Excitation-inhibition imbalance of GABAergic interneurons is predisposed to develop chronic temporal lobe epilepsy (TLE). We have previously shown that virtually every neuronal nitric oxide synthase (nNOS)-positive cell is a GABAergic inhibitory interneuron in the denate gyrus. The present study was designed to quantify the number of nNOS-containing hilar interneurons using stereology in pilocapine- and kainic acid (KA)-exposed transgenic adult mice that expressed GFP under the nNOS promoter. In addition, we studied the properties of miniature excitatory postsynaptic current (mEPSC) and paired-pulse response ratio (PPR) of evoked EPSC in nNOS interneurons using whole cell recording techniques. Results showed that there were fewer nNOS-immunoreactive interneurons of chronically epileptic animals. Importantly, patch-clamp recordings revealed reduction in mEPSC frequency, indicating diminished global excitatory input. In contrast, PPR of evoked EPSC following the granule cell layer stimulation was increased in epileptic animals suggesting reduced neurotransmitter release from granule cell input. In summary, we propose that impaired excitatory drive onto hippocampal nNOS interneurons may be implicated in the development of refractory epilepsy.

As a medical student (Granada University Medical School, Spain), interested in Pediatrics, expended countless hours at the hospital pediatric facilities and got to know many of the children and their medical problems. A particular case, still vivid on my mind, awaken my scientific curiosity. One day, walking and talking with a seven years old child he unexpectedly felt down unconscious with multiple, incontrollable and erratic muscular contractions involving face, body and extremities and salivating. I was overwhelmed thinking it was the child’ last hour. At the time, my knowledge of epilepsy was nil. Following the seizures, the child was up, talking and walking with me as if nothing has happened and without any knowledge of the event. What could have caused the brain motor cortex to suddenly discharge that amount of altered activity causing generalized and erratic muscular contractions remains inexplicable. I migrated to USA, become a Pediatric (Developmental) Pathologist and Director of the Pediatrics Autopsy Service (1962-1999) at the Dartmouth-Hitchcock Medical Center, New Hampshire. I carried out countless postmortem studied of children brains, normal (unaltered) as well as those altered by hemorrhagic, hypoxic-ischemic and/or traumatic damage. With an NIH Fellowship, I spend one year (1967-68) at the Cajal Institute (Madrid, Spain) studying Cajal’ old Golgi preparations and learning about the method. Some of my Golgi studies of children’ brains have been published: The Human Brain. Prenatal Development and Structure, Springer, Heidelberg, Germany, 2012. The present monograph explores the developmental neuropathology of selected perinatal cortical injuries through their acute, subacute and chronic stages. Including: a) how an altered neuronal activity evolves in a damaged cortical region; b) how it moves through the cortex (epileptic auras); and c) how it reaches the motor cortex to be discharged as erratic and incontrollable muscular contractions. Understanding these processes should provide insights into the pathogenesis of epilepsy secondary to perinatal brain damage.

It is known that the class of p-normed spaces (0 < p ≤ 1) is an important generalization of usual normed spaces with rich topological and geometrical structure, but the most of tools and general principles in nature with nonlinearity have not been developed yet, thus the main goal of this paper is to develop tools for nonlinear analysis under the framework of p-vector spaces. In particular, we first develop the general fixed point theorems which provide solutions to answer Schauder conjecture since 1930’s in the affirmative for p-vector spaces when p = 1 (which is just general topological vector spaces); then the one best approximation result for upper semi-continuous mappings is given, which is used as a powerful tool to establish fixed points for non-self set-valued mappings with either inward or outward set conditions; and finally we establish comprehensive existence results of solutions for Birkhoff-Kellogg Problems, and the general principle of nonlinear alternative by including Leray-Schauder alternative and related results. The results given in this paper not only include the corresponding results in the existing literature as special cases, but also expected to be useful tools for the study of nonlinear problems arising from theory to practice.

The main aim of this paper is to set some correlations between Boole polynomials and p-adic gamma function in conjunction with p-adic Euler contant. We develop diverse formulas for p-adic gamma function by means of their Mahler expansion and fermionic p-adic integral on ℤ_{p}. Also, we acquire two fermionic p-adic integrals of p-adic gamma function in terms of Boole numbers and polynomials. We then provide fermionic p-adic integral of the derivative of p-adic gamma function and a representation for the p-adic Euler constant by means of the Boole polynomials. Furthermore, we investigate an explicit representation for the aforesaid constant covering Stirling numbers of the first kind.

Hard yellow maize is a crucial crop in Peruvian agriculture, playing a significant role in food security and livestock production. However, intensive fertilization practices in agronomic management have negatively impacted soil health. To explore more sustainable agricultural technologies, researchers have investigated using microorganisms to enhance plant growth. This study assessed the synergistic effects of microbial inoculants and mineral fertilization on INIA 619 and Dekal B-7088 maize varieties' yield and nutritional quality. A split-plot design was employed, incorporating four inoculation treatments—no inoculant, Bacillus subtilis, Trichoderma viride, and Pseudomonas putida—combined with fertilization levels of 0%, 50%, 75%, and 100%. The findings revealed that Bacillus subtilis boosted yields by 13.1% in INIA 619 and 55.5% in Dekal B-7088. Additionally, combined with 100% fertilization, microbial inoculation increased protein content by 47% and carbohydrates by 6% in INIA 619, while maintaining nutritional quality with 75% fertilization. Similarly, in Dekal B-7088, inoculation with total fertilization enhanced protein content by 54% and fiber by 27%. These results demonstrate that microbial inoculation can reduce mineral fertilization by up to 25% while sustaining high yields and improving the nutritional quality of maize.

Background: Total gastrectomy with D2 lymph node dissection is standard for resectable esophagogastric junctional and gastric cancer, but high morbidity challenges perioperative care. ERAS guidelines advise against routine drains, yet conflicting evidence leads to inconsistent practice. Methods: The DRAG (DRains After Gastrectomy) Trial is a prospective, non-randomized study conducted from February 2020 to March 2023 at the 1st Propaedeutic Surgery Department, Hippocration General Hospital, Athens. Patients undergoing open D2 total gastrectomy had perianastomotic drains placed based on newly established criteria, offering a more tailored approach. Immediate and short-term postoperative outcomes, including recovery milestones and complications, were assessed. Results: Sixty patients were included, with 40 receiving a drain. The non-drain group had significantly lower pain scores, earlier mobilization, less postoperative nausea and vomiting, and a shorter hospital stay. Among those with complications, significant differences in surgical site infections, delayed mobilization, extra-abdominal issues, length of stay, readmissions, and reoperations suggest that drain use may increase complications and hinder recovery. Conclusion: Our study suggests that routine prophylactic drain use can be avoided in gastrectomy for esophagogastric junctional and gastric cancer when experienced surgeons in high-volume centers follow clearly defined criteria. Implementing these criteria may improve patient outcomes and reduce complications.

Research background: The globalization processes are not only of an economic and cultural nature but also unify trends in the organization and management of administration, including at the local level. The idea of economizing administration was promoted within the broad stream of reforms described as New Public Management (NPM). This idea was often expressed as a postulate for the territorial reorganization of local governments. These reforms, motivated by the economies of scale, aimed to eliminate the allegedly overly fragmented nature of local government structures. Critics of these reforms advocate for glocalization, which takes local institutional conditions into account. They argue that the NPM concept should emphasize a long-term balance between economics, environment, and society, which are the paradigms of sustainable development (SD). According to them, this approach provides a more holistic and effective method for public management.

A new 2 parameter unit Weibull distribution is defined on the unit interval (0,1). The methodology of deducing its PDF, some of its properties and related functions are discussed. The paper is supplied by many figures illustrating the new distribution and how this can make it illegible to fit a wide range of skewed data. The new distribution holds a name (Attia) as a nickname.

The concept of Palliative Care (PC) is more and more known in medicine and the need for this type of approach is growing in a world with great longevity and exponentially increasing chronic diseases. More and more cases from internal medicine, gastroenterology or cardiology wards could benefit from a better care if their medical team would align with the PC concept and principles. In this sense we try to present the specifical needs for Romanian patients in accordance with the current standards of care and how they must be adapted to the reality of the medical system in which they are cared for. We consider also that for medical staff from chronic disease wards it may be necessary to recapitulate the most important principles that govern medical practice of palliation, emphasizing some important aspects of applicability in daily clinical activity.

This study examines the significant impact of Houthi insurgent activities on maritime traffic within the strategic Red Sea and Suez Canal routes, essential conduits for global trade. It explores the correlation between regional instability, exemplified by Houthi actions from November 19, 2023, to February 5, 2024, and changes in maritime traffic patterns and operational efficiency. This study seeks to answer a critical question in transport geography: How does regional instability, exemplified by Houthi insurgent activities, affect maritime traffic patterns and the operational efficiency of the Red Sea and Suez Canal? Using descriptive statistics, qualitative analysis, and geospatial methods, the research highlights recent trends in maritime traffic and incidents, revealing spatial and geopolitical challenges in this crucial trade route.Findings indicate a notable decline in maritime activity in the Gulf of Aden and Suez Canal due to security concerns from Houthi attacks, prompting a significant shift to alternative routes, particularly around the Cape of Good Hope. This shift underscores the broader implications of regional instability on global trade and the importance of maintaining uninterrupted maritime flow. The study also emphasizes the economic ramifications, such as increased operational costs and freight rates due to longer transit times and enhanced security measures.The research concludes with a call for improved maritime security protocols and international cooperation to protect these strategic maritime pathways. It contributes to the discourse on transport geography by quantifying the direct impacts of regional conflicts on maritime logistics and proposing strategies for future resilience, highlighting the interconnected nature of global trade and security and the need for collective action against evolving geopolitical challenges.

The fall armyworm (FAW), Spodoptera frugiperda, a major pest in maize production, was assessed for its temporal and spatial distribution in maize fields during both the off and rainy seasons of 2021 and 2022. In this study, 30 and 50 maize plants were randomly sampled using a "W" pattern during the dry and rainy seasons, respectively. Larval density, infestation rates, and damage severity were monitored over time. Taylor's power law and the mean crowding aggregation index were applied to evaluate the dispersion patterns of the larvae. The results indicate a higher infestation rate and larval density in agroecological zone AZE 8 (fisheries zone of South Benin) compared to AZE 6 (ferralitic soils zone) during the off-season. In the rainy season, while the percentage of damaged plants was higher in AZE 8, no significant differences in larval density between the two zones were observed. The dispersion analysis revealed moderate aggregation (aggregation index = 1.25) with a basic colony of 2.08 larvae, reflecting the aggregation oviposition behavior of FAW. This study provides valuable monitoring data on the FAW's distribution, offering insights for further research on population dynamics and developing predictive models for integrated pest management strategies.

Objective: To explore the acceptability and feasibility of conducting comprehensive, community-based, hy-brid (in-person and virtual) mental health screening and feedback with diverse youth in the community. Methods: The Screening and Support for Youth intervention provides comprehensive assessment and thera-peutic feedback in community settings including symptoms, diagnoses, functional impairment, suicide, and clinical risk. Symptom severity, seven diagnoses and suicidality were assessed with the Kiddie Computer-ized Adaptive Test. Functional impairment was evaluated by youth self-report on the Weiss Functional Im-pairment Rating Scale. Measures were scored according to nationally developed norms and an algorithm was developed to aggregate symptoms and functioning to determine clinical risk. The results were discussed with participants in a motivational interview to promote insight and engagement in an online intervention. Results: Methodological innovations included using a QR code for recruitment, integrated in-person and virtual participation, and expansion from in-person recruitment within the schools to virtual engagement with youth throughout the community. The final sample included disproportionately more Black or African American and Hispanic youth as compared to school and community statistics, suggesting that hybrid re-search may facilitate recruitment of diverse populations. Qualitative interviews indicated that the screening and feedback raised youth awareness of their wellbeing and/or distress, its impact on their functioning, and engagement with options for improving wellbeing. Conclusion: Hybrid research, developed as a necessity during the pandemic, proved advantageous to the feasibility and acceptability of community-based recruit-ment of at risk, minoritized youth.

In order to deal with imprecision, ambiguity, and uncertainty in data analysis, Pawlak introduced rough set theory in 1982. This paper aims to expand the scope of basic set theory developed by presenting the notions of δP-upper and δP-lower approximations, that are based on the notion of δP-open sets, we additionally examine a few of their fundamental characteristics.

This work reports the role of structure and composition on the determination of the performances of p-type SnOx TFTs deposited by rf magnetron sputtering at room temperature, followed by a post-annealed step up to 200 °C at different oxygen partial pressures (Opp), between 0% and 20%, but where the p-type conduction was only observed between 2.8–3.8%. The role of structure and composition were evaluated by XRD and Mössbauer spectroscopic studies. The study allows to identify the best phases/compositions and thicknesses (around 12 nm) to be used that lead to the production of TFTs with a bottom gate configuration, on glasses coated with conductive Indium Tin Oxide, followed by Aluminium Titanium Oxide dielectric layer with saturation mobility of 4.6 cm²V⁻¹s⁻¹ and on-off ratio above 7 × 10⁴, operating at the enhancement mode with a saturation voltage of −10 V.

In this paper, we investigate several relations for p-adic gamma function by means of their Mahler expansion and fermionic p-adic q-integral on ℤ_{p}. We also derive two fermionic p-adic q-integrals of p-adic gamma function in terms of q-Boole polynomials and numbers. Moreover, we discover fermionic p-adic q-integral of the derivative of p-adic gamma function. We acquire a representation for the p-adic Euler constant by means of the q-Boole polynomials. We finally develop a novel, explicit and interesting representation for the p-adic Euler constant including Stirling numbers of the first kind.

In this paper, we investigate p-adic q-integral (q-Volkenborn integral) on ℤ_{p} of p-adic gamma function via their Mahler expansions. We also derived two q-Volkenborn integrals of p-adic gamma function in terms of q-Daehee polynomials and numbers and q-Daehee polynomials and numbers of the second kind. Moreover, we discover q-Volkenborn integral of the derivative of p-adic gamma function. We acquire the relationship between the p-adic gamma function and Stirling numbers of the first kind. We finally develop a novel and interesting representation for the p-adic Euler constant by means of the q-Daehee polynomials and numbers.

The aim of this study is to assess of rare earth elements (REE) content in hair samples in children, living in Lovozero village, near REE mining site, and possible effects of REEs on the prevalence of nervous system diseases in the Lovozersky district (Murmansk region, Kola Peninsula). School-age children (53 persons) were recruited for analysis of REE content in their hair samples. REEs (Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu) content was estimated by inductively coupled plasma mass spectrometry (ICP-MS). Analysis of REE content in the hair of children living in the Russia, Kazakhstan and China indicates REEs intake from environment. A possible contribution of REEs to the nervous system disorders is supported by the link between REE content in the hair samples of children, living near REE mining (China) and by manifesting cognitive disorders in these children. It also turn out that highest prevalence of the nervous system diseases in children 15-17 years old manifested in the Lovozersky district then in other area in the Murmansk region. The paper discusses the possible contribution of REEs to the prevalence of episodic paroxysmal disorders (G40-G47), cerebral palsy (G80-G83), epilepsy and status epilepticus (G40-G41).

This review explores the transformative role of induced pluripotent stem cells (iPSCs) and organoids in advancing neuropathology research. Focused on Alzheimer's disease, epilepsy, Parkinson's disease, and spinal cord injury, iPSCs offer patient-specific disease modeling with regenerative therapy potential. The versatility of iPSCs, their ability to differentiate into the main neuronal cell types, and their integration into three-dimensional organoid models enable the recreation of complex tissues in vitro. Improvement of organoid and iPSCs generation protocols and the selection of appropriate donor cell types are highlighted as crucial steps toward the application of these new technologies to overcome tumorigenic potential and other challenges. iPSCs demonstrate promise in regenerative therapies, as evidenced by successful applications in animal models.

Dravet syndrome (DS), also known as severe myoclonic epilepsy of infancy, is a rare and drug-resistant form of developmental and epileptic encephalopathies, which is both debilitating and challenging to manage, typically arising during the first year of life, with seizures often triggered by fever, infections, or vaccinations. It is characterized by frequent and prolonged seizures, developmental delays, and various other neurological and behavioral impairments. Most cases result from pathogenic mutations in the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene, which encodes a critical voltage-gated sodium channel subunit involved in neuronal excitability. Precision medicine offers significant potential for improving DS diagnosis and treatment. Early genetic testing enables timely and accurate diagnosis. Advances in our understanding of DS's underlying genetic mechanisms and neurobiology have enabled the development of targeted therapies, such as gene therapy, offering more effective and less invasive treatment options for patients with DS. Targeted and gene therapies provide hope for more effective and personalized treatments. However, research into novel approaches remains in its early stages, and their clinical application remains to be seen. This review addresses the current understanding of clinical DS features, genetic involvement in DS development, and outcomes of novel DS therapies.

Electroencephalography (EEG) is essential for tracking brain activity and identifying seizure effects. However, epileptic behaviour can only be detected after a specialist has carefully analysed all EEG recordings along with a proper history of the patient. A skilled physician is required for the right epilepsy diagnosis and therapy. But most of the time, patients visit the clinician in the interictal stage with no proper history documented. Therefore, it was essential to the automatic prediction of stages of seizure. K nearest neighbours (KNN) and random forest (RF) models using raw EEG signals, preictal, ictal, postictal, and interictal stages were identified in this study. The possibility of these characteristics is explored by examining how well time-domain signals work in the prediction of epileptic stages using intracranial EEG datasets from Freiburg Hospital (FH), Children's Hospital Boston-Massachusetts Institute of Technology (CHB-MIT), and Temple University Hospital (TUHEEG). To test the viability of this approach, two different types of simulations were carried out on three binary classifications (interictal vs. preictal, interictal vs. ictal, preictal vs. postictal, and interictal vs. postictal), and one four-class problem (interictal vs. preictal vs. ictal vs. postictal) was performed for each model. The average accuracy when using time-domain signals in the FH database was 90.5% and 75.0%; CHB-MIT was 92.87% and 75.9%; and TUHEEG was 94.46% and 76.8%, respectively, for the KNN and RF models.

The vacuolar H+-ATPase is a multisubunit enzyme which plays an essential role in the acidification and functions of lysosomes, endosomes, and synaptic vesicles. Many genes encoding subunits of V-ATPases, namely ATP6V0C, ATP6V1A, ATP6V0A1 and ATP6V1B2, have been associated with neurodevelopmental disorders and epilepsy. The autosomal dominant ATP6V1B2 p.Arg506* variant can cause both deafness, congenital, with onychodystrophy, autosomal dominant (DDOD) and deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures syndromes (DOORS). Some but not all individuals with this truncating variant have intellectual disability and/or epilepsy, suggesting incomplete penetrance and/or variable expressivity. To further explore the impact of the p.Arg506* variant in neurodevelopment and epilepsy, we generated Atp6v1b2emR506* mutant mice and performed standardized phenotyping using the International Mouse Phenotyping Consortium (IMPC) pipeline. In addition, we assessed the EEG profile and seizure susceptibility of Atp6v1b2emR506* mice. Behavioral tests revealed that the mice present locomotor hyperactivity and show less anxiety-associated behaviors. Moreover, EEG analyses indicate that Atp6v1b2emR506* mutant mice have interictal epileptic activity and that both heterozygous (like patients) and homozygous mice have reduced seizure thresholds to pentylenetetrazol. Our results confirm that variants in ATP6V1B2 can cause seizures and that the Atp6v1b2emR506* heterozygous mouse model is a valuable tool to further explore the pathophysiology and potential treatments for vacuolar ATPases-associated epilepsy and disorders.

Seizure development relies on two factors. One is the existence of an overexcitable neuronal network and the other is a trigger that switches normal activity of that network into a paroxysmal state. While mechanisms of local overexcitation have been the focus of many studies, the process of triggering remains poorly understood. We suggest that, apart from the known exteroceptive sources of reflex epilepsy – visual, auditory or olfactory, there is a range of interoceptive triggers, relevant for seizure development in Temporal Lobe Epilepsy (TLE). The hypothesis proposed here aims to explain the prevalence of epileptic activity in sleep and in drowsiness states and provide a detailed mechanism of seizure triggering by interoceptive signals.

This research refers to the creation of a method of medical technology such as a device that can collect, encode, temporarily store, and transfer electroencephalographic signals from epileptic patients for study and evaluation. For applying the specific apparatus related to neurostimulation technologies such as Deep Brain Stimulation (DBS) and Responsive Neurostimulation (RNS) the approaches followed concern three basic levels. The first level is concerned with initial modelling and creating the template for the following two stages. Further on, the second level is based on developing code for programming integrated circuits and simulation with the appropriate software. The third and final stage is the most substantial, as the transmitter’s construction is attempted at the evaluation level. In particular, more than one software and device are involved in this phase for the most realistic performance of the desired result. However, it is worth noting that the principal goal of this study is to achieve low consumption rates for the device’s complete and smooth operation. As a result, this research aims to evolve this device so that it can send data wirelessly and simultaneously provide energy efficiency.

Abstract Epilepsy is a disorder of the brain and a seriously debilitating condition, which has been associated with injury, social stigmatisation and in some cases, sudden unexpected and premature death. A sense of profound isolation is felt by many individuals with epilepsy, and this community has expressed an urgent desire for an early warning system to allow them time to prepare for seizure onset. Surveys of dog owners with epilepsy have previously reported that some dogs can predict the onset of a seizure. The current study used an experimental design to investigate the alleged propensity of untrained pet dogs to react to human epileptic seizures. We hypothesised that seizures are associated with specific volatile organic compounds resulting in detectable odours which are the biomarker that triggers these reported behavioural changes in the dogs. Here we provide details of the first empirical test to demonstrate that pet dogs display several significant behavioural changes when they are exposed to seizure-related odours that apparently emanate from their owners. Using a repeated measures design experiment, recordings were made of the reactions of 19 untrained pet dogs to odours from sweat samples provided by three people with epilepsy and by two people without epilepsy (controls). The seizure-associated sweat samples were captured pre-seizure, during seizure and post-seizure. All samples were randomly delivered to individual dogs in a test area, using two bespoke pieces of apparatus called Remote Odour Delivery Mechanisms (RODM). One RODM delivered only experimental odours, the other delivered only control odours. Behavioural changes by the dogs on encountering the odour samples were recorded by video for later analysis. Consistent with our hypothesis, seizure-associated odours evoked significant behavioural changes in the dogs which were affiliative in nature and directed at their owners.

Dynamical system tools offer a complementary approach to detailed biophysical seizure modeling, with a high potential for clinical applications. This review describes the theoretical framework that provides a basis for theorizing certain properties of seizures and for their classification according to their dynamical properties at onset and offset. We describe various modeling approaches spanning different scales, from single neurons to large-scale networks. This narrative review provides an accessible overview of this field, including non-exhaustive examples of key recent works.

Background: Temporal lobe epilepsy (TLE) is the most common focal epilepsy subtype in adults and is frequently accompanied by depression, anxiety and psychosis. Aberrations in total paraoxonase (PON)1 status may occur in TLE and those psychiatric conditions. Methods: We examined paraoxonase (PON)1 status, namely Q192R PON1 genotypes and PON1 enzymatic activities, in 40 normal controls and 104 TLE patients, 27 without comorbidities, and 77 with comorbidities including mood disorders (n=25), anxiety disorders (n=27) and psychosis (n=25). Outcomes: CMPAase and arylesterase activities were significantly lower in TLE and mesial temporal sclerosis (MTS) with and without psychiatric comorbidities than in normal controls. The areas under the ROC curve of CMPAase were 0.893 (0.037) for TLE and 0.895 (±0.037) for MTS. Partial Least Squares (PLS) path analysis showed that there were specific indirect effects of PON1 genotype on TLE severity (p<0.0001) and psychopathology (p<0.0001), which were both mediated by lowered CMPAase activity, while arylesterase activity was not significant. The severity of TLE was significantly associated with psychopathology scores. Furthermore, PON1 CMPAase activity was inversely associated with Mini Mental State Examination scores. Interpretation: The severity of TLE and comorbidities are to a large extent explained by lowered PON1 enzyme activities and by effects of the Q192R genotype which are mediated by lowered CMPAase activity. Total PON1 status plays a key role in the pathophysiology of TLE, MTS and psychiatric comorbidities by increasing the risk of oxidative toxicity. PON1 enzyme activities are new drug targets in TLE to treat seizure frequency and psychiatric comorbidities.

It is increasingly common for experiments in biology and medicine to involve large numbers of hypothesis tests. A natural graphical method for visualizing these tests is to construct a histogram from the p-values of these tests. In this article, we examine the shapes, both normal and abnormal, that these histograms can take on, as well as present simple inferential procedures that help to interpret the shapes in terms of diagnosing potential problems with the experiment. We examine potential causes of these problems in detail, and discuss potential remedies. Throughout, examples of abnormal-looking p-value histograms are provided and based on case studies involving real biological experiments.

Background: Significant intraoperative and postoperative blood loss are rare but possibly life-threatening complications after lung resection surgery either during open or minimally invasive procedure. Microporous Polysaccharide Hemospheres (ARISTA™AH) have demonstrated time-efficient haemostasis, lower post-operative blood volumes and a lower blood transfusion requirement, without any identified adverse events across other specialities.The primary aim of our study was to evaluate the impact of haemostatic agents on short-term postoperative outcomes in thoracic surgery. Methods: We retrospectively reviewed a prospectively collected database of consecutive early-stage lung cancer patients surgically treated in two European centres(October 2020-December 2022).Exclusion criteria:open surgery,patients with coagulopathy/anticoagulant medication,major intraoperative bleeding,non-anatomical lung resection and age <18 years.The cohort was divided into 5 groups according to the haemostatic agent used.Propensity score matching was used to estimate the effect of ARISTA™AH on various intra- and post-operative parameters(continuous and binary outcome modelling). Results:482 patients(M/F:223/259; VATS 97/RATS 385)with a mean age of 68.9(±10.6)years were analysed.In 253 cases ARISTA™AH was intraoperatively used to control bleeding.This cohort of patients had a significant reduction in total drain volume by 135 mls(standard error 53.9; p=0.012).The use of ARISTA™AH did reduce the average length of hospital stay(-1.47 days)and duration of chest drainage(-0.596 days)albeit not significant.In the ARISTA™AH group,we observed no postoperative bleeding,no blood transfusion required,no 30-day mortality and no requirement for redo-surgery.The use of ARISTA™AH significantly reduced the odds of post-operative complications,need for transfusion and redo surgery. Conclusion: Our data showed that Microporous Polysaccharide Hemospheres are a safe and effective haemostatic device.Its use has a positive effect in short term postoperative outcomes of patients surgically treated for early-stage lung cancer.

This study investigates the impact of water stress on grapevines, specifically examining the role of rootstocks and aquaporins. Two experiments on potted plants were conducted in central Chile during the summer, under conditions of high water demand, involving various rootstock genotypes and combinations of Cabernet Sauvignon (CS) grafted onto rootstocks. Significant differences were observed among plants in terms of stem water potential, stomatal conductance, and growth rate. Notably, the CS/CS combination consistently displayed the slowest growth rate, regardless of the irrigation treatment. The study also analyzed the expression levels of plasma membrane intrinsic proteins (PIPs) and tonoplast intrinsic proteins (TIPs) aquaporins in the leaves of grafted plants. Specifically, VvPIP2;2 aquaporins showed reduced expression after 14 days without irrigation, whereas VvTIP1;1 and VvTIP2;1 expression levels correlated positively with gs responses in grafted plants, suggesting their role in modulating water content in leaves under water stress. TIP aquaporins likely play a significant role in the differential responses of CS plants towards nearly isohydric or anisohydric behaviour. The CS/CS combination exhibited near isohydric behavior, correlating with lower TIP aquaporin expression, while the combination of CS onto 1103P and 101-14 showed higher expression, indicating anisohydric behavior. The findings suggest that grafted plants are more resilient to water stress, supporting the idea that rootstocks can mitigate the effects of water stress on the scion.

Breast cancer is currently the second leading cause of death worldwide, accounting for 15% of all deaths (8.2 million deaths). Approximately 20% of breast cancer diagnoses are triple-negative breast cancer (TNBC), a type of cancer that lacks receptors for estrogen (ER negative), progesterone (PR negative), and human epidermal growth factor receptor 2 (HER2/neu negative). Consequently, TNBC doesn’t respond to hormonal or targeted therapies, making it challenging to treat due to its rapid growth, metastasis, and high recurrence rate within the first three years of therapy. Alternative chemotherapies are needed to address this problem. Pharmacological dose of vitamin C (high-dose VC) has been identified as a potential treatment for some cancer cells. The present study aimed to evaluate whether VC has a therapeutic effect on TNBC using MDA-MB-231 cells as the model. MTT assay, Hoechst 33342 staining, Nuclear ID Red/Green staining, Rhodamine 123 staining, and Western blot analysis were employed to test the hypothesis that pharmacological dose of VC can kill TNBC cells. Upregulation of Apaf-1, caspases -3, -6, -7, -8, and -9, inhibition of matrix metalloproteinases (MMP-2 and MMP-9), reduction in cell cycle protein expression, and enhancement of tumor suppressor proteins such as p53 and p21 indicated that pharmacological dose of VC has promising anti-cancer properties in the treatment of TNBC.

The rapid pace of urbanization, coupled with the growing need for environmental sustainability and technological innovation, has brought smart city initiatives to the forefront of global urban development. This paper provides a comparative analysis of smart city policies from leading cities such as Oslo, Zurich, and Canberra, and derives strategic insights for Qatar. By examining the strategies, priorities, outcomes, and challenges associated with implementing smart city initiatives in these cities, the study identifies areas of alignment and divergence with Qatar's own smart city policy framework. The research highlights potential opportunities for cross-learning and suggests how Qatar can leverage lessons from international best practices to enhance its smart city initiatives. Key areas of focus include fostering strategic partnerships, promoting innovation, and ensuring effective governance and data management systems. The findings provide actionable insights to improve the effectiveness of Qatar's smart city projects, aligning them with the Qatar National Vision 2030.

Recent studies with ApoE knockout (ApoE-/-) mice deficient for PACAP (pituitary adenylate cyclase-activating polypeptide) or its receptor PAC1 provide evidence for a possible involve-ment of immune- and vasoregulatoy PACAP signaling at the PAC1 receptor in atherogenesis and plaque associated vascular inflammation. Therefore, we tested the PAC1 receptor agonist Maxadilan and the PAC1 selective antagonist M65 on plaque development and lumen stenosis in the ApoE-/- atherosclerosis model for possible anti-atherogenic effects. Adult male ApoE-/- mice were fed a cholesterol-enriched diet (CED) or standard chow (SC) treat-ed with Maxadilan, M65 or Sham. Effects of treatment on atherosclerotic plaques, lumen stenosis, apoptosis and pro-inflammatory signatures were analyzed in the brachiocephalic trunk (BT). The percentage of Maxadilan treated mice exhibiting plaques under SC and CED was lower than that of Sham or M65 treatment indicating opposite effects of Maxadilan and M65. Maxadilan ap-plication inhibited lumen stenosis under SC and CED compared to Sham. In spite of significantly increased cholesterol levels, lumen stenosis of Maxadilan-treated mice was similar under CED and SC. In contrast, M65 under SC or CED did not reveal a significant influence on lumen steno-sis. Maxadilan significantly reduced the TNF-α+ area in the plaques under CED, but not under SC. In contrast, the IL-1β+ area was reduced after Maxadilan treatment under SC, but remained unchanged under CED compared to Sham. Maxadilan reduced the caspase-3+ area in the media under both SC and CED without affecting lipid content in plaques. Despite persisting hypercholesterolemia, Maxadilan reduces lumen stenosis, apoptosis and TNF-α driven inflammation. Our data suggest that Maxadilan provides atheroprotection by act-ing downstream of cholesterol-induced vascular inflammation. This implicates the potential of PAC1-specific agonist drugs against atherosclerosis even beyond statins and PCSK-9.

Background: Urinary tract infections (UTI) are a significant health concern, particularly in women, with almost half of them experiencing at least one UTI in their lifetime. This problem is further compounded by the high recurrence rate within 6-12 months. Postmenopausal women are especially vulnerable to recurrent UTI due to the natural decline in estrogen levels, which alters the urogenital epithelium and subsequently affects the urogenital microbiome. Methods: This study included 674 female patients that were admited at "Dr. Carol Davila" Central Military Emergency University Hospital in Bucharest over a period of 3 years. Results: Of the 674 women with urinary tract infection, 435 (79.3%) had more than one positive culture, and 239 (35.4%) experienced at least one recurrent urinary tract infection 6-12 months after the initial diagnosis. The mean age of women with urinary tract infection was 63 (± 15.61 years). Recurrent urinary tract infections were most prevalent in those aged 65-80 years (52%). Escherichia coli was detected in 71% of the positive cultures. Conclusions: The management of recurrent urinary tract infections in women presents a complex challenge that necessitates a multifaceted approach. The emerging understanding of the urobiome and its role in bladder health offers promising avenues for developing targeted interventions. As research in this field advances, it is imperative to integrate these new insights into clinical practice to balance traditional antibiotic treatments with novel strategies that consider the intricate microbial ecosystem of the urinary tract.

Disruptions in power quality have a negative impact on many energy consumers. These include lighting, where interference manifests itself, among others, in the form of light flickering. The article presents phenomena accompanying the operation of modern light sources against the background of exemplary results of studies on the flicker of conventional light sources, such as incandescent or fluorescent lamps. To assess the effects of these phenomena, it is necessary to use measures other than those traditionally used. The results of measurements carried out in accordance with different recommendations take into account both power supply disturbances and the properties of modern light sources.

Psoriasis is a chronic, immune-mediated skin disease significantly impacting women, with disease severity often modulated by hormonal fluctuations. This review examines the influence of hormonal changes on the course of psoriasis in women, focusing on key life stages—including the menstrual cycle, pregnancy, postpartum, and menopause—and their impact on disease progression and symptomatology. Estrogen, the principal female sex hormone, plays a critical role in immune modulation. Variations in estrogen levels, which occur naturally throughout a woman's life, are associated with fluctuations in psoriasis severity. Low estrogen levels, as seen during menstruation or menopause, are linked to symptom exacerbation, while elevated levels during pregnancy may reduce symptoms in some women. However, responses are variable, with others experiencing no change or worsening during pregnancy. Postpartum, the rapid decline in estrogen often triggers severe flare-ups, while menopause, marked by a sustained estrogen reduction, frequently correlates with increased disease severity and flare frequency. The review also addresses the profound impact of psoriasis on women’s quality of life, including physical discomfort, psychological distress, and social stigma. Additionally, fertility concerns are discussed, as severe psoriasis and associated treatments may increase the risk of adverse pregnancy outcomes. Consideration is given to hormonal therapies, lifestyle modifications, and their effects on psoriasis, underscoring the need for personalized treatment approaches that account for hormonal influences. Understanding these hormonal dynamics is essential for developing targeted, effective management strategies that enhance quality of life for women affected by psoriasis.

introduction In the professional practice of nursing, differences have been described between the habitus shared in the academic training process and the professional practice developed in the field of health systems; in this scenario, nurses tend to be affected by how their professional habitus has been established, which, in some way, alters the cultural capital established in their academic training process. The research objective was to identify aspects that facilitate and limit the development of the theoretical component in nursing practice.Method: The research was based on a qualitative hermeneutic study addressed from a critical approach that linked Bourdieu's field theory. The study included 17 students, 11 nurses active in health services, and six university professors. Data were collected from a sociodemographic questionnaire, episodic interviews, and focus groups. The information collected was analyzed using the hermeneutic understanding process from the grounded theory.Results: The research revealed a central thematic core called clarification of the role of the nurse (professional habitus) and three secondary thematic cores related to the need to strengthen the nursing essence (identity habitus), the adjustment of training processes (optimization habitus) and, finally, the strengthening of the nurse's credibility (validation habitus).Conclusion: The professional habitus of nursing professionals is shaped by different elements of the social field of the health system. This field is repressed by hierarchical structures that succeed in disconnecting theory from praxis. Aspects such as subordination to the hegemonic biological discourse and the medical profession, the limited appreciation of humanized care, restrictions on the recognition of the nursing process by health institutions, and limited solidarity and leadership end up conditioning the accumulation of symbolic capital and social capital of nursing, which leads to the loss of autonomy and the advancement of professional development.

The present paper tackles the important issue of tensile ultimate strength of ceramic matrix composites, using a multiscale approach. The ultimate strength is investigated at the successive increasing length scales inherent to 2D woven SiC/SiC composites, i.e. single filaments, fiber tow, minicomposites reinforced with a single tow, and 2D woven composite. First experimental results on tensile behavior under strain-controlled conditions are summarized for tows, minicomposites and composites. Then, models of tow ultimate failure under controlled force and strain are presented. A criterion of tow failure is developed for filament fracture initiation and then propagation based on applied stress and on filament strength gradient. The model of ultimate failure of minicomposite under strain-controlled condition is based on the strength of filaments in the presence of matrix cracks and the overstress induced by interactions of broken filaments and the matrix. The variability of ultimate strengths of filaments, minicomposites and composites at various gauge lengths is described by linear p-quantile diagrams which indicates that the data follow normal distribution function. The contribution of structural effects to variability of composite and minicomposite strength under strain-controlled loading is analyzed. Their dependence on specimen size is related to reproducibility of critical flaw population and structural effects.

Helium is a strategic rare gas resource related to national security and the development of high-tech industries, the high-quality development of helium industry chains has a great significance to improve the security of helium resource. This paper through literature and market research, summarizes the progress of helium resource endowmen, exploration and development, supply and demand pattern, trade market and industrial technology, equipment through literature and market research in the world, analyses the development situation of global helium resources industry chains. This study proposes the development status and challenges of China's helium industry and the corresponding development path of helium industry based on the upstream, midstream, downstream and downstream indicators. Most of the countries in the world have not started helium exploration or remain in low exploration level, but the exploration practice shows that global helium resource potential is considerable; helium exploration and development subjects become diversified in recent years, which may change the global helium supply and demand pattern; The helium reservoir forming theory and exploration and development technology are underdeveloped, and the helium extraction equipment is continuously improved; The global helium production capacity, supply and demand，trade pattern market would be profoundly changing. For a long time, the United States has had an absolute say in the global helium trade system, the contradiction between supply and demand would persist for a long time and significant price fluctuations. China's helium development challenges and opportunities coexist considering the global helium industry chain existing pattern and the new trend of development. There is an urgent need to build an independent and controllable , stable and resilient helium industrial chain, and provide helium resources guarantee for the development of high-tech industries.

The proliferation of cloud computing has given rise to challenges in security that established perimeter-based models cannot easily adapt to. The new buzzword Zero Trust, which is based on the principle of "never trust, always verify," has been looked up as one of the promising solutions. Is Zero Trust a certainty or pie in the sky for security in the cloud? This is discussed further in this paper. This philosophical approach leads us through the earlier work and scientific literature available on the subject, presenting Zero Trust's capabilities, advantages when introduced into cloud security architecture, and obstacles about its incorporation. The study finds that Zero Trust holds the potential to enhance cloud security significantly, but it is no silver bullet and demands careful implementation and further studies to understand its intricacies as well as pitfalls.

Insurance companies need to calculate solvency capital requirements in order to ensure that they can meet their future obligations to policyholders and beneficiaries. The solvency capital requirement is a risk management tool essential for, when extreme catastrophic events occur, resulting in a high number of possibly interdependent claims. This paper studies the problem of aggregating the risks coming from several insurance business lines and analyses the effect of reinsurance in the level of risk. Our starting point is to use a Hierarchical Risk Aggregation method, which was initially based on 2-dimensional elliptical copulas. We then propose the use of copulas from the Archimedean family and a mixture of different copulas. Our results show that a mixture of copulas can provide a better fit to the data than an individual copula and consequently avoid over or underestimating of the capital requirement of an insurance company. We also investigate the significance of reinsurance in reducing the insurance company’s business risk and its effect on diversification. The results show that reinsurance does not always reduce the level of risk, but can also reduce the effect of diversification for insurance companies with multiple business lines.

The primary goal of Theory of Everything (ToE) is to unify General Relativity and Quantum Mechanics, establishing a theoretical framework that explains all natural phenomena and fundamental laws of the universe. The rapid development of artificial intelligence in the 21st century presents new opportunities for the establishment of TOE. Research has revealed that the observer and the agent, as key concepts in physics and intelligence science respectively, share intrinsic consistency. Using this as a breakthrough point, we first proposed Standard Agent Model, which, from the perspective of information processing, establishes a unified structure for agents. This model posits that any agent possesses five essential capabilities: input, output, storage, creation, and control of these four capabilities.By setting the values of these five essential capabilities in Standard Agent Model to either zero or infinity, we identify two extreme states of agents: Absolute Zero Agent (α Point) and Omniscient and Omnipotent Agent (Ω Point). Based on the evolution of agents towards these two extreme states, we derive two driving forces for agent evolution: α Gravity and Ω Gravity. These elements collectively form General Model of Agent Evolution.Building on the first two models, we further derive Intelligent Universe Evolution Model, proposing that Universe, as an agent, evolves dynamically between α Point and Ω Point under the influence of α Field and Ω Field. These three models together constitute "Theory of Universal Intelligent Evolution," abbreviated as Ω Theory. According to Ω Theory, we demonstrate that the observer in physics and a wide range of research objects can be unified within the framework of Standard Agent Model. Additionally, we argue that the four fundamental forces have the potential to be unified into α Gravity and Ω Gravity.Within the framework of Ω Theory, through theoretical analysis and experimental validation, it has been demonstrated that the differences between classical mechanics, relativity, and quantum mechanics stem from the varying intelligence levels assigned to observers. Furthermore, it has been discovered that the differences in intelligent characteristics between the theoretical Universe proposed by these three major physical theories and Universe in which humanity currently resides are the root cause of the varying precision and limitations of these theories.

As the global economy pays increasing attention to sustainable development and environmental protection, the role of green finance in promoting regional technological innovation is becoming more and more prominent. This study aims to analyse the impact of green finance on regional technological innovation and its mechanism of action, with special attention to the mediating effect of R&D inputs and the moderating role of regional characteristics. By analysing the panel data of 30 provinces in China from 2008 to 2021 with fixed and mediated effect models, the results show that green finance significantly promotes regional technological innovation. R&D investment intensity partially mediates this effect, while regional innovation and entrepreneurship capacity plays a significant moderating role in this relationship. Specifically, regional innovation and entrepreneurship capacity reinforces the positive impact of green finance on R&D investment, but the marginal effect of R&D investment is reduced in regions with stronger innovation and entrepreneurship capacity. The findings provide a theoretical basis for formulating relevant policies to promote green finance development and sustainable innovation in regional economies.

Here, we describe the bicomplex (p,q)- Fibonacci numbers and the bicomplex (p,q)- Fibonacci quaternions that are based on these numbers and give some of their equations, including the Binet formula, generating function, Catalan, Cassini, d’Ocagne’s identities, and some summation formulas for both of them. Finally, we create a matrix for bicomplex (p,q)- Fibonacci quaternions, and we obtain a determinant of a special matrix that gives the terms of that quaternion.

In this paper, some convexity properties and some inequalities for the (p,k)-analogue of the Gamma function, Г_p,k(x) are given. In particular, a (p,k)-analogue of the celebrated Bohr-Mollerup theorem is given. Furthermore, a (p,k)-analogue of the Riemann zeta function, ζ_p,k(x) is introduced and some associated inequalities are derived. The established results provide the (p,k)-generalizations of some known results concerning the classical Gamma function.

The main inhibitory neurotransmitter in the mammalian brain is 4-aminobutyric acid (GABA). Phthalimide acts as a sodium channel antagonist, one of the finest targets for treating epilepsy is the sodium channel and JNK kinase activity is inhibited to treat epilepsy. a novel compound with multiple targets of action for the treatment of epilepsy also anti-oxidant activity has been designed. The compounds are designed in two series aldehydes and aniline. Docking of all the designed compounds has been done with the suitable protein GABA-AT, sodium channel, JNK protein, and anti-oxidant from protein bank. QSAR was done for constructing many linear regression models. In combination with the developed Docking and QSAR outcomes, ADMET has been performed for the active compounds. The result shows that 11 of the compounds have excellent binding energy in docking with all the receptors and also have good QSAR results and follow the ADMET. The structural understanding of human GABA-AT inhibition was obtained from molecular dynamics simulation studies for compound no. 11 at 5 nanoseconds. Synthesis and pharmacological activity also suggest that the designed compound no.11 be considered the best Novel Compound.

Epilepsy is a chronic neurological disorder characterized by recurring seizures resulting from abnormal neuronal hyperexcitability. In the case of pharmacoresistant epilepsy requiring resection surgery, identifying the epileptogenic zone (EZ) is crucial. Fast ripples (FRs; 200-600 Hz) are one of the promising biomarkers that can aid in EZ delineation. However, recording FRs requires small surface electrodes. These microelectrodes suffer from high impedance, which significantly impacts FR observability and detection. In this study, we explored the potential of a conductive polymer coating to enhance FR observability. We employed biophysical modeling to compare two types of microelectrodes: Gold (Au) and Au coated with the conductive polymer poly(3,4-ethylenedioxythiophene)-poly(styrene sulfonate) (Au/PEDOT:PSS). These electrodes were then implanted in the CA1 hippocampal neural network of epileptic mice to record FRs during epileptogenesis. Results showed that polymer-coated electrodes demonstrate two-order lower impedance and a higher transfer function amplitude and cut-off frequency. Consequently, FRs recorded with the PEDOT:PSS coated microelectrode yielded significantly higher signal energy compared to the uncoated one. The coating with PEDOT:PSS improved the observability of recorded FRs and therefore their detection. This work paves the way for the development of signal-specific microelectrodes design allowing better targeting of pathological biomarkers.

Epilepsy is a neurological disorder that affects approximately 1% of the world's population. To diagnose and estimate the occurrence of epilepsy, the analysis of recorded brain activity is performed by a neurologist, which is not only time-consuming and tedious but also occasionally accompanied by human error. Therefore, in recent decades, researchers have aimed to unravel an approach for designing and building an automated method for diagnosing and estimating the occurrence of epilepsy. Accordingly, the present study proposed two new-fangled ways based on brain signals and a convolutional neural network (CNN). Moreover, this research implements a CNN with a sequential three-layer structure. Numerous experiments were performed, and the accuracy of estimating epilepsy using the developed methods was achieved at 95% without feedback and 97% with feedback. The proposed methods were proven to be more accurate than the previous techniques and can be employed as a physician's assistant once entering the field of operation.

Glioblastoma is a solid, infiltrating and the most frequent highly malignant primary brain tumor. Our aim was to find the prognostic value of mutations of IDH1, MGMT, EGFR, p53, ATRX, Ki67 genes and the correlation between sex, age, presenting with seizures, number of interventions, extent of resection with Overall Survival (OS), Progression Free Survival (PFS) and Karnofsky performance status (KPS) score. A randomized retrospective analysis of 122 patients treated by a single operator at Sapienza University of Rome, was carried out. After surgery patients followed standard treatment Stupp protocol [6]. Exclusion criteria were: patients with primitive brainstem and spinal cord gliomas and patients who underwent partial resections (resection < 90%) and cases of brain biopsy exclusively for diagnostic purposes. Statistical analysis with a simultaneous regression model was carried on by SPSS 25 ® (IBM) program. Results showed statistically significant survival increase in four groups: 1) patients treated with gross total resection (p< 0.03); 2) patients with methylated MGMT promoter (p<0.005); 3) patients with non EGFR amplification or EGFRvIII mutation (p<0.035); 4) mutated IDH1/IDH2 (p<0.0161). Higher survival rates (but not statistically significant) were observed also in patients with: age < 75 years, Ki 67 <10%, lesions in non eloquent areas, ATRX gene mutation and presentation with seizures.

We introduce the notion of p-adic equiangular lines and derive the first fundamental relation between common angle, dimension of the space and the number of lines. More precisely, we show that if {τj} n j=1 is p-adic γ-equiangular lines in Qd p , then (1) |n| 2 ≤ |d| max{|n|, γ2 }. We call Inequality (1) as the p-adic van Lint-Seidel relative bound. We believe that this complements fundamental van Lint-Seidel [Indag. Math., 1966] relative bound for equiangular lines in the p-adic case. Keywords: Equiangular lines, p-adic Hilbert space.

This article presents a proposed system that enables energy transfer from the dc grid to a single-phase onboard grid, operating at an hi frequency. In addition to the energy transfer function, it additionally enables compensation of reactive power in the ac grid when the converter operates at less than rated power. To operate in compensator mode, it is necessary to decouple the current from the grid into active and reactive components and control them independently. To achieve good dynamics, synchronizers that operate in the dq system are used. In the case of a single-phase grid, it requires such a synchronizer to generate virtual quadrature signals. The used systems based on second-order generalized integrator are good, but to improve dynamics in the work a quadrature generator based on trigonometric calculations was proposed. The developed system was implemented in a proportional resonant current control system. Tests performed in steady state and in dynamic states related to typical grid disturbances showed better dynamic properties than the standard integrator-based system.Keywords: power transfer; compensator; P+R controller

Arc sensors have been used in seam tracking and widely studied since the 80s; commercial arc sensing products for T and V shaped grooves have been developed. However, it is difficult to use these arc sensors in narrow gap welding because arc stability and sensing accuracy are not satisfactory. Pulse gas melting arc welding (P-GMAW) has been successfully applied in narrow gap welding and all position welding processes, so it is worthwhile to research P-GMAW arc sensing technology. In this paper, we derived a linear mathematical P-GMAW model for arc sensing, and the assumptions for the model are verified through experiments and finite element methods. Finally, the linear characteristics of the mathematical model were investigated. In torch height changing experiments, uphill experiments, and groove angle changing experiments the P-GMAW arc signals all satisfied the linear rules. In addition, the faster the welding speed, the higher the arc signal sensitivities; the smaller the groove angle, the greater the arc sensitivities. The arc signal variation rate needs to be modified according to the welding power, groove angles, and swing or rotate speed.

Pardosa pseudoannulata is one of the most common wandering spiders in agricultural fields and a potentially good bioindicator for heavy metal contamination. However, little is known about the mechanism by which spiders respond to heavy metals at the molecular level. In this study, high-throughput transcriptome sequencing was employed to characterize the de novo transcriptome of the spiders and to identify differentially expressed genes (DEGs) after cadmium exposure. We obtained 60,489 assembled unigenes, 18,773 of which were annotated in the public databases. Ultimately, 3450 cDNA simple sequence repeats were identified and validated as potential molecular markers in the unigenes. A total of 2939, 2491 and 3759 DEGs were detected among the three libraries of two Cd-treated groups and the control. Functional enrichment analysis revealed that metabolism processes and digestive system function were predominately enriched in response to Cd stress. At the cellular and molecular levels, significantly enriched pathways in lysosomes and phagosomes as well as replication, recombination and repair demonstrated that oxidative damage resulted from Cd exposure. Based on the selected DEGs, certain critical genes involved in defence and detoxification were analysed. These results may elucidate the molecular mechanism underlying spiders' responses to heavy metal stress.

The emergence of mRNA vaccines represents a significant advancement in public health by conferring protection against a variety of infectious diseases. However, concerns regarding the potential risk of inducing or exacerbating autoimmune disorders, particularly connective tissue diseases (CTDs), have arisen. This paper explores the mechanisms by which mRNA vaccines may lead to the onset or worsening of CTDs, focusing on the immune responses induced by Pathogen-Associated Molecular Patterns (PAMPs), the interactions between Toll-like receptors 7/8 and 9 (TLR7/8 and TLR9), and the activation of self-reactive B cells. Furthermore, guidelines are suggested for administering vaccines to individuals at elevated risk, such as those with a positive antinuclear antibody (ANA) test or specific rheumatic disease genes. Our findings underscore the necessity for targeted vaccination strategies that mitigate risks while maintaining public health efficacy.

Tick-borne encephalitis (TBE) is the most significant arboviral infection in Croatia. The aim of the study was to analyse and correlate 17-year TBE seroprevalence data with winter temperature, precipitation and wildlife abundance to identify possible patterns that can be predictive of TBE incidence. TBE diagnosis was based on IgM/IgG anti-TBE antibodies and individual clinical interpretation of the results. Of the 19,094 analysed patients, 4.2% had acute TBE, significantly more often in older age (p<0.001) and in men (p<0.001). Overall seroprevalence of TBE among the tested population was 5.8%, and varied annually from 2.8% to 10.7%. The mean acute TBE incidence rate was 1.1 per 100.000 population with significant regional differences: 1.7 in the continental vs. 0.2 and 0.5 in the Mediterranean and Alpine regions, respectively. Particularly high incidence of 3.1 was recorded in northern Croatia. TBE displayed a seasonal pattern, peaking in June and July. Moderate negative correlations were observed between TBE acute cases and winter temperatures from December to February (r=-0.461; p=0.062), relative rodent abundance (r=-0.414; p=0.098) and yearly precipitation from one year before (r=-0.401; p=0.123). Considerable efforts are needed to understand the impact on TBE incidence to improve disease prevention.

Understanding the factors that contribute to slope failures, such as soil saturation, is essential for mitigating rainfall-induced landslides. Cost-effective capacitive soil moisture sensors have the po-tential to be widely implemented across multiple sites for landslide early warning systems. How-ever, these sensors need to be calibrated for specific applications to ensure high accuracy in readings. In this study, a soil-specific calibration was performed in a laboratory setting to integrate the soil moisture sensor with an automatic monitoring system using the Internet of Things (IoT). This re-search aims to evaluate a low-cost soil moisture sensor (SKU:SEN0193) and develop calibration equations for the purpose of slope model experiment under artificial rainfall condition using silica sand. The results indicate that a polynomial function is the best fit, with a coefficient of determi-nation (R²) ranging from 0.92 to 0.98 and a root mean square error (RMSE) ranging from 1.17 to 2.67. The calibration equation was validated through slope model experiments, with soil samples taken from the model after the experiment finished. Overall, the moisture content readings from the sensors showed approximately a 10% deviation from the actual moisture content. The findings suggest that the cost-effective capacitive soil moisture sensors has the potential to be used for the development of landslide early warning system.

In the present study, we introduce the two dimensional Chlodovsky type Bernstein operators based on (p,q)−integer. We examine approximation properties of our new operator by the help of Korovkin-type theorem. Further, we present the local approximation properties and establish the rates of convergence by means of the modulus of continuity and the Lipschitz type maximal function. Also, we give a Voronovskaja type theorem for this operators. And, we investigate weighted approximation properties of these operators and estimate rate of convergence in the same space. Finally, with the help of Maple, illustrative graphics show the rate of convergence of these operators to certain functions . The optimization of approximation speeds by operators during system control provides significant improvements in stability and performance. As a result, the control and modeling of dynamic systems become more efficient and effective through innovative methods. These advancements in the fields of modeling fractional differential equations and control theory offer substantial benefits to both modeling and optimization processes, expanding the range of applications in these areas.

This article advances the discourse on sustainable and energy-efficient software by examining the performance and energy efficiency of intelligent algorithms within the framework of green and sustainable computing. Building on previous research, it explores the theoretical implications of Bremermann's Limit on efforts to enhance computer performance through more extensive methods. The study presents an empirical investigation into heuristic methods for search and optimisation, demonstrating the energy efficiency of various algorithms in both simple and complex tasks. It also identifies key factors influencing the energy consumption of algorithms and their potential impact on computational processes. Furthermore, the article discusses cognitive concepts and their interplay with computational intelligence, highlighting the role of cognition in the evolution of intelligent algorithms. The conclusion offers insights into the future directions of research in this area, emphasising the need for continued exploration of energy-efficient computing methodologies.

Epilepsy is known to cause alterations in neural networks. However, many details of these changes remain poorly understood. The objective of this study was to investigate changes in the properties of hippocampal CA1 pyramidal neurons and their synaptic inputs in a rat lithium-pilocarpine model of epilepsy. In the chronic phase of the model, we found a marked loss of pyramidal neurons in the CA1 area. However, the membrane properties of the neurons remained essentially unal-tered. The results of the electrophysiological and morphological studies indicate that the direct pathway from the entorhinal cortex to CA1 neurons is reinforced in epileptic animals, whereas the inputs to them from CA3 are either unaltered or even diminished. In particular, the dendritic spine density in the str. lacunosum moleculare, where the direct pathway from the entorhinal cortex ter-minates, was found to be 2.5 times higher in epileptic rats than in control rats. Furthermore, the summation of responses upon stimulation of the temporoammonic pathway was enhanced by approximately twofold in epileptic rats. This enhancement is believed to be a significant con-tributing factor to the heightened epileptic activity observed in the entorhinal cortex of epileptic rats using an ex vivo 4-aminopyridine model.

Epilepsy is one of the most prevalent and serious brain disorders, affecting 70 million people worldwide. Antiseizure medications (ASMs) though relieve symptoms and prevent the occurrence of future seizures in epileptic patients have limited effect on epileptogenesis. Addressing the multifaceted nature of epileptogenesis and its association with Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated neuroinflammation requires a comprehensive understanding of the underlying mechanisms for development of targeted therapeutic strategies beyond conventional antiseizure treatments. Several types of NLRP3 inhibitors have been developed and their effect has been validated both in vitro and in vivo models of epileptogenesis. In this review, we discuss the advances in understanding the regulatory mechanisms of NLRP3 activation as well as progress made and challenges facing in the development of NLRP3 inhibitors for the treatment of epilepsy.

Ketogenic dietary therapies (KDTs) are an effective and safe non-pharmacological treatment for drug-resistant epilepsy, but adherence can be challenging for both patients and caregivers. In Europe, there are no adequate tools to measure it other than monitoring ketosis. This study aimed to adapt and validate the Brazilian adherence questionnaire, Keto-check, into the Italian version: iKetoCheck. Using the Delphi technique, 12 judges validated the contents through agreement rate and the Content Validity Index (CVI). The iKetocheck was self-completed electronically by drug-resistant epilepsy or GLUT1 deficiency patients within an interval of 15 days to measure its reproducibility. Test-retest reliability was evaluated using Pearson correlation and relative significance test. Exploratory and confirmatory factorial analyses were made using Factor software. The final tool, iKetoCheck, consists of 10 questions with 5-point Likert scale answers. It evaluates various aspects such as informing caregivers about the diet, organization of meals, measurement of ketosis, weighing food consumed, diet negligence, use of carbohydrate-free medications, attending follow-up visits, reading food labels, consulting an expert for dietary concerns, and cooking at home. The factorial analysis resulted in three factors: "attention," "organization," and "precision," with satisfactory results for indices in exploratory and confirmatory analyses. Although higher mean values of ketonemia measurement were observed in patients with a higher adherence score, these values were not statistically significant (p=0.284). In conclusion, iKetoCheck is a valid tool for evaluating KDTs' adherence in Italian drug-resistant epilepsy or GLUT1 deficiency patients. It can provide valuable information to improve patient management and optimize the effectiveness of KDTs.

The KCNA1 gene encodes Kv1.1 voltage-gated potassium channel α subunits, which are crucial for maintaining healthy neuronal firing and preventing hyperexcitability. Mutations in the KCNA1 gene can cause several neurological diseases and symptoms, such as episodic ataxia and epilepsy, which may occur alone or in combination, making it challenging to establish simple genotype-phenotype correlations. Previous analyses of human KCNA1 variants have shown that epilepsy-linked mutations tend to cluster in regions critical for the channel’s pore, whereas EA1-associated mutations are evenly distributed across the length of the protein. In this review, we examine 17 recently discovered pathogenic or likely pathogenic KCNA1 variants to gain new insights into the molecular genetic basis of KCNA1 channelopathy. We provide the first systematic breakdown of disease rates for KCNA1 variants in different protein domains, uncovering potential location biases that influence genotype-phenotype correlations. Our examination of the new mutations strengthens the proposed link between the pore region and epilepsy and reveals new connections between epilepsy-related variants, genetic modifiers, and respiratory dysfunction. Additionally, the new variants include the first two gain-of-function mutations ever discovered for KCNA1, the first frameshift mutation, and the first mutations located in the cytoplasmic N-terminal domain, broadening the functional and molecular scope of KCNA1 channelopathy. Moreover, the recently identified variants highlight emerging links between KCNA1 and musculoskeletal abnormalities and nystagmus, conditions not typically associated with KCNA1. These findings improve our understanding of KCNA1 channelopathy and promise to enhance personalized diagnosis and treatment for individuals with KCNA1-linked disorders.

Despite of over 20 years of community directed treatment with ivermectin (CDTI), a high prevalence of onchocerciasis and onchocerciasis-associated epilepsy were observed in rural villages in Mahenge, Tanzania. Therefore, we assessed the knowledge, attitude and practice about onchocerciasis in four rural villages in the Mahenge area. This was a qualitative study conducted between June and July 2019. Eleven focus group discussions were organized with persons with epilepsy and their caretakers, community resource persons, and community drug distributors (CDDs), and two in-depth interviews with district programme coordinators of neglected tropical diseases (NTD). Most participants were aware about symptoms of onchocerciasis using local terminologies such as “ukurutu/rough dry skin” and “kuwashwa/itching”. A small proportion of people did not take ivermectin during CDTI for fear of adverse reactions such as itching and swelling. Some men believed that ivermectin may decrease libido. Challenges for high CDTI coverage included, long walking distance by CDDs to deliver drugs to households, persons being away for farming, low awareness of the disease and limited supervision by the NTD coordinators. In conclusion, ivermectin uptake in Mahenge should be optimised by continuous advocacy about the importance of taking ivermectin to prevent onchocerciasis-associated morbidity and by improving supervision during CDTI.

A major challenge in the clinical management of patients with mesial temporal lobe epilepsy (MTLE) is identifying those who do not respond to antiseizure medication (ASM), allowing for the timely pursuit of alternative treatments, such as epilepsy surgery. Here, we investigated changes in plasma metabolites as biomarkers of pharmacoresistance in patients with MTLE. Furthermore, we used the metabolomics data to gain insights into the mechanisms underlying MTLE and response to ASM. We performed an untargeted metabolomic method using magnetic resonance spectroscopy and multi- and univariate statistical analyses to compare data obtained from plasma samples of 28 patients with MTLE compared to 28 controls. The patients were further divided according to response to ASM: 20 patients were refractory to treatment, and eight were responsive to ASM. We only included patients using carbamazepine in combination with clobazam. We compared the group of patients with controls and found that the profiles of glucose (p = 0.01), saturated lipids (p = 0.0002), isoleucine (p = 0.0001), β-hydroxybutyrate (p = 0.0003), and proline (p = 0.02) were different in patients compared to controls (p &lt; 0.05). In addition, lipoproteins (p = 0.05), lactate (p = 0.05), glucose (p = 0.05), unsaturated lipids (p = 0.05), isoleucine (p = 0.05), and proline (p = 0.05), could discriminate between the two groups of patients classified according to response to ASM. The identified metabolites were linked to different biological pathways related to cell energy metabolism, and pathways linked to inflammatory processes and the modulation of neurotransmitter release and activity in MTLE. In contrast, we found that pyruvate metabolism may be linked to resistance to ASM. In conclusion, in addition to insights into the mechanisms underlying MTLE and the response to treatment with ASM, our results suggest that plasma metabolites may be used as biomarkers of disease and response to ASM in patients with MTLE. These findings warrant further studies exploring the clinical use of metabolites to assist in decision-making when treating patients with MTLE.

Epilepsy is one of the most common disorders of the central nervous system, impacting nearly 50 million people around the world. Heterogeneous in nature, epilepsy presents in children and adults alike. Currently, surgery is the only treatment that can cure epilepsy. However, not all individuals are eligible or have successful outcomes. Difficulty in accessing samples of human brain tissue along with advances in sequencing technology have driven researchers to investigate sampling liquid biopsies in blood, serum, plasma, and cerebrospinal fluid within the context of epilepsy. Liquid biopsies provide minimal or non-invasive sample collection approaches and can be assayed relatively easily across multiple time points, unlike tissue-based sampling. Various efforts have investigated circulating nucleic acids from these samples including microRNAs, cell-free DNA, transfer RNAs, and long non-coding RNAs. Here, we review nucleic acid-based liquid biopsies in epilepsy to improve understanding of etiology, diagnosis, prediction, and therapeutic monitoring.

The KARS gene encodes the aminoacyl-tRNA synthetase (aaRS) which activates and joins the lysin with its corresponding transfer RNA (tRNA), through the ATP-dependent aminoacylation of the amino acid. The KARS gene mutations have been linked to diverse neurologic phenotypes such as: neurosensorial hearing loss, leukodistrophy, microcephaly, developmental delay or regression, peripheral neuropathy, cardiomyopathy, impairment of the mitochondrial respiratory chain, hyperlactatemia, among others. This article presents the case of a Colombian pediatric patient with two pathological missense variants in a compound heterozygous state in the KARS gene.

This article explores how Artificial Intelligence (AI) is drastically changing the logistics industry by transforming operations and significantly improving customer satisfaction. Through meticulous analysis of real-life cases and extensive examination of numerical data, this comprehensive research thoroughly investigates the profound impact of AI on supply chain management. The findings clearly reveal the multifaceted role of AI in significantly reducing costs, greatly improving delivery accuracy, and significantly enhancing inventory control. AI is not just an incremental advancement, but rather a revolutionary leap forward for the future logistics industry, firmly paving the way for unparalleled automation, digital transformation, and operational effectiveness.

Pancreatic cancer, one of the deadliest cancers worldwide, necessitates improved therapeutics due to its low survival rate (12% in 5 years) and typically late-stage diagnosis [1]. This malignancy tends to present asymptomatically until advanced stages, leading to high rates of metastasis and limiting surgical options [2]. Genetic mutations in key genes like KRAS, CDKN2A, TP53, and SMAD4 are central to pancreatic cancer pathogenesis, driving uncontrolled cell proliferation and making treatment difficult [3]. Current treatment modalities include surgery, chemotherapy, radiation, and emerging immunotherapies. Surgery, particularly the Whipple procedure, offers the only potential cure but is applicable in just 15-20% of cases due to the late diagnosis [4]. Chemotherapy, though commonly used, offers limited long-term survival benefits [5]. Radiation therapy has seen advancements with techniques like stereotactic body radiation therapy (SBRT), which shows promise in reducing toxicity and improving outcomes [6] . Immunotherapy, particularly mRNA vaccines, has demonstrated potential in prolonging recurrence-free survival (>18 months), especially when combined with traditional therapies (13.4 months with surgical resection alone) [7] . Combinations of different treatments have been found to be effective. The challenge of early pancreatic cancer diagnosis mirrors the difficulty of disease management. Prophylactic immunotherapies, like vaccines, could offer a crucial breakthrough for prevention and recurrence reduction. As pancreatic cancer remains difficult to treat effectively, continued research and development in preventative and therapeutic strategies are essential to improving outcomes.

In an outstanding article published in 2008, Suzuki obtained a nice generalization of the Banach contraction principle from which derived a characterization of metric completeness. Although Suzuki’s theorem has been successfully generalized and extended in several directions and contexts, we here show by means of a simple example that the problem of achieving, in an obvious way, its full extension to the framework of w-distances does not have an emphatic response. Motivated by this fact we introduce the concept of presymmetric w-distance on metric spaces, we give some properties and examples of this new structure and show that it provides a reasonable setting to obtain a real and hardly forced w-distance generalization of Suzuki’s theorem. This is realized in our main result, which is a fixed point theorem that involves presymmetric w-distances and certain contractions of Suzuki-type. We also discuss the relationship between our main result and the well-known w-distance full generalization of the Banach contraction principle, due to Suzuki and Takahashi. Connected to this approach we prove another fixed point result that compare with our main result through some examples. Finally, we state a characterization of metric completeness by using our fixed point results.

Polychlorinated dibenzo-p-dioxins and polychlorinated dibenzo-p-furans (PCDD/Fs) are environmental pollutants with a great persistence, capacity of bioaccumulation, and well known important toxic effects in humans and animals. Incinerators of hazardous, municipal and medical waste, chlorine bleaching of paper pulp, cement plants, and the traffic of motor vehicles are the most frequent emission sources of these compounds. The diet, followed at a great distance by inhalation, is generally the main way of human exposure to PCDD/Fs. Human biomonitoring is of a great importance to prevent potential adverse effects derived from exposure to chemicals such as PCDD/Fs. In relation to this, blood is among the most used biological monitors. In the current review, we have summarized the recent information (2000-2009) published in the scientific literature (databases: Scopus and PubMed) on the concentrations of PCDD/Fs in blood samples of non-occupationally exposed populations, as well as in some groups of occupationally exposed individuals. We have revised a number of studies conducted in various African American, Asian and European countries, and Australia. Unfortunately, the information is quite limited. No data are available for most countries over the world. Based on the results here reviewed –where available- the current health risks for the general populations do not seem to be of concern. Moreover, taking into account the important reductions observed in the levels of PCDD/Fs in foodstuffs, new decreases in the concentrations of PCDD/Fs in blood -and other biological tissues- are very probable in the immediate years.

The earthquake alert of the early warning systems is based on the delay that the S waves have in reference to the P waves and on the interpretation of the P waves’ specific parameters. One of the most used parameters for estimating the moment magnitude of an earthquake is the characteristic period measured in the first 3 seconds of the appearance of the P wave. The typical method determines the characteristic period in the time domain, based on the velocity wave and the displacement wave. In the present work, we present a method for estimating the frequency of the characteristic period. This method includes zero padding of the P wave sequence, conversion of the extended sequence from the time domain to the frequency domain, the identification of local frequency maxima and the calculation of the weighted average of the frequency based on the identified maxima. Tests conducted on synthetic signals, as well as standard deviation evaluation tests for simultaneous recordings on several stations, reveal better performance to the usual method.

Cell migration crucial contributor to metastasis, a critical process associated with the mortality of cancer patients. The initiation of metastasis is triggered by epithelial-mesenchymal transition (EMT), along with the changes of the expression of EMT marker proteins. Inflammation plays a significant role in carcinogenesis and metastasis. Lipopolysaccharide (LPS), a typical inflammatory agent, promoted the generation of superoxide through the activation of p-Tyr42 RhoA, Rho-dependent kinase 2 (ROCK2) and the phosphorylation of p47phox. In addition, p-Tyr42 RhoA activated phospholipase D1 (PLD1), with PLD1 and phosphatidic acid (PA) being involved in superoxide production. PA also regulated the expression of EMT maker proteins. Consequently, we have identified MHY9 (Miosin IIA, NMIIA) as a PA-binding protein in response to LPS. MYH9 also contributed cell migration and the alteration of the expression of EMT marker proteins. P-Tyr42 RhoA, PLD1 and MYH9 associated to form a complex, which was distributed in both the cytosol and nucleus. In addition, we have found that p-Tyr42 RhoA and PLD1 associated with the ZEB1 promoter. Taken together, we propose that p-Tyr42 RhoA and PLD1, responsible for producing PA, and PA-bound MYH9 are involved in the regulation of ZEB1 expression, thereby promoting cell migration.

Abstract: (1) Background: Surgery is the best curative option for Gastric Cancer (GC). However, morbimortality associated with surgery still a significant problem. Thus, it is essential to determine the preoperative surgical risk, to optimize outcomes in higher risk patients. (2) Methods: Patients who underwent curative gastrectomy between January 2010 and December 2013 were included, obtaining a sample of 131 patients, and the acuity of the scales understudy was evaluated. The predictive power of the scales was evaluated through calibration and discrimination. (3) Results and Conclusions: Regarding mortality, the scales demonstrated good calibration, with POSSUM and P-POSSUM obtaining the best O:E ratio. The scales presented good discrimination, with POSSUM showing the best result. Considering morbidity, the scales showed good calibration and discrimination. POSSUM and P-POSSUM seem to have potential in predicting morbidity and mortality when applied to the studied population, but there is a need for further studies in this area.

Emerging evidence has shown that microRNAs play pivotal roles in wound healing. MicroRNA-21 (miR-21) was previously found to upregulate in order to fulfill an anti-inflammation role for wounds. Exosomal miRNAs have been identified and explored as essential markers for diagnostic medicine. However, the role of exosomal miR-21 in wounds has yet to be well studied. In order to facilitate the early management of poorly healing wounds, we developed an easy-to-use, rapid, paper-based microfluidic-exosomal miR-21 extraction device to determine wound prognosis in a timely manner. We isolated and then quantitatively examined exosomal miR-21 in wound fluids from normal tissues, acute and chronic wounds. Eight improving wounds displayed lower levels of exosomal miR-21 expression after wound debridement. However, four instances of increased exosomal miR-21 expression levels were notably associated with patients with poor healing wounds despite aggressive wound debridement, indicating a predictive role of tissue exosomal miR-21 for wound outcome. Paper-based nucleic acid extraction device provides a rapid and user-friendly approach for evaluating exosomal miR-21 in wound fluids as a means of monitoring wounds. Our data suggest that tissue exosomal miR-21 is a reliable marker for determining current wound status.

If an algebra of type $A$ contains a subalgebra which is also an algebra of type $B$, then it is a Smarandache $B$-type $A$-algebra provided the subalgebra of type $B$ contains at least two elements. This generalizes the notion of Smarandache group, where the group of order $\geq 2$ is a subsemigroup of a semigroup. In this paper we investigate a number of such pairings and we deduce a number of conclusions as a consequence.

This study explores the impact and significance of implementing a comprehensive education system for children with special needs. The research aims to understand how inclusive practices influence the academic, social, and emotional development of these students. Using a mixed-methods approach that includes case study analysis, reviews of global education models, and theoretical frameworks, the study identifies key strategies for fostering inclusivity. The findings reveal that inclusive education not only enhances academic performance but also promotes social integration and emotional well-being. The analysis compares inclusive practices with traditional special education models and highlights the advantages of equity-driven, accessible learning environments. The study also addresses the challenges faced, such as inadequate resources and the need for continuous teacher training. Recommendations include policy reforms, increased funding, and the adoption of assistive technologies to support diverse learning needs. The research underscores the importance of a collaborative approach involving educators, parents, policymakers, and the community in creating an education system where every child has the opportunity to thrive.

The Median Based Unit Weibull is a new 2 parameter unit Weibull distribution defined on the unit interval (0,1). Estimation of the parameters using MLE encountered some problems like large variance. Using generalized method of moments (GMMs) and percentile method may ameliorate this condition. This paper introduces GMMs and the percentile methods for estimating the parameters of the new distribution with illustrative real data analysis.

Interspecific competition between mosquito larvae may affects adult vectorial capacity, potentially reducing disease transmission. It also influences population dynamics, cannibalistic and predatory behaviors. However, knowledge of interspecific competition between Ae. aegypti and Anopheles species is limited. The study examined interspecific competition between Ae. aegypti larvae and either An. arabiensis, An. gambiae, or An. funestus on individual fitness in semi-field settings. The experiments involved density combinations of 100:100, 200:0, and 0:200 (Ae. aegypti: Anopheles), reared with and without food, in small habitat (8.5 cm height × 15 cm diameter) with 0.5 litre and medium habitats (15 cm height × 35 cm diameter) with 1 litre of water. The first group received Tetramin® fish food (0.02 g), while the second group was unfed to assess cannibalism and predation. While, interspecific competition affected both genera, Anopheles species experienced greater effect, with reduced survival and delayed development, compared to Ae. aegypti. The mean wing lengths of all species were significantly small in small habitats in mixed population (p &lt; 0.001). The presence of food reduced cannibalism and predation compared to its absence. These interactions have implications for diseases transmission dynamics and can serve as biological indicators to signal the impacts of vector control interventions.

In response to a perceived epidemic of coronary heart disease, Ancel Keys introduced the lipid-heart hypothesis in 1953 which asserted that high intakes of total fat, saturated fat, and cholesterol lead to atherosclerosis and that consuming less fat and cholesterol, and replacing saturated fat with polyunsaturated fat, would reduce serum cholesterol and consequently the risk of heart disease. Keys proposed an equation that would predict the concentration of serum cholesterol (DChol.) from consumption of saturated fat (DS), polyunsaturated fat (DP), and cholesterol (DZ): ΔChol. = 1.2(2ΔS − ΔP) + 1.5ΔZ. However, the Keys equation conflated natural saturated fat and industrial trans-fat into a single parameter and considered only linoleic acid as the polyunsaturated fat. This ignored the widespread consumption of trans-fat and its effects on serum cholesterol and promoted an imbalance of omega-6 to omega-3 fatty acids in the diet. Numerous observational, epidemiological, interventional, and autopsy studies have failed to validate the Keys equation and the lipid-heart hypothesis. Nevertheless, these have been the cornerstone of national and international dietary guidelines which have focused disproportionately on heart disease and much less so on cancer and metabolic disorders, which have steadily increased since the adoption of this hypothesis.

In this paper, we define and investigate modified p-Leonardo, p-Leonardo-Lucas and p-Leonardo sequences as special cases of the generalized Leonardo sequence. We present Binet's formulas, generating functions, Simson formulas, and the summation formulas for these sequences. Moreover, we give some identities and matrices related with these sequences. Furthermore, we show that there are close relations between modified p-Leonardo, p-Leonardo-Lucas, p-Leonardo numbers and Fibonacci, Lucas numbers.

For evaluating probabilities of arbitrary random events with respect to a given multivariate probability distribution, specific techniques are of great interest. An important two-dimensional high risk limit law is the Gauss-exponential distribution whose probabilities can be dealt with based upon the Gauss-Laplace law. The latter will be considered here as an element of the newly introduced family of (p,q)-spherical distributions. Based upon a suitably defined non-Euclidean arc-length measure on (p,q)-circles we prove geometric and stochastic representations of these distributions and correspondingly distributed random vectors, respectively. These representations allow dealing with the new probability measures similarly like with elliptically contoured distributions and more general homogeneous star-shaped ones. This is demonstrated at hand of a generalization of the Box-Muller simulation method. En passant, we prove an extension of the sector and circle number functions.

Epilepsy is a non-communicable neurological disease characterized by abnormal brain activity with conceivable peripheral implications. Few studies examine the role of peripheral and brain inflammation in the relationship between seizure predisposition and nonalcoholic fatty liver disease. Severe early-life infections leading to sepsis results in increased inflammation that can aggravate epilepsy and hepatic damage progression both associated with increased odds for hospital admissions in epileptic patients. Here, we examined the effect of early LPS challenge (1 mg/kg, i.p. at post-natal day3, PND3) in inducing hepatic damage in a genetic model of young epileptic WAG/Rij rats (PND45), evaluating the intra- and inter-gender differences on systemic and liver inflammation, hepatic lipid dysmetabolism and oxidative damage associated to mitochondrial functional impairment. First, epileptic rats exposed to LPS, regardless of gender, displayed increased serum hepatic enzymes and altered lipid profile. Early LPS challenge induced a major inflammatory and immune response in male epileptic rats than females in both serum and liver, increasing pro-inflammatory cytokines and hepatic immune cell recruitment. Conversely, LPS-insulted females showed a marked alteration in hepatic metabolic and lipid profile and the reduction in mitochondrial fatty acid oxidation. The two different gender-related mechanisms of LPS-induced liver injury converge in mitochondrial oxidative damage with intensified ROS production in both sexes, that notably induced a compensatory increase in antioxidant defense only in females. Our study with a translational potential points out that early postnatal infections predispose epileptic rats to develop or worsen hepatic disorders in a sex-dependent manner, amplifying inflammation, lipid dysmetabolism, and mitochondrial impairment.

Febrile seizures in early childhood can lead to developmental disorders in the CNS. However, the specific mechanisms behind the impact of febrile seizures on the developing brain are not well-understood. To address this gap in knowledge, we employed a hyperthermic model of febrile seizures in 10-day-old rats and tracked their development over two months. Our objective was to determine the degree to which the properties of the hippocampal glutamatergic system are modified. We analyzed whether pyramidal glutamatergic neurons in the hippocampus die after febrile seizures. Our findings indicate that there is a reduction in the number of neurons in various regions of the hippocampus in the first two days after seizures. The CA1 field showed the greatest susceptibility, and the reduction in the number of neurons in post-FS rats in this area appeared to be long-lasting. Electrophysiological studies indicate that febrile seizures cause a reduction in glutamatergic transmission, leading to decreased local field potential am-plitude. This impairment could be attributable to diminished glutamate release probability as evidenced by decreases in frequency of miniature excitatory postsynaptic currents and increases in pair-pulse ratio of synaptic responses. We also found higher threshold current causing hindlimb extension in the maximal electroshock seizure threshold test of rats 2 months after febrile seizures compared to control animals. Our research suggests that febrile seizures can impair glutamatergic transmission, which may protect against future seizures.

Whole-brain radiation therapy and stereotactic radiosurgery are two treatment modalities commonly utilized to treat brain metastases (BMs). The aim of this study is to retrospectively analyze the main radio-oncologic and clinical-demographic aspects of a cohort of BM patients treated with Volumetric Modulated Arc Therapy for radiosurgery (VMAT-RS). This is a cross-sectional observational design study with retrospective review of medical records of patients with brain metastases treated with VMAT- RS between 2012 and 2018. Clinical and demographic data, with special attention to sex, age, primary tumor, brain tumor-related epilepsy (BTRE), number and brain location of BMs, Karnofsky Performance Status (KPS), the updated DS-GPA prognostic index and the survival estimated according to the Kaplan-Meier model from the date of radiosurgery were analyzed. One hundred and twenty-one patients with 229 BMs were treated with VMAT-RS. Patients presented 1-4 BMs, which were treated with 5 non-coplanar VMAT arcs. Sixty-eight percent of the patients had lung cancer and 35% of the BMs were in the frontal lobe. Proportion of local control was 88.5%. BTRE prevalence was 30.6%. The median survival time (MST) was 7.7 months. In the multivariate analysis of the Cox Regression model KPS70 (HRKPS&lt;70=2.59; p=0.001) and higher DS-GPA (HRDS-GPAII =0.55, p=0.022; HRDS-GPAIII-IV =0.38, p=0.006) were associated with improved survival. In the univariate analysis, primary tumor, age and the presence of metastases in the posterior fossa (PFBMs) were also significative. In conclusion, the VMAT-RS is a technique with an overall survival comparable to other radiosurgery techniques. The median survival is significantly longer in those with higher KPS and DS-GPA. Other variables such as the type of primary tumor, age and PFBMs could also influence survival, although further studies are needed.

The etiopathogenesis of autism spectrum disorder (ASD) remains largely unclear. Among other biological hypotheses, researchers have evidenced an imbalance in the endocannabinoid (eCB) system, which regulates some functions typically impaired in ASD, such as emotional responses and social interaction. Also, cannabidiol (CBD), the non-intoxicating component of Cannabis sativa, has been recently approved for treatment-resistant epilepsy. Seizures represent frequent medical comorbidities of ASD and could be responsible for the onset or worsening of behavioral problems. Thus, it has been hypothesized that cannabinoids could be useful in improving some ASD symptoms. Our systematic review was conducted according to the PRISMA guidelines and aimed to summarize the literature regarding the use of cannabinoids in ASD. After searching in Web of Knowledge^TM, PsycINFO, and Embase, we included ten studies (eight papers and two abstracts). Four ongoing trials were retrieved in ClinicalTrials.gov. Findings are promising, as cannabinoids appeared to improve problem behaviors, sleep, hyperactivity, and communication deficits, with limited cardiac and metabolic side effects. Interestingly, they generally allowed to reduce the number of prescribed medications and decreased the frequency of seizures in epileptic patients. Mechanisms of action could be linked to the excitatory/inhibitory imbalance found in people with ASD. However, further trials need to be implemented with better characterization and homogenization of samples, and well-defined outcomes.

Once a wheat sheaf has been sealed and tied up, its packed down straws display the same orientation and zero-divergence. This observation brings us to the mathematical notion of presheaf, i.e., a topological structure in which diverging functions are locally superimposed. We show how the concepts of presheaves and the correlated globular sets, borrowed from category theory and algebraic topology, allow a well-founded mathematical approach to otherwise elusive activities of the brain. The mathematical assessment of brain functions in terms of presheaves: a) explains why spontaneous random spikes synchronize; b) leads to the counterintuitive intuition of antidromic effects in neuronal spikes: when an entrained oscillation propagates from A to B, changes in B lead to changes in A. We provide testable previsions: a) we suggest the proper locations of transcranial magnetic stimulation’s coils to improve the clinical outcomes of drug-resistant epilepsy; b) we advocate that axonal stimulation by external sources backpropagates and alters the neuronal electric oscillatory frequency. Further, we describe how the hierarchical information transmission inside globular sets provides fresh insights concerning different issues at various coarse-grained scales, such as object persistence, memory reinforcement in spite of random noise, Bayesian inferential circuits.

In this research paper, we implement the theory of the primorial function, to develop the Supremum and Infimum bounds for the sum of (log(p))². There are, however, considerable computational difficulties related to these bounds. Therefore, from a pragmatic point of view, a set of Upper and Lower bounds had been developed to bypass this issue. Despite the increased estimation error, the Upper and Lower bounds are still considered sufficiently accurate, while facilitating an easy and fast computation of the estimate of the sum.

Polyhedral cages (p-cages) describe the geometry of some families of artificial protein cages. We identify the p-cages made out of families of equivalent polygonal faces such that the faces of 1 family has 5 neighbours and P_1 edges, while those of the other family have 6 neighbours and P_2 edges. We restrict ourselves to polyhedral cages where the holes are adjacent to at most 4 faces. We characterise all the p-cages with a deformation of the faces, compared to regular polygons, not exceeding 10%.

Mevcut çalışmada, (p, q)−tam sayıya dayalı iki boyutlu Chlodovsky tipi Bernstein operatörlerini tanıtıyoruz. Yeni operatörümüzün yaklaşıklık özelliklerini Korovkin tipi teorem yardımıyla inceliyoruz. Ayrıca, yerel yaklaşıklık özelliklerini sunuyoruz ve süreklilik modülü ve Lipschitz tipi maksimal fonksiyon vasıtasıyla yakınsama oranlarını belirliyoruz. Ayrıca, bu operatörler için bir Voronovskaja tipi teorem veriyoruz. Ve, bu operatörlerin ağırlıklı yaklaşıklık özelliklerini inceliyoruz ve aynı uzayda yakınsama oranını tahmin ediyoruz. Son olarak, Maple'ın yardımıyla, açıklayıcı grafikler bu operatörlerin belirli fonksiyonlara yakınsama oranlarını göstermektedir. Sistem kontrolü sırasında operatörler tarafından yaklaşıklık hızlarının optimizasyonu, kararlılık ve performansta önemli iyileştirmeler sağlar. Sonuç olarak, dinamik sistemlerin kontrolü ve modellenmesi yenilikçi yöntemlerle daha verimli ve etkili hale gelir. Kesirli diferansiyel denklemlerin modellenmesi ve kontrol teorisi alanındaki bu gelişmeler, hem modelleme hem de optimizasyon süreçlerine önemli faydalar sunarak bu alanlardaki uygulama yelpazesini genişletmektedir.

In our previous study of 291 cancer patients, we showed that 20% did not respond to two doses of COVID-19 vaccine administered six weeks apart. Here we investigated if psychological factors (distress, anxiety and depressive symptoms) affected antibody response and markers of vaccine activation (D-dimer) after 6 months from initial vaccination. Overall, 31 subjects (14.2%) had no antibody response at 6 months. Our analysis revealed significant predictors of vaccine failure, including stage of metastatic disease and high stress levels (OR=2.46, 95% CI, 1.05-5.77, p=0.04). Notably, nonresponders showed twice the prevalence of distress than responders (21% vs. 10%, p=0.04). Longitudinal measurements of IgG levels indicated that participants with high depressive symptoms at baseline maintained lower antibody levels over six months (p=0.003). In addition, women with high anxiety showed reduced levels of D-dimer at 6 month time (p=0.03). The data also showed that smokers and former smokers had significantly lower antibody levels than their nonsmoking counterparts (p=0.0004). At baseline, the high discomfort rate (≥5) was 34.4% in women and 23.8% in men; only men experienced an increase in median discomfort during the observation period. Moreover, higher educational level was related to increased distress among women (p=0.046). These findings underscore a critical association between elevated psychological distress and reduced immune responses to the COVID-19 vaccine, emphasizing the urgent need for targeted psychological and behavioral support within this vulnerable population.

CO₂-soluble surfactant foam systems have garnered significant attention in the fields of enhanced oil and gas recovery, environmental protection, and greenhouse gas emission reduction. This review provides a comprehensive explanation of the basic theory of CO₂-soluble surfactant foam, the mechanism of enhanced oil recovery, and the classification and application of various CO₂-soluble surfactants.The mechanism of enhanced oil recovery by CO₂-soluble surfactant foam involves the effective reduction of CO₂ fluidity, the decrease in oil-air flow ratio, and the stabilization of the displacement front. Foam plays a vital role in mitigating the issues of channeling and gravity separation often caused by simple CO₂ injection. The reduction in gas fluidity can be attributed to the increase in apparent viscosity and trapped gas fraction.Future research should prioritize the development of more efficient and environmentally-friendly CO₂-soluble surfactants. It is essential to further explore the advantages and challenges associated with their practical applications in order to maximize their potential impact.

Objectives: Cardiogenic shock [CS] is associated with a high-mortality. Suitable patients maybe successfully bridged using newer intravascular micro-axial left-ventricular assist devices [M-LVAD] for recovery or determination of definitive therapy. Methods: Between January-2020 and July-2024, 107 patients underwent placement of M-LVAD for CS. The cohort was divided into 4 groups based on their destination; group-1: 34 patients [32%] receiving transplant; group-2: 25 patients [23%] receiving durable LVAD; group-3: 42 patients [39%] bridging from post-cardiotomy CS [PCCS]; and group-4: 6 patients [5.6%] bridging decision/recovery [these were excluded from analysis]. Multivariable logistic-regression [MLR] and Cox-regression [MCR] models identified predictors of early-hospital and late mortality, with data reported as odds ratios [ORs], and hazard ratios [HRs], respectively. P<0.05 was statistically significant. Results: Complications included device-malfunction [n=6, 6%], gastrointestinal bleed [n=9, 9%], stroke [n=11, 11%]; long-term hemodialysis [n=21, 21%]. Early-hospital mortality included 13 patients [13%]: 2 in group-1, 1 in group-2 and 10 in group-3 [p=0.02]. In the MLR model, the category of cardiogenic shock requiring M-LVAD placement was statistically significant [OR=4.7 (0.9-24), P=0.05]. Patients were followed for up to 4.5-years, and 23 deaths occurred; group-1: 3 patients, group-2: 5 patients, and group-3: 15 patients [p=0.019]. At 4.5-years, actuarial survival was 90.7±5.1% in group-1, 79.2±8.3% in group-2, and 62.8%±7.7% in group-3 [P=0.01]. In the MCR model, M-LVAD category [HR=3.63 (1.03-12.9) P=0.04], and long-term postoperative dialysis [HR=3.9 (1.6-9) P=0.002], emerged as statistically significant predictors of long-term mortality. Conclusions: In cardiogenic shock, our mid-term outcomes demonstrate good survival with M-LVADs as bridge to transplant and durable LVAD, and reasonable survival as bridge to recovery following cardiotomy, reduced ECMO usage and early ambulation/rehabilitation.

Antimalarial drug resistance has become a real public health problem despite WHO measures. New sequencing technologies make it possible to investigate genomic variations associated with resistant phenotypes at the genome-wide scale. Based on the use of hemisynthetic nanopores, the PromethION technology from Oxford Nanopore Technologies can produce long-read sequences, in contrast to previous short-read technologies used as gold-standard to sequence Plasmodium. Two clones of P.falciparum (Pf3D7 and PfW2) were sequenced in long-read using the PromethION sequencer from Oxford Nanopore Technologies without genomic amplification. This made it possible to create a processing analysis pipeline for human Plasmodium with ONT Fastq only. De novo assembly revealed N50 lengths of 18,488 kb and 17,502 kb for the Pf3D7 and PfW2, respectively. The genome size was estimated at 23,235,407 base pairs for the Pf3D7 clone and 21,712,038 base pairs for the PfW2 clone. The average genome coverage depth was estimated at 787X and 653X for the Pf3D7 and PfW2 clones, respectively. This study proposes an assembly processing pipeline for the human Plasmodium genome using software’s adapted to large ONT data and the high AT percentage of Plasmodium. This search provides all the parameters, which have been optimized, for use with the software selected in the pipeline.

This study aims to explore methods for automating the replication of correlated portfolios across shares using various algorithms. The goal is to select one algorithm for implementation in a visualization tool that will facilitate portfolio building. The dynamics of the stock market provide a comprehensive view of the global economy, acting as a catalyst for stakeholders to participate and benefit various sectors financially, primarily through investments in companies that yield returns and contribute to the economy. The evaluation and comparison of these algorithms are crucial for making well-informed decisions regarding the core objectives of the study. Ultimately, a determination will be made as to whether the program can effectively analyse data from Yahoo finance to provide a quick overview of the financial market state of companies in the S&P 500 US stock prices.

Porphyromonas gingivalis is the major pathogenic bacteria found in the subgingival plaque of patients with periodontitis, leading to neuroinflammation. The bacteria destroy periodontal tissue through its virulence factors which are retained in the bacteria’s outer membrane vesicles (OMV). The purpose of this study was to determine the real time effect of intraperitoneal in-jection of P. gingivalis OMV on the production and expression of inflammatory markers as well as histopathological changes in the central nervous system (CNS) of adult zebrafish. Fol-lowing the LD50 (21 µg of OMV), the zebrafish were injected intraperitoneally with 18 µg of OMV and control group with normal saline at 7 different time points. Brains of experimental zebrafish were dissected at desired time points for colorimetric assays, ELISA and histology. This study discovered that nitric oxide and PGE2 were significantly increased at 45 minutes while IL-1β and IL-6 were expressed at subsequent 12- and 24-hours. respectively. Histopatho-logical changes such as blood coagulation, astrocytosis, oedema, spongiosis, and necrosis were also observed between 6- and 24-hours. The two apoptotic enzymes, caspases 3 and 9 were not expressed at any time point. In summary, the OMV induced neuroinflammatory responses and histopathological changes in adult zebrafish were time point dependent

Aluminum (Al) toxicity and low phosphorus availability (LP) are the top two co-existing edaphic constraints limiting agriculture productivity in acid soils. Plants have evolved versatile mechanisms to cope with the two stresses alone or simultaneously. However, the specific and common molecular mechanisms, especially those on flavonoids and carbohydrate metabolism, are still unclear. Laboratory studies were conducted on two wheat genotypes, Fielder (Al-tolerant and P-efficient) and Ardito (Al-sensitive and P-inefficient), exposed to 50 μM Al and 2 μM Pi (LP) in hydroponic solutions. After 4 days of stress, wheat roots were analyzed via transcriptomic and targeted metabolomic techniques. A total of 2296 differentially expressed genes (DEGs, 1535 up and 761 down) under Al and 3029 DEGs (1591 up and 1438 down) under LP were identified in Fielder. Similarly, 4404 DEGs (3191 up and 1213 down) under Al and 1430 DEGs (1176 up and 254 down) under LP were identified in Ardito. The GO annotation analysis results that 4079 DEGs annotated to the metabolic processes term. These DEGs were significantly enriched in the phenylpropanoid, flavonoid, flavone and flavonol biosynthesis, and carbohydrate metabolism pathways by performing the KEGG enrichment analysis. The targeted metabolome analysis detected 19 flavonoids and 15 carbohydrate components in Fielder and Ardito under Al and LP. More responsive genes and metabolites were involved in flavonoid metabolism under LP than Al in the Fielder, while an opposite trend in the Ardito. In the carbohydrate metabolism pathway, the genes and metabolites were higher in Fielder than in Ardito. The combined transcriptome and metabolome analysis revealed that the flavonoid and carbohydrate genes and metabolites differed between Fielder and Ardito under Al and LP, which may be an important reason for Fielder’s high Al and LP resistance. The results of this study lay a foundation for pyramiding genes and breeding multi-resistance varieties.

Flexible capacity applications demands to large energy storage density and high breakdown electric field strength of flexible films. Here, P(VDF-HFP) with ultra-thin Al2O3 nanosheets composite films were designed and fabricated through an electrospinning process followed by hot-pressing in sandwich structured. The results show that the insulating ultra-thin Al2O3 nanosheets and the sandwich structure can enhance the composites' breakdown field (by 24.8%) and energy density (by 30.6%) remarkedly to P(VDF-HFP) polymer matrix. An energy density of 23.5 J/cm3 at the ultrahigh breakdown field of 740kV/mm can be therefore realized. Insulating test and phase-field simulation results reveal that ultra-thin nanosheets insulating buffer layers can reduce the leakage current in composites, thus it effects the electric field spatial distribution to enhance breakdown strength. Our research provides a feasible method to increase the breakdown strength of ferroelectric polymers, which is comparable to those of non-ferroelectric polymers.

The role of biomarkers in the diagnosis of inflammatory bowel disease is not fully characterized. C-reactive protein has a short half-life and elevates quickly after the onset of an inflammatory process, the performance is better in Crohn’s disease than in ulcerative colitis. Erythrocyte sedimentation rate is easy to determine, widely available, and cheap but the long half-life the influence of age, anemia, smoking, and drugs limit its usefulness. Fecal markers have good specificity, but suboptimal accuracy. Microbial antibodies and novel immunological markers show promise but need further evidence before entering clinical practice. Proteomic methods could represent the dawn of a new era of stool protein/peptide biomarker panels able to select patients at risk of inflammatory bowel disease.

Background: Hypovitaminosis D is a public health problem due to its implications for various diseases. Vitamin D has numerous functions, such as modulating the metabolism of some cellular tissues, and is expressed through the VDR gene that may influence gene expression modulation, which plays an important role in vitamin D metabolism. Objective: To evaluate the effect of the genotypes of single nucleotide polymorphism (SNP) BsmI of the vitamin D receptor (VDR) gene on VDR, SOD2, and CYP24A1 gene expression in individuals with low serum vitamin D levels. Methods: This was a cross-sectional analytical study. Individuals were invited to participate and, after signing the informed consent form, answered a structured questionnaire with identification data. Blood was collected for biochemical analysis, and vitamin D was measured by chemiluminescence; BsmI polymorphism was determined using real-time polymerase chain reaction (PCR) assays with TaqMan allelic discrimination, and gene expression was conducted by qRT-PCR using QuantiFast SYBR® Green PCR Master Mix. Data were analyzed using the SPSS 20.0 software, and differences were considered significant at p&lt;0.05. Results: 98 individuals with vitamin D ≤20 ng/dL were evaluated, and the SNP BsmI of the VDR gene showed CYP24A1 overexpression and low SOD2 expression. Conclusion: SNP Bsm I of the VDR gene can modulate the expression of the genes evaluated without interfering with serum levels.

The multidrug efflux transporter ABCB1 is clinically important for drug absorption and distribution and can be a determinant of chemotherapy failure. Recent structure data shows that three glutamines donate hydrogen bonds to co-ordinate taxol in the drug binding pocket. This is consistent with earlier drug structure-activity relationships that implicated the importance of hydrogen bonds in drug recognition by ABCB1. By replacing the glutamines with alanines we have tested whether any or all of Q347, Q725 and Q990 are important for the transport of three different drug classes. Flow cytometric transport assays show that Q347A and Q990A act synergistically to reduce transport of Calcein-AM, BODIPY-verapamil and OREGON GREEN-taxol bisacetate but the magnitude of the effect was dependent on the test drug and no combination of mutations completely abrogated function. Surprisingly, Q725A mutants generally improved transport of Calcein-AM and BODIPY-verapamil, suggesting that engagement of the wild-type Q725 in a hydrogen bond is inhibitory for the transport mechanism. To test transport of unmodified taxol, stable expression of Q347/725A and the triple mutant was engineered and shown to confer equivalent resistance to the drug as the wild-type transporter, further indicating that none of these potential hydrogen bonds between transporter and transport substrate are critical for function of ABCB1. The implications of the data for plasticity of the drug binding pocket are discussed.

During their complex life cycles, the Apicomplexan parasites, Plasmodium falciparum and Toxoplasma gondii employ several genetic switches to regulate their gene expression. One such switch is mediated at the level of translation through upstream Open Reading Frames (uORFs). As uORFs are found in the upstream regions of a majority of genes in both the parasites, it is essential that their roles in translational regulation be appreciated to a greater extent. This review provides a comprehensive summary of studies that show uORF-mediated gene regulation in these parasites and highlights examples of clinically and physiologically relevant proteins that exhibit uORF-mediated regulation. In addition to these examples, several studies that use bioinformatics, transcriptomics, proteomics, and ribosome profiling also indicate the possibility of widespread translational regulation by uORFs. Further analysis of genome-wide datasets will reveal novel genes involved in key biological pathways such as cell-cycle progression, stress-response, and pathogenicity. The cumulative evidence from studies presented in this review suggests that uORFs will play crucial roles in regulating gene expression during clinical disease caused by these important human pathogens.