribution and the exponentiated generalized double Lomax distribution. Their properties are studied. Usefulness of the new distributions is shown by fitting them to stock returns datasets.

For decades since the central dogma, cancer biology research has been focusing on the involvement of genes encoding proteins. It has been not until more recent times that a new molecular class has been discovered, named non-coding RNA (ncRNA), which has been shown to play crucial roles in shaping the activity of cells. An extraordinary number of studies into shown that ncRNAs represent an extensive and prevalent group of RNAs, including both oncogenic or tumor suppressive molecules. Henceforth, various clinical trials involving ncRNAs as extra ordinary biomarkers or therapies have started to emerge. In this review, we will focus on the prognostic and diagnostic role of ncRNAs for breast cancer.

Rheumatoid arthritis (RA) is a chronic, systemic, abnormal inflammatory immune response. It is characterized by the involvement of the synovium and multiple organs and the destruction of joints and articular cartilage. Over the past 30 years, several promising novel compounds and antibodies have been developed for the treatment of RA. The introduction of new drugs and precision medicine for all forms of RA raises several issues related to access to novel treatments by patients, optimal regimen selection, cost-effectiveness, prognosis monitoring and outcome surveillance, particularly with regarding to the development of low drug response rates, drug resistance and adverse side effects. Tremendous attention has been given to the identification of optimized drug combinations for the treatment of RA, particularly in early high-risk vulnerable and early individuals. Addressing these issues requires novel therapeutic approaches with new mechanisms and the establishment of accurate guidelines for drug selection, drug recombination, and non-chemical therapeutic efforts. In this study, we reviewed the most exciting recently established or ongoing novel drugs and methods according to the clinical trial database maintained by the United States National Library of Medicine and discussed the trends in RA drug development and challenges in the treatment, providing a reference significant for the accurate treatment of RA and the research direction in the future.

In the development of the safety-critical systems, it is important to perform Failure Modes and Effects Analysis (FMEA) process to identify potential failures. However, traditional FMEA activities tend to be considered difficult and time-consuming tasks. To compensate for the difficulty of the FMEA task, various types of tools are used to increase the quality and the effectiveness of the FMEA reports. This paper explains an Automatic FMEA tool which integrates the Model-based Design (MBD), FMEA, and Simulated Fault Injection techniques in a single environment. The Automatic FMEA tool has the following advantages compared to the existing FMEA analysis tool. First, the Automatic FMEA tool automatically generates FMEA reports compared to the traditional spreadsheet-based FMEA tools. Second, the Automatic FMEA tool analyzes the causality between the failure modes and the failure effects by performing model-based fault injection simulation. In order to demonstrate the applicability of the Automatic FMEA, we used the electronic fuel injection system (EFI) Simulink model. The results of the Automatic FMEA were compared to that of the legacy FMEA.

Natural compounds have diverse structures and are present in different forms of life. Metabolites such as tannins, anthocyanins, and alkaloids, among others, serve as a defense mechanism in live organisms and are undoubtedly compounds of interest for the food, cosmetic and pharmaceutical industries. Plants, bacteria, and insects represent a source of biomolecules with diverse activities, poorly studied in many cases. To use these molecules for different applications, it is essential to know their structure, concentrations, and biological activity potential. In vitro techniques that evaluate the biological activity of the molecules of interest have been developed since the 1950s. Currently, different methodologies have emerged to overcome some of the limitations of these traditional techniques, mainly the reduction of time and costs. However, emerging technologies continue to appear due to the urgent need to expand the analysis capacity of a growing number of reported biomolecules and the lack of therapeutic options to treat various diseases. This review presents an updated summary of the conventional and current methods to evaluate natural compounds' biological activity, including a diagram that summarizes the minimum techniques essential for correctly assessing molecules with biological potential.

Chemotherapy-induced peripheral neuropathy (CIPN) develops as a challenging nerve-damaging adverse effect of anticancer drugs used in chemotherapy. The disorder may require a dose reduction of chemo-therapy and its most common sensory symptoms are severe pain, tingling, and numbness in the hands and feet. CIPN affects dramatically the patient's quality of life (QoL). Pain and sensory abnormalities may occur for months, or even years after the termination of chemotherapy. This disease has complicated pathophysiology featured by underlying mechanisms not completely known. Although many pharmaco-logical and non-pharmacological therapeutic approaches have been tested to overcome these symptoms, there is currently no standardized cure to prevent or treat CIPN. According to current guidelines, Duloxe-tine is the only recommended agent for painful neuropathic symptoms. Therefore, finding effective thera-pies for CIPN is mandatory. The purpose of this review is to dissect CIPN, the target and immunothera-py-based approaches to this disorder, as well as to offer new insights for novel therapeutic perspectives.

Zephyranthes citrina Baker is a bulbous herb, commonly known as yellow rain lily belongs to the family Amaryllidaceae. It is a native of tropical and subtropical America but nowadays it is cultivated as a popular ornamental herb in several parts of the world including India. This herb represents one of the richest sources of phytochemicals, especially alkaloids and possesses great potential for pharmaceutical applications. It shows remarkable antiprotozoal, antimicrobial, anti-Alzheimer, cytotoxic, antioxidant, anti-inflammatory, analgesic, and dye removal activities. This review is an effort to give a detailed study of the literature on the biological activities of Zephyranthes citrina. This review concludes that Zephyranthes citrina has a great potential to treat various diseases and could be used as a source for novel healthcare products in the near future, which requires further experimentation.

Since the discovery of the Coronavirus disease 2019 (COVID-19) outbreak, a vast majority of studies have been carried out that confirmed the worst outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in people with preexisting health conditions, including diabetes, obesity, hypertension, cancer, and cardiovascular diseases. Likewise, diabetes itself is one of the leading causes of global public health concerns that impose a heavy global burden on public health as well as socio-economic development. Both diabetes and SARS-CoV-2 infection have their independent ability to induce the pathogenesis and severity of multi-system organ dysfunction, while the co-existence of these two culprits can accelerate the pathophysiology and magnify the severity of the diseases. However, the exact pathophysiology of multi-system organ failure in diabetic patients after SARS-CoV-2 infection is still obscure. This review summarized the organ-specific possible molecular mechanisms of SARS-CoV-2 and diabetes-induced pathophysiology of several diseases of multiple organs, including the lungs, heart, kidney, brain, eyes, gastrointestinal system, and bones, and subsequent manifestation of multi-system organ failure.

As its capital, Jakarta plays a critical role in boosting Indonesia’s economic growth and setting the precedent for broader change outside of the city. One crucial avenue of inquiry to better understand, and prepare for, the future of a country so heavily impacted by disastrous weather events is understanding the effects of climate change through data. This study investigates meteorological data collected from 1996 to 2021 and compares the application of the SARIMA and the Holt-Winters methods to predict the future influence of climatic parameters on Jakarta’s weather. The performance of the SARIMA method is proven to provide better results than the Holt-Winter models and both methods showed the best performances when forecasting the humidity data. The results of the forecast are able to demonstrate the characteristic of the climate in Jakarta, with dry season ranging from May to October and wet season ranging from November to April.

The cuttlebone-like structure is a complex porous bionic structure with asymmetric sinusoidal S-shaped wall structure connecting laminar septa, and studies have shown that the cuttlebone-like structure has light weight, high strength and excellent energy absorption capability. It has become an important research to investigate the mechanical mechanism of cuttlebone-like structure and to design a bionic structure beyond nature structure based on it. In order to investigate the mechanical properties of the static compression and shearing processes of the cuttlebone-like structure, this paper establishes theoretical formulas and analyzes the influence of dimensionless parameters such as height-to-thickness ratio $\lambda$, period-to-thickness ratio $\xi$ and amplitude to period ratio $\eta$ on the compression and shearing processes with the help of ABAQUS finite element software.The parameter sensitivity analysis method was used to compare the important influence degree of each dimensionless parameter on the mechanical properties of the structure and to determine the relative optimal parameters of the structural mechanical properties under compression and shearing. Based on the relatively optimal parameter of the cuttlebone-like structure, the cross-sectional geometry of the structure is improved to build a new cuttlebone-like structure.The experimental results showed that the new cuttlebone-like structure with revised cross-section improved the mechanical properties of the cuttlebone-like structure.The study results are of theoretical guidance to enhance the mechanical properties and geometric design of cuttlebone-like structures.

Background The spread of COVID-19 continues, the mutation of SARS-COV-2 is still difficult to control, and the need for antiviral drugs to treat COVID-19 remains urgent. The use of arbidol in the treatment of COVID-19 is limited and controversial. Methods To clarify the efficacy of arbidol on COVID-19, we collected 25 cases and 178 related studies. We analyzed the treatment information of arbidol based on the obtained cases, expanded the scope of the study, and collected current studies on the treatment of COVID-19 in various databases for in-depth analysis. Results History analysis showed that arbidol was effective (76% cure rate) compared with other drugs. However, compared with other antiviral drugs or standard therapy, the arbidol group had no significant advantage in reducing the time to negative virus transformation, length of hospital stays, or improvement in CT (MD=0.22, 95%CI -0.29-0.73; MD = 0.61, 95% CI 1.46 to 2.67; RR=1.15, 95%CI 0.88-1.50); Analysis of adverse events showed no significant difference between the arbidol group and the other groups (RR=0.82, 95%CI 0.25-2.71). Conclusion Our study showed that arbidol had no significant effect on COVID-19, but showed a slight advantage in CT improvement and adverse events. Our study objectively evaluated the efficacy of arbidol in the treatment of COVID-19 and provided some guidance for arbidol in the treatment of COVID-19.

Buildings can generate heats which are mostly generated from the machinery using inside the buildings, and these heats generally released to the atmosphere. Buildings can also block the wind flow by their canopies and trap the heat by using low albedo materials. These causes pointedly contribute to urban heat island and greenhouse effects. Likewise, urban development and building construction in Cambodia are growing rapidly. The construction has been recognized as a key development sector while thousands of buildings are being built and have been operated in the main cities. However, those buildings mostly have not been considered to incorporate sustainability concepts while the major final energy consumers in the country are buildings. The buildings’ energy consumption is also projected to increase more than double until 2040. Hence, sustainable building promotion in Cambodia is necessary, and sustainable building criteria are completely required. This research aims to find out significant sustainable building criteria for Cambodia and focused on planning and design criteria because having proper planning and design is a smart start leading to achieving building sustainability in all stages. This research used the Delphi methods to validate the relevant sustainable building criteria available in the literature and then select the significant ones for Cambodia based on the Delphi consensus. The results showed that ninety-nine consensus planning and design criteria were found to be significant for sustainable buildings in Cambodia.

It is shown that the representation theory of some finitely presented groups thanks to their $SL_2(\mathbb{C})$ character variety is related to algebraic surfaces. We make use of the Enriques-Kodaira classification of algebraic surfaces and the related topological tools to make such surfaces explicit. We study the connection of $SL_2(\mathbb{C})$ character varieties to topological quantum computing (TQC) as an alternative to the concept of anyons. The Hopf link $H$, whose character variety is a Del Pezzo surface $f_H$ (the trace of the commutator), is the kernel of our view of TQC. Qutrit and two-qubit magic state computing, derived from the trefoil knot in our previous work, may be seen as TQC from the Hopf link. The character variety of some two-generator Bianchi groups as well as that of the fundamental group for the singular fibers $\tilde{E}_6$ and $\tilde{D}_4$ contain $f_H$. A surface birationally equivalent to a $K_3$ surface is another compound of their character varieties.

The one-to-one structural correspondence between any conjugated hydrocarbon CnHm and the borane BnHm+n is extended here, with the B3LYP/cc-pVDZ model, to pure conjugated carbon systems with the example of buckminsterfullerene C60 with the corresponding icosahedral isoelectronic system closo-borane B60H60, and the fluorine substituted systems B60F30H30 and B60F60 , all with icosahedral Ih symmetry. All systems correspond to energy minima in the potential energy hypersurface, except for B60(F30)in(H30)out . Selected electronic structure methods are used to characterize all systems: molecular electrostatic potentials (MEP), atomic charges, bond orders, and topological properties of the electron density within quantum theory of atoms-in-molecules (QTAIM) and electron-localization function (ELF) theory. In the particular case of B60H60 we use the recently developed Hückeloid model to characterize this system. The stability of the energy minimum icosahedral structure B60F60 could have an origin in F···F attractive interactions of the inner fluorine atoms of the cage.

Proteases or peptidases are hydrolases that catalyze the breakdown of polypeptide chains into smaller peptide subunits. Proteases exist in all life forms, including archaea, bacteria, protozoa, insects, animals, and plants, due to their vital functions in cellular processing and regulation. There are several classes of proteases in the MEROPS database based on their catalytic mecha-nisms. This review focuses on the post-proline cleaving enzymes (PPCEs), especially the prolyl endoprotease/oligopeptidase (PEP/POP). To date, most PPCEs studied are of microbial and ani-mal origins. Recently, there are reports of new plant PPCEs. The most common PEP/POP are members of the S9 family that comprise two conserved domains. The substrate-limiting β-propeller domain prevents unwanted digestion, while the α/β hydrolase catalyzes reaction at the carboxyl-terminal of proline residues. PPCEs have diverse applications, are widely used in the beer brewing industry, and have potential as therapeutic agents for Alzheimer’s disease and celiac disease by targeting proline-rich substrates. Protein engineering via mutagenesis has been performed to improve heat resistance, pepsin-resistant capability, specificity, and protein turno-ver of PPCEs for pharmacological applications. This is the first comprehensive review to cover the biotechnological applications of PPCEs and discuss the unique prolyl cleaving activity of dif-ferent enzymes based on the recent structure-function studies from diverse taxa.

Starting from a very simple economic scenario, we build on it a game and then we introduce a general strategy able to reduce a regression problem to an equivalent binary classification problem. This reduction scheme (that we call adaptive reduction or also dynamic reduction) can be also used to derive a new boosting algorithm for regression problems named bOOst^d. The bOOst^d algorithm is very simple to implement, and it can use any learning algorithm with no priori assumptions. We present a conjecture for bOOst^d performances, which ensures a little error on training set. More important we can also provide a very good theoretical upper bound for the generalization error. We give a set of preliminary experimental results that seems to confirm our conjecture for bOOst^d performances on training set and the theoretical assumptions for the generalization error. We also provide a possible justification of why boosting often does not overfit. Finally, we leave some open problems and argue that in the future an adaptive single boosting (with an unique code) algorithm for binary, multi class and regression problems can be derived.

During the last decades, zebrafish (Danio rerio) has become one of the most important model organisms to study different physiological and biological phenomena. Research field of carbonic anhydrases (CAs) and carbonic anhydrase related proteins (CARPs) is not an exception in this. The best-known known function of CAs is the regulation of acid-base balance. However, studies performed with zebrafish, among others, have revealed important roles for these proteins in many other physiological processes, some of which have been unpredicted in the light of the previous studies and suggestions. Examples are roles in zebrafish pigmentation as well as motor coordination. Disruption of the function of these proteins may generate even lethal outcomes. In this review, we summarize the current knowledge of CA-related studies performed in zebrafish.

Even though hard, low friction coatings such as diamond like carbon (DLC) would be beneficial for the per-formance and longevity of rubber seals, a crucial challenge – as graphically illustrated in Figure 1.a – remains. The elastic mismatch of rubber substrate and DLC coating prevents a fracture free coating application. In this work a nature inspired approach (Figure 1.b) is applied to render the stiff coating flexible and resilient to delamination at the same time by direct patterning. Rubber substrates were laser structured with tile patterns and subsequently DLC-coated. Tensile and tribology tests were performed on structured and unstructured samples. Unstructured DLC-coatings showed a crack pattern induced by the coating process, which was further fragmented by tensile stress. Coatings with tile patterns did not experience a further fragmentation under load. During continuous tribological loading, less heterogenous damage is produced for tile structured samples. The findings are ascribed to the relief of induced coating stress by the tile structure, meaning a more resilient coating.

A key goal of modern neuroscience involves understanding how connections in the brain form and function. Such a knowledge is essential to better inform how defects in the exquisitely complex steps of nervous system growth underlie neuropsychiatric and neurodevelopmental disorders. In the last 40 years, studies of the nervous system in the fruit fly Drosophila melanogaster enabled the discovery of a wealth of molecular and genetic mechanisms that drive the development of these synaptic connections – specialized cell-to-cell connections that are the essential substrate for information flow and processing in the nervous system. The major driver of knowledge focused on studies at the neuromuscular junction due to its ease of examination. Analogous studies in the central nervous system lagged behind due to a lack of genetic accessibility of specific central neuron classes, appropriate synaptic labels compatible with cell-type specific access, and high resolution, quantitative imaging strategies. However, understanding how synapses in central circuits form remains a prerequisite to understanding brain development. In the last decade, a host of new tools and techniques made possible the extension of genetic studies of synapse organization into central circuits and greatly enhanced our understanding of central synapse formation, organization, and maturation. In this review, we consider the current state-of-the-field, focusing on two major elements. We first discuss the tools, technologies, and strategies developed to visualize and quantify synapses in vivo in genetically identifiable neurons of the Drosophila CNS. Second, we explore in depth how these tools enabled a clearer understanding of synaptic development and organization in different circuits of the fly brain and discovered novel molecular mechanisms that underlie synapse formation. These studies establish multiple brain regions in the fly as powerful in vivo genetic models that offer novel insights into synaptogenic regulators and mechanisms of neural development.

Optical motion capture systems are prone to the errors connected with markers recognition – occlusion, leaving the scene or mislabelling – all these errors are then corrected in the software, but still, the process is not perfect, resulting in artifact distortions. In the article, we examine four existing types of artifacts, then propose the method for detection and classification of the distortions. The algorithm is based on the derivative analysis, low-pass filtering, mathematical morphology and loose predictor. The tests involved multiple simulations using synthetically distorted sequences, comparison of performance to the human operators on real life data and applicability analysis for the distortion removal.

Epilepsy and Alzheimer's disease (AD) incidence increase with age. There are reciprocal relationships between epilepsy and AD. Epilepsy is a risk factor for AD and, in turn, AD is an independent risk factor for developing epilepsy in old age and abnormal AD biomarkers in PET and or CSF are frequently found in late onset epilepsies of unknown etiology. Accordingly, epilepsy and AD share pathophysiological processes including neuronal hyperexcitability and an early excitatory-inhibitory dysregulation leading to dysfunction in the inhibitory GABAergic and excitatory glutamatergic systems. Moreover, both β-amyloid and tau protein aggregates, the anatomopathological hallmarks of AD, have proepileptic effects. Finally, these aggregates have been found in the resection material of refractory temporal lobe epilepsies suggesting that epilepsy leads to amyloid and tau aggregates. Some epileptic syndromes, such as medial temporal lobe epilepsy share structural and functional neuroimaging findings with AD, leading to overlapping symptomatology such as episodic memory deficits and toxic synergistic effects. In this respect, the existence of epileptiform activity and electroclinical seizures in AD appears to accelerate progression of cognitive decline and the presence of cognitive decline is much more prevalent in epileptic patients than in elderly without epilepsy. Notwithstanding their clinical significance, the diagnosis of clinical seizures in AD is a challenge. Most are focal and manifest with altered level of consciousness without motor symptoms, and are often interpreted as cognitive fluctuations. Finally, despite the frequent association of epilepsy and AD dementia, there is a lack of clinical trials to guide the use of antiseizure medications (ASM). There is also a potential role for ASMs to be used as disease-modifying drugs in AD.

An increasing body of evidence shows that seaweeds, including kelp, can be used as a tool to neutralize or remove excess nutrients and metals from the water column. Here we report on a preliminary field assessment showing potential nutrient and carbon removal differences by sugar kelp and ribbon kelp grown in common gardens. Seawater and tissue samples were collected systematically from two farms in Alaska. Results show differences between % N and % C content between ribbon kelp (Alaria marginata) and sugar kelp (Saccharina latissima). Results also show that tissue nitrogen in ribbon kelp varies sharply due to nitrogen availability in the water column. In contrast, the percentage of tissue N in sugar kelp remains comparatively stable. Our outcomes provide insight into potential differences in nutrient removal and harvest timing for different kelp species.

Long-term, multi-decade research on planted tree survival in urban settings is sparse. One understudied urban environment is highway rights-of-way (ROW), lands adjacent to high-speed, unsignalized roadways. We conducted a re-inventory of tree planting cohort in northern Illinois, U.S. on a 48 km-long highway near Chicago which were 10-, 21-, and 30-years old to evaluate long-term patterns of survival and diversity. Using each randomly selected planting site along the highway as a unit of observation and analysis, we compared the number of trees documented in record drawing to the number of trees currently alive to determine percent survival. We evaluated 224 planting sites which originally contained 2,944 trees and collected data about the planting site location. For the oldest cohort, 26% of trees were still alive in 2018 (median survival by species = 16%, Q1 = 0%, Q3 = 48%), while 31% of the 21-year-old cohort (med. = 6%, Q1 = 0%, Q3 = 47%) and 86% of the 10-year-old cohort were still alive (med. = 85%, Q1 = 74%, Q3 = 96%). The survival of the 21- and 30-year-old cohort matches urban tree survival estimates by other researchers, while the 10-year-old survival is higher than expected. The only planting location characteristic that significantly affected survival was traffic islands (areas between the highway and entrance/exit ramps). Species with low drought tolerance were less likely to be alive for the 10-year-old cohort. Waterlogging tolerant species were more likely to be alive in the 10-year-old cohort. Since some species in the 21- and 30-year-old cohorts had very low survival, the tree species richness and diversity s in study areas declined between the initial record drawings and reinventory. This study demonstrates the challenges of maintaining long-term survival and diversity in the highway ROW and emphasizes the importance of species selection.

Two once-through steam generators and a combination of a steam generator and a gas preheater for supplying feed gases to solid-oxide electrolysis stacks were evaluated for their carryover characteristics of contaminants from the feed-water into the steam phase. The concentrations of various trace impurities in the steam were determined by sampling the steam condensates and screening them with inductively coupled plasma - mass spectrometry for 19 elements and liquid ion chromatography and continuous flow analysis for chloride and ammonium. Steam soluble species like boric acid undergo complete volatilization and transfer into the steam phase. During unstable evaporation in the steam generators an extensive physical carryover of alloying metal species was observed. At realistic operation conditions for steam electrolysis, the gas preheater caused a considerable release of silicon into the steam phase. Two stack experiments were performed with common preheater temperatures and showed largely increased cell voltage degradation at higher operation temperatures. The post-test chemical analysis of cell samples revealed significant concentrations of silicon in the samples that are regarded as primary cause for increased degradation. These findings could partially explain the wide spread of degradation rates reported for solid-oxide steam electrolysis experiments.

The time symmetry of T_c = CT is redefined based on the 4-D Euclidean space. The time inversion symmetry of T_c = CT changes the signs of the charge (q) and absolute time (ct) of the particle. The P symmetry changes the signs of the space momenta and handedness of the particle. The T_c symmetry changes the signs of the time momentum (P_t=E/c) and charges. The handedness are classified as the left-handedness and right-handedness on the 3-D space. The charges (|q| = cDt) and energies (E= cDtDV) of the particles are originated from the upward warping (q>0) and downward warping (q<0) of the particles along the time axis. The evolution of our matter universe with P_t > 0 since the big bang can be interpreted based on the CTP symmetry with the partner antimatter universe with p_t < 0. The photon space is called as the vacuum space. Then the E and M waves are the space fluctuations, and the gravitational G wave is the time fluctuations. And the E, M and G fields are newly explained. The zero E and M fields of the photon space indicates that the photon space and gamma ray are the 2EM waves. The rest mass energy of the particle is the 4-D space volume of the warped photon space. In the present work, the quantum wave function is considered as the 4-D vector with the space wave function and time axis wave function in the 4-D Euclidean space. The warped photon space corresponds to the squared wave function which is the probability density. It is concluded that, in the quantum mechanics, the imaginary number concept is introduced in the quantum wave functions instead of the time axis component of the 4-D wave function vector. The left-handed neutrino puzzle is explained from the handedness partner relation with the right-handed dark matters. Finally, the modified Lorentz transformations derived in the 4-D Euclidean space are compared with the Lorentz transformations of the special and general relativity theories in the 4-D Minkowski space.

Urban flood risk mapping is an important tool for the mitigation of flooding in view of human activities and climate change. Many developing countries, however, lack sufficiently detailed data to produce reliable risk maps with existing methods. Thus, improved methods are needed that can improve urban flood risk management in regions with scarce hydrological data. Given this, we estimated the flood risk map for Rasht City (Iran), applying a composition of decision-making and machine learning methods. Flood hazard maps were produced applying six state-of-the-art machine learning methods such as classification and regression trees (CART), random forest (RF), boosted regression trees (BRT), multivariate adaptive regression splines (MARS), multivariate discriminant analysis (MDA), and support vector machine (SVM). Flood conditioning parameters applied in modeling were elevation, slope angle, aspect, rainfall, distance to river (DTR), distance to streets (DTS), soil hydrological group (SHG), curve number (CN), distance to urban drainage (DTUD), urban drainage density (UDD), and land use. In total, 93 flood location points were collected from the regional water company of Gilan province combined with field surveys. We used the Analytic Hierarchy Process (AHP) decision-making tool for creating an urban flood vulnerability map, which is according to population density (PD), dwelling quality (DQ), household income (HI), distance to cultural heritage (DTCH), distance to medical centers and hospitals (DTMCH), and land use. Then, the urban flood risk map was derived according to flood vulnerability and flood hazard maps. Evaluation of models was performed using receiver-operator characteristic curve (ROC), accuracy, probability of detection (POD), false alarm ratio (FAR), and precision. The findings showed that the CART method is most accurate method (AUC = 0.947, accuracy = 0.892, POD = 0.867, FAR = 0.071, and precision = 0.929). The results also demonstrated that DTR, UDD, and DTUD played important roles in flood hazard modeling; whereas, the population density was the most significant parameter in vulnerability mapping. These findings indicated that machine learning methods can improve urban flood risk management significantly in regions with limited hydrological data.

IT auditing quality has been defined by results obtained in the process. Meanwhile, multiple studies have been done to enhance it therefore, it continues to be a topic interest and research so it is worth mentioning that its quality relies on trained competent auditors and experts able to develop a process correctly, adapting to clients and to manage auditing inherent risks According to results from the IT audit, low quality and security levels have been identified in terms of the human, technical and contextual factors, affecting audit quality. The objective of this investigation is to identify metrics and to determine their own corresponding factor applying an exploratory type of research. In order to achieve such aim, a targeted survey was designed and implemented at the Institute of Internal Auditors of Ecuador since they have the knowledge and expertise in the field. A factor analysis statistics technique was applied to data gathered to verify that it relates to the identified factors as dimensions are reduced, thus the most impacting metrics may assess the quality of IT audits. Analysis results yielded a mean score for each one of the assessed metrics, concluding that the technical factor is the most significative since it relates roles and task performance during the auditing process as well as control proce-dures. Finally, most auditing quality-related issues are mainly the outcome of an inferior management auditing process, therefore it is crucial that collegiate groups and professionals in the field validate the auditing process.

Analyzing the records of Advanced LIGO and Virgo gravitational observatories, we found a specific time-domain asymmetry inherent only to the signals of their gravitational detectors. Experiments with different periodic signals, Gaussian and non-Gaussian noises, made it possible to conclude that the noise of gravitational detectors is an unusual mixture of signals. We also developed a specialized Pearson correlation analyzer to recognize the gravitational-wave events. It turned out that the LIGO detectors’ output signals include a significant (– 6 dB) component, which has the properties of records of reliably recognized gravitational waves. It allows us to argue that the gravitational background noise is largely due to the processes of merging astronomical objects. Since the specific signal is registered by the detectors continuously, we can consider the sub-kilohertz band gravitational oscillations field as detected. Our analysis method also allows us to estimate the contribution of the gravitational background component to the total signal energy. With its help, it will be possible not only to provide the radio-frequency estimation of the magnitude of gravitational disturbances but also, possibly, to construct a map of the gravitational noise of the sky.

Tumor cells evolve in a complex and heterogeneous environment composed of different cell types and an extracellular matrix. Current 2D culture methods are very limited in their ability to mimic the cancer cell environment. In recent years, various 3D models of cancer cells have been developed, notably in the form of spheroids/organoids, using scaffold or cancer-on-chip devices. However, these models have the disadvantage of not being able to precisely control the organization of multiple cell types in complex architecture and are sometimes not very reproducible in their production, and this is especially true for spheroids. Three-dimensional bioprinting can produce complex, multi-cellular, and reproducible constructs in which the matrix composition and rigidity can be adapted locally or globally to the tumor model studied. For these reasons, 3D bioprinting seems to be the technique of choice to mimic the tumor microenvironment in vivo as closely as possible. In this review, we discuss different 3D-bioprinting technologies, including bioinks and crosslinkers that can be used for in vitro cancer models, and the techniques used to study cells grown in hydrogels; finally, we provide some applications of bioprinted cancer models.

In this paper, we examine the weak deflection angle and greybody factor of magnetized regular black hole. We implement the Gauss-Bonnet theorem on magnetized regular black hole to get the deflection angle. Moreover, we analyze the influence of plasma and non-plasma mediums on deflection angle of magnetized regular black hole. We observe the graphical behaviour of plasma and non-plasma mediums on deflection angle of magnetized regular black hole. Lastly, we study the rigorous bound phenomenon of the greybody factor of magnetized regular black hole. For this purpose we calculate greybody factor results and analyze the graphical behaviour of greybody bound for the different values of the parameters.

Since 1974, when Heinz von Foerster made the distinction between “the cybernetics of observed systems” as first-order cybernetics (1oC) and “the cybernetics of observing systems” as second-order cybernetics (2oC), cybernetics has been dominated by this observer-centric paradigm that he claimed cannot be extended meaningfully to a third-order. Rather than attempting to extend his paradigm, we derive an alternative, model-centric paradigm from first principles of regulation that naturally extends to three orders, where the third order is ethical regulation. We thus consider a type of regulator that requires a third model and a third observer: If the third model is a model of acceptable (ethical) situations, then a third observer is a necessary element of the system’s “conscience” that prevents or detects any violations of the model of ethical situations. In this paradigm, the cybernetics of systems that are designed to exhibit ethical behaviour can be characterized as third-order cybernetics (3oC). By being able to extend the paradigm to include ethical systems, the model-centric paradigm brings clarity and utility that is not possible using the philosopher-friendly observer-centric paradigm and its under-specified (abstract) observers. Finally new definitions for cybernetics are proposed that clearly differentiate between the science and the philosophy, of cybernetics.

Due to a lack of knowledge about arthropod biodiversity in Egyptian organic agro-ecosystems; the study aimed to introduce information on the diversity, richness, and distribution of insect and mite species in two organic agro-ecosystems, also, to investigate the impact of plant-arthropod interactions. Samples collected from two organic farms, i) Shampoliah farm, Fayoum (GCS 29°21'07.4"N 30°44'17.8"E), and ii) SEKEM farm, Sharkia (GCS 18 30°22'56.1"N 31°39'17.4"E). Results shown 39 species recorded in Shampoliah farm, and 35 species in SEKEM of mite, insect, medicinal, and weed species. When 14 species shared among two sites. Study has measured the H', D and 1/D indices within each location, and the similarity/dissimilarity between locations. The study hypothesized the possible plant-arthropod interactions that explain why diversity differs from an ecosystem to another; due to; plant size, plant morphological characters, soil fertilization, plant nutritional content, and the prey-predator interactions. The added hypothesis; is to show that the importance of natural habitat is supporting natural enemies and distribution of arthropods, which could vary dramatically with the type of pest species, IPM, and landscape type considered.

The National Research Centre’s experimental research station (NRCERS) locates in Wadi El Natrun, Egypt 30°29'54.22"N 30°19'10.94"E. The NRCERS has various crop yields (vegetables, fruits, ornamental, and field crops) for different experimental treatments. It followed conventional agricultural procedures in vegetation, fertilisation, irrigation, and plant protection. Such policies have not been evaluated for their impacts on arthropod diversity and distribution. Thus, this study conclusion aims to sufficiently map the arthropod species (pest/predators) distribution, measure the biodiversity indices, to the NRCERS agricultural policies to be modified to support arthropod diversity.

Fungi kingdom comprises ubiquitous forms of life with 1.5 billion years, mostly phytopathogenic and commensal for humans and animals. However, in the presence of impaired conditions fungi may cause disease by intoxicating, infecting or sensitizing with allergy. Different genera may be implicated as etiological agents for humans and animals, with Alternaria, Aspergillus, dermatophytes like Microsporum and Trichophyton, and Malassezia as the commonly implicated. Alternaria and Malassezia stand as the most commonly associated to either allergy or infection, immediately followed by Aspergillus, while dermatophytes are usually associated to ring worm skin infection. Research in veterinary field is not much but necessary.

Biosecurity is a tool used to alleviate the introduction, emergence and spread of diseases caused by infectious agents. It comprises different health-management activities that need to be followed to reduce the passage and dissemination of infectious agents within and among farms, poultry flocks, and humans, as well as within a country, among countries, or the whole globe. In terms of public health measures, biosecurity applies to practices that will reduce contact between poultry and humans and thereby reduce zoonotic disease transmission. Two of the common biosecurity measures are bioexclusion and biocontainment which themselves are further categorized as segregation/isolation, movement control and hygiene/sanitation/disinfection. Isolation is about putting poultry under an exclusively isolated environment where it lives alone without any interference from any source external to the poultry or at least under reduced and controlled interference. Movement/traffic control and sanitation measures are practices to follow the isolation of poultry or preparatory phase as in the case of sanitation of poultry houses before introduction of poultry. These techniques have been effective in controlling poultry diseases like avian influenza, exotic Newcastle, Marek’s disease, and any other diseases. Depending upon the underlying situation either bioexclusion or biocontainment measure will be used to control these infectious diseases of poultry.

With the current technological transformation in the automotive industry, autonomous vehicles are getting closer to the Society of Automative Engineers (SAE) automation level 5. This level corresponds to the full vehicle automation, where the driving system autonomously monitors and navigates the environment. With SAE-level 5, the concept of a Shared Autonomous Vehicle (SAV) will soon become a reality and mainstream. The main purpose of an SAV is to allow unrelated passengers to share an autonomous vehicle without a driver/moderator inside the shared space. However, to ensure their safety and well-being until they reach their final destination, it is required an active monitoring of all passengers. In this context, this article presents a microphone-based sensor system that is able to localize sound events inside an SAV. The solution is composed of a Micro-Electro-Mechanical System (MEMS) microphone array with a circular geometry connected to an embedded processing platform that resorts to Field-Programmable Gate Array (FPGA) technology to successfully process in hardware the sound localization algorithms.

NF-κB is a central mediator of inflammation, response to DNA damage and oxidative stress. As a result of its central role in so many important cellular processes, NF-κB dysregulation has been implicated in the pathology of important human diseases. NF-κB activation causes inappropriate inflammatory responses in diseases including rheumatoid arthritis (RA) and multiple sclerosis (MS). Thus, modulation of NF-κB signaling is being widely investigated as an approach to treat chronic inflammatory diseases, autoimmunity and cancer. The emergence of COVID-19 in late 2019, the subsequent pandemic and the huge clinical burden of patients with life-threatening SARS-CoV-2 pneumonia led to a massive scramble to repurpose existing medicines to treat lung inflammation in a wide range of healthcare systems. These efforts continue and these efforts continue to be con-troversial. Drug repurposing strategies are a promising alternative to de-novo drug development, as they minimize drug development timelines and reduce the risk of failure due to unexpected side effects. Different experimental approaches have been applied to identify existing medicines which inhibit NF-κB that could be repurposed as anti-inflammatory drugs.

New setting is introduced to study the alliances. Alliances are about a set of vertices which are applied into the setting of neutrosophic graphs. Neighborhood has the key role to define these notions. Also, neighborhood is defined based on the edges, strong edges and some edges which are coming from connectedness. These three types of edges get a framework as neighborhood and after that, too close vertices have key role to define offensive alliance, defensive alliance, t-offensive alliance, and t-defensive alliance based on three types of edges, common edges, strong edges and some edges which are coming from connectedness. The structure of set is studied and general results are obtained. Also, some classes of neutrosophic graphs containing complete, empty, path, cycle, bipartite, t-partite, star and wheel are investigated in the terms of set, minimal set, number, and neutrosophic number. In this study, there’s an open way to extend these results into the family of these classes of neutrosophic graphs. The family of neutrosophic graphs aren’t study but it seems that analogous results are determined. There’s a question. How can be related to each other, two sets partitioning the vertex set of a graph? The ideas of neighborhood and neighbors based on different edges illustrate open way to get results. A set is alliance when two sets partitioning vertex set have uniform structure. All members of set have different amount of neighbors in the set and out of set. It leads us to the notion of offensive and defensive. New ideas, offensive alliance, defensive alliance, t-offensive alliance, t-defensive alliance, strong offensive alliance, strong defensive alliance, strong t-offensive alliance, strong t-defensive alliance, connected offensive alliance, connected defensive alliance, connected t-offensive alliance, and connected t-defensive alliance are introduced. Two numbers concerning cardinality and neutrosophic cardinality of alliances are introduced. A set is alliance when its complement make a relation in the terms of neighborhood. Different edges make different neighborhoods. Three types of edges are applied to define three styles of neighborhoods. General edges, strong edges and connected edges are used where connected edges are the edges arising from connectedness amid two endpoints of the edges. These notions are applied into neutrosophic graphs as individuals and family of them. Independent set as an alliance is a special set which has no neighbor inside and it implies some drawbacks for this notions. Finding special sets which are well-known, is an open way to purse this study. Special set which its members have only one neighbor inside, characterize the connected components where the cardinality of its complement is the number of connected components. Some problems are proposed to pursue this study. Basic familiarities with graph theory and neutrosophic graph theory are proposed for this article.

Abstract: In network science and big data, the concept of finding meaningful infrastructures in networks has emerged as a method of finding groups of entities with similar properties within very complex systems. The whole concept is generally based on finding subnetworks which have more properties (links) amongst nodes belonging to the same cluster than nodes in other groups (A concept presented by Girvan and Newman, 2002). Today meaningful infrastructure identification is applied in all types of networks from computer networks, to social networks to biological networks. In this article we will look at how meaningful infrastructure identification is applied in biological networks. This concept is important in biological networks as it helps scientist discover patterns in proteins or drugs which helps in solving many medical mysteries. This article will encompass the different algorithms that are used for meaningful infrastructure identification in biological networks. These include Genetic Algorithm, Differential Evolution, Water Cycle Algorithm (WCA), Walktrap Algorithm, Connect Intensity Iteration Algorithm (CIIA), Firefly algorithms and Overlapping Multiple Label Propagation Algorithm. These al-gorithms are compared with using performance measurement parameters such as the Mod-ularity, Normalized Mutual Information, Functional Enrichment, Recall and Precision, Re-dundancy, Purity and Surprise, which we will also discuss here.

Presently power control and management play a vigorous role in information technology and power management. Instead of non-renewable power manufacturing, renewable power manufacturing is preferred by every organization for controlling resource consumption, price reduction and efficient power management. Smart grid efficiently satisfies these requirements with the integration of machine learning algorithms. Machine learning algorithms are used in a smart grid for power requirement prediction, power distribution, failure identification etc. The proposed Random Forest-based smart grid system classifies the power grid into different zones like high and low power utilization. The power zones are divided into number of sub-zones and map to random forest branches. The sub-zone and branch mapping process used to identify the quantity of power utilized and the non-utilized in a zone. The non-utilized power quantity and location of power availabilities are identified and distributed the required quantity of power to the requester in a minimal response time and price. The priority power scheduling algorithm collect request from consumer and send the request to producer based on priority. The producer analysed the requester existing power utilization quantity and availability of power for scheduling the power distribution to the requester based on priority. The proposed Random Forest based sustainability and price optimization technique in smart grid experimental results are compared to existing machine learning techniques like SVM, KNN and NB. The proposed random forest-based identification technique identifies the exact location of the power availability, which takes minimal processing time and quick responses to the requestor. Additionally, the smart meter based smart grid technique identifies the faults in short time duration than the conventional energy management technique is also proven in the experimental results.

At the level of the 50 U.S. states, an interconnected nexus of well-being variables exists. These variables have been shown to strongly correlate with estimates of state IQ in interesting ways. But the state IQ estimates (McDaniel 2006) are now more than 16 years old, and the state well-being estimates (Pesta et al., 2010) are over 12 years old. Updated state IQ and well-being estimates are therefore needed. I thus first created new state IQ estimates by analyzing scores from both the Program for the International Assessment of Adult Competency (for adults), and the National Assessment of Educational Progress (for fourth and eighth grade children) exams. I also created new global well-being scores by analyzing state variables from the following four well-being subdomains: crime, income, health, and education. When validating the nexus, several interesting correlations existed among the variables. For example, state IQ most strongly predicted FICO credit scores, alcohol consumption (directly), income inequality, and state temperature. Interestingly, state IQ derived here also correlated .58 with state IQ estimates from over 100 years ago. Global well-being likewise correlated with many old and new variables in the nexus, including a correlation of .80 with IQ. In sum, at the level of the U.S. state, a nexus of important, strongly correlated variables exists. These variables comprise well-being, and state IQ is a central node in this network.

Transcription factors (TFs) are proteins that recognize specific DNA fragments in order to decode the genome and ensure its optimal functioning. TFs work at the local and global scales by specifying cell type, cell growth and death, cell migration, organization and timely tasks. We investigate the structure of DNA-binding motifs with the theory of finitely generated groups. The DNA ‘word’ in the binding domain -the motif- may be seen as the generator of a finitely generated group Fdna on four letters, the bases A, T, G and C. It is shown that, most of the time, the DNA-binding motifs have subgroup structure close to free groups of rank three or less, a property that we call ‘syntactical freedom’. Such a property is associated to the aperiodicity of the motif when it is seen as a substitution sequence. Examples are provided for the major families of TFs such as leucine zipper factors, zinc finger factors, homeo-domain factors, etc. We also discuss the exceptions to the existence of such a DNA syntactical rule and their functional role. This includes the TATA box in the promoter region of some genes, the single nucleotide markers (SNP) and the motifs of some genes of ubiquitous role in transcription and regulation.

So-called ‘zero’ or ‘null’ tenses have often been characterized as functionally deficient forms, deprived of any inherent content. In this paper, we will focus on the semantics of a morpho-phonologically null inflectional verbal paradigm in Anindilyakwa (Groote Eylandt, N.T., Australia, which is both temporally and aspectually underspecified. Through a quantitative corpus study conducted in the paper, we establish that ‘zero inflection’ in this language, contra prior works on such tenses in general (e.g. Bybee 1990) and in Anindilyakwa in particular (Bednall 2019), presents various degrees of sensitivity to traditional Vendlerian aspectual parameters. We show that while telicity is not a significant predictor for the temporal interpretation of zero-inflected Anindilyakwa verbs, and dynamicity is a good but not very good predictor, only a very broad opposition between change-of-state (including qua boundedness) and non-change-of-state, or perfective/imperfective, gives very significant biases towards past vs. present anchoring. We also show that atomic telicity is the only categorical Aktionsart predictor for temporal anchoring in this context correctly predict the temporal anchoring of such verbs, and stativity is not biased towards present interpretations, thereby questioning currently received typological theories of the semantics of so-called ‘zero-tenses’ / aspectuo-temporally underspecified tenses.

We report the strong coupling between plasmonic surface lattice resonances (SLRs) and photonic Fabry-Pérot (F-P) resonances in a microcavity embedded with two-dimensional periodic array of metal-insulator-metal nanopillars. For such a plasmonic-photonic system, we show that the SLR can be strongly coupled to the F-P resonances of both the odd- and even orders, and that the splitting energy reaches as high as 138 meV in the visible regime. We expect that this work will provide a new scheme for strong coupling between plasmonic and photonic modes.

Familial colorectal cancer (CRC) is only partially explained by known germline predisposing genes. We performed whole genome sequencing in 15 Polish families of many affected individuals, without mutations in known CRC predisposing genes. We focused on loss-of-function variants and functionally characterized them. We identified a frameshift variant in the CYBA gene (c.246delC) in one family and a splice site variant in the TRPM4 gene (c.25-1 G>T) in another family. While both variants were absent or extremely rare in gene variant databases, we identified four additional Polish familial CRC cases and two healthy elderly individuals with the CYBA variant (odds ratio 2.46, 95% confidence interval 0.48-12.69). Both variants led to a premature stop codon and to a truncated protein. Functional characterization of the variants showed that knockdown of CYBA or TRPM4 depressed generation of reactive oxygen species (ROS) in LS174T and HT-29 cell lines. Knockdown of TRPM4 resulted in decreased MUC2 protein production. CYBA encodes a component in the NADPH oxidase system which generates ROS and controls, e.g., bacterial colonization in the gut. Germline CYBA variants are associated with early onset inflammatory bowel disease, supported with experimental evidence on loss of intestinal mucus barrier function due to ROS deficiency. TRPM4 encodes a calcium-activated ion channel, which in a human colonic cancer cell line controls calcium-mediated secretion of MUC2, a major component of intestinal mucus barrier. We suggest that the gene defects in CYBA and TRPM4 mechanistically involve intestinal barrier integrity through ROS and mucus biology, which converges in chronic bowel inflammation.

Several preclinical and clinical reports have demonstrated that levels of circulating high mobility group box 1 protein (HMGB1) are increased early after trauma and are associated with systemic inflammation and clinical outcomes. However, the mechanisms of the interaction between HMGB1 and inflammatory mediators that lead to the development of remote organ damage after trauma remain obscure. HMGB1 and inflammatory mediators were analyzed in plasma from 54 combat casualties, collected on admission to a military hospital in Iraq, and at 8 and 24 hours after admission. Forty-five (83%) of these patients had traumatic brain injury (TBI). Nine healthy volunteers were enrolled as controls. HMGB1 plasma levels were significantly increased in the first 8 hours after admission, and were found to be associated with systemic inflammatory responses, injury severity score, and presence of TBI. These data provided the rationale for designing experiments in rats subjected to blast injury and hemorrhage, to explore the effect of HMGB1 inhibition by CX-01. Animals were cannulated, then recovered for 5-7 days before blast injury in a shock tube and volume-controlled hemorrhage. Blast injury and hemorrhage induced an early increase in HMGB1 plasma levels that coincided with severity of tissue damage and mortality. CX-01 inhibited systemic HMGB1 release, decreased local and systemic inflammatory responses, significantly reduced tissue and organ damage, and tended to increase survival. These data suggest that CX-01 has potential as an adjuvant treatment for traumatic hemorrhage.

Cherries have been largely investigated due to their high content in phenolics in order to fully ex-plore their health-promoting properties. Therefore, this work aimed to assess, for the first time, the anti-inflammatory potential of phenolic-targeted fractions of Saco cherry, using RAW 264.7 mac-rophages stimulated with lipopolysaccharide. Additionally, the cytotoxic effects on gastric ade-nocarcinoma (AGS), neuroblastoma (SH-SY5Y) and normal human dermal fibroblast (NHDF) cells were evaluated, as well as the ability to protect these cellular models against induced oxidative stress. The obtained data revealed that cherry fractions can interfere with cellular nitric oxide (NO) levels by capturing NO radicals and decreasing inducible nitric oxide synthase and cyclooxygen-ase-2 expression. Furthermore, it was observed that all cherry fractions exhibited dose-dependent cytotoxicity against AGS cells, presenting cytotoxic selectivity for these cancer cells when compared to SH-SY5Y and NHDF cells. Regarding their capacity to protect cancer cells against oxidative injury, in most assays, the total cherry extract was the most effective. Overall, this study reinforces the sweet cherries incorporation in new pharmaceutical products, smart foods and nutraceuticals.

The modern paradigm of studying the processes of carcinogenesis and vital activity of tumor tissues implies increased attention to constituents of tumor microenvironment (TME) and their interactions. These interactions between the cells in TME can be mediated via protein junctions of different types. Connexins (Cnxs) are one of the major contributors to intercellular communication. They form gap junctions responsible for the transfer of ions, metabolites, peptides, miRNA, etc. between neighboring tumor cells as well as between tumor and stromal cells. Cnx hemichannels mediate purinergic signaling and bidirectional molecular transport with the extracellular environment. Additionally, Cnxs were reported to localize in tumor-derived exosomes and facilitate the release of their cargo. A large body of evidence implies that the role of connexins in cancer is multifaceted. Pro- or anti-tumorigenic properties of connexins are determined by their abundance, localization and functionality as well as channel assembly and non-channel functions. In this review we have summarized the data on the Cnxs contribution in TME and to the cancer initiation and progression.

Adipor1^tm1Dgen and Mfrp^rd6 mutant mice share similar eye disease characteristics. Previously, studies established a functional relationship of ADIPOR1 and MFRP proteins in maintaining retinal lipidome homeostasis and visual function. However, the independent and/or interactive contribution of both the genes to similar disease phenotypes, including fundus spots, decreased axial length and photoreceptor degeneration has yet to be examined. We performed a gene-interaction study where homozygous Adipor1^tm1Dgen and Mfrp^rd6 mice were bred together and the resulting doubly heterozygous F1 offspring were intercrossed to produce 210 F2 progeny. Four-month-old mice from all nine genotypic combinations obtained in the F2 generation were assessed for white spots by fundus photo documentation, for axial length by caliper measurements, and for photoreceptor degeneration by histology. Two-way factorial ANOVA was performed to study individual as well as gene interaction effects on each phenotype. Here, we report the first observation of reduced axial length in Adipor1^tmlDgen homozygotes. We show that while Adipor1 and Mfrp interact to affect spotting and degeneration, they act independently to control axial length, highlighting the complex functional association between these two genes. Further examination of the molecular basis of this interaction may help in uncovering mechanisms by which these genes perturb ocular homeostasis.

Cutaneous lymphocytosis (CL) is an uncommon and controversial lymphoproliferative disorder described in dogs and cats. CL is generally characterized by a heterogeneous clinical presentation and histological features that may overlap with epitheliotropic lymphoma. Therefore, its neoplastic or reactive nature is still debated. Here, we describe clinicopathological, immunohistochemical and clonality features of a retrospective case series of 19 cats and 10 dogs with lesions histologically compatible with CL. In both species, alopecia, erythema and scales were the most frequent clinical signs. Histologically, a dermal infiltrate of small to medium-sized lymphocytes, occasionally extending to the subcutis, was always identified. Conversely, when present, epitheliotropism was generally mild. In cats, the infiltrate was consistently CD3+; in dogs, a mixture of CD3+ and CD20+ lymphocytes was observed only in 4 cases. The infiltrate was polyclonal in all cats, while BCR and TCR clonal rearrangements were identified in dogs. Overall, cats had a long-term survival (median overall survival=1080 days) regardless of the treatment received, while dogs showed a shorter and variable clinical course, with no evident associations with clinicopathological features. In conclusion, our results support a reactive nature of the disease in cats, associated with prolonged survival; despite a similar histological picture, canine CL was associated with a more heterogeneous lymphocytic infiltrate, clonality results, and response to treatment.

Deficiency of Cytochrome P450 Steroid 21-hydroxylase (CYP21A2) represents 90% of cases in congenital adrenal hyperplasia (CAH), an autosomal recessive disease caused by defects in cortisol biosynthesis. Computational prediction along with functional studies are often the only way to classify variants to understand the links to disease-causing effects. Here we investigated the pathogenicity of uncharacterized variants in the CYP21A2 gene reported in the Brazilian and Portuguese populations. Physicochemical alterations, residue conservation, and effect on protein structure were accessed by computational analysis. The enzymatic performance was obtained by functional assay with the wild-type and mutant CYP21A2 proteins expressed in HEK293 cells. Computational analysis showed that p.W202R, p.E352V, and p.R484L have severely impaired the protein structure, while p.P35L, p.L199P, and p.P433L have moderate effects. The p.W202R, p.E352V, p.P433L, and p.R484L variants showed residual 21OH activity consistent with the simple virilizing phenotype. The p.P35L and p.L199P variants showed partial 21OH efficiency associated with the non-classical phenotype. Additionally, p.W202R, p.E352V and p.R484L also modified the protein expression level. We have determined how the selected CYP21A2 gene mutations affect the 21OH activity through structural and activity alteration contributing to the future diagnosis and management of 21OH deficiency.

Today, more disciplines are intercepting each other, giving rise to “cross-disciplinary” research. Technological advancements in material science and device structure and production have paved the way towards development of new classes of multi-purpose sensory devices. Organic phototransistors (OPTs) are photo-activated sensors based on organic field-effect transistors that convert incident light signals into electrical signals. The organic semiconductor (OSC) layer and three-electrode structure of an OPT offer great advantages for light detection compared to conventional photodetectors and photodiodes, due to their signal amplification and noise reduction characteristics. Solution processing of the active layer enables mass production of OPT devices at significantly reduced cost. The chemical structure of OSCs can be modified accordingly to fulfil detection at various wavelengths for different purposes. Organic phototransistors have attracted substantial interest in a variety of fields, namely biomedical, medical diagnostics, healthcare, energy, security, and environmental monitoring. Lightweight and mechanically flexible and wearable OPTs are suitable alternatives not only at clinical levels but also for point-of-care and home-assisted usage. In this review, we aim to explain different types, working mechanism and figures of merit of organic phototransistors and highlight the recent advances from the literature on development and implementation of OPTs for a broad range of research and real-life applications.

Hypercytokinemia, or cytokine storm, is one of the severe complications of viral and bacterial infections, involving the release of abnormal amounts of cytokines, resulting in a massive inflammatory response. Cytokine storm is associated with COVID-19 and sepsis high mortality rate by developing epithelial dysfunction and coagulopathy, leading to thromboembolism and multiple organ dysfunction syndrome. The anticoagulant therapy is an important tactic to prevent thrombosis in sepsis and COVID-19, but recent data show the incompatibility of modern direct oral anticoagulants and antiviral agents. It seems relevant to develop dual-action drugs with antiviral and anticoagulant properties. At the same time it was shown that azolo[1,5-a]pyrimidines are heterocycles with a broad spectrum of antiviral activity. We have synthesized a new family of azolo[1,5-a]pyrimidines and their condensed polycyclic analogs by cyclocondensation reactions and direct CH-functionalization and studied their anticoagulant properties. Five compounds among 1,2,4-triazolo[1,5-a]pyrimidin-7-ones and 5-alkyl-1,3,4-thiadiazolo[3,2-a]purin-8-ones demonstrated higher anticoagulant activity than the reference drug, dabigatran etexilate. Antithrombin activity of lead compounds was confirmed using lipopolysaccharide (LPS) treated blood to mimic conditions of cytokine release syndrome. The studied compounds affected only the thrombin time value, reliably increasing it 6.5–15.2 times as compared to LPS-treated blood.

Polycystic ovary syndrome (PCOS) is increasingly recognized as a complex metabolic disorder that manifests in genetically susceptible women following a range of negative exposures to nutritional and environmental factors related to contemporary lifestyle. The hypothesis that PCOS phenotypes are derived from a mismatch between ancient genetic survival mechanisms and modern lifestyle practices is supported by a diversity of research findings. The proposed evolutionary model of the pathogenesis of PCOS incorporates evidence related to evolutionary theory, genetic studies, in-utero developmental epigenetic programming, transgenerational inheritance, metabolic features including insulin resistance, obesity and the apparent paradox of lean phenotypes, reproductive effects and subfertility, the impact of the microbiome and dysbiosis, endocrine disrupting chemical exposure, and the influence of lifestyle factors such as poor quality diet and physical inactivity. Based on these premises, the diverse lines of research are synthesized into a composite evolutionary model of the pathogenesis of PCOS. It is hoped that this model will assist clinicians and patients to understand the importance of lifestyle interventions in the prevention and management of PCOS and provide a conceptual framework for future research. It is appreciated that this theory represents a synthesis of the current evidence and that it is expected to evolve and change over time.

This work presents a control scheme to control the grid-connected single-phase photovoltaic (PV) system. The considered system has four 250W solar panels, a non-inverting buck-boost DC-DC converter, and DC-AC inverter with LCL filter. The control system aims to track and operate at the maximum power point (MPP) of PV panels, regulate the voltage of DC link, and supply the grid with a unity power factor. To well achieve these goals, the proposed control system consists of three parts, that are MPP tracking controller module with a fuzzy-based modified incremental conductance (INC) algorithm, a DC-link voltage regulator with a hybrid fuzzy proportional-integral (PI) controller, and a Current Controller module using the linear quadratic regulator (LQR) for grid-connected power. Based on fuzzy control and LQR, this work introduces a full control solution for grid-connected single-phase PV systems. The key novelty of this research is to analyze and prove that the newly proposed method is more successful in numerous aspects by comparing and evaluating the previous and present control methods. The designed control system settles quickly, which is critical for output stability. In addition, as compared to backstepping approach used in our past study, the LQR technique is more resistant to sudden changes and disturbances. Furthermore, backstepping method produces the larger overshoot, which has a detrimental impact on efficiency. Simulation findings under various weather conditions were compared to theoretical ones to indicate that the system can deal with variations in weather parameters.

Footprints are powerful indicators for evaluating the impact of the bioeconomy of a country on environmental goods, domestically and abroad. In this study, we apply a hybrid approach combining a Multi-Regional Input-Output model and land use modelling to compute the agricultural land footprint (aLF). Furthermore, we added information on land-use change to the analysis and allocated land conversion to specific commodities. The German case study shows that the aLF abroad is larger by a factor of 2.5 to 3 than the aLF in Germany. In 2005 and 2010, conversion of natural and semi-natural land-cover types abroad allocated to Germany due to import increases was 2.5 times higher than the global average. Import increases to Germany slowed down in 2015 and 2020, reducing land conversion attributed to the German bioeconomy to the global average. The case study shows that the applied land footprint provides clear and meaningful information for policymakers and other stakeholders. The presented methodological approach can be applied to other countries and regions covered in the underlying database EXIOBASE. It can be adapted, also for an assessment of other ecosystem functions, such as water or soil fertility.

Polysaccharides from marine algae exhibit beneficial biological activities. In this study, we examined the effect of polysaccharides from Codium fragile (PCF) on prebiotic and anti-obesity activity. PCF increases the growth of specific beneficial microbial populations with concomitant decrease in pathogenic microbes. Further, total phenolic content (TPC), total flavonoid content (TFC), and DPPH radical scavenging activity (DPPH activity) after fermentation with PCF as carbon source were higher than for the glucose as control. Moreover, PCF inhibited adipocyte differentiation by inducing differentiation-related factors when the induction of 3T3-L1 preadipocytes into adipocytes was induced. Therefore, we suggest that PCF can be used as prebiotic material with anti-obesity for human health.

The aim of this study was to evaluate the Hapo ms, a passive upper limbs exoskeleton developed to assist workers for tasks with arms in front of the body. Twelve participants had to perform a static task, a manual handling task and a load carrying task two times: with and without the exoskeleton. In all cases subjective (perceived effort in arm and back areas, comfort) and objective (muscular activity, postural balance) criteria were evaluated. Results have shown a decrease in anterior deltoid (-12 to -18% depending of the task) and in biceps brachii (-19% to -33% depending of the task) muscular activity. No significant difference was pointed out in back muscle and postural balance was not significantly perturbed due to the wear of the exoskeleton. Finally, perceived effort reduction was observed during the three tasks (except in back area for task 1). To conclude, the Hapo ms seems well adapted to assist upper arms during tasks with arms in front of the body.

From new understanding of pectin molecular structure and physiological effects on man up to new production methods and new applications, significant new knowledge of pectin has emerged in the last two decades (2010-2020). These developments open the route to new and unexpected applications of this uniquely complex heteropolysaccharide ubiquitous in plants and fruits well beyond its traditional use as food hydrocolloid. This study provides a unified perspective on the new science and technology of pectin. Furthermore, we offer an insight into forthcoming pectin uses from an expanded perspective taking into account selected technology and economic factors that, we argue in this study, will shortly impact the pectin production and uptake in many countries.

In addition to CD4+ T lymphocytes, myeloid cells, and, particularly, differentiated macrophages, are targets of the human immunodeficiency virus type-1 (HIV-1) infection via interaction of gp120Env with CD4 and CCR5 or CXCR4. Both T cells and macrophages support virus replication although with substantial differences. In contrast to activated CD4+ T lymphocytes, HIV-1 replication in macrophages occurs in nondividing cells and it is characterized by virtual absence of cytopathicity both in vitro and in vivo. These general features should be considered in evaluating the role of cell-associated restriction factors aiming at preventing of curtailing virus replication in macrophages and T cells particularly in the context of designing strategies to tackle the viral reservoir in infected individuals receiving combination antiretroviral therapy. In this regard, we will here also discuss a model of reversible HIV-1 latency in primary human macrophages and the role of host factor determining restriction or reactivation of virus replication in myeloid cells.

Pericentromeric regions of chromosomes enriched in tandemly repeated satellite DNA although representing a significant part of eukaryotic genomes are still understudied mainly due to interdisciplinary knowledge gaps. Recent studies suggest their important role in genome regulation, karyotype stability and evolution. Thus, the idea of satellite DNA as a junk part of the genome was refuted. Integration of data about molecular composition, chromosome behaviour and details of in situ organization of pericentromeric regions is of great interest. The objective of this work was a cytogenetic analysis of the interactions of pericentromeric regions non-homologous chromosomes in mouse spermatocytes using immuno-FISH. We analysed two events: the associations between cerntomeric regions of X chromosome and autosomes, and associations between centromeric regions of autosomal bivalents forming chromocenters. We conclude that X chromosome form temporary synaptic associations with different autosomes in early meiotic prophase I which normally can be found at pachytene-diplotene without signs of pachytene arrest. These associations are formed between the satellite DNA-enriched centomeric regions of X chromosome and different autosomes but not involve the satellite-poor centromeric region of Y-chromosome. We suggest the mechanism of X chromosome competitive replacement from such associations during synaptic correction. We showed that centromeric region of the X chromosome remains free of γH2Ax-dependent chromatin inactivation, while Y chromosome is completely inactivated. This findings highlights the predominant role of associations between satellite DNA-enriched regions of different chromosomes including X. We assume that X-autosome temporary associations is a manifestation of an additional synaptic disorders checkpoint. These associations are normally corrected before the late diplotene. We revealed that the intense spreading conditions applied to the spermatocytes I nuclei did not lead to destruction of stretched chromatin fibers i.e. elongated chromocenters enriched in satellite DNA. Revealed by us tight associations between pericentromeric regions of different autosomal bivalents and X chromosome may represent the basis for repeat stability maintenance in autosomes an X chromosome. The consequences of our findings are discussed. We obtained the preparations of mouse spermatocytes nuclei in the meiotic prophase I using two approaches: standard and extremely intense surface spread techniques. Using immuno-FISH we visualized tandemly repeated mouse Major and Minor satellite DNA located in the pericentromeric regions of chromosomes and performed a morphological comparison of the standard- and intensely spreaded meiotic nuclei. Based on our results, we assume the remarkable strength of the chromocenter-mediated associations, “chromatin “bridges”, between different bivalents at the pachytene and diplotene stages. We have demonstrated that the chromocenter “bridges” between the centromeric ends of meiotic bivalents are enriched in both tandemly repeated Major and Minor satellite DNA. Association of centromeric regions of autosomal bivalents and X-chromosome but not with Y-chromosome correlates with the absence of Major and Minor satellites on Y-chromosome. We suggest that revealed tight associations between pericentromeric regions of bivalents may represent the network-like system providing dynamic stability of chromosomal territories, as well as add new data for the hypothesis of ectopic recombination in these regions which supports sequence homogeneity between non-homologous chromosomes and does not contradict the meiotic restrictions imposed by the crossing-over interference near centromeres. We conclude that nuclear architecture in meio-sis may play an essential role in contacts between the non-homologous chromosomes providing the specific characteristics of pericentromeric DNA.

Access and Benefit Sharing (ABS) is a framework which refers to a relatively recent type of legal requirements for access to and/or use of “genetic resources”. They are based on diverse national and regional laws and regulations, which mostly result from the implementation of the United Nations’ Convention on Biological Diversity (CBD) and its supplementary agreement, the Nagoya Protocol. Their ambition is to achieve fair and equitable sharing of benefits arising out of the use of genetic resources as an incentive to conserve and sustainably use them. This paper describes the experiences, practical constraints and complexities encountered by users of genetic resources when dealing with ABS legislation, with a focus on users from the private sector. We provide insights on how ABS laws have fundamentally changed the way of working with genetic resources in the hope that it inspires re-thinking of the ABS framework, to better support the overall objectives of the CBD.

Starch is a biopolymer with wide potential for the generation of new biodegradable packages due to its high availability and low price. However, due to its weak functional properties, it is necessary to limit the interaction of some hydroxyl, and to evaluate blends with other polymers to improve their performance. Glycerol plasticized acetylated corn starch films were developed by the casting method, and the impact of incorporating chitosan (TPS:CH) at various proportions (75:25, 50:50, and 25:75 v/v) was studied. The effect of the chitosan ratios on the films' physical, mechanical, water vapor barrier, and thermal properties was evaluated. Chitosan protonated amino groups promote the formation of intermolecular bonds, improving the tensile strength, the thermal stability, the water adsorption capacity, and the gas barrier of starch films. Where the film composed of TPS25-CH75 was the one that presented the best barrier to water vapor. These composite films are a good option for development of biodegradable packaging.

Evidence points to a link between gluten-free diet or celiac disease and eating disorders, but not with orthorexia. This study is the first to examine adults with celiac disease in terms of the prevalence of risk of orthorexia. The study included 130 adults diagnosed with celiac disease. The standardized ORTHO-15 questionnaire was used to assess the risk of orthorexia. Cronbach's alpha test was used to determine the reliability of the ORTHO-15 questionnaire. Eating habits of the subjects were assessed using a questionnaire. The effect of celiac disease on diet was assessed on a 5-point scale. A risk of orthorexia was found in 69% of subjects with celiac disease. A statistically significant (p&lt;0.005) positive correlation was observed between age and ORTHO-15 test scores (rho=0.37). In the group with orthorexia risk, meals were more often self-prepared (93.3%) compared to those without orthorexia (80%) (p=0.023). For 80% of those at risk for orthorexia versus 20% without risk, mood was a factor influencing dietary choices (p=0.001). The study observed a strong association between celiac disease and the presence of orthorexia risk. The numerous risk factors for orthorexia suggest the need for holistic care, including nutritional and psychological support among individuals with celiac disease.

During cartilage development, the lineage commitment and condensation of stem cells into chondrocytes and their differentiation involves a ubiquitous signaling cascades and huge numbers of transcriptional factors. The kinetic requirements and the stoichiometry for the expression of key transcriptional factors are relevant and must be met to form proper and functionally competent cartilage tissue. More interestingly also, an exact and precise spatio-temporal distribution of these molecules are as necessary in the proper tissue morphogenesis and patterning as the relevant physical conditions and micro environmental forces playing at the background during embryogenesis. A milestone of experimental achievements has been obtained over the years on several signaling pathways involved in cartilage development. Several fate determining transcriptional factors has also been investigated and determined with regards to the transition of stem cells (pluripotent, embryonic, etc.) into chondrocytes. These transcriptional factors serve as master controllers in chondrocytes proliferation and hypertrophy. Concerns that variability in signaling and transcriptional factors have detrimental effect on cartilage formation and could potentiate most cartilage related diseases have led most scientists to investigate the role of signaling molecules and transcriptional factors implicated in osteoarthritis, rheumatoid arthritis, and other cartilage degenerative diseases. On bases of spatio-temporal distribution of transcriptional factors, there exist functional overlaps, hence, it is difficult to draw a hard line of demarcation of roles at each point of the cell’s life, nonetheless, it is also markedly established that some factors are skewed to the chondrocyte’ survival and proliferation, and others known for their master’s role in the cell’s apoptotic, necrotic and senescence. Here we review some published works on selected signaling pathways and transcriptional factors that are preferentially expressed in chondrogenic cells and their role as major players in cartilage formation, cartilage diseases, along with some highlights of unique signaling molecules that are indispensable in cartilage tissue regeneration and management.

Recent years have shown that traditional regulatory techniques alone are not effective in achieving behavior change in important fields such as environmental sustainability. Governments all over the world have been progressively including behaviourally informed considerations in policy and law-making with the aim of improving the acceptance and impact of sustainability-oriented measures. This led to the arrival of alternative regulatory tools, such as nudges. The effectiveness of nudges for environmental sustainability (green nudges) has been largely reported but the practical and ethical implications are still largely neglected by academic research. In this contribution, “nudges” are conceptually distinguished from “boosts” and their ethical briefly explained. The analysis is made at the light of the current mostly European and US American academic literature.

Ethanol produced from various biobased sources (bioethanol) has been gaining high attention lately due to its potential to cut down net emissions of carbon dioxide while reducing burgeoning world dependence on fossil fuels. Global ethanol production has increased more than six-fold from 18 billion liters at the turn of the century to 110 billion liters in 2019 (1,2). Sugar cane and corn have been used as the major feedstocks for ethanol production. Lignocellulosic biomass has recently been considered as another potential feedstock. This paper reviews recent developments and current status of commercial production of ethanol across the world. The review includes the ethanol production processes used for each type of feedstock, both currently practiced at commercial scale and newly developed technologies, and production trends in various regions and countries in the world.

Additive manufacturing has already been established as a highly versatile manufacturing technique with demonstrated potential to completely transform conventional manufacturing in the future. The objective of this paper is to review the latest progress and challenges associated with the fabrication of multi-material parts using additive manufacturing technologies. Various manufacturing processes and materials used to produce functional components were investigated and summarized. The latest applications of multi-material additive manufacturing (MMAM) in automotive, aerospace, biomedical and dentistry field were demonstrated. Investigation on the current challenges were also carried out to predict the future direction of MMAM processes. It is concluded that the further research and development needed in the design of multi-material interfaces, manufacturing processes and material compatibility of MMAM parts are necessary.

An explanation of aerodynamic lift still is under controversial discussion as can be seen, for example, in a recent published article in Scientific American [1]. In contrast to an approach via integral conservation laws we here review an approach via the classical Kutta-Condition and its relation to boundary layer theory. Thereby we summarize known results for viscous correction to the lift coefficient for thin aerodynamic profiles and try to remember the work on triple-deck or higher order Boundary Layer theory, its connection to interactive boundary layer theory, viscous/inviscid coupling as implemented to well-known engineering code Xfoil. Finally we compare its findings to simple 2D numerical solution of full Navier Stokes equations (CFD)models. As a conclusion, a clearer definition of terms like understanding and explanation applied to the phenomenon of aerodynamic lift will be given.

Atherosclerosis is a leading cause of cardiovascular disease and mortality worldwide. Alterations in the gut microbiota composition, known as gut dysbiosis, have been shown to contribute to atherosclerotic cardiovascular disease (ACVD) development through several pathways. Disruptions in gut homeostasis are associated with activation of immune processes and systemic inflammation. The gut microbiota produces several metabolic products, namely trimethylamine (TMA), which is used to produce the proatherogenic metabolite trimethylamine-N-oxide (TMAO). Short chain fatty acids (SCFAs), including acetate, butyrate, and propionate, and certain bile acids (BAs) produced by the gut microbiota lead to inflammation resolution and decrease atherogenesis. Chronic low-grade inflammation is associated to common risk factors for atherosclerosis, including metabolic syndrome, type 2 diabetes mellitus (T2DM), and obesity. Novel strategies for reducing ACVD include the use of nutraceuticals such as resveratrol, modification of glucagon-like peptide 1 (GLP-1) levels, supplementation with probiotics, and administration of prebiotic SCFAs and BAs. Investigation into the relationship between the gut microbiota and its metabolites, and the host immune system could reveal promising insight into ACVD development, prognostic factors, and treatments.

Traumatic spinal cord injury (SCI) elicits an acute inflammatory response which comprises numerous cell populations. It is driven by the immediate response of macro-phages and reactive M1 microglia, which triggers activation of genes responsible for the dysregulated microenvironment within the lesion site and in the spinal cord parenchyma immediately adjacent to the lesion. Recently published data indicate that microglia induces astrocyte activation and determines the fate of astrocytes. Conversely, astrocytes have the potency to trigger microglial activation and control their cellular functions. Here we review current information about the release of diverse signaling molecules (pro-inflammatory vs anti-inflammatory) in individual cell phenotypes (microglia, astrocytes, blood inflammatory cells) in acute and subacute SCI stages, and how they contribute to delayed neuronal death in a the surrounding spinal cord tissue which is spared and functional but reactive. In addition, temporal correlation in progressive degeneration of neurons and astrocytes and their functional interactions after SCI are discussed. Finally, the review highlight the time-dependent transformation of reactive mi-croglia (M1) and astrocytes (A1) into their neuroprotective phenotypes (M2a, M2c and A2) which are crucial for spontaneous post-SCI locomotor recovery. We also provide sug-gestions on how to increase functional outcome after SCI and discuss key therapeutic approaches.

A deep relationship is identified between the Coulomb Force and Gravity. A gravitational constant for strong gravity is calculated from the relationship. The equivalence between mass and charge is explored. Implications are given for the expansion of Einstein's Field Equations to include vector gravity.

MiRNAs are 20-22 nucleotide long single-stranded non-coding RNA sequences, which can regulate post transcriptional activity of mRNA by binding with it at 3’UTR region (untranslated region). Thus deregulation of miRNA expression is responsible for dysregulating mRNA function which contributes in developing various diseases as well as cancerous phenotypes. Alteration of single nucleotide in miRNA sequence is one of the reasons behind deregulation of miRNA expression. The most frequent carcinoma in current day is breast cancer which causes a high mortality among women around the world as well as India. Despite of the advancement of diagnostic tools, strategies and treatment, the cases of breast cancer is increasing every year. There are plenty of biomarkers like ER, PR, Her2, Ki-67, etc available which are frequently used in diagnosis and treatment of breast cancer. After the discovery of MiRNA in 1993 in Caenorhabiditis elegans, it is attracting all the limelight in diagnosis and treatment of different carcinomas as well as breast cancer. In this review we will discuss on involvement of different types of MiRNAs and miR SNPs in breast cancer occurrence and susceptibility in a detailed manner.

Agriculture is the mainstay of the Ethiopian and a key sector of its economy. However, Lack of productive and environmentally friendly technology is not widely applicable elsewhere. Likewise, the vermicomposting technology is a recently emerging science which not effectively transferred to the users across the country. Thus, this review is aimed to shine the importance, unexploited opportunities and the challenges hindered for further expansions in Ethiopian context. Vermicompost is among the powerful organic fertilizers which enhance soil Fertility and productivity. As agrarian society; there are plenty of raw byproducts and weed species which are not center of focus (i.e cattle waste, crop residues and invasive weeds like P.Juliflora, P.hysterophorus and E.crassipes respectively). However, there are many constraints there like policy issue, handling problems and sensitivity of the worms for different environmental factors which hindered to invest on a wide range. Generally, the number and weight of vermiculture as well as amount of produced casts are promised and every possible ways were recommended to entertain on the large scale.

In the field of 18F-chemistry for the development of radiopharmaceuticals for positron emission tomography (PET), various labeling strategies by the use of prosthetic groups have been im-plemented, including chemoselective 18F-labeling of biomolecules. Among those, chemoselec-tive 18F-fluoroglycosylation methods focus on the sweetening of pharmaceutical radiochemistry by offering a highly valuable tool for the synthesis of 18F-glycoconjugates with suitable in vivo properties for PET imaging studies. A previous review covered the various 18F-fluoroglycosylation methods that have been developed and applied as of 2014 [Maschauer and Prante, BioMed. Res. Int. 2014, 214748]. This paper is an updated review, providing the recent progress in 18F-fluoroglycosylation reactions and the preclinical application of 18F-glycoconjugates, including small molecules, peptides, and high-molecular-weight proteins.

The is a sequential article to an initial review suggesting that Microbiome First medical approaches to human health and wellness could both aid the fight against noncommunicable diseases and conditions (NCDs) and help to usher in sustainable healthcare. This current review article specifically focuses on public health programs and initiatives and what has been termed by medical journals as a catastrophic record of recent failures. Included in the review is a discussion of the four priority behavioral modifications (food choices, cessation of two drugs of abuse, and exercise) advocated by the World Health Organization as the way to stop the ongoing NCD epidemic. The lack of public health focus on the majority of cells and genes in the human superorganism, the microbiome, is highlighted as is the “regulatory gap” failure to protect humans, particularly the young, from a series of mass population toxic exposures (e.g., asbestos, trichloroethylene, dioxin, polychlorinated biphenyls, triclosan, bisphenol A and other plasticizers, polyfluorinated compounds, herbicides, food emulsifiers, high fructose corn syrup, certain nanoparticles, endocrine disruptors, obesogens). The combination of early life toxicity for the microbiome and connected human physiological systems (e.g., immune, neurological), plus a lack of attention to the importance of microbial rebiosis has facilitated rather than suppressed, the NCD epidemic. This review article concludes with a call to place the microbiome first and foremost in public health initiatives as a way to both rescue public health effectiveness and reduce the human suffering connected to co-morbid NCDs.

Accurate transfer learning of clinical outcomes, e.g., of the effects and side effects of drugs or other interventions, from one cellular context to another (in-vitro versus ex-vivo versus in-vivo, or across tissues), between cell-types, developmental stages, omics modalities or species, is considered tremendously useful. Ultimately, it may avoid most drug development failing in translation, despite large investments in the preclinical stages, which includes animal experiments requiring careful justification. Thus, when transferring a prediction task from a source (model) domain to a target domain, what counts is the high quality of the predictions in the target domain, requiring molecular states or processes common to both source and target that can be learned by the predictor, reflected by latent variables. These latent variables may form a compendium of knowledge that is learned in the source, to enable predictions in the target; usually, there are few, if any, labeled target training samples to learn from. Transductive learning then refers to the learning of the predictor in the source domain, transferring its outcome label calculations to the target domain, considering the same task. Inductive learning considers cases where the target predictor is performing a different yet related task as compared to the source predictor, making some labeled target data necessary. Often, there is also a need to first map the variables in the input/feature spaces (e.g. of gene names to orthologs) and/or the variables in the output/outcome spaces (e.g. by matching of labels). Transfer across omics modalities also requires that the molecular information flow connecting these modalities is sufficiently conserved. Only one of the methods for transfer learning we reviewed offers an assessment of input data, suggesting that transfer learning is unreliable in certain cases. Moreover, source domains feature their very own particularities, and transfer learning should consider these, e.g., as differences in pharmacokinetics, drug clearance or the microenvironment. In light of these general considerations, we here discuss and juxtapose various recent transfer learning approaches, specifically designed (or at least adaptable) to predict clinical (human in-vivo) outcomes based on molecular data, towards finding the right tool for a given task, and paving the way for a comprehensive and systematic comparison of the suitability and accuracy of transfer learning of clinical outcomes.

The current Global Climate Change, the 2030 Agenda and the Planetary boundaries have driven new development strategies, such as the circular economy, bioeconomy and biorefineries. In this framework, this study analyzes the potential availability and sustainability of the wood supply chain for a small-scale biorefinery aiming at producing 280–300 L of bioethanol per ton dry biomass, consuming 30,000 t of dry biomass per year harvested in a 50 km radius. This wood production goal was assessed from Eucalyptus grandis stands planted for solid wood in northeastern Uruguay. Moreover, to understand the environmental performance of this biomass supply chain, the energy return on investment (EROI), carbon footprint (CF) and potential soil erosion were also assessed. The results showed that the potential wood production would supply an average of 81,800 t of dry mass per year, maintaining the soil erosion below the upper threshold recommended, an EROI of 2.3 and annual CF of 1.22 kg CO_2-eq m^–3 (2.6 g CO_2-eq MJ^–1). Combined with the environmental performance of the bioethanol biorefinery facility, these results would show acceptable values of sustainability according to EU Directive 2009/28/ec because the bioethanol CF becomes 1.7% of this petrol’s CF.

The ketogenic diet and walking exercise training activity are two key public health lifestyle factors. The potential of combined lifestyle factors interventions focused on getting to compliance in forced exercise. A balanced ketogenic diet and regular exercise activity is a key modifiable factor to the prevention and management of chronic diseases. Influence health across the lifespan and reduction of the risk of premature death through several biological mechanisms. Community older group’s lifestyle factors interventions contribute identity in their natural living environment. While the older health benefits of walking exercise training strategies are commonly to study, combined ketogenic diet and walking exercise interventions have induced greater benefits in community older groups.

FPGA-based data acquisition and processing systems play an important role in modern high-speed, multichannel measurement systems, especially in High-Energy and Plasma Physics. Such FPGA-based systems require an extended control and diagnostics part corresponding to the complexity of the controlled system. Managing the complex structure of registers while keeping the tight coupling between hardware and software is a tedious and potentially error-prone process. Various existing solutions aimed at helping that task do not perfectly match all specific requirements of that application area. The paper presents a new solution based on the XML system description, facilitating the automated generation of the control system’s HDL code and software components and enabling easy integration with the control software. The emphasis is put on reusability, ease of maintenance in case of system modification, easy detection of mistakes, and the possibility of use in modern FPGAs. The presented system has been successfully used in data acquisition and preprocessing projects in High-Energy Physics experiments. It enables easy creation and modification of the control system definition and convenient access to the control and diagnostic blocks. The presented system is an open-source solution and may be adopted by the user for particular needs.

The crystal nucleation and overall crystallization kinetics of cross-linked poly(ε-caprolactone) was studied experimentally by fast scanning calorimetry in a wide temperature range. With an increasing degree of cross-linking, both the nucleation and crystallization half-times increase. Concurrently, the glass transition range shifts to higher temperatures. In contrast, the temperatures of the maximum nucleation and the overall crystallization rates remain the same independent of the degree of cross-linking. The cold crystallization peak temperature generally increases as a function of heating rate, reaching an asymptotic value near the temperature of the maximum growth rate. A theoretical interpretation of these results is given in terms of classical nucleation theory. In addition, it is shown that the average distance between the nearest cross-links is smaller than the estimated lamellae thickness, which indicates the inclusion of cross-links in the crystalline phase of the polymer.

For public safety and physical security, currently more than a billion closed-circuit television (CCTV) cameras are deployed around the world. Proliferation of artificial intelligence (AI) and machine learning (ML) technologies has gained significant applications including crowd surveillance. The state-of-the-art distance and area estimation algorithms either need multiple cameras or a reference scale as a ground truth. It is an open question to obtain an estimation using a single camera without a scale reference. In this paper, we propose a novel solution called E-SEC, which estimates interpersonal distance between a pair of dynamic human objects, area occupied by a dynamic crowd, and density using a single edge camera. The E-SEC framework comprises edge CCTV cameras responsible for capture a crowd on video frames leveraging a customized YOLOv3 model for human detection. E-SEC contributes an interpersonal distance estimation algorithm vital for monitoring the social distancing of a crowd, and an area estimation algorithm for dynamically determining an area occupied by a crowd with changing size and position. A unified output module generates the crowd size, interpersonal distances, social distancing violations, area, and density per every frame. Experimental results validate the accuracy and efficiency of E-SEC with a range of different video datasets.

The accurate prediction of molecular properties such as lipophilicity and aqueous solubility are of great importance and pose challenges in several stages of the drug discovery pipeline. Machine learning methods like graph-based neural networks (GNNs) have shown exceptionally good performance in predicting these properties. In this work, we introduce a novel GNN architecture, called directed edge graph isomorphism network (D-GIN). It is composed of two distinct sub-architectures (D-MPNN, GIN) and achieves an improvement in accuracy over its sub-architectures employing various learning, and featurization strategies. We argue that combining models with different key aspects help make graph neural networks deeper and simultaneously increase their predictive power. Furthermore, we address current limitations in assessment of deep-learning models, namely, comparison of single training run performance metrics, and offer a more robust solution.

Acute lymphoblastic leukemia is the most common malignancy in children and is characterized by numerous genetic and epigenetic abnormalities. Epigenetic mechanisms, which involve DNA methylations and histone modifications, result in the heritable silencing of genes without a change in their coding sequence. Emerging studies are increasing our understanding of the epigenetic role of leukemogenesis and have demonstrated the potential of DNA methylations and histone modifications as a biomarker for lineage and subtypes classification, predicting relapse, and disease progression in ALL. Epigenetic abnormalities are relatively reversible when treated with some small molecule-based agents compared to genetic alterations. In this review, we conclude the genetic and epigenetic characteristics in ALL and discuss the future role of DNA methylation and histone modifications in predicting relapse, finally focus on the individual and precision therapy targeting epigenetic alterations.

Obesity-associated metabolic abnormalities comprise of a cluster of conditions including dyslipidemia, insulin resistance, diabetes, and cardiovascular diseases that has affected more than 650 million people all over the globe. Obesity results from accumulation of white adipose tissues mainly due to the chronic imbalance of energy intake and energy expenditure. Variety of approaches to treat or prevent obesity, including lifestyle interventions, surgical weight loss procedures and pharmacological approaches to reduce energy intake and increase energy expenditure have failed to substantially decrease the prevalence of obesity. Brown adipose tissue (BAT), the primary source of thermogenesis in infants and small mammals may represent a promising therapeutic target to treat obesity by promoting energy expenditure through non-shivering thermogenesis mediated by mitochondrial uncoupling protein 1 (UCP1). Since the confirmation of functional BAT in adult humans by several groups, approximately a decade ago and its association with a favorable metabolic phenotype, intense interest on the significance of BAT in adult human physiology and metabolic health has emerged within the scientific community to explore its therapeutic potential for the treatment of obesity and metabolic diseases. Substantially decreased BAT activity in individuals with obesity indicates a role for BAT in setting of human obesity. On the other hand, BAT mass and its prevalence has been reported to correlate with lower body mass index (BMI), decreased age and glucose levels, leading to lower incidence of cardio metabolic diseases. Increased cold exposure in adult humans with undetectable BAT was associated with decreased body fat mass and increased insulin sensitivity. Deeper understanding of the role of BAT in human metabolic health and its inter-relationship with body fat distribution and deciphering proper strategies to increase energy expenditure by either increasing functional BAT mass, or inducing white adipose browning holds the promise for possible therapeutic avenues for the treatment of obesity and associated metabolic disorders.

The heavy metal lead (Pb) can irreversibly damage the human nervous system. To help understand Pb-induced damage, we applied a genetically encoded Förster resonance energy transfer (FRET)-based Pb biosensor Met-lead 1.44 M1 to two living systems to monitor the concentration of Pb: induced pluripotent stem cell (iPSC)-derived cardiomyocytes as a semi-tissue platform, and Drosophila melanogaster fruit flies as an in vivo animal model. Different FRET imaging modalities were used to obtain FRET signals, which represented the presence of Pb in the tested samples in different spatial dimensions. Using iPSC-derived cardiomyocytes, the relationship between beating activity (20–24 beats per minute, bpm) determined from the fluctuation of fluorescent signals and the concentrations of Pb represented by the FRET emission ratio values of Met-lead 1.44 M1 was revealed from simultaneous measurements. Pb (50 μM) affected the beating activity of cardiomyocytes, whereas two drugs that stop the entry of Pb differentially affected this beating activity: verapamil (2 μM) did not reverse the cessation of beating, whereas 2-APB (50 μM) partially restored this activity (16 bpm). The results clearly demonstrate a potential of this biosensor system as an anti-Pb drug screening application. In the Drosophila model, Pb was detected within the adult brain or larval central nervous system (Cha-gal4>UAS-Met-lead 1.44 M1) using fast epifluorescence and high-resolution two-photon 3D FRET ratio image systems. The tissue-specific expression of Pb biosensors provides an excellent opportunity to explore the possible Pb-specific populations within living organisms. We believe that this integrated Pb biosensor system can be applied to the prevention of Pb poisoning and advanced research on Pb neurotoxicology.

Use of a multi-sensor approach can provide citizens a holistic insight in the air quality in their immediate surroundings and assessment of personal exposure to urban stressors. Our work, as part of the ICARUS H2020 project, which included over 600 participants from 7 European cities, discusses data fusion and harmonization on a diverse set of multi-sensor data streams to provide a comprehensive and understandable report for participants, and offers possible solutions and improvements. Harmonizing the data streams identified issues with the used devices and protocols, such as non-uniform timestamps, data gaps, difficult data retrieval from commercial devices, and coarse activity data logging. Our process of data fusion and harmonization allowed us to automate the process of generating visualizations and reports and consequently provide each participant with a detailed individualized report. Results showed that a key solution was to streamline the code and speed up the process, which necessitated certain compromises in visualizing the data. A thought-out process of data fusion and harmonization on a diverse set of multi-sensor data streams considerably improved the quality and quantity of data that a research participant receives. Though automatization accelerated the production of the reports considerably, manual structured double checks are strongly recommended.

The polymer cures as it enters the ballast, forming a three-dimensional geo-composite reinforcing cage. Although there will be some adherence to the ballast in dry conditions, the polymer's primary job is to construct this reinforcing cage. Polymer penetration is controlled by altering the rheology of the polymer. The method is also said to include a built-in safety system, with the track reverting to a ballast state in the event of a polymer or geo-composite failure. Many of the sites were considered unmaintainable before the polymer was put. The design method was utilized to forecast track behaviour before and after treatment, allowing the most appropriate polymer rheology, polymer distribution, and loading levels to be designed in order to achieve optimum performance and confirm that the procedure worked. This method can be utilized to tackle these types of long-standing problems by displaying actual polymer application profiles at a typical important location.

The preparation of new materials based on starch for the development of biodegradable packaging is increasing, however, the poor properties of this biopolymer for this application causes an area of opportunities for the improvement of water vapour permeability (WVP), mechanical properties, thermal properties, hydrophilicity, water absorption, among others. Hence, starch has been combined with other polymers such as polyvinyl alcohol, which has shown an improvement in the mechanical properties of starch, also, the use of clays suggests that the properties of response to water can be improved. Therefore, in this work, the preparation and characterization of starch-PVA-nanoclay films prepared by solvent casting is reported. The results obtained suggest that the sonication of nanoclay is necessary to reach a good dispersion, which promotes a strong interaction among starch-PVA-nanoclay. In addition, the properties of WVP and mechanical properties of films improved with incorporation of nanoclay, the concentration of 0.5% w/v of nanoclay showed to be the best concentration due to concentrations of 1.0 and 1.5% w/v were poorer than 0.5% w/v. Accordingly, the successful incorporation of nanoclays into the matrix starch-PVA suggests that this material is a good candidate for use as packaging.

This research will examine the computational methods to calculate the nonlinear optical process of second harmonic generation (SHG) that will be hypothesized to be present during lithium ion insertion into silicon nanowires. First it will be determined whether the medium in which SHG is conveyed is non-centrosymmetric or whether the medium is inversion symmetric where SHG as a part of the second-order nonlinear optical phenomenon does not exist. It will be demonstrated that the main interaction that determines SHG is multiphoton absorption on lithium ions. The quantum harmonic oscillator (QHO) is used as the background that generates coherent states for electrons and photons that transverse the length of the silicon nanowire. The matrix elements of the Hamiltonian which represents the energy of the system will be used to calculate the probability density of second-order nonlinear optical interactions which includes collectively SHG, sum-frequency generation (SFG) and difference-frequency generation (DFG). As a result it will be seen that at varies concentrations of lithium ions (Li+) within the crystallized silicon (c-Si) matrix the second-order nonlinear optical process has probabilities substantial enough to create second harmonic generation that could possibly be used for such applications as second harmonic imaging microscopy.

Alzheimer’s disease (AD) predominantly occurs as a late-onset form (LOAD), involving neurodegeneration and cognitive decline with progressive memory loss. Over time, risk factors and aging promote accumulation of well-known AD hallmarks in oxidative stress, amyloid-beta and tau protein pathology, as well as inflammation. Homeostatic glial functions regulate and suppress these AD hallmarks; however, other glial states involve increased pro-inflammatory cytokine release and further hallmark accumulation. Different stresses can additionally induce cellular senescence, or an irreversible differentiation process resulting in decreased supportive functions and increased, pro-inflammatory cytokine release. While these pathophysiological underpinnings all contribute to LOAD, they require temporal and mechanistic integration. This Perspective proposes that traditional AD hallmarks induce glial senescence in LOAD, where sufficient senescent glia exacerbate ongoing AD pathology and primarily drive LOAD into clinical, cognitive decline. We first explore age-related increases in pro-inflammatory glial activity, and then discuss emerging evidence linking oxidative stress, neurons containing tau pathology, and amyloid-beta to microglia, oligodendrocyte progenitor, and astrocyte senescence. Our evidence-based model mainly predicts that senescent astrocytes and oligodendrocyte progenitors together pressure microglia to phagocytose neurons containing tau pathology, where resulting senescent microglia create neuritic plaques and induce paracrine senescence transitioning into and progressing clinical, dementia presentation. This predictive model accounts for why medications used to treat LOAD fail, as previous treatments have not reduced senescent glial burden. It is also coherent with the predominant hypotheses surrounding LOAD involving the amyloid cascade, tau, glia and inflammation, creates testable hypotheses about LOAD, and increases rationale in testing senolytics as targeted treatments for LOAD arrest and reversal.

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that instigates several signaling cascades, including the NF-kB signaling pathway, to induce cell differentiation and proliferation. Overexpression and mutations of EGFR are found in up to 30% of solid tumors and correlate with a poor prognosis. Although it is known that EGFR-mediated NF-kB activation is involved in tumor development, the signaling axis is not well elucidated. Here, we found that PKP2 and the LUBAC complex were required for EGFR-mediated NF-kB activation. Upon EGF stimulation, EGFR recruited PKP2 to the plasma membrane, and PKP2 bridged HOIP, the catalytic E3 ubiquitin ligase in the LUBAC, to the EGFR complex. The recruitment activated the LUBAC complex and the linear ubiquitination of NEMO, leading to IkB phosphorylation and subsequent NF-kB activation. Furthermore, EGF-induced linear ubiquitination was critical for tumor cell proliferation and tumor development. Knockout of HOIP impaired EGF-induced NF-kB activity and reduced cell proliferation. HOIP knockout also abrogated the growth of A431 epidermal xenograft tumors in nude mice by more than 70%. More importantly, the HOIP inhibitor, HOIPIN-8, inhibited EGFR-mediated NF-kB activation and cell proliferation of A431, MCF-7, and MDA-MB-231 cancer cells. Overall, our study reveals a novel linear ubiquitination signaling axis of EGFR, and perturbation of HOIP E3 ubiquitin ligase activity is potential targeted cancer therapy.

Malaysia is a developing country and agro-industries contribute country’s economy. However, it is largely unknown the scenarios of agricultural practice and food supply over the years. To understand the fact, this study was designed to explore the agricultural land use changes and domestic food supply for last 50 years in Malaysia. The result showed that oil palm plantation area and yield, both are increased by folds, conforming “oil palm” mono-culture practice. Rice cultivation area remained almost unchanged but the yield increased. However, both area of plantation and yield in case of rubber, coca and coconut were decreased. When, it comes to domestic food supply, in 1973 food grain (Rice, Wheat, Maize) import was lower than domestic production. However, the import increased more than 3 times than the domestic production in 2013. Domestic production of vegetables and vegetables import was almost 50:50. Fruits import increased almost 3 times of domestic production, though domestic production was increased. In conclusion, it is understood that Malaysian agriculture economy is standing on “oil palm” wearers domestic food supply is import dependent. It is high time to reshuffle the policy for sustainable development and achieving food sovereignty.

The Schwarzschild metric describes a non-rotating and charge-free celestial body, and it results in things stopping at the event horizon of a black hole and spending infinite time across the event horizon by the observer far away from the black hole. The analysis of the particle’s behavior at the event horizon tells us that this solution predicts an un-expanded black hole which violates the astronomical observations and our knowledge about the black hole. Although some alternative metrics have been proposed, the singularity problem is still unsolved. In this research, the degenerate Fermi electron gas is used to reveal that the Fermi electron gas cannot shrink to a point no matter how large energy it obtains, so the singularity exists at the center very unreasonably. In order to avoid these problems, a finite-size nucleus of the black hole is proposed and reasonably explained by the behaviors of the Fermi electron gas and the Fermi neutron gas there. On the other hand, the Kerr-Newman metric is the one describing the rotating and charged black hole and the equation of the light velocity at each space point can be obtained. It tells us that there are two real and non-imaginary solutions for the radial speed of light at the position larger than the Schwarzschild radius.