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Key Message: Key message This study identified stable QTL, promising candidate genes and developed novel KASP markers for heat tolerance, providing genomic resources to assist breeding for the development of high-yielding and heat-tolerant wheat germplasm and varieties. To understand the genetic architecture of eleven agronomic traits under heat stress, we used a doubled-haploid population (177 lines) derived from a heat-sensitive cultivar (PBW343) and a heat-tolerant genotype (KSG1203). This population was evaluated under timely, late and very late sown conditions over locations and years comprising fifteen environments. Best linear unbiased estimates and a genetic map (5,710 SNPs) developed using sequencing-based genotyping were used for QTL mapping. The identified 66 QTL (20 novel) were integrated into wheat physical map (14,263.4 Mb). These QTL explained 5.3% (QDth.ccsu-4A for days to heading and QDtm.ccsu-5B for days to maturity) to 24.9% (QGfd.ccsu-7D for grain filling duration) phenotypic variation. Thirteen stable QTL explaining high phenotypic variation were recommended for marker-assisted recurrent selection (MARS) for optimum/heat stress environments. Selected QTL were validated by their presence in high-yielding doubled-haploid lines. Some QTL for 1000-grain weight (TaERF3-3B, TaFER-5B, and TaZIM-A1), grain yield (TaCol-B5), and developmental traits (TaVRT-2) were co-localized with known genes. Specific known genes for traits like abiotic/biotic stress, grain quality and yield were co-located with 26 other QTL. Furthermore, 209 differentially expressed candidate genes for heat tolerance in plants that encode 28 different proteins were identified. KASP markers for three major/stable QTL, namely QGfd.ccsu-7A for grain filling duration on chromosome 7A (timely sown), QNgs.ccsu-3A for number of grains per spike on 3A, and QDth.ccsu-7A for days to heading on 7A (late and very late sown) environments were developed for MARS focusing on the development of heat-tolerant wheat varieties/germplasm., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

With every 1°C rise in temperature, yields are predicted to decrease by 5%-6% for both cool and warm season crops, threatening food production, which should double by 2050 to meet the global demand. While high night-time temperature (HNT) stress is expected to increase due to climate change, limited information is available on the genetic control of the trait, especially in wheat (Triticum aestivum L.). To identify genes controlling the HNT trait, we evaluated a doubled haploid (DH) population developed from a cross between an HNT tolerant line KSG1203 and KSG0057, a selection out of a mega variety PBW343 from South East Asia that turned out to be HNT susceptible. The population, along with the parents, were evaluated under 30°C night-time (HNT stress) keeping the daytime temperature to normal 22°C. The same daytime and 16°C night-time temperature were used as a control. The HNT treatment negatively impacted all agronomic traits under evaluation, with a percentage reduction of 0.5%-35% for the tolerant parent, 8%-75% for the susceptible parent, and 8%-50% for the DH population. Performed using sequencing-based genotyping, quantitative trait locus (QTL) mapping identified 19 QTLs on 13 wheat chromosomes explaining 9.72%-28.81% of cumulative phenotypic variance for HNT stress tolerance, along with 13 that were for traits under normal growing conditions. The size of QTL intervals ranged between 0.021 and 97.48 Mb, with the number of genes ranging between 2 and 867. A candidate gene analysis for the smallest six QTL intervals identified eight putative candidates for night-time heat stress tolerance., (© 2024 The Author(s). The Plant Genome published by Wiley Periodicals LLC on behalf of Crop Science Society of America.)

Introduction: This study was undertaken to find the clinical correlation of resistive index (RI) in the anterior cerebral artery (ACA) of preterm neonates admitted to the Neonatal Intensive care unit (NICU) with comorbidities such as perinatal asphyxia, neonatal sepsis, and necrotizing enterocolitis (NEC)., Methods: An observational analytical study was conducted, including preterm neonates (<35 weeks) admitted to the NICU. Ultrasound cranium scans were performed on days 1-3 and 7 of life as per the study protocol. Baseline and clinical data of asphyxia, sepsis, and NEC were obtained. Images were acquired using a 4-8-MHz probe on a Sonosite M-turbo machine (Bothell, WA, USA). All statistical calculations were done using SPSS version 21.0 (SPSS Inc., Chicago, IL, USA) with the application of the Kolmogorov-Smirnov test and the Mann-Whitney test., Results: During the study period, a total of 739 neonates were admitted. Of these, 73 neonates constituted the study group. Among the 73 patients, 33 were preterm neonates without comorbidities and 40 neonates had comorbidities such as perinatal asphyxia, sepsis, and NEC stage 2 and 3 (necrotizing enterocolitis). In the present study, the mean RI on day 3 of life was 0.76 ± 0.04 in neonates without comorbidities and 0.77 ± 0.04 in neonates with comorbidities, with a p -value of 0.247. On the 7th day of life, the mean RI was 0.82 ± 0.03 in both groups, with a p -value of 0.42., Conclusion: We could not find any significant clinical correlation of RI in the ACA of preterm neonates <35 weeks of gestation with comorbidities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Gill, Gupta, Pooni and Bhargava.)

Purpose: Hypertensive disorders of pregnancy cause significant neonatal complications. Disease severity is often used to predict neonatal outcomes, however gestational age (GA) at delivery may be a better predictor. We aimed to assess whether disease severity or GA was more predictive of adverse neonatal outcomes., Methods: We included 165 participants with confirmed HELLP syndrome or severe preeclampsia (sPE). Two predictive models were constructed to assess the ability of disease severity compared to GA to predict a composite adverse neonatal outcome. The composite outcome included low birth weight, SGA, IUGR, Apgar score, and neonatal death., Results: Using severity as a predictor of binary neonatal outcome had an AUC of 0.73 (0.65-0.81), with a sensitivity (SE) of 70.3% and a specificity (SP) of 64.4%. For GA, we observed an AUC of 0.82 (0.75-0.89), with a SE of 75.7% and a SP of 76.7%., Conclusion: For the composite neonatal outcome, GA was a better predictor than ACOG diagnosis (severity). This observation underscores the need for further research to validate these findings in larger cohorts and to determine their applicability to maternal outcomes., (© 2024. The Author(s).)

Global chickpea production is restricted by Ascochyta blight caused by the necrotrophic fungi Ascochyta rabiei . Developing locally adapted disease-resistant cultivars is an economically and environmentally sustainable approach to combat this disease. However, the lack of genetic variability in cultivated chickpeas and breeder-friendly markers poses a significant challenge to Ascochyta blight-resistant breeding efforts in chickpeas. In this study, we screened the mini-core germplasm of Cicer reticulatum against a local pathotype of A. rabiei . A modified mini-dome screening approach resulted in the identification of five accessions showing a high level of resistance. The mean disease score of resistant accessions ranged between 1.75 ± 0.3 and 2.88 ± 0.4 compared to susceptible accessions, where the mean disease score ranged between 3.59 ± 0.62 and 8.86 ± 0.14. Genome-wide association study revealed a strong association on chromosome 5 , explaining ∼58% of the phenotypic variance. The underlying region contained two candidate genes ( Cr&#95;14190.1&#95;v2 and Cr&#95;14189.1&#95;v2 ), the characterization of which showed the presence of a DNA-binding domain (cl28899 and cd18793) in Cr&#95;14190.1&#95;v2 and its orthologs in C. arietinum , whereas Cr&#95;14190.1&#95;v2 carried an additional N-terminal domain (cl31759). qPCR expression analysis in resistant and susceptible accessions revealed ∼3- and ∼110-fold higher transcript abundance for Cr&#95;14189.1 and Cr&#95;14190.1 , respectively., Competing Interests: One of the co-authors (K. S. Gill) is the CEO and co-owner of the company where the work was performed.

Our study aimed to assess the effect of weekend versus weekday hospital admissions on all-cause mortality in patients with acute myocardial infarction (AMI) and COVID-19 during the COVID-19 pandemic. We analyzed data from the National Inpatient Sample (NIS) 2020, identifying patients with co-existing AMI and COVID-19 admitted on weekdays and weekends. Baseline demographics, comorbidities, and outcomes were assessed. A multivariable regression analysis was conducted, adjusting for confounders to determine the odds of all-cause mortality. Among 74,820 patients, 55,145 (73.7%) were admitted on weekdays, while 19,675 (26.3%) were admitted on weekends. Weekend admissions showed slightly higher proportions of men (61.3% vs. 60%) and whites (56.3% vs. 54.9%) with a median age of 73 years (range: 62-82). The overall all-cause mortality had an odds ratio (OR) of 1.00 (95% CI, 0.92-1.09; P = 0.934). After adjusting for covariates, there was no significant associations between mortality and hospital type (rural: OR = 1.04; 95% CI, 0.78-1.39; P = 0.789; urban teaching: OR = 1.04; 95% CI, 0.94-1.14; P = 0.450) or geographic region (Northeast: OR = 1.16; 95% CI, 0.96-1.39; P = 0.12; Midwest: OR = 0.99; 95% CI, 0.83-1.17; P = 0.871; South: OR = 0.97; 95% CI, 0.85-1.12; P = 0.697; West: OR = 0.94; 95% CI, 0.77-1.15; P = 0.554). There was no significant difference in the rate of all-cause mortality among patients admitted for AMI and COVID-19 between weekdays and weekends., Competing Interests: The authors declare no conflict of interest., (© 2024 by the authors.)

Atrial fibrillation (AF) recurrence has become common in patients who have undergone catheter ablation. High neutrophil lymphocyte ratios (NLR) have been linked to an increased risk of recurrent AF. The research is, however, not conclusive. This meta-analysis addressed the value of easily accessible and affordable pre- and postablation NLR levels as indicators of AF recurrence in patients who had undergone ablation. We searched PubMed, SCOPUS, and Google Scholar for pertinent studies through May 2023. Using random effects models, the aggregated odds ratio (OR) of pre- and post-NLR and AF recurrence was estimated. Inter-study heterogeneity was described using I 2 statistics and leave-one-out sensitivity analysis. A p -value < .05 was considered statistically significant. The literature search yielded 270 studies, seven of which were included in this meta-analysis of 1923 patients who experienced AF recurrence after undergoing ablation. There are five retrospective and two prospective studies with a mean follow-up of 20.5 months. The unadjusted odds ratio (OR) of AF recurrence for preablation NLR was 1.33 (95% CI: 1.04-1.71, p  < .01, I 2  = 95.49%), while the adjusted OR was 1.45 (95% CI: 0.87-2.43, p  < .01, I 2  = 95.1%). The unadjusted odds ratio (OR) for postablation NLR was 1.21 (95% CI: 1.09-1.36, p  < .01, I 2  = 85.9%), and the adjusted odds ratio (OR) was 1.28 (95% CI: 0.93-1.76), demonstrating significant heterogeneity ( I 2  = 95.32%) with a p -value < .01. NLR was significantly associated with AF recurrence prediction. To detect AF recurrence, we recommend that clinicians add a simple NLR blood test to their diagnostic modalities., Competing Interests: Authors declare no conflict of interests for this article., (© 2024 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society.)

Atom-interferometric quantum sensors could revolutionize navigation, civil engineering, and Earth observation. However, operation in real-world environments is challenging due to external interference, platform noise, and constraints on size, weight, and power. Here we experimentally demonstrate that tailored light pulses designed using robust control techniques mitigate significant error sources in an atom-interferometric accelerometer. To mimic the effect of unpredictable lateral platform motion, we apply laser-intensity noise that varies up to 20% from pulse-to-pulse. Our robust control solution maintains performant sensing, while the utility of conventional pulses collapses. By measuring local gravity, we show that our robust pulses preserve interferometer scale factor and improve measurement precision by 10× in the presence of this noise. We further validate these enhancements by measuring applied accelerations over a 200 μg range up to 21× more precisely at the highest applied noise level. Our demonstration provides a pathway to improved atom-interferometric inertial sensing in real-world settings., (© 2023. The Author(s).)

Chemokine receptors are members of the rhodopsin-like class A GPCRs whose signaling through G proteins drives the directional movement of cells in response to a chemokine gradient. Chemokine receptors CXCR4 and CCR5 have been extensively studied due to their roles in leukocyte development and inflammation and their status as coreceptors for HIV-1 infection, among other roles. Both receptors form dimers or oligomers of unclear function. While CXCR4 has been crystallized in a dimeric arrangement, available atomic resolution structures of CCR5 are monomeric. To investigate their dimerization interfaces, we used a bimolecular fluorescence complementation (BiFC)-based screen and deep mutational scanning to find mutations that change how the receptors self-associate, either via specific oligomer assembly or alternative mechanisms of clustering in close proximity. Many disruptive mutations promoted self-associations nonspecifically, suggesting they aggregated in the membrane. A mutationally intolerant region was found on CXCR4 that matched the crystallographic dimer interface, supporting this dimeric arrangement in living cells. A mutationally intolerant region was also observed on the surface of CCR5 by transmembrane helices 3 and 4. Mutations predicted from the scan to reduce BiFC were validated and were localized in the transmembrane domains as well as the C-terminal cytoplasmic tails where they reduced lipid microdomain localization. A mutation in the dimer interface of CXCR4 had increased binding to the ligand CXCL12 and yet diminished calcium signaling. There was no change in syncytia formation with cells expressing HIV-1 Env. The data highlight that multiple mechanisms are involved in self-association of chemokine receptor chains., Competing Interests: Conflict of interest E. P. is an employee and shareholder of Cyrus Biotechnology, Inc. The other authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Pneumonia has been directly responsible for a huge number of deaths all across the globe. Pneumonia shares visual features with other respiratory diseases, such as tuberculosis, which can make it difficult to distinguish between them. Moreover, there is significant variability in the way chest X-ray images are acquired and processed, which can impact the quality and consistency of the images. This can make it challenging to develop robust algorithms that can accurately identify pneumonia in all types of images. Hence, there is a need to develop robust, data-driven algorithms that are trained on large, high-quality datasets and validated using a range of imaging techniques and expert radiological analysis. In this research, a deep-learning-based model is demonstrated for differentiating between normal and severe cases of pneumonia. This complete proposed system has a total of eight pre-trained models, namely, ResNet50, ResNet152V2, DenseNet121, DenseNet201, Xception, VGG16, EfficientNet, and MobileNet. These eight pre-trained models were simulated on two datasets having 5856 images and 112,120 images of chest X-rays. The best accuracy is obtained on the MobileNet model with values of 94.23% and 93.75% on two different datasets. Key hyperparameters including batch sizes, number of epochs, and different optimizers have all been considered during comparative interpretation of these models to determine the most appropriate model.

Introduction: Erenumab, an anti-calcitonin gene-related peptide (CGRP) receptor monoclonal antibody (mAb), was approved by the US Food and Drug Administration in May 2018. Constipation with serious complications was added to the Warning and Precautions section in the erenumab Prescribing Information in October 2019 after events were observed during post-marketing surveillance. We aimed to assess and compare the risk of inpatient constipation, and, separately, inpatient constipation with serious complications, among patients with migraine treated with CGRP mAbs and standard of care antiepileptic drugs (AEDs)., Methods: Within Optum's Electronic Health Record Research Database, patients with migraine who initiated erenumab, other CGRP mAbs, and AEDs were identified from May 2018 through March 2020. Erenumab initiators were propensity score-matched separately to initiators of other CGRP mAbs and AEDs. Incident inpatient constipation events, and serious complications, were identified using multiple risk windows for outcome assessment (30-, 60-, 90-day risk windows, and all available follow-up). Odds ratios (ORs) were calculated comparing inpatient constipation risk among matched erenumab initiators relative to comparators., Results: We identified 17,902 erenumab, 13,404 other CGRP mAb, and 49,497 AED initiators who met study criteria. Among matched initiators, the risk of inpatient constipation was 0.46% (95% confidence interval (CI) 0.35-0.60) for erenumab and 0.44% (95% CI 0.33-0.58) for other CGRP mAbs within the 90-day risk window, with a corresponding OR of 1.06 (95% CI 0.72-1.55). Among matched erenumab and AED initiators, inpatient constipation risk was 0.53% (95% CI 0.42-0.66) and 0.76% (95% CI 0.62-0.92), respectively, and the OR was 0.69 (95% CI 0.51-0.94). Few serious complications were observed., Conclusion: Patients initiating erenumab had similar risk of inpatient constipation within 90 days of treatment initiation versus patients initiating other CGRP mAbs, and lower risk versus patients initiating AEDs. These findings provide context to events observed during post-marketing surveillance., (© 2022. The Author(s).)

Introduction: First bite syndrome (FBS) is a rare but potentially debilitating complication observed after surgery involving the upper cervical region. Patients classically complain of severe facial pain in the ipsilateral parotid region with the first few bites of a meal., Objective: The aim of this study is to shed light on the incidence and potential risk factors of FBS, including a series of cases depicting FBS observed after parotidectomy., Methods: Retrospective review of 419 patients who underwent parotidectomy at a single tertiary care facility between December 2016 and June 2020., Results: With a mean follow-up time of 16.5 months, 8 (2%) patients were documented to have symptoms of FBS after parotid gland surgery. Six of these patients underwent partial parotidectomy by dissection of the deep lobe of the parotid (DLP)., Conclusion: Patients undergoing dissection of the DLP are particularly at risk for the development of FBS. All patients should be appropriately counseled during informed consent discussions, especially in high-risk cases.

Background: Reconstruction after parotidectomy can include fat grafting, which allows for symmetry, but grafts have demonstrated volume loss over time., Objectives: To provide quantitative evidence for the rate of volume loss of fat grafts., Methods: Patients who received parotidectomy with fat graft reconstruction at a single institution from August 2016 to October 2020 were identified. Relationships between clinical factors and the logarithmic rate of fat graft volume loss were analyzed., Results: Twelve patients received parotidectomy, fat graft reconstruction, and underwent a postoperative magnetic resonance imaging (MRI) scan. Rate of fat graft volume loss was a mean of 1.8% per month (standard deviation [SD]: 2.1% per month). Total parotid fat graft volume loss was a mean of 57.4% (SD: 67.5%). The mean follow-up time was 35.5 months (range: 9-89.8 months). Correlations between body mass index (BMI), history of smoking, and history of alcohol consumption and logarithmic rates of fat graft volume loss were increased but not significantly., Conclusions: Fat grafts have the potential of 60% volume loss at approximately 1 year. If there is clinical suspicion that patients will require adjuvant radiation or have clinical factors such as a smoking or alcohol-use history, volume requirements may be even greater to maintain adequate parotid volume for aesthetic purposes., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by Mutaz B. Habal, MD.)

Recent technological advances in next-generation sequencing (NGS) technologies have dramatically reduced the cost of DNA sequencing, allowing species with large and complex genomes to be sequenced. Although bread wheat ( Triticum aestivum L.) is one of the world's most important food crops, efficient exploitation of molecular marker-assisted breeding approaches has lagged behind that achieved in other crop species, due to its large polyploid genome. However, an international public-private effort spanning 9 years reported over 65% draft genome of bread wheat in 2014, and finally, after more than a decade culminated in the release of a gold-standard, fully annotated reference wheat-genome assembly in 2018. Shortly thereafter, in 2020, the genome of assemblies of additional 15 global wheat accessions was released. As a result, wheat has now entered into the pan-genomic era, where basic resources can be efficiently exploited. Wheat genotyping with a few hundred markers has been replaced by genotyping arrays, capable of characterizing hundreds of wheat lines, using thousands of markers, providing fast, relatively inexpensive, and reliable data for exploitation in wheat breeding. These advances have opened up new opportunities for marker-assisted selection (MAS) and genomic selection (GS) in wheat. Herein, we review the advances and perspectives in wheat genetics and genomics, with a focus on key traits, including grain yield, yield-related traits, end-use quality, and resistance to biotic and abiotic stresses. We also focus on reported candidate genes cloned and linked to traits of interest. Furthermore, we report on the improvement in the aforementioned quantitative traits, through the use of (i) clustered regularly interspaced short-palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated gene-editing and (ii) positional cloning methods, and of genomic selection. Finally, we examine the utilization of genomics for the next-generation wheat breeding, providing a practical example of using in silico bioinformatics tools that are based on the wheat reference-genome sequence., Competing Interests: HB and BA are employed by Montana BioAg Inc., VK is employed by KWS, TU is employed by Ficus Biotechnology, and PD is employed by Florimond Desprez Group. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hussain, Akpınar, Alaux, Algharib, Sehgal, Ali, Aradottir, Batley, Bellec, Bentley, Cagirici, Cattivelli, Choulet, Cockram, Desiderio, Devaux, Dogramaci, Dorado, Dreisigacker, Edwards, El-Hassouni, Eversole, Fahima, Figueroa, Gálvez, Gill, Govta, Gul, Hensel, Hernandez, Crespo-Herrera, Ibrahim, Kilian, Korzun, Krugman, Li, Liu, Mahmoud, Morgounov, Muslu, Naseer, Ordon, Paux, Perovic, Reddy, Reif, Reynolds, Roychowdhury, Rudd, Sen, Sukumaran, Ozdemir, Tiwari, Ullah, Unver, Yazar, Appels and Budak.)

Objectives: To determine the clinical profile and outcome of children requiring noninvasive ventilation (NIV) in a PICU., Methods: This prospective observational study was conducted in the PICU at Dayanand Medical College and Hospital, Punjab. Children (1 mo-18 y) with moderate-to-severe respiratory distress who received NIV during one-year period were included. Failure was defined as the need for endotracheal intubation. The patients received bilevel positive airway pressure (BiPAP) with inspiratory and expiratory positive airway pressure (8-18 cm H 2 O and 4-8 cm), respectively and indigenous continuous positive airway pressure (CPAP) were included. Vital signs (heart rate, respiratory rate) and gasometric parameters (pH, HCO 3 , pCO 2 , pO 2 ) were recorded., Results: Out of total 115 patients, 81.7% were successfully treated by NIV whereas 18.3% constituted NIV failure group. Two types of NIV were used, 65.2% were started on BiPAP and 34.8% on indigenous bubble CPAP. Most common diagnosis was tropical fever (24.3%), bronchopneumonia (20%), and sepsis with multiple organ dysfunction syndrome (MODS) (7.8%). Commonest indication of NIV was respiratory distress (70.4%) and prevention of postextubation respiratory failure (20.8%). Seven patients (6.9%) died during the study. NIV failure is higher in children with sepsis with MODS, abnormal blood gas (acidosis), and moderate-to-severe acute respiratory distress syndrome (ARDS)., Conclusions: This study demonstrates that NIV is an effective form of respiratory support for children with acute respiratory distress/failure. Sepsis with MODS, acidosis and ARDS (moderate to severe) were predictors of NIV failure. Careful patient selection may help in judicious use of NIV in PICU., (© 2021. Dr. K C Chaudhuri Foundation.)

Background: Cardiovascular surgeries increase the risk of receiving blood transfusions. Erythropoietin stimulating agents (ESAs) have been used to decrease the transfusion rate. The objective of this study was to evaluate the administration of blood products post-cardiothoracic surgery after receiving ESAs., Methods: This is a single-center, retrospective cohort study., Results: Between May 2017 to May 2018, 52 adult patients underwent cardiac surgery and received ESAs pre-operatively and/or post-operatively. A total of 35 patients were included in the study and 21 (60%) patients did not require a blood transfusion while 14 (40%) patients required a blood transfusion ( p = 0.597). The change in hemoglobin (Hgb = 0.773 g/dL, 1.7 g/dL; p = 0.002) and hematocrit (Hct = 2.31%, 4.3%; p = 0.04) was significantly different in patients who received ESAs alone versus ESAs with blood transfusion. Adverse drug reactions showed no significant difference between groups., Conclusions: In patients undergoing cardiac surgery, ESAs did not significantly reduce the need for blood transfusion. Future and larger studies are necessary to evaluate the effect of ESAs on blood transfusion.

Objective In this study, we aimed to explore the potential diagnostic utility of human epidermal growth factor receptor 2 (HER2) expression in colorectal carcinoma. We investigated the association of HER2 expression with the type and grade of the tumor along with the pattern, staining intensity, and the percentage of cells stained. Methods This was an observational study involving 50 cases of colorectal carcinoma that underwent immunohistochemistry to analyze the HER2 expression. Results The positive expression of HER2 was seen in 16 (32%) cases. The majority of the study population was between the fifth-seventh decades of life. The most commonly diagnosed tumor was conventional adenocarcinoma with grade II, cytoplasmic pattern, +2 positivity, and moderate intensity. The maximum positivity for HER2 was seen in tumors of the rectum in eight (16%) cases. Conclusion A substantial rate of HER2 overexpression paves the way for it to become a potential future target in cancer therapeutics., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Kaur et al.)

Brassica juncea L. is the most widely cultivated oilseed crop in Indian subcontinent. Its seeds contain oil with very high concentration of erucic acid (≈50%). Of late, there is increasing emphasis on the development of low erucic acid varieties because of reported association of the consumption of high erucic acid oil with cardiac lipidosis. Erucic acid is synthesized from oleic acid by an elongation process involving two cycles of four sequential steps. Of which, the first step is catalyzed by β-ketoacyl-CoA synthase (KCS) encoded by the fatty acid elongase 1 ( FAE1 ) gene in Brassica. Mutations in the coding region of the FAE1 lead to the loss of KCS activity and consequently a drastic reduction of erucic acid in the seeds. Molecular markers have been developed on the basis of variation available in the coding or promoter region(s) of the FAE1 . However, majority of these markers are not breeder friendly and are rarely used in the breeding programs. Present studies were planned to develop robust kompetitive allele-specific PCR (KASPar) assays with high throughput and economics of scale. We first cloned and sequenced FAE1.1 and FAE1.2 from high and low erucic acid (<2%) genotypes of B. juncea (AABB) and its progenitor species, B. rapa (AA) and B. nigra (BB). Sequence comparisons of FAE1.1 and FAE1.2 genes for low and high erucic acid genotypes revealed single nucleotide polymorphisms (SNPs) at 8 and 3 positions. Of these, three SNPs for FAE1.1 and one SNPs for FAE1.2 produced missense mutations, leading to amino acid modifications and inactivation of KCS enzyme. We used SNPs at positions 735 and 1,476 for genes FAE1.1 and FAE1.2 , respectively, to develop KASPar assays. These markers were validated on a collection of diverse genotypes and a segregating backcross progeny. KASPar assays developed in this study will be useful for marker-assisted breeding, as these can track recessive alleles in their heterozygous state with high reproducibility., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gill, Kaur, Kaur, Kaur, Kaur Sra, Kaur, Gurpreet, Sharma, Bansal, Chhuneja and Banga.)

Terminal heat stress causes irreversible damage to wheat crop productivity. It reduces the vegetative growth and flowering period that consequently declines the efficiency to capture available stem reserves (carbohydrates) in grains. Markers associated with thermotolerant traits ease in marker assisted selection (MAS) for crop improvement. It identifies the genomic regions associated with thermotolerant traits in wheat, but the scarcity of markers is the major hindrance in crop improvement. Therefore, 158 wheat genotypes were subjected to genotyping with 165 simple sequence repeat markers dispersed on three genomes (A, B and D). Allelic frequency and polymorphic information content values were highest on genome A (5.34 (14% greater than the lowest value at genome D) and 0.715 (3% greater than the lowest value at genome D)), chromosome 4 (5.40 (16% greater than the lowest value at chromosome 2) and 0.725 (5% greater than the lowest value at chromosome 6)) and marker xgwm44 (13.0 (84% greater than the lowest value at marker xbarc148 ) and 0.916 (46% greater than the lowest value at marker xbarc148 )). Bayesian based population structure discriminated the wheat genotypes into seven groups based on genetic similarity indicating their ancestral origin and geographical ecotype. Linkage disequilibrium pattern had highest significant (P < 0.001) linked loci pairs 732 on genome A at r 2  > 0.1 whereas, 58 on genome B at r 2  > 0.5. Linkage disequilibrium decay (P < 0.01 and r 2  > 0.1) had larger LD block (5-10 cM) on genome A. Highly significant MTAs (P < 0.000061) under heat stress conditions were identified for flag leaf area ( xwmc336 ), spikelet per spike ( xwmc553 ), grains per spike ( cxfa2147 , xwmc418 and xwmc121 ), biomass ( xbarc7 ) and grain yield ( xcfa2147 and xwmc671 ). The identified markers in this study could facilitate in MAS and gene pyramiding against heat stress in wheat., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Published by Elsevier B.V. on behalf of King Saud University.)

Background: Few studies have highlighted multiple psychosocial and physical outcomes in patients with COVID-19 infection after recovery. However, the data from developing countries is limited., Aim: To evaluate psychological morbidity, post-traumatic stress disorder (PTSD), fatigue, and perceived stigma among patients with COVID-19 after recovery from the acute phase of COVID-19 infection., Methods: In a cross-sectional online survey, 206 adult patients (age>18 years), recovered from COVID-19 infection completed the Patient Health Questionnaire-4 (PHQ-4), the Impact of Events Scale-Revised (IES-R), Fatigue Severity Scale (FSS), 4 items self-designed questionnaire evaluating cognitive deficits and self-designed questionnaire to evaluate perceived stigma. Additionally, they completed the information about demographic and clinical information., Results: The prevalence of anxiety, depressive symptoms, and PTSD in the study sample was 24.8 %, 23.8 %, and 30 % respectively. About three-fifths of the participants (61.2 %) had at least one fatigue symptom as per the FSS with the mean FSS score being 32.10 ± 15.28. About one-fourth of the participants (23.7 %) reported "feeling confused and always feeling mentally foggy", and 38 % of patients reported experiencing at least one cognitive problem. The level of felt stigma related to self was seen in 31.1 %, 20 % reported stigma related to family, and 50 % reported stigma in relation to neighbors and society. Those reporting higher PTSD scores had higher anxiety and depressive scores, reported more fatigue and stigma, and had a higher level of cognitive deficits. A higher fatigue score was also associated with higher anxiety, depression, and cognitive deficits., Conclusions: Our study reveals that a significant proportion of patients after recovery from COVID-19 experience psychological morbidities, fatigue, cognitive problems, and stigma. Efforts should be made to take care of these issues in routine post-COVID follow-up care., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Oral cyclophosphamide (CYP) is an important therapeutic agent in treatment of steroid-sensitive nephrotic syndrome having a steroid-dependent (SD) or frequent relapsing (FR) course. This retrospective observational study aimed to determine response to oral CYP and factors associated with positive response in these patients., Methods: We studied 100 children (male; 75) with FR (19%) and SD (81%) NS treated with CYP in the Pediatric Nephrology clinic. Responders were defined as children in whom steroids were stopped for at least 6 months following CYP and factors affecting response were analysed. Relapse-free survival was estimated by Kaplan-Meier method., Results: Median age at onset of NS was 3 years (IQR 2-5.2). Median age at CYP was 5.7 years (IQR 3.7-7.9). Fifty percent of patients were in the responder group at 6 months of CYP. Relapse-free survival post CYP therapy was 31% at 1 year, 11% at 2 years. Factors predicting good response were age at onset of NS > 3 years with 61.2% response at 6 months (p = 0.028) and older age at CYP initiation (> 5 years) with 61% response (p = 0.008). Multivariate regression analysis showed age at start of CYP > 5 years was an independent factor for good response (p = 0.044, OR = 2.903, CI -1.03 to 8.18)., Conclusions: Judicious selection of patients, especially with age of onset of NS more than 3 years and initiation of CYP after age of 5 years, can predict better response in this group of patents., (© 2021. IPNA.)

Precis: The peripapillary choriocapillaris (CC) was observed to be significantly impaired in normal tension glaucoma (NTG) subjects compared with normal controls using optical coherence tomography angiography (OCTA)., Purpose: The aim was to quantitatively evaluate the peripapillary CC in NTG, primary open-angle glaucoma (POAG), and control eyes using OCTA., Materials and Methods: Ninety eyes (30 controls, 30 NTG, and 30 POAG) from 73 patients were imaged using the Zeiss Plex Elite 9000. Five repeat 3×3 mm OCTA scans were acquired both nasally and temporally to the optic disc and subsequently averaged. Four CC flow deficit (FD) measures were calculated using the fuzzy C-means approach: FD density (FDD), mean FD size (MFDS), FD number (FDN), and FD area (FDA)., Results: Temporal NTG CC parameters were associated with visual field index and mean deviation (P<0.05). The control group showed a significantly lower nasal FDD (nasal: 3.79±1.26%, temporal: 4.48±1.73%, P=0.03), FDN (nasal: 156.43±38.44, temporal: 178.40±45.68, P=0.02), and FDA (nasal: 0.22±0.08, temporal: 0.26±0.10, P=0.03) when compared with temporal optic disc. The NTG group showed a significantly higher FDD (NTG: 5.04±2.38%, control: 3.79±1.26%, P=0.03), FDN (NTG: 185.90±56.66, control: 156.43±38.44, P=0.04), and FDA (NTG: 0.30±0.14 mm2, control: 0.22±0.08 mm2, P=0.03) nasal to the optic disc compared with controls., Conclusions: Association between CC parameters and glaucoma severity in NTG, but not POAG subjects, suggests vascular abnormalities may be a potential factor in the multifactorial process of glaucoma damage in NTG patients., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Wheeze is seen in 40% of preschool children, one-third of these may develop recurrent wheeze. Montelukast is an oral, once a day, easy to give therapy but there is no definite evidence to support its use in a recent meta-analysis. Present study was done to evaluate role of daily montelukast and various factors affecting the outcome after therapy in multitrigger wheeze (MTW)., Methods: A prospective study conducted in Pediatric chest clinic over 18 months at DMCH, Ludhiana. Children from 6 months to 5 years, diagnosed cases of MTW were started on montelukast. Diagnosis based on symptoms of recurrent wheeze triggered by various allergens/precipitants was made by pediatrician in charge of chest clinic. Children were followed up at 1 and 3 months. They were labeled as controlled, partially controlled, or uncontrolled as per global initiative for asthma guidelines. Data were used to compare the outcome related to various factors., Results: Total 139 out of 150 children came for regular follow-up. At the end of 3 months, 94 (67.7%) were controlled, 8 (5.7%) partially controlled, and 37 (26.6%) children remained uncontrolled on montelukast. Factors associated with poor control were onset of symptoms at younger age (<6 months of age), family history of allergies, prior multiple visits or hospitalizations due to MTW, use of MDI in the past. No significant side effects were reported by parents., Conclusion: Symptomatically two-third of children became better after starting montelukast. There were few factors which resulted in poorer control in subset of patients., (© 2021 Wiley Periodicals LLC.)

Two wheat genotypes forming high and low biomass (HB and LB), exhibiting differential expression of an isoflavone reductase-like (IRL) gene, and resulting in contrasting grain yield under heat stress field conditions, were analyzed in detail for their responses under controlled heat and elevated CO2 conditions. Significant differences in IRL expression between the two lines were hypothesized to be the basis of their differential performance under the tested conditions and their stress tolerance potential. By a holistic approach integrating advanced cell physiological phenotyping of the antioxidative and phytohormone system in spikes and leaves with measurements of ecophysiological and agronomic traits, the genetic differences of the genotypes in IRL expression were assessed. In response to heat and elevated CO2, the two genotypes showed opposite regulation of IRL expression, which was associated with cytokinin concentration, total flavonoid contents, activity of superoxide dismutase, antioxidant capacity and photosynthetic rate in leaves and cytokinin concentration and ascorbate peroxidase activity in spikes. Our study showed that IRL expression is associated with wheat yield performance under heat stress at anthesis, mediated by diverse physiological mechanisms. Hence, based on our results, the IRL gene is a promising candidate for developing genetic markers for breeding heat-tolerant wheat., (© Crown copyright. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

Most high-yielding, semidwarf wheat (Triticum aestivum L.) grown around the world contains either Rht1 or Rht2 genes. The success of these high-yielding cultivars is greatest in the most productive farming environments but provide marginal benefits in less favorable growing conditions such as shallow soils and low-precipitation dryland farming. Further, growing evidence suggests semidwarf genes not only affect early seedling growth but limit grain yield, especially under abiotic stress conditions. There are 23 other reduced-height mutants reported in wheat, most of which have not been functionally characterized. We evaluated these mutants along with their parents for several traits affecting seedling emergence, early seedling growth, and photosynthetic efficiency. Two- to seven-fold differences in coleoptile length, first leaf length, root length, and root angle were observed among the genotypes. Most of the mutations had a positive effect on root length, while the root angle narrowed. Coleoptile and first leaf lengths were strongly correlated with emergence. A specialized deep planting experiment identified Rht5, Rht6, Rht8, and Rht13 with significantly improved seedling emergence compared to the parent. Among the mutants, Rht4, Rht19, and Rht12 ranked highest for photosynthetic traits while Rht9, Rht16, and Rht15 performed best for early seedling growth parameters. Considering all traits collectively, Rht15 showed the most promise for utilization in marginal environments followed by Rht19 and Rht16. These wheat mutants may be useful for deciphering the underlying molecular mechanisms of understudied traits and breeding programs in arid and semiarid regions where deep planting is practiced., (© 2021 Scandinavian Plant Physiology Society.)

Objectives: Pain and analgesic requirements after functional endoscopic sinus surgery (FESS) vary widely. This study aims to quantify pain after routine FESS and determine the most commonly used pain management regimen., Methods: Retrospective chart review of 100 patients who underwent FESS from Oct 2017 to May 2019. Patients prospectively completed a daily pain diary and reported pain levels that were categorized into no pain (0), mild (1-3), moderate (4-7), or severe (8-10). Patients were categorized into narcotics, non-narcotics, combination, or none based on type of analgesic used., Results: Sixty-nine patients were included. Majority of patients reported either mild (39%) or no pain (28%) during the first 5 PODs. Mean POD1 pain score was 3.98, which decreased with each subsequent POD. On POD1, 37% used opioids (n = 37), 32% used non-opioids (n = 32), 22% used a combination (n = 22), and 9% used no pain meds (n = 9). Mean number of narcotic pills used within the first 5 PODs was 2 pills on any given day. Age was inversely associated with reported POD1 pain scores ( P = .003) and use of preoperative steroids in patients with sinonasal polyposis was associated with lower POD1 pain scores ( P = .03)., Conclusions: Even on POD1, majority of patients experienced either mild or no pain, and this decreases with each POD. Narcotics are grossly overprescribed and underutilized by patients postoperatively after FESS. We advocate for more judicious prescribing habits of narcotics by Otolaryngologists after FESS, and emphasize relying on non-narcotic alternatives like Acetaminophen or NSAIDS to diminish narcotic use and abuse in the postoperative period., Level of Evidence: 4., Competing Interests: No financial disclosure or conflicts of interest to report for any authors., (© 2021 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC. on behalf of The Triological Society.)

Cloacal disease is considered a common presenting complaint in companion parrots. The purpose of this study was to better characterize the prevalence of cloacal disease within a population of owned psittacine birds. Medical records of all owned parrots presented to an exotic animal specialty service between July 2012 and January 2018 were retrospectively reviewed for the presence of cloacal disease. Cloacal disease was identified in 43 of 1137 cases (3.8%). Cockatoos presented with cloacal disease significantly more often than other psittacine groups ( P < .001). Female parrots presented with cloacal disease significantly more often than males and unsexed birds ( P < .001). Cockatoos with cloacal disease predominantly presented with prolapse of the cloaca itself ( P = .006). There was no significant difference in outcome based on taxonomic group, sex, or primary cloacal pathology. Prospective studies with parrot species are encouraged to have an increased understanding of the behavioral and medical conditions that result in cloacal disease. These studies would hopefully facilitate the development of better treatment options for this relatively common disease presentation.

Purpose: Studies exploring the association of cigarette smoking and long-term survival outcomes following radical cystectomy have yielded mixed results. We performed a systematic review and meta-analysis to investigate the impact of tobacco smoking exposure, duration, intensity and cessation on response to neoadjuvant chemotherapy and long-term survival outcomes in patients undergoing radical cystectomy for bladder cancer., Materials and Methods: We systematically searched PubMed®, MEDLINE®, Embase® and Cochrane® Library databases for original articles published before April 2019. Primary end points were neoadjuvant chemotherapy response, overall and cancer specific mortality, and recurrence-free survival after radical cystectomy. Observational studies reporting Cox proportional hazards regression or logistic regression analysis were independently screened. Available multivariable hazard ratios and corresponding 95% CIs were included in the quantitative analysis. Sensitivity analyses were performed as appropriate. A risk of bias assessment was completed for nonrandomized studies., Results: Our electronic search identified a total of 649 articles. After a detailed review we selected 17 studies that addressed the impact of smoking status on survival outcomes in 13,777 patients after radical cystectomy for bladder cancer. Pooled meta-analysis revealed that active smokers have an increased risk of overall mortality (HR 1.21, 95% CI 1.08-1.36; p=0.001, I 2 =0%), cancer specific mortality (HR 1.24, 95% CI 1.13-1.36; p <0.00001, I 2 =0%) and bladder cancer recurrence (HR 1.24, 95% CI 1.12-1.38; p <0.0001, I 2 =3%). Sensitivity analyses evaluating only patients who underwent neoadjuvant chemotherapy followed by radical cystectomy showed an advantage of non/never smokers in terms of neoadjuvant chemotherapy complete response rate (HR 0.47, 95% CI 0.29-0.75; p=0.001, I 2 =0%)., Conclusions: Smoking status is associated with lower neoadjuvant chemotherapy response rates and higher overall and cancer specific mortality as well as bladder cancer recurrence after radical cystectomy. Appropriate preoperative counseling, together with tightened followup, may have a pivotal role in improving the smoking-related long-term survival outcomes in patients with bladder cancer.

Unraveling the metabolic and phytohormonal changes in anthers exposed to heat stress would help identify mechanisms regulating heat stress tolerance during the sensitive reproductive stage. Two spring wheat genotypes contrasting for heat tolerance were exposed to heat stress during heading in controlled environment chambers. Anthers were collected from main and primary spikes for metabolic and phytohormonal profiling. A significant reduction in seed set (38%), grain number (54%) and grain weight (52%) per plant was recorded in the sensitive (KSG1177) but not in the tolerant (KSG1214) genotype under heat stress compared to control. Anther metabolite accumulation did not vary quantitatively between main and primary spikes. Hierarchical clustering of the genotypes and treatments using metabolites and phytohormones revealed a distinct cluster for KSG1177 under heat stress from that of control and KSG1214. A significant increase in N-based amino acids, ABA, IAA-conjugate and a decrease in polyamines and organic acids were observed in wheat anthers exposed to heat stress. Unlike KSG1214, a significantly higher accumulation of amino acids, ABA and IAA-conjugate in anthers of the sensitive KSG1177 was recorded under heat stress. These findings provide the rationale and direction towards developing molecular markers for enhancing heat stress tolerance in wheat., (© 2020 Scandinavian Plant Physiology Society.)

A trimeric glycoprotein complex on the surface of human cytomegalovirus (HCMV) binds to platelet-derived growth factor (PDGF) receptor α (PDGFRα) to mediate host cell recognition and fusion of the viral and cellular membranes. Soluble PDGFRα potently neutralizes HCMV in tissue culture, and its potential use as an antiviral therapeutic has the benefit that any escape mutants will likely be attenuated. However, PDGFRα binds multiple PDGF ligands in the human body as part of developmental programs in embryogenesis and continuing through adulthood. Any therapies with soluble receptor therefore come with serious efficacy and safety concerns, especially for the treatment of congenital HCMV. Soluble virus receptors that are orthogonal to human biology might resolve these concerns. This engineering problem is solved by deep mutational scanning on the D2-D3 domains of PDGFRα to identify variants that maintain interactions with the HCMV glycoprotein trimer in the presence of competing PDGF ligands. Competition by PDGFs is conformation-dependent, whereas HCMV trimer binding is independent of proper D2-D3 conformation, and many mutations at the receptor-PDGF interface are suitable for functionally separating trimer from PDGF interactions. Purified soluble PDGFRα carrying a targeted mutation succeeded in displaying wild type affinity for HCMV trimer with a simultaneous loss of PDGF binding, and neutralizes trimer-only and trimer/pentamer-expressing HCMV strains infecting fibroblasts or epithelial cells. Overall, this work makes important progress in the realization of soluble HCMV receptors for clinical application., Competing Interests: E.P. is the inventor on a provisional patent filing by the University of Illinois covering aspects of this work. E.P. is a co-founder of Orthogonal Biologics Inc, which has licensed the intellectual property for preclinical development.

Modern day research, in an attempt to determine the potential therapeutic and adverse effects of illicit substances, is a growing field, but one that faces many regulatory challenges. Due to the potential abuse of illicit substances such as Cannabis, 3,4-methylenedioxymethamphetamine (MDMA), lysergic acid diethylamide (LSD) and psilocybin, regulations have been conceived with the intent of preventing harm and addiction. However, these regulations have also become a major barrier for the scientific community as they suffocate attempts of the scientists to acquire illicit substances for research purposes. Therefore, it is imperative to modify the current regulations of drug scheduling, leading to a reclassification of illicit substances that would allow for extensive testing in research settings. This reclassification effort could advance the potentially life-saving research of illicit substances.

Heat Shock Protein 101 (HSP101), the homolog of Caseinolytic Protease B (CLPB) proteins, has functional conservation across species to play roles in heat acclimation and plant development. In wheat, several TaHSP101/CLPB genes were identified, but have not been comprehensively characterized. Given the complexity of a polyploid genome with its phenomena of homoeologous expression bias, detailed analysis on the whole TaCLPB family members is important to understand the genetic basis of heat tolerance in hexaploid wheat. In this study, a genome-wide analysis revealed thirteen members of TaCLPB gene family and their expression patterns in various tissues, developmental stages, and stress conditions. Detailed characterization of TaCLPB gene and protein structures suggested potential variations of the sub-cellular localization and their functional regulations. We revealed homoeologous specific variations among TaCLPB gene copies that have not been reported earlier. A study of the Chromosome 1 TaCLPB in four wheat genotypes demonstrated unique patterns of the homoeologous gene expression under moderate and extreme heat treatments. The results give insight into the strategies to improve heat tolerance by targeting one or some of the TaCLPB genes in wheat.

Adverse pharmacokinetic interactions between illicit substances and clinical drugs are of a significant health concern. Illicit substances are taken by healthy individuals as well as by patients with medical conditions such as mental illnesses, acquired immunodeficiency syndrome, diabetes mellitus and cancer. Many individuals that use illicit substances simultaneously take clinical drugs meant for targeted treatment. This concomitant usage can lead to life-threatening pharmacokinetic interactions between illicit substances and clinical drugs. Optimal levels and activity of drug-metabolizing enzymes and drug-transporters are crucial for metabolism and disposition of illicit substances as well as clinical drugs. However, both illicit substances and clinical drugs can induce changes in the expression and/or activity of drug-metabolizing enzymes and drug-transporters. Consequently, with concomitant usage, illicit substances can adversely influence the therapeutic outcome of coadministered clinical drugs. Likewise, clinical drugs can adversely affect the response of coadministered illicit substances. While the interactions between illicit substances and clinical drugs pose a tremendous health and financial burden, they lack a similar level of attention as drug-drug, food-drug, supplement-drug, herb-drug, disease-drug, or other substance-drug interactions such as alcohol-drug and tobacco-drug interactions. This review highlights the clinical pharmacokinetic interactions between clinical drugs and commonly used illicit substances such as cannabis, cocaine and 3, 4-Methylenedioxymethamphetamine (MDMA). Rigorous efforts are warranted to further understand the underlying mechanisms responsible for these clinical pharmacokinetic interactions. It is also critical to extend the awareness of the life-threatening adverse interactions to both health care professionals and patients.

The Ph1 gene is the principal regulator of homoeologous chromosome pairing control (HECP) that ensures the diploid-like meiotic chromosome pairing behavior of polyploid wheat. The HECP control was speculated to have evolved after the first event of polyploidization. With the objective to accurately understand the evolution of the HECP control, wild emmer wheat accessions previously known to differ for HECP control were characterized for the structure and expression of the candidate Ph1 gene, C-Ph1. The C-TdPh1-5A and 5B gene copies of emmer wheat showed 98 and 99% DNA sequence similarity respectively with the corresponding hexaploid wheat copies. Further, the C-TdPh1-5B carried the C-Ph1-5B specific structural changes and transcribed three splice variants as observed in the hexaploid wheat. Further, single nucleotide changes differentiating accessions varying for HECP control were identified. Analyzed by quantitative expression analysis, the wild emmer accessions with HECP control showed ~ 10,000-fold higher transcript abundance of the C-TdPh1-5B copy during prophase-I compared to accessions lacking the control. Differential transcriptional regulation of C-TdPh1-5B splice variants further revealed that C-Ph1-5B alt1 variant is mainly responsible for differential accumulation of C-Ph1-5B copy in accessions with HECP control. Taken together, these results showed that the HECP control evolved via transcriptional regulation of splice variants during meiosis.

Auxin is an important phytohormone that regulates response, differentiation, and development of plant cell, tissue, and organs. Along with its local production, long-distance transport coordinated by the efflux/influx membrane transporters is instrumental in plant development and architecture. In the present study, we cloned and characterized a wheat (Triticum aestivum) auxin efflux carrier ABCB1. The TaABCB1 was physically localized to the proximal 15% of the short arm of wheat homoeologous group 7 chromosomes. Size of the Chinese spring (CS) homoeologs genomic copies ranged from 5.3-6.2 kb with the 7A copy being the largest due to novel insertions in its third intron. The three homoeologous copies share 95-97% sequence similarity at the nucleotide, 98-99% amino acid, and overall Q-score of 0.98 at 3-D structure level. Though detected in all analyzed tissues, TaABCB1 predominantly expressed in the meristematic tissues likely due to the presence of meristem-specific activation regulatory element identified in the promoter region. RNAi plants of TaABCB1 gene resulted in reduced plant height and increased seed width. Promoter analysis revealed several responsive elements detected in the promoter region including that for different hormones as auxin, gibberellic acid, jasmonic acid and abscisic acid, light, and circadian regulated elements.

Antibiotic resistance is a growing public health concern. Antibiotics continue to be prescribed by some clinicians to resolve dental pain even though research indicates that antibiotics are not effective for treating conditions such as irreversible pulpitis. The objective of this study was to determine the extent to which current research and evidence around irreversible pulpitis has been translated into dental practice and the gaps in dentists' knowledge. An on-line clinical vignette format survey questionnaire about treatment of irreversible pulpitis was distributed to the members of the Academy of Operative Dentistry and Academy of General Dentistry (US based international dental bodies). Their responses were recorded and evaluated. A total of 403 dentists participated in the survey. Over a third (39.3%) indicated they would prescribe antibiotics for symptomatic irreversible pulpitis in a permanent tooth occurring without any signs of systemic infection. The rest indicated they would not prescribe antibiotics; most of them would prescribe an analgesic combined with pulpectomy. Those who had undertaken advanced education training achieved a significantly higher mean knowledge score compared to those with just a primary dental degree (p=0.011). Similarly, full or part time academicians had a higher mean knowledge score than the clinicians who work only in private practice (p=0.014). Some dentists continue to prescribe antibiotics inappropriately for alleviating pain due to irreversible pulpitis. Antibiotic prescribing practices of dentists with advanced education or academic engagement were better as compared to the other participants. There is clear evidence of antibiotic over-prescribing for irreversible pulpitis which needs to be addressed urgently.

HIV-1 infection is initiated by viral Env engaging the host receptor CD4, triggering Env to transition from a "closed" to "open" conformation during the early events of virus-cell membrane fusion. To understand how Env sequence accommodates this conformational change, mutational landscapes decoupled from virus replication were determined for Env from BaL (clade B) and DU422 (clade C) isolates interacting with CD4 or antibody PG16 that preferentially recognizes closed trimers. Sequence features uniquely important to each bound state were identified, including glycosylation and binding sites. Notably, the Env apical domain and trimerization interface are under selective pressure for PG16 binding. Based on this key observation, mutations were found that increase presentation of quaternary epitopes associated with properly conformed trimers when Env is expressed at the plasma membrane. Many mutations reduce electrostatic repulsion at the Env apex and increase PG16 recognition of Env sequences from clades A and B. Other mutations increase hydrophobic packing at the gp120 inner-outer domain interface and were broadly applicable for engineering Env from diverse strains spanning tiers 1, 2, and 3 across clades A, B, C, and BC recombinants. Core mutations predicted to introduce steric strain in the open state show markedly reduced CD4 interactions. Finally, we demonstrate how our methodology can be adapted to interrogate interactions between membrane-associated Env and the matrix domain of Gag. These findings and methods may assist vaccine design. IMPORTANCE HIV-1 Env is dynamic and undergoes large conformational changes that drive fusion of virus and host cell membranes. Three Env proteins in a trimer contact each other at their apical tips to form a closed conformation that presents epitopes recognized by broadly neutralizing antibodies. The apical tips separate, among other changes, to form an open conformation that binds tightly to host receptors. Understanding how Env sequence facilitates these structural changes can inform the biophysical mechanism and aid immunogen design. Using deep mutational scans decoupled from virus replication, we report mutational landscapes for Env from two strains interacting with conformation-dependent binding proteins. Residues in the Env trimer interface and apical domains are preferentially conserved in the closed conformation, and conformational diversity is facilitated by electrostatic repulsion and an underpacked core between domains. Specific mutations are described that enhance presentation of the trimeric closed conformation across diverse HIV-1 strains., (Copyright © 2019 American Society for Microbiology.)

Pancreatic cancer is one of the most lethal cancers with high metastatic potential and strong chemoresistance. The capability of a tumor to grow and propagate is dependent on a small subset of cells within a tumor, termed cancer stem cells. Cancer stem cells exhibit great tumorigenicity and are closely correlated with drug resistance and tumor recurrence. The aim of our study was to illustrate electrochemotherapy as an effective treatment for pancreatic cancer along with the expression change in stemness genes (Nanog, Sox2 and Oct3/4) in pancreatic cancer cells post electrochemotherapy with bleomycin, cisplatin and oxaliplatin. Our results showed the enhanced expression of Nanog and decreased expression level of Oct3/4 after electrochemotherpy. We thus propose that these stemness markerS may have important roles in the initiation and/or recurrence of pancreatic cancer, and consequently may serve as important molecular diagnostics and/or therapeutic targets for the development of novel treatment strategies in pancreatic cancer patients. In conclusion, targeting these stemness factors could potentially improve electrochemotherapy as a treatment and preventing recurrence., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Osteosarcoma accounts for roughly 60% of all malignant bone tumors in children and young adults. The five-year survival rate for localized tumors after surgery and chemotherapy is approximately 70% whilst it drastically reduces to 15-30% in metastatic cases. Metabolic modulation is known to increase sensitivity of cancers to chemotherapy. A novel treatment strategy in Osteosarcoma is needed to battle this devastating malady., Results: Electroporation-delivered metabolic modulators were more effective in halting the cell cycle of Osteosarcoma cells and this negatively affects their ability to recover and proliferate, as shown in colony formation assays. Electroporation-delivered metabolic modulators increase the sensitivity of Osteosarcoma cells to chemotherapy and this combination reduces their survivability., Conclusion: This novel treatment approach highlights the efficacy of electroporation in the delivery of metabolic modulators in Osteosarcoma cells, and increased sensitivity to chemotherapy allowing for a lower dose to be therapeutic., Methods: Metabolic modulations of two Osteosarcoma cell lines were performed with clinically available modulators delivered using electroporation, and its combination with low-dose Cisplatin. The effects of Dicholoroacetic acid, 2-Deoxy-D-glucose and Metformin on cell cycle and recovery of Osteosarcoma cells were assessed. Their sensitivity to chemotherapy was also assessed when treated in combination with electroporation-delivered metabolic modulators., Competing Interests: CONFLICTS OF INTEREST Authors do not have any conflicts of interests.

Short-statured plants revolutionized agriculture during the 1960s due to their ability to resist lodging, increased their response to fertilizers, and improved partitioning of assimilates which led to yield gains. Of more than 21 reduced-height ( Rht ) genes reported in wheat, only three- Rht-B1b , Rht-D1b , and Rht8 -were extensively used in wheat breeding programs. The remaining reduced height mutants have not been utilized in breeding programs due to the lack of characterization. In the present study, we determined the inheritance of Rht18 and developed a genetic linkage map of the region containing Rht18 . The height distribution of the F₂ population was skewed towards the mutant parent, indicating that the dwarf allele ( Rht18 ) is semi-dominant over the tall allele ( rht18 ). Rht18 was mapped on chromosome 6A between markers barc146 and cfd190 with a genetic distance of 26.2 and 17.3 cM, respectively. In addition to plant height, agronomically important traits, like awns and tiller numbers, were also studied in the bi-parental population. Although the average tiller number was very similar in both parents, the F₂ population displayed a normal distribution for tiller number with the majority of plants having phenotype similar to the parents. Transgressive segregation was observed for plant height and tiller number in F₂ population. This study enabled us to select a semi-dwarf line with superior agronomic characteristics that could be utilized in a breeding program. The identification of SSRs associated with Rht18 may improve breeders' effectiveness in selecting desired semi-dwarf lines for developing new wheat cultivars.

Chemokine receptors CXCR4 and CCR5 regulate WBC trafficking and are engaged by the HIV-1 envelope glycoprotein gp120 during infection. We combine a selection of human CXCR4 and CCR5 libraries comprising nearly all of ∼7000 single amino acid substitutions with deep sequencing to define sequence-activity landscapes for surface expression and ligand interactions. After consideration of sequence constraints for surface expression, known interaction sites with HIV-1-blocking Abs were appropriately identified as conserved residues following library sorting for Ab binding, validating the use of deep mutational scanning to map functional interaction sites in G protein-coupled receptors. Chemokine CXCL12 was found to interact with residues extending asymmetrically into the CXCR4 ligand-binding cavity, similar to the binding surface of CXCR4 recognized by an antagonistic viral chemokine previously observed crystallographically. CXCR4 mutations distal from the chemokine binding site were identified that enhance chemokine recognition. This included disruptive mutations in the G protein-coupling site that diminished calcium mobilization, as well as conservative mutations to a membrane-exposed site (CXCR4 residues H79 2.45 and W161 4.50 ) that increased ligand binding without loss of signaling. Compared with CXCR4-CXCL12 interactions, CCR5 residues conserved for gp120 (HIV-1 BaL strain) interactions map to a more expansive surface, mimicking how the cognate chemokine CCL5 makes contacts across the entire CCR5 binding cavity. Acidic substitutions in the CCR5 N terminus and extracellular loops enhanced gp120 binding. This study demonstrates how comprehensive mutational scanning can define functional interaction sites on receptors, and novel mutations that enhance receptor activities can be found simultaneously., (Copyright © 2018 by The American Association of Immunologists, Inc.)

Key Message: Rubisco activase of plants evolved in a stepwise manner without losing its function to adapt to the major evolutionary events including endosymbiosis and land colonization. Rubisco activase is an essential enzyme for photosynthesis, which removes inhibitory sugar phosphates from the active sites of Rubisco, a process necessary for Rubisco activation and carbon fixation. The gene probably evolved in cyanobacteria as different species differ for its presence. However, the gene is present in all other plant species. At least a single gene copy was maintained throughout plant evolution; but various genome and gene duplication events, which occurred during plant evolution, increased its copy number in some species. The exons and exon-intron junctions of present day higher plant's Rca, which is conserved in most species seem to have evolved in charophytes. A unique tandem duplication of Rca gene occurred in a common grass ancestor, and the two genes evolved differently for gene structure, sequence, and expression pattern. At the protein level, starting with a primitive form in cyanobacteria, RCA of chlorophytes evolved by integrating chloroplast transit peptide (cTP), and N-terminal domains to the ATPase, Rubisco recognition and C-terminal domains. The redox regulated C-terminal extension (CTE) and the associated alternate splicing mechanism, which splices the RCA-α and RCA-β isoforms were probably gained from another gene in charophytes, conserved in most species except the members of Solanaceae family.