Use of adenine base editing and homology-independent targeted integration strategies to correct the cystic fibrosis causing variant, W1282X.

Small molecule drugs known as modulators can treat ~90% of people with cystic fibrosis (CF), but do not work for premature termination codon variants such as W1282X (c.3846G>A). Here we evaluated two gene editing strategies, Adenine Base Editing (ABE) to correct W1282X, and Homology-Independent Targeted Integration (HITI) of a CFTR superexon comprising exons 23-27 (SE23-27) to enable expression of a CFTR mRNA without W1282X. In Flp-In-293 cells stably expressing a CFTR expression minigene bearing W1282X, ABE corrected 24% of W1282X alleles, rescued CFTR mRNA from nonsense mediated decay and restored protein expression. However, bystander editing at the adjacent adenine (c.3847A>G), caused an amino acid change (R1283G) that affects CFTR maturation and ablates ion channel activity. In primary human nasal epithelial cells homozygous for W1282X, ABE corrected 27% of alleles, but with a notably lower level of bystander editing, and CFTR channel function was restored to 16% of wild-type levels. Using the HITI approach, correct integration of a SE23-27 in intron 22 of the CFTR locus in 16HBEge W1282X cells was detected in 5.8% of alleles, resulting in 7.8% of CFTR transcripts containing the SE23-27 sequence. Analysis of a clonal line homozygous for the HITI-SE23-27 produced full-length mature protein and restored CFTR anion channel activity to 10% of wild-type levels, which could be increased three-fold upon treatment with the triple combination of CF modulators. Overall, these data demonstrate two different editing strategies can successfully correct W1282X, the second most common class I variant, with a concomitant restoration of CFTR function.

Investigation of CFTR Function in Human Nasal Epithelial Cells Informs Personalized Medicine.

We broaden the clinical versatility of human nasal epithelial (HNE) cells. HNEs were isolated from 10 participants harboring CFTR variants: nine with rare variants (Q359R [n=2], G480S, R334W [n=5], and R560T) and one person harboring R117H;7T;TG10/5T;TG12. Cultures were differentiated at air-liquid interface. CFTR function was measured in Ussing chambers at three conditions - baseline, ivacaftor, and elexacaftor+tezacaftor+ivacaftor (ETI). Four participants initiated modulators. Q359R HNEs had 5.4% (%WT) baseline CFTR function and 25.5% with ivacaftor. With therapy, sweat [Cl-] decreased and symptoms resolved. G480S HNEs had 4.1% baseline and 32.1% CFTR function with ETI. Clinically, FEV1 increased and sweat [Cl-] decreased (119 to 46mmol/L) with ETI. In vitro cultures derived from five individuals harboring R334W showed a moderate increase in CFTR function with exposure to modulators. For one of these participants, ETI was begun in vivo; symptoms and FEV1 improved. c.1679G>C (R560T) HNEs had <4% baseline CFTR function and no modulator response. RNA analysis confirmed that c.1679G>C completely mis-splices. A symptomatic patient harboring R117H;7T;TG10/5T;TG12 exhibited reduced CFTR function (17.5%) in HNEs, facilitating mild CF diagnosis. HNEs responded to modulators (ivacaftor: 32.8%, ETI: 55.5%) and, since beginning therapy, lung function improved. While reaffirming HNE use for guiding therapeutic approaches, we inform predictions on modulator response (e.g. R334W) and closely assess variants affecting splicing (e.g. c.1679G>C). Notably, functional studies in HNEs harboring R117H;7T;TG10/5T;TG12 facilitated mild CF diagnosis, suggesting use for HNE functional studies as a clinical diagnostic test.

A near dimensionally invariable high-capacity positive electrode material.

Delivering inherently stable lithium-ion batteries is a key challenge. Electrochemical lithium insertion and extraction often severely alters the electrode crystal chemistry, and this contributes to degradation with electrochemical cycling. Moreover, electrodes do not act in isolation, and this can be difficult to manage, especially in all-solid-state batteries. Therefore, discovering materials that can reversibly insert and extract large quantities of the charge carrier (Li+), that is, high capacity, with inherent stability during electrochemical cycles is necessary. Here lithium-excess vanadium oxides with a disordered rocksalt structure are examined as high-capacity and long-life positive electrode materials. Nanosized Li8/7Ti2/7V4/7O2 in optimized liquid electrolytes deliver a large reversible capacity of over 300 mAh g-1 with two-electron V3+/V5+ cationic redox, reaching 750 Wh kg-1 versus metallic lithium. Critically, highly reversible Li storage and no capacity fading for 400 cycles were observed in all-solid-state batteries with a sulfide-based solid electrolyte. Operando synchrotron X-ray diffraction combined with high-precision dilatometry reveals excellent reversibility and a near dimensionally invariable character during electrochemical cycling, which is associated with reversible vanadium migration on lithiation and delithiation. This work demonstrates an example of an electrode/electrolyte couple that produces high-capacity and long-life batteries enabled by multi-electron transition metal redox with a structure that is near invariant during cycling.

A Monte Carlo simulation-based decision support system for radiation oncologists in the treatment of glioblastoma multiforme.

In the present research, we have developed a model-based crisp logic function statistical classifier decision support system supplemented with treatment planning systems for radiation oncologists in the treatment of glioblastoma multiforme (GBM). This system is based on Monte Carlo radiation transport simulation and it recreates visualization of treatment environments on mathematical anthropomorphic brain (MAB) phantoms. Energy deposition within tumour tissue and normal tissues are graded by quality audit factors which ensure planned dose delivery to tumour site thereby minimising damages to healthy tissues. The proposed novel methodology predicts tumour growth response to radiation therapy from a patient-specific medicine quality audit perspective. Validation of the study was achieved by recreating thirty-eight patient-specific mathematical anthropomorphic brain phantoms of treatment environments by taking into consideration density variation and composition of brain tissues. Dose computations accomplished through water phantom, tissue-equivalent head phantoms are neither cost-effective, nor patient-specific customized and is often less accurate. The above-highlighted drawbacks can be overcome by using open-source Electron Gamma Shower (EGSnrc) software and clinical case reports for MAB phantom synthesis which would result in accurate dosimetry with due consideration to the time factors. Considerable dose deviations occur at the tumour site for environments with intraventricular glioblastoma, haematoma, abscess, trapped air and cranial flaps leading to quality factors with a lower logic value of 0. Logic value of 1 depicts higher dose deposition within healthy tissues and also leptomeninges for majority of the environments which results in radiation-induced laceration.

Vogt striae: Demystified.

Background: To study the correlation of different variables of Vogt striae to other attributes of keratoconus and to suggest a new grading system for Vogt striae to exactly represent the configuration and extent in each individual keratoconic cornea. Methods: The study was an observational and data review study. A total of 386 eyes of 207 keratoconus patients were screened from February 2016 to August 2018. Patients with prior history of collagen cross linking were excluded from the study as measurement of corneal thickness is less reliable for many months after collagen cross linking, and patients may have superficial corneal striae and scarring after collagen cross linking. Patients with history or clinical features suggestive of corneal hydrops or who had undergone lamellar or full thickness corneal transplants and intracorneal ring segments were also excluded from the study. Results: Of total 52 eyes with Vogt striae, 31 eyes (59.6%) had vertical orientation, 3 (5.8%) had horizontal, 11 (21.2%) had oblique while 7 eyes (13.5%) had mixed orientation of Vogt striae. Mean uncorrected distance visual acuity (UCVA) in the vertical group was 0.76 logMAR, horizontal group was 0.80 logMAR, oblique group was 0.65 logMAR, and mixed group was 1.17 logMAR units. Corneal scarring was present in 15 eyes (28.8%) and absent in 37 (71.2%) eyes with Vogt striae. In the mixed Vogt striae group, 85.7% eyes (6 eyes of 7) had corneal scarring, while 16.1% in vertical group (5 eyes of 31), and 27.3% in oblique group (3 of 11) had corneal scarring. Based on three attributes of Vogt striae, that is orientation, number, and corneal scarring, a new grading for Vogt striae was also suggested. Conclusion: This is the first study to report the presence of mixed Vogt striae (combination of horizontal and/or vertical and/or oblique Vogt striae in a single cornea) in cases of keratoconus. For the first time, oblique Vogt striae have been described, and clear limits have been set to call it horizontal, oblique, or vertical striae. A new grading for Vogt striae is also suggested.

Effects of kangaroo mother care on maternal and paternal health: systematic review and meta-analysis.

Objective: To investigate the effect of kangaroo mother care for low-birth-weight and preterm infants on parents' mental and physical health. Methods: The Cochrane Central Register of Controlled Trials, Cochrane Register of Studies Online, PubMed®, Web of Science, Scopus and EMBASE® databases were searched on 16 January 2023 for randomized and quasi-randomized trials on kangaroo mother care. Records identified were screened independently by two reviewers. Pooled relative risks (RRs) are reported for categorical variables, and standardized mean differences (SMDs) or mean differences are reported for continuous variables. Evidence quality was assessed using the GRADE approach. Findings: The search identified 30 studies involving 7719 preterm or low-birth-weight infants. There was high-certainty evidence that kangaroo mother care substantially reduced the risk of moderate-to-severe postpartum maternal depressive symptoms compared with no kangaroo mother care (RR: 0.76; 95% confidence interval, CI: 0.59 to 0.96). In addition, there was low-certainty evidence that kangaroo mother care reduced scores for maternal stress (SMD: -0.82; 95% CI: -1.32 to -0.32) and anxiety (SMD: -0.62; 95% CI: -1.01 to -0.23) and increased mother-infant attachment and bonding scores (SMD: 1.19; 95% CI: 0.27 to 2.10). Limited evidence indicated father-infant interactions may be improved, though no marked effect on paternal depression or stress was observed. No trial reported parental physical health outcomes. Conclusion: Kangaroo mother care for preterm and low-birth-weight infants was associated with less postpartum maternal depression, stress and anxiety and better mother-infant attachment and bonding. More research is required to evaluate effects on paternal health.

In situ synthesis of Cu(II) dicarboxylate metal organic frameworks (MOFs) and their application as battery materials.

New materials for battery electrodes are paramount to ensuring future battery supply can meet the ever-increasing demand for energy storage. Furthermore, detailed investigation on the various physical and chemical aspects of these materials is required to allow the same level of nuanced microstructural and electrochemical tuning that is available for conventional electrode materials. Here a comprehensive investigation is undertaken on the poorly understood in situ reaction between dicarboxylic acids and the copper current collector that occurs during electrode formulation, using a series of simple dicarboxylic acids. Specifically, we focus on the relationship between the extent of the reaction and the properties of the acid. Additionally, the extent of the reaction was demonstrated to affect both the electrode microstructure and the electrochemical performance. Scanning electron microscopy (SEM), X-ray diffraction (XRD) and small and ultra-small angle neutron scattering (U/SANS) are used to provide unprecedented detail on the microstructure ultimately leading to a deeper understanding of formulation based performance enhancing techniques. Ultimately, it was determined that the copper-carboxylates are the active material, not the parent acid, and in some cases i.e., copper malate, capacities as high as 828 mA h g-1 were achieved. This work lays the foundation for future studies that use the current collector as an "active" component in electrode formulation and function rather than simply an inactive component of a battery.

Framework structured Ce2(C2O4)3·10H2O as a pseudocapacitive electrode of a hybrid (asymmetric) supercapacitor (HSC) for large scale energy storage applications.

The electrochemical kinetics of the electrode material plays a crucial role in the development of various energy storage devices such as batteries, supercapacitors, and hybrid supercapacitors. Battery-type hybrid supercapacitors are envisaged as excellent candidates to bridge the performance gap between supercapacitors and batteries. Due to its open pore framework structure and more structural stability, porous cerium oxalate decahydrate (Ce2(C2O4)3·10H2O) is found here to be a potential energy storage material partly because of the presence of planer oxalate anions (C2O42-). Superior specific capacitance equivalent to 78 mA h g-1 (capacitance: 401 F g-1) at 1 A g-1 in the potential window of -0.3 to 0.5 V was observed in an aqueous 2 M KOH electrolyte. The predominant pseudocapacitance mechanism seems to operate because of the high charge storage capacity of the electrode as intercalative (diffusion control) and surface control charges stored by the porous anhydrous Ce2(C2O4)3·10H2O, which were close to 48% and 52%, respectively, at a 10 mV s-1 scan rate. Further, in the full cell asymmetric supercapacitor (ASC) mode in which porous Ce2(C2O4)3·10H2O is the positive electrode and activated carbon (AC) is the negative electrode, at the operating potential window of 1.5 V, the highest specific energy of 96.5 W h kg-1 and a specific power of ∼750 W kg-1 at 1 A g-1 current rate and a high power density of 1453 W kg-1, the hybrid supercapacitor still attains an energy density of 10.58 W h kg-1 at a 10 A g-1 current rate, which was obtained with a high cyclic stability. The detailed electrochemical studies confirm a high cyclic stability and a superior electrochemical charge storage property of porous Ce2(C2O4)3·10H2O making it a potential pseudocapacitive electrode for use in large energy storage applications.

Formulation and mechanism of copper tartrate - a novel anode material for lithium-ion batteries.

Batteries play an increasingly critical role in the functioning of contemporary society. To ensure future proofing of battery technology, new materials and methods that overcome the current shortcomings need to be developed. Here we report the use of the inexpensive and off the shelf metal-carboxylate, copper tartrate, as a high-capacity anode material for lithium-ion batteries, providing a specific capacity of 744 mA h g-1 when cycled at 50 mA g-1. Additionally, an unusual capacity gain with cycling is investigated using advanced techniques including X-ray absorption spectroscopy (XAS), X-ray diffraction (XRD), and small and ultra-small angle neutron scattering (SANS and USANS), providing insight into the structure-performance relationship of the electrode. Subsequently, a novel method of in situ generation of the active material is demonstrated using the reaction between the parent acid, tartaric acid, and the copper current collector during electrode formulation. This serves to increase and stabilise the electrode performance, as well as to make use of a cheaper feedstock (tartaric acid), and reduce some of the "dead mass" of the copper current collector.

Evaluation of both exonic and intronic variants for effects on RNA splicing allows for accurate assessment of the effectiveness of precision therapies.

Elucidating the functional consequence of molecular defects underlying genetic diseases enables appropriate design of therapeutic options. Treatment of cystic fibrosis (CF) is an exemplar of this paradigm as the development of CFTR modulator therapies has allowed for targeted and effective treatment of individuals harboring specific genetic variants. However, the mechanism of these drugs limits effectiveness to particular classes of variants that allow production of CFTR protein. Thus, assessment of the molecular mechanism of individual variants is imperative for proper assignment of these precision therapies. This is particularly important when considering variants that affect pre-mRNA splicing, thus limiting success of the existing protein-targeted therapies. Variants affecting splicing can occur throughout exons and introns and the complexity of the process of splicing lends itself to a variety of outcomes, both at the RNA and protein levels, further complicating assessment of disease liability and modulator response. To investigate the scope of this challenge, we evaluated splicing and downstream effects of 52 naturally occurring CFTR variants (exonic = 15, intronic = 37). Expression of constructs containing select CFTR intronic sequences and complete CFTR exonic sequences in cell line models allowed for assessment of RNA and protein-level effects on an allele by allele basis. Characterization of primary nasal epithelial cells obtained from individuals harboring splice variants corroborated in vitro data. Notably, we identified exonic variants that result in complete missplicing and thus a lack of modulator response (e.g. c.2908G>A, c.523A>G), as well as intronic variants that respond to modulators due to the presence of residual normally spliced transcript (e.g. c.4242+2T>C, c.3717+40A>G). Overall, our data reveals diverse molecular outcomes amongst both exonic and intronic variants emphasizing the need to delineate RNA, protein, and functional effects of each variant in order to accurately assign precision therapies.

Hybrid Recommendation Network Model with a Synthesis of Social Matrix Factorization and Link Probability Functions.

Recommender systems are becoming an integral part of routine life, as they are extensively used in daily decision-making processes such as online shopping for products or services, job references, matchmaking for marriage purposes, and many others. However, these recommender systems are lacking in producing quality recommendations owing to sparsity issues. Keeping this in mind, the present study introduces a hybrid recommendation model for recommending music artists to users which is hierarchical Bayesian in nature, known as Relational Collaborative Topic Regression with Social Matrix Factorization (RCTR-SMF). This model makes use of a lot of auxiliary domain knowledge and provides seamless integration of Social Matrix Factorization and Link Probability Functions into Collaborative Topic Regression-based recommender systems to attain better prediction accuracy. Here, the main emphasis is on examining the effectiveness of unified information related to social networking and an item-relational network structure in addition to item content and user-item interactions to make predictions for user ratings. RCTR-SMF addresses the sparsity problem by utilizing additional domain knowledge, and it can address the cold-start problem in the case that there is hardly any rating information available. Furthermore, this article exhibits the proposed model performance on a large real-world social media dataset. The proposed model provides a recall of 57% and demonstrates its superiority over other state-of-the-art recommendation algorithms.

Development and evaluation of Hedyotis corymbosa (L.) extract containing phytosomes: a preclinical approach for treatment of neuropathic pain in rodent model.

PURPOSE: The study was aimed to encapsulate Hedyotis corymbosa extract (HCE) into phytosomes to improve its therapeutic efficacy in neuropathic pain by enhancing the bioavailability of chief chemical constituent Hedycoryside -A (HCA). METHODS: For preparing phytosomes complexes (F1, F2, and F3), HCE and phospholipids were reacted in disparate ratio. F2 was chosen to assess its therapeutic efficacy in neuropathic pain induced by partial sciatic nerve ligation. Nociceptive threshold and oral bioavailability were also estimated for F2. RESULTS: Particle size, zeta potential and entrapment efficiency for F2 were analysed as 298.1 ± 1.1 nm, -3.92 ± 0.41 mV and 72.12 ± 0.72% respectively. F2 gave enhanced relative bioavailability (158.92%) of HCA along with a greater neuroprotective potential showing a significant antioxidant effect and augmentation (p < 0.05) in nociceptive threshold with the diminution in damage to nerves. CONCLUSION: F2 is an optimistic formulation for enhancing the HCE delivery for the effective treatment of neuropathic pain.

Examining the microbial composition of natural springs in Bhaderwah, Jammu and Kashmir, India.

Natural springs are the main source of water supply for domestic and agricultural use for humans living in the mountainous regions of Asia. Increasing anthropogenic activities with associated waste load, coupled with inadequate sanitation, and contamination of natural water resources and the environment are emerging as important public health issues. We performed a prospective microbiological and physicochemical investigation of water samples from seven distinct natural springs situated at an altitude of 1615 m in the Bhaderwah region of Jammu and Kashmir, India. Bacterial groups belonging to opportunistic pathogens such as members of Moraxellaceae (Acinetobacter), Arcobacteraceae (Pseudoarcobacter), Pseudomonadaceae (Pseudomonas), Oxalobacteraceae (Massilia), and Flavobacteriaceae (Flavobacterium) were observed. The total coliform test indicated an intermediate level of risk of fecal contamination of the springs, except for one site. Through a questionnaire-based survey of the local population, we discovered that around 40% of participants had suffered from waterborne diseases including typhoid (~14%) and diarrhea (~11%). Our data suggests that increased surveillance of fecal contamination and heterotrophic opportunistic pathogens is needed to enhance water quality and reduce health risks for people living in mountainous regions.

Effect of organic food production and consumption on the affective and cognitive well-being of farmers: analysis using prism of NVivo, etic and emic approach.

Extant research studies support has stressed the significance of nourishment on the physical health of humans. Some of the past academic literature has also hinted at an interconnect between food, thoughts, and action that becomes especially significant in the current era of Anthropocene. Organic farming production and consumption can not only enhance economic well-being but also promote social well-being along with subject well-being. Beyond the individual level, a community level facilitates fostering physical emotional physical and emotional ecosystems. However, several studies have inferred seemingly dubious claims about the impact of natural food intake on the mental well-being of an individual. In light of this impinging need, this first-of-its-kind study focused to search the impact of organic food consumption on the cognitive behaviour of individuals. Interview-based qualitative field research with 30 peasants' families was conducted in two phases in the model organic village of Manj Gaon of Uttarakhand. Results indicate that organic farming has positively impacted the mental well-being of the farmers, and apart from it, physical health, food security, and financial security are the fringe benefits for native organic farmers. However, there are many bottlenecks from the policy perspective such as non-availability of organic seeds, lack of marketplaces, lack of transportation infrastructure, and almost no facility of cold storage and warehouse, especially during the time of summer season. All these significantly hamper the adoption and sustenance of organic food production and consumption. Although many farmers exhibit the attributes of subjective well-being, as an outcome, it is rooted in the consumption of organic food, because better intake leads to a better thought process and eventually the results get reflected in the form of a better human being. To conclude, better thoughts, emotions, mind, and health of a human individual and society are strongly rooted in the adoption of chemical and pesticide-free food, i.e. organic.

Virosome: An engineered virus for vaccine delivery.

The purpose of immunization is the effective cellular and humoral immune response against antigens. Several studies on novel vaccine delivery approaches such as micro-particles, liposomes & nanoparticles, etc. against infectious diseases have been investigated so far. In contrast to the conventional approaches in vaccine development, a virosomes-based vaccine represents the next generation in the field of immunization because of its balance between efficacy and tolerability by virtue of its mechanism of immune instigation. The versatility of virosomes as a vaccine adjuvant, and delivery vehicle of molecules of different nature, such as peptides, nucleic acids, and proteins, as well as provide an insight into the prospect of drug targeting using virosomes. This article focuses on the basics of virosomes, structure, composition formulation and development, advantages, interplay with the immune system, current clinical status, different patents highlighting the applications of virosomes and their status, recent advances, and research associated with virosomes, the efficacy, safety, and tolerability of virosomes based vaccines and the future prospective.

Eosinophilic gastroenteritis as an uncommon cause of ascites recurrence in a young female.

Ascites appear as a clinical manifestation of various disorders, and the presence of raised levels of eosinophils in the peritoneal fluid characterizes eosinophilic ascites, which is an extremely rare disorder. Eosinophilic gastroenteritis is one of the uncommon causes of ascites. If not investigated thoroughly, ascites recurrence in a young female with a history of tuberculosis may be wrongly attributed to tuberculosis recurrence in an endemic country. The etiology of ascites in our case was correctly identified as the subserosal form of eosinophilic ascites. Oral corticosteroids form the mainstay of treatment in such cases. Eosinophilic gastroenteritis is a rare disease, but a thorough workup and a strong clinical suspicion may help in the successful diagnosis and treatment of such cases.

Transcriptome-wide analyses of adipose tissue in outbred rats reveal genetic regulatory mechanisms relevant for human obesity.

Transcriptomic analysis in metabolically active tissues allows a systems genetics approach to identify causal genes and networks involved in metabolic disease. Outbred heterogeneous stock (HS) rats are used for genetic mapping of complex traits, but to-date, a systems genetics analysis of metabolic tissues has not been done. We investigated whether adiposity-associated genes and gene coexpression networks in outbred heterogeneous stock (HS) rats overlap those found in humans. We analyzed RNAseq data from adipose tissue of 415 male HS rats, correlated these transcripts with body weight (BW) and compared transcriptome signatures to two human cohorts: the "African American Genetics of Metabolism and Expression" and "Metabolic Syndrome in Men." We used weighted gene coexpression network analysis to identify adiposity-associated gene networks and mediation analysis to identify genes under genetic control whose expression drives adiposity. We identified 554 orthologous "consensus genes" whose expression correlates with BW in the rat and with body mass index (BMI) in both human cohorts. Consensus genes fell within eight coexpressed networks and were enriched for genes involved in immune system function, cell growth, extracellular matrix organization, and lipid metabolic processes. We identified 19 consensus genes for which genetic variation may influence BW via their expression, including those involved in lipolysis (e.g., Hcar1), inflammation (e.g., Rgs1), adipogenesis (e.g., Tmem120b), or no previously known role in obesity (e.g., St14 and Ms4a6a). Strong concordance between HS rat and human BW/BMI associated transcripts demonstrates translational utility of the rat model, while identification of novel genes expands our knowledge of the genetics underlying obesity.

The Sigma-1 receptor is an ER-localized type II membrane protein.

The Sigma-1 receptor (S1R) is a transmembrane protein with important roles in cellular homeostasis in normal physiology and in disease. Especially in neurodegenerative diseases, S1R activation has been shown to provide neuroprotection by modulating calcium signaling, mitochondrial function and reducing endoplasmic reticulum (ER) stress. S1R missense mutations are one of the causes of the neurodegenerative Amyotrophic Lateral Sclerosis and distal hereditary motor neuronopathies. Although the S1R has been studied intensively, basic aspects remain controversial, such as S1R topology and whether it reaches the plasma membrane. To address these questions, we have undertaken several approaches. C-terminal tagging with a small biotin-acceptor peptide and BirA biotinylation in cells suggested a type II membrane orientation (cytosolic N-terminus). However, N-terminal tagging gave an equal probability for both possible orientations. This might explain conflicting reports in the literature, as tags may affect the protein topology. Therefore, we studied untagged S1R using a protease protection assay and a glycosylation mapping approach, introducing N-glycosylation sites. Both methods provided unambiguous results showing that the S1R is a type II membrane protein with a short cytosolic N-terminal tail. Assessments of glycan processing, surface fluorescence-activated cell sorting, and cell surface biotinylation indicated ER retention, with insignificant exit to the plasma membrane, in the absence or presence of S1R agonists or of ER stress. These findings may have important implications for S1R-based therapeutic approaches.

Density functional theory studies on molecular geometry, spectroscopy, HOMO-LUMO and reactivity descriptors of titanium(IV) and oxidozirconium(IV) complexes of phenylacetohydroxamic acid.

The molecular geometry of new titanium(IV) and oxidozirconium(IV) phenylacetohydroxamate complexes [TiCl2 (L1)2 ] (I) and [ZrO(L1)2 ] (II) (where L1 = Potassium phenylacetohydroxamate = C6 H5 CH2 CONHOK) computed by B3LYP/6-311++G(d,p) method has shown these to be distorted octahedral and square pyramidal, respectively. A comparison of computed characteristic bond lengths (CO, CN, and NO) of complexes with that of free ligand has shown chelation through carbonyl and hydroxamic oxygen atoms (O, O coordination). The TiO/ZrO bond lengths in complexes are suggestive of weak coordination through (carbonyl CO) and strong covalent (hydroxamic NO) bonding of the ligand. The magnitude of ClTiCl bond angle involving two chloride atoms is suggestive of cis-conformation at titanium metal in (I). The thermodynamic parameters Gibbs free energy, enthalpy, entropy, nuclear internal energy, constant volume heat capacity, and internal energy of ligand and complexes have been computed. From the energies of highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO), the global reactivity descriptors such as ionization potential (IP), electron affinity (EA), chemical potential (µ), hardness (η), softness (S), electronegativity (χ), electrophilicity index (ω), and dipole moment have been calculated. The computed vibrational frequencies, 1 H and 13 C NMR spectra have substantiated the molecular structure of complexes. The thermal behavior of complexes has been studied by thermogravimetric techniques (TGA, DTG, and DTA) in N2 atmosphere has shown complexes are thermally stable.

Crop variety management for climate adaptation supported by citizen science.

Crop adaptation to climate change requires accelerated crop variety introduction accompanied by recommendations to help farmers match the best variety with their field contexts. Existing approaches to generate these recommendations lack scalability and predictivity in marginal production environments. We tested if crowdsourced citizen science can address this challenge, producing empirical data across geographic space that, in aggregate, can characterize varietal climatic responses. We present the results of 12,409 farmer-managed experimental plots of common bean (Phaseolus vulgaris L.) in Nicaragua, durum wheat (Triticum durum Desf.) in Ethiopia, and bread wheat (Triticum aestivum L.) in India. Farmers collaborated as citizen scientists, each ranking the performance of three varieties randomly assigned from a larger set. We show that the approach can register known specific effects of climate variation on varietal performance. The prediction of variety performance from seasonal climatic variables was generalizable across growing seasons. We show that these analyses can improve variety recommendations in four aspects: reduction of climate bias, incorporation of seasonal climate forecasts, risk analysis, and geographic extrapolation. Variety recommendations derived from the citizen science trials led to important differences with previous recommendations.