Predictive, preventive, and personalized medicine in breast cancer: targeting the PI3K pathway.

Breast cancer (BC) is a multifaceted disease characterized by distinct molecular subtypes and varying responses to treatment. In BC, the phosphatidylinositol 3-kinase (PI3K) pathway has emerged as a crucial contributor to the development, advancement, and resistance to treatment. This review article explores the implications of the PI3K pathway in predictive, preventive, and personalized medicine for BC. It emphasizes the identification of predictive biomarkers, such as PIK3CA mutations, and the utility of molecular profiling in guiding treatment decisions. The review also discusses the potential of targeting the PI3K pathway for preventive strategies and the customization of therapy based on tumor stage, molecular subtypes, and genetic alterations. Overcoming resistance to PI3K inhibitors and exploring combination therapies are addressed as important considerations. While this field holds promise in improving patient outcomes, further research and clinical trials are needed to validate these approaches and translate them into clinical practice.

Chemistry Aspects and Designing Strategies of Flexible Materials for High-Performance Flexible Lithium-Ion Batteries.

In recent years, flexible and wearable electronics such as smart cards, smart fabrics, bio-sensors, soft robotics, and internet-linked electronics have impacted our lives. In order to meet the requirements of more flexible and adaptable paradigm shifts, wearable products may need to be seamlessly integrated. A great deal of effort has been made in the last two decades to develop flexible lithium-ion batteries (FLIBs). The selection of suitable flexible materials is important for the development of flexible electrolytes self-supported and supported electrodes. This review is focused on the critical discussion of the factors that evaluate the flexibility of the materials and their potential path toward achieving the FLIBs. Following this analysis, we present how to evaluate the flexibility of the battery materials and FLIBs. We describe the chemistry of carbon-based materials, covalent-organic frameworks (COFs), metal-organic frameworks (MOFs), and MXene-based materials and their flexible cell design that represented excellent electrochemical performances during bending. Furthermore, the application of state-of-the-art solid polymer and solid electrolytes to accelerate the development of FLIBs is introduced. Analyzing the contributions and developments of different countries has also been highlighted in the past decade. In addition, the prospects and potential of flexible materials and their engineering are also discussed, providing the roadmap for further developments in this fast-evolving field of FLIB research.

Synthesis of Electrical Conductive Metal-Organic Frameworks for Electrochemical Applications.

Electrical conductivity is very important property of nanomaterials for using wide range of applications especially energy applications. Metal-organic frameworks (MOFs) are notorious for their low electrical conductivity and less considered for usage in pristine forms. However, the advantages of high surface area, porosity and confined catalytic active sites motivated researchers to improve the conductivity of MOFs. Therefore, 2D electrical conductive MOFs (ECMOF) have been widely synthesized by developing the effective synthetic strategies. In this article, we have summarized the recent trends in developing the 2D ECMOFs, following the summary of potential applications in the various fields with future perspectives.

DNA repair pathways in breast cancer: from mechanisms to clinical applications.

BACKGROUND: Breast cancer (BC) is a complex disease with various subtypes and genetic alterations that impact DNA repair pathways. Understanding these pathways is essential for developing effective treatments and improving patient outcomes. AREA COVERED: This study investigates the significance of DNA repair pathways in breast cancer, specifically focusing on various pathways such as nucleotide excision repair, base excision repair, mismatch repair, homologous recombination repair, non-homologous end joining, fanconi anemia pathway, translesion synthesis, direct repair, and DNA damage tolerance. The study also examines the role of these pathways in breast cancer resistance and explores their potential as targets for cancer treatment. CONCLUSION: Recent advances in targeted therapies have shown promise in exploiting DNA repair pathways for BC treatment. However, much research is needed to improve the efficacy of these therapies and identify new targets. Additionally, personalized treatments that target specific DNA repair pathways based on tumor subtype or genetic profile are being developed. Advances in genomics and imaging technologies can potentially improve patient stratification and identify biomarkers of treatment response. However, many challenges remain, including toxicity, resistance, and the need for more personalized treatments. Continued research and development in this field could significantly improve BC treatment.

Hypertension in Pregnancy: What We Now Know.

PURPOSE OF REVIEW: Hypertensive disorders of pregnancy remain a highly morbid condition that affects both the mother and fetus, complicate approximately 10% of pregnancies worldwide, and contribute to immediate and long-term cardiovascular outcomes. There is still much to learn regarding pathogenesis and treatment goals. RECENT FINDINGS: There is updated information on the pathogenesis of preeclampsia and treatment thresholds for HTN in pregnancy. l-Kynurenine, a metabolite of the essential amino acid l-tryptophan, has been implicated in preeclampsia as decreased levels were found in a uninephrectomized pregnant mouse model of preeclampsia, where replacement of l-kynurenine rescued the preeclamptic state. Further, data from CHIPS (The Control of HTN in Pregnancy Study) and CHAP (Chronic HTN and Pregnancy) trials demonstrate not only the safety of lowering blood pressure to either a diastolic goal of 85 mmHg (CHIPS) or less than 160/105 mmHg (CHAP) without detriment to the fetus but the CHAPS trial has also shown a decrease in the rate of preeclampsia in the treatment group. SUMMARY: We will summarize the different types of hypertensive disorders in pregnancy, updates on the pathogenesis of preeclampsia, and appropriate HTN management based on the latest evidence in order to better care for mother and child.

Navigating mental health in a post-COVID world: the experience of colorectal cancer patients.

The impact of the post-COVID-19 pandemic on individuals with colorectal cancer (CRC) was evaluated in a study with 465 cases and controls. Participants completed a questionnaire, and data analysis was conducted using SPSS software. Results showed a higher prevalence of emotional stress symptoms such as fear, depression, and worry among cases compared to controls. Additionally, cases reported greater physiological stress symptoms, such as low energy levels. The results also indicated that cases had higher rates of racing thoughts, pessimism, and avoidance of responsibilities compared to controls. These findings highlight the significant negative impact of the pandemic on individuals with CRC and the need for prompt attention and support.

Changes in lung cancer staging and emergency presentations during the first year of the COVID-19 pandemic.

Aim: This study retrospectively analyses the impact of the 1st year of the COVID-19 pandemic on route of presentation and staging in lung cancer compared to the 2 years before and after implementation of the Leicester Optimal Lung Cancer Pathway (LOLCP) in Leicester, United Kingdom. Method: Electronic databases and hospital records were used to identify all patients diagnosed with lung cancer in 2018 (pre-LOLCP), 2019 (post-LOLCP), and March 2020-2021 (post-COVID-19 lockdown). Information regarding patient characteristics, performance status, stage, and route of diagnosis was documented and analysed. Emergency presentation was defined as diagnosis of new lung cancer being made after unscheduled attendance to urgent or emergency care facility. Results: Following implementation of the LOLCP pathway, there was a significant decrease in emergency presentations from 26.8 to 19.6% (p = 0.002) with a stage shift from 33.9% early stage disease to 40.3%. These improved outcomes were annulled during the COVID-19 pandemic, with emergency presentations increasing to 38.9% (p < 0.001) and a reduction in early-stage lung cancer diagnoses to 31.5%. There was a 61% decline in 2 week wait referrals but no significant decline in the LOLCP direct-to-CT referrals. Conclusion: We have demonstrated a significant increase in late-stage lung cancer diagnoses and emergency presentations during the first year of the COVID-19 pandemic. The causes for these changes are likely to be multifactorial. The long-term effect on lung cancer mortality remains to be seen and is an important focus of future study.

An Unprecedented Fireproof, Anion-Immobilized Composite Electrolyte Obtained via Solidifying Carbonate Electrolyte for Safe and High-Power Solid-State Lithium-Ion Batteries.

The update of electrolytes from a liquid state to a solid state is considered effective in improving the safety and energy density of lithium-ion batteries (LIBs). Although numerous efforts have been made, solid-state electrolytes' (SSEs) insufficient charge transfer capability remains a significant obstruction to practical applications. Herein, a fireproof and anion-immobilized composite electrolyte is designed by solidifying carbonate electrolyte, exhibiting superior Li-ion conductivity (11.5 mS cm-1 at 30 °C) and Li-ion transference number (0.90), which endows LIBs excellent rate capability and cycling stability. Elaborate characteristics and theoretical calculations demonstrate the presence of robust anion-molecule coordination (composed of lithium bond and Coulomb force) enables a more efficient ion transport, where the mobility of Li+ ion is enhanced meanwhile the anions are immobilized. This work highlights how the strong interactions between electrolyte components can be used to simultaneously regulate the migration of Li+ ion and anion, and realize a one-step conversion of inflammable liquid-state electrolyte to nonflammable solid-state electrolyte.

Endophytic bacteria perform better than endophytic fungi in improving plant growth under drought stress: A meta-comparison spanning 12 years (2010-2021).

Drought stress is a serious issue that affects agricultural productivity all around the world. Several researchers have reported using plant growth-promoting endophytic bacteria to enhance the drought resistance of crops. However, how endophytic bacteria and endophytic fungi are effectively stimulating plant growth under drought stress is still largely unknown. In this article, a global meta-analysis was undertaken to compare the plant growth-promoting effects of bacterial and fungal endophytes and to identify the processes by which both types of endophytes stimulate plant growth under drought stress. Moreover, this meta-analysis enlightens how plant growth promotion varies across crop types (C3 vs. C4 and monocot vs. dicot), experiment types (in vitro vs. pots vs. field), and the inoculation methods (seed vs. seedling). Specifically, this research included 75 peer-reviewed publications, 170 experiments, 20 distinct bacterial genera, and eight fungal classes. On average, both endophytic bacterial and fungal inoculation increased plant dry and fresh biomass under drought stress. The effect of endophytic bacterial inoculation on plant dry biomass, shoot dry biomass, root length, photosynthetic rate, leaf area, and gibberellins productions were at least two times greater than that of fungal inoculation. In addition, under drought stress, bacterial inoculation increased the proline content of C4 plants. Overall, the findings of this meta-analysis indicate that both endophytic bacterial and fungal inoculation of plants is beneficial under drought conditions, but the extent of benefit is higher with endophytic bacteria inoculation but it varies across crop type, experiment type, and inoculation method.

Abandoned agriculture soil can be recultivated by promoting biological phosphorus fertility when amended with nano-rock phosphate and suitable bacterial inoculant.

In semi-arid regions, post-restoration vegetation recovery on abandoned agricultural lands often fails due to inherently low organic matter content and poor soil fertility conditions, including phosphorus (P). As such, amending these soils with controlled release P fertilizer, especially with suitable P solubilizing bacteria (PSB) may promote plant growth and productivity by stimulating biological P fertility. To this aim, a pot study was performed to evaluate the agronomic potential of maize and soil biological P pools, using encapsulated (ENRP) and non-encapsulated (NRP) nano-rock phosphate as the P fertilizer source, on reclaimed agricultural soil in the presence and absence of PSB inoculant. The experiment was setup following a 3 × 2 factorial arrangement with four replicates. Without PSB, NRP treatment showed marginal positive effects on plant growth, P nutrition and P use efficiency (PUE) compared to control treatment. Although larger gains with NRP treatment were more noticeable under PSB inoculation, ENRP was the most convenient slow-release P fertilizer, increasing plant growth, P nutrition and grain yield compared to all treatments. Importantly, PSB inoculation with ENRP resulted in significantly higher increase in soil CaCl2-P (8.91 mg P kg soil-1), citrate-P (26.98 mg P kg soil-1), enzyme-P (18.98 mg P kg soil-1), resin-P (11.41 mg P kg soil-1), and microbial-P (18.94 mg P kg soil-1), when compared to all treatment combinations. Although a decrease in soil HCl-P content was observed with both types of P fertilizer, significant differences were found only with PSB inoculation. A significant increase in soil biological P pools could be due to the higher specific area and crystalline structure of nano materials, providing increased number of active sites for PSB activity in the presence of biobased encapsulated shell. Furthermore, the increase in PSB abundance, higher root carboxylate secretions, and decreased rhizosphere pH in response to nano-structured P fertilizer, implies greater extension of rhizosphere promoting greater P mobilization and/or solubilization, particularly under PSB inoculated conditions. We conclude that cropping potential of abandoned agricultural lands can be enhanced by the use of nano-rock phosphate in combination with PSB inoculant, establishing a favorable micro-environment for higher plant growth and biochemical P fertility.

Groundwater quality assessment and its vulnerability to pollution: a study of district Nowshera, Khyber Pakhtunkhwa, Pakistan.

Groundwater is the drinking water source for the majority of rural settlements of district Nowshera, Khyber Pakhtunkhwa, Pakistan. The study aimed to analyze the groundwater quality and its vulnerability to pollution and to develop its spatial distribution mapping. For this purpose, forty-eight groundwater samples were collected from dug wells, tube wells, and hand pumps of sixteen villages and analyzed for physicochemical parameters. The XY coordinates of the sample's sources were marked by Magellan Triton 1500 handheld global positioning system (GPS). The results were compared with WHO and Pak-EPA guidelines. The results of the majority of selected parameters were found within the WHO and Pak-EPA guidelines; however, in certain areas the concentration of total dissolved solids (TDS), chlorides (Cl-), and alkalinity were higher than the guideline limits. Based on cumulative water quality the excellent water quality prevails over an area of 376 km2 (21% of district area), good water quality 726 km2 (42%), poor 424 km2 (24%), very poor 116 km2 (6%), and unfit for drinking 84 km2 (4%). The water of the Nizampur and Rashaki areas were categorized unfit for drinking. The groundwater quality of nearly one-half of the district varies from poor to very poor, and the soil type and vadose zone sediment/material was found the key reason for groundwater contamination. Based on the infiltration capacity of vadose zone material, the study area was divided into four water pollution vulnerable zones. The low vulnerable zone covers an area of 104 km2, moderate 862 km2, high 667 km2, and very high 93 km2. The most important factor which determines the vulnerability of the groundwater to contamination is the vadose zone material/sediment which in turn determines the soil infiltration capacity. The generated groundwater susceptibility and water quality maps provide critical information for identifying optimal locations for supply wells.

Formulation and assessment of controlled release tablets of famotidine by using eudragit RL 100 polymer.

Controlled release in drug release kinetics denotes reproducibility and predictability, implying that drug release from delivery devices follows a kinetically predictable and repeatable rate profile from dose to dose. In the current study controlled release tablets of famotidine were prepared by direct compression technique using Eudragit RL 100 polymer. Four different formulations of controlled release tablets of famotidine as (F1, F2, F3 and F4) were prepared by adding different drug to polymer ratio. The pre compression and the post compression of the formulation, characteristics were compared. All results obtained were within the specified standard limits. FTIR studies showed that both the drug and the polymer were compatible. In vitro dissolution study were conducted by Method II (Paddle Method) in phosphate buffer (pH 7.4), at 100rpm. Power law kinetic model was applied for drug release mechanism. The difference similarity of the dissolution profile was determined. The formulation F1 and F2 were released 97 and 96 % in 24 hours and other formulations F3 and F4 were released subsequently 93% and 90% in 24 hours. The results showed that incorporation of Eudragit RL 100 in the formulation of controlled release tablets prolong the drug release rates for 24 hours. The release mechanism was Non-Fickian diffusion mechanism. It was deducted from the current study that the Eudragit RL 100 can be efficiently incorporated in the formulation of controlled release dosage forms with predictable kinetics.

Appraising the potential of EPS-producing rhizobacteria with ACC-deaminase activity to improve growth and physiology of maize under drought stress.

Rhizobacteria containing 1-aminocyclopropane-1-carboxylic acid-deaminase (ACC-deaminase) and exopolysaccharides (EPS) activity are important to induce stress tolerance in plants. The present study was conducted to screen and characterize plant growth-promoting rhizobacteria (PGPR) with ACC-deaminase and EPS-producing activity for improving maize growth under drought stress. Eighty-five rhizobacterial strains were isolated from the rain-fed areas, among those 69 isolates were able to utilize ACC and 31 strains were found positive for EPS production. These strains containing ACC-deaminase and/or EPS-producing activity were subjected to drought tolerance assay by inducing water stress in media using polyethylene glycol 6000. Based on results of the drought tolerance bioassay, 12 most prominent strains were selected to evaluate their growth-promoting abilities in maize under water-stressed conditions by conducting jar trial. The impact of strains on maize growth parameters was variable. Strains with co-existence of ACC-deaminase and EPS-producing activity showed comparatively better results than those with either ACC-deaminase or EPS-producing activity only. These strains were also significantly better in improving the plant physiological parameters including photosynthesis rate, stomatal conductance, vapor pressure, water-use efficiency and transpiration rate. The strain D3 with co-existence of ACC-deaminase and EPS-producing activity was significantly better in colonizing maize roots, improving plant growth and physiological parameters. The strain was named as Bacillus velezensis strain D3 (accession number MT367633) as confirmed through results of 16S rRNA partial gene sequencing. It is concluded that the strains with co-existence of ACC-deaminase and EPS-producing activity could be better suited for improving crop growth and physiology under drought stress.

Does biochar accelerate the mitigation of greenhouse gaseous emissions from agricultural soil? - A global meta-analysis.

Greenhouse gaseous (GHGs) emissions from cropland soils are one of the major contributors to global warming. However, the extent and pattern of these climatic breakdowns are usally determined by the management practices in-place. The use of biochar on cropland soils holds a great promise for increasing the overall crop productivity. Nevertheless, biochar application to agricultural soils has grown in popularity as a strategy to off-set the negative feedback associated with agriculture GHGs emissions, i.e., CO2 (carbon dioxide), CH4 (methane), and N2O (nitrous oxide). Despite increasing efforts to uncover the potential of biochar to mitigate the farmland GHGs effects, there has been little synthesis of how different types of biochar affect GHGs fluxes from cropland soils under varied experimental conditions. Here, we presented a meta-analysis of the interactions between biochar and GHGs emissions across global cropland soils, with field experiments showing the strongest GHG mitigation potential, i.e. CO2 (RR = -0.108) and CH4 (RR = -0.399). The biochar pyrolysis temperature, feedstock, C: N ratio, and pH were also found to be important factors influencing GHGs emissions. A prominent reduction in N2O (RR = -0.13) and CH4 (RR = -1.035) emissions was observed in neutral soils (pH = 6.6-7.3), whereas acidic soils (pH ≤ 6.5) accounted for the strongest mitigation effect on CO2 compared to N2O and CH4 emissions. We also found that a biochar application rate of 30 t ha-1 was best for mitigating GHGs emissions while achieving optimal crop yield. According to our meta-analysis, maize crop receiving biochar amendment showed a significant mitigation potential for CO2, N2O, and CH4 emissions. On the other hand, the use of biochar had shown significant impact on the global warming potential (GWP) of total GHGs emissions. The current data synthesis takes the lead in analyzing emissions status and mitigation potential for three of the most common GHGs from cropland soils and demonstrates that biochar application can significantly reduce the emissions budget from agriculture.

Carbon neutrality target for G7 economies: Examining the role of environmental policy, green innovation and composite risk index.

To achieve zero carbon or achieving carbon neutrality target is of great importance to many countries around the globe especially post Paris climate agreement. This study, unlike previous studies, evaluates the role of environmental policy, green innovation, composite risk index, and renewable energy R&D in achieving carbon neutrality targets for G7 economies from 1990 to 2019. The results confirmed the validity of the EKC hypothesis for G7 economies. Further, the result shows that environmental policy, green innovation, composite risk index, and renewable energy R&D help control carbon emissions. In contrast, income reveals a positive influence on environmental degradation. Furthermore, bidirectional causality has been reported in environmental policy, composite risk index, green innovation, and the CO2 emissions, while unidirectional causality running from GDP and renewable energy R&D to CO2 emissions. Based on the empirical findings, it is suggested that environmental policies should be strengthened, promote green innovation and renewable energy research and development expenditures, and political stability and institutional quality must be stabilized to lowers sectoral risks that would help a sustainable environment.

Nitrous oxide emission from agricultural soils: Application of animal manure or biochar? A global meta-analysis.

Organic amendments (animal manure and biochar) to agricultural soils may enhance soil organic carbon (SOC) contents, improve soil fertility and crop productivity but also contribute to global warming through nitrous oxide (N2O) emission. However, the effects of organic amendments on N2O emissions from agricultural soils seem variable among numerous research studies and remains uncertain. Here, eighty-five publications (peer-reviewed) were selected to perform a meta-analysis study. The results of this meta-analysis study show that the application of animal manure enhanced N2O emissions by 17.7%, whereas, biochar amendment significantly mitigated N2O emissions by 19.7%. Moreover, coarse textured soils increased [lnRR‾ = 182.6%, 95% confidence interval (CI) = 151.4%, 217.7%] N2O emission after animal manure, in contrast, N2O emission mitigated by 7.0% from coarse textured soils after biochar amendment. In addition, this study found that 121-320 kg N ha-1 and ⩽ 30 T ha-1 application rates of animal manure and biochar mitigated N2O emissions by 72.3% and 22.5%, respectively. Soil pH also played a vital role in regulating the N2O emissions after organic amendments. Furthermore, > 10 soil C: N ratios increased N2O emissions by 121.4% and 27.6% after animal and biochar amendments, respectively. Overall, animal manure C: N ratios significantly enhanced N2O emissions, while, biochar C: N ratio had not shown any effect on N2O emissions. Overall, average N2O emission factors (EFs) for animal manure and biochar amendments were 0.46% and -0.08%, respectively. Thus, the results of this meta-analysis study provide scientific evidence about how organic amendments such as animal manure and biochar regulating the N2O emission from agricultural soils.

Comparative Analysis of Ethylene/Diene Copolymerization and Ethylene/Propylene/Diene Terpolymerization Using Ansa-Zirconocene Catalyst with Alkylaluminum/Borate Activator: The Effect of Conjugated and Nonconjugated Dienes on Catalytic Behavior and Polymer Microstructure.

The copolymerization of ethylene‒diene conjugates (butadiene (BD), isoprene (IP) and nonconjugates (5-ethylidene-2-norbornene (ENB), vinyl norbornene VNB, 4-vinylcyclohexene (VCH) and 1, 4-hexadiene (HD)), and terpolymerization of ethylene-propylene-diene conjugates (BD, IP) and nonconjugates (ENB, VNB, VCH and HD) using two traditional catalysts of C2-symmetric metallocene-silylene-bridged rac-Me2Si(2-Me-4-Ph-Ind)2ZrCl2 (complex A) and ethylene-bridged rac-Et(Ind)2ZrCl2 (complex B)-with a [Ph3C][B(C6F5)4] borate/TIBA co-catalyst, were intensively studied. Compared to that in the copolymerization of ethylene diene, the catalytic activity was more significant in E/P/diene terpolymerization. We obtained a maximum yield of both metallocene catalysts with conjugated diene between 3.00 × 106 g/molMt·h and 5.00 × 106 g/molMt·h. ENB had the highest deactivation impact on complex A, and HD had the most substantial deactivation effect on complex B. A 1H NMR study suggests that dienes were incorporated into the co/ter polymers' backbone through regioselectivity. ENB and VNB, inserted by the edo double bond, left the ethylidene double bond intact, so VCH had an exo double bond. Complex A's methyl and phenyl groups rendered it structurally stable and exhibited a dihedral angle greater than that of complex B, resulting in 1, 2 isoprene insertion higher than 1, 4 isoprene that is usually incapable of polymerization coordination. High efficiency in terms of co- and ter- monomer incorporation with higher molecular weight was found for complex 1. The rate of incorporation of ethylene and propylene in the terpolymer backbone structure may also be altered by the conjugated and nonconjugated dienes. 13C-NMR, 1H-NMR, and GPC techniques were used to characterize the polymers obtained.

'Pleural Triage' facilitates effective management of a pleural service in the COVID-19 era.

The COVID-19 pandemic has created new challenges for management of pleural diseases. As resources and staff have been redirected to manage acutely unwell COVID-19 patients, routine medical practice and service provision for pleural diseases have been severely disrupted. We recognised the impact this had for patients with pleural diseases, who can be highly vulnerable to infection and often have conditions for which treatment cannot be safely delayed. The pleural service was reviewed in a tertiary centre, focusing on the changes that allowed maintenance of a service whilst maximising patient and staff safety, with the aim that these service transformations can be adopted elsewhere to improve care for pleural patients during and beyond COVID-19.

A unique primary structure of RDL (resistant to dieldrin) confers resistance to GABA-gated chloride channel blockers in the two-spotted spider mite Tetranychus urticae Koch.

The primary structure of the second transmembrane (M2) segment of resistant to dieldrin (RDL), an ionotropic γ-aminobutyric acid receptor (GABAR) subunit, and the structure-function relationships in RDL are well conserved among insect species. An amino acid substitution at the 2' position in the M2 segment (Ala to Ser or Gly) confers resistance to non-competitive antagonists (NCAs) of GABARs. Here, a cDNA encoding RDL was cloned from the two-spotted spider mite Tetranychus urticae Koch. Unlike insect homologs, native TuRDL has His at the 2' position (H305) and Ile at 6' (I309) in the M2 segment and is insensitive to NCAs. Single and multiple mutations were introduced in the M2 segment of TuRDL, and the mutant proteins were expressed in Xenopus oocytes and examined for the restoration of sensitivity to NCAs. The sensitivity of a double mutant (H305A and I309T in the M2 segment) was greatly increased but was still considerably lower than that of insect RDLs. We therefore constructed chimeric RDLs consisting of TuRDL and Drosophila melanogaster RDL and examined their sensitivities to NCAs. The results show that the N-terminal region containing the Cys-loop as well as the M2 segment confers functional specificity; thus, our current understanding of the mechanism underlying NCA binding to GABARs requires reappraisal.

Influence of Consanguinity and Medication on the Development of Parkinson's Disease.

INTRODUCTION: Parkinson's disease is the second most common neurodegenerative disease. The disease is more prevalent in aged individuals compared to young ones. AIM: The present study aimed to investigate the factors associated with PD in the population of Khyber Pakhtunkhwa, Pakistan. METHODS: In this study, the questionnaire was filled from 600 PD patients, which include 54 familial cases, and 1,200 control subjects. To study the risk of PD in familial cases, questionnaires were also filled from the cases and controls. RESULTS: This study revealed that depression symptomology is common in PD patients. Moreover, the risk of PD was higher in patients with consanguineous marriages compare to controls (OR = 3.96, 95% Cl = 1.98-7.89). The first-degree relatives (59.3%) of PD patients are more likely to develop PD compared to a second- (29.5%) or third-degree (11.1%) relatives. Furthermore, the risk of PD is higher in individuals whose parents get married to first-cousin (OR: 4.76, 95% Cl: 1.81-12.5) than second- (OR: 1.34, 95% Cl: 0.54-3.32) or third-cousin marriages (OR = 0.18, 95% Cl: 0.06-0.49). Moreover, the use of paracetamol (OR: 0.39; 95% Cl: 0.25-0.59) and ibuprofen (OR: 0.35; 95% Cl: 0.17-0.70) were higher in control subjects. CONCLUSION: This study concludes that consanguineous marriages and first-degree relation with PD patients increase the risk of PD, while the use of certain medications may decrease the risk of PD. Further study is warranted in a population of Pakistan.