RTN3L and CALCOCO1 function in parallel to maintain proteostasis in the endoplasmic reticulum.

Reticulophagy is mediated by autophagy receptors that function in one of the two domains of the ER, tubules or flat sheets. Three different conserved mammalian receptors mediate autophagy in ER tubules: RTN3L, ATL3 and CALCOCO1. Previous studies have shown that RTN3L maintains proteostasis by targeting mutant aggregation-prone proteins for autophagy at distinct foci in ER tubules that we named ERPHS (ER-reticulophagy sites). The role for ATL3 and CALCOCO1 in proteostasis has not been addressed. Here we analyzed three different misfolded disease-causing RTN3L substrates and show that ATL3 and CALCOCO1 target the same cargoes for autophagy. Colocalization and knock down studies revealed that RTN3L and ATL3 are both required for the formation of RTN3L-containing ERPHS, while CALCOCO1 is not. We propose that RTN3L, ATL3 and CALCOCO1 work in parallel to maintain proteostasis within the ER network by targeting cargoes at different sites in the tubules.Abbreviation ATL3: atlastin GTPase 3; Baf: bafilomycin A1; CALCOCO1: calcium binding and coiled-coil domain 1; Epr1: ER-phagy receptor 1; ER: endoplasmic reticulum; ERAD: ER-associated protein degradation; ERPHS: ER-reticulophagy sites; LAMP1: lysosomal associated membrane protein 1; PGRMC1: progesterone receptor membrane component 1; POMC: proopiomelanocortin; Pro-AVP: pro-arginine vasopressin; RETREG1: reticulophagy regulator 1; reticulophagy: endoplasmic reticulum selective autophagy; RTN3L: reticulon 3 long isoform; VAPA: VAMP associated protein A.

GRASP negatively regulates the secretion of the virulence factor gp63 in Leishmania.

Metalloprotease-gp63 is a virulence factor secreted by Leishmania. However, secretory pathway in Leishmania is not well defined. Here, we cloned and expressed the GRASP homolog from Leishmania. We found that Leishmania expresses one GRASP homolog of 58 kDa protein (LdGRASP) which localizes in LdRab1- and LPG2-positive Golgi compartment in Leishmania. LdGRASP was found to bind with COPII complex, LdARF1, LdRab1 and LdRab11 indicating its role in ER and Golgi transport in Leishmania. To determine the function of LdGRASP, we generated LdGRASP knockout parasites using CRISPR-Cas9. We found fragmentation of Golgi in Ld:GRASPKO parasites. Our results showed enhanced transport of non-GPI-anchored gp63 to the cell surface leading to higher secretion of this form of gp63 in Ld:GRASPKO parasites in comparison to Ld:WT cells. In contrast, we found that transport of GPI-anchored gp63 to the cell surface is blocked in Ld:GRASPKO parasites and thereby inhibits its secretion. The overexpression of dominant-negative mutant of LdRab1 or LdSar1 in Ld:GRASPKO parasites significantly blocked the secretion of non-GPI-anchored gp63. Interestingly, we found that survival of transgenic parasites overexpressing Ld:GRASP-GFP is significantly compromised in macrophages in comparison to Ld:WT and Ld:GRASPKO parasites. These results demonstrated that LdGRASP differentially regulates Ldgp63 secretory pathway in Leishmania.

Exploring the Complex Connection Between Diabetes and Cardiovascular Disease: Analyzing Approaches to Mitigate Cardiovascular Risk in Patients With Diabetes.

Cardiovascular disease (CVD) is the primary cause of morbidity and mortality in individuals diagnosed with diabetes mellitus. This narrative review offers a comprehensive examination of the complex correlation between diabetes and cardiovascular complications. The objective of this review is to analyze the most recent evidence on preventive measures and treatment options for mitigating cardiovascular risk in patients with diabetes, by synthesizing existing literature. Insulin resistance plays a crucial role in connecting diabetes and CVD, leading to the development of dyslipidemia and atherogenesis. As a result, the risk of cardiovascular events in individuals with diabetes is significantly elevated. Moreover, the presence of hyperglycemia-induced oxidative stress and inflammation serves to intensify endothelial dysfunction and vascular damage, thereby exacerbating the risk of cardiovascular complications. The interaction between diabetes and CVD frequently speeds up the development of atherosclerotic plaque, making the plaque more prone to rupture. This can lead to severe cardiovascular events such as myocardial infarction and stroke. It is crucial to comprehend the intricate relationship between diabetes and CVD in order to formulate effective strategies aimed at enhancing patient outcomes and mitigating the burden associated with these interconnected chronic conditions. Healthcare practitioners can enhance the quality of life and reduce mortality rates associated with CVD in diabetic patients by thoroughly examining evidence-based preventive measures and treatment options. This approach allows them to make informed decisions when managing cardiovascular risk. In summary, this narrative review provides a valuable resource for healthcare professionals and researchers, presenting a comprehensive analysis of the complex relationship between diabetes and CVD. By providing a comprehensive analysis of the latest evidence and elucidating the underlying mechanisms, this review seeks to establish a foundation for the development of innovative strategies in diabetes management. These strategies have the potential to significantly improve cardiovascular outcomes and enhance overall patient care.

Phosphoinositides in plant-pathogen interaction: trends and perspectives.

Phosphoinositides are important regulatory membrane lipids, with a role in plant development and cellular function. Emerging evidence indicates that phosphoinositides play crucial roles in plant defence and are also utilized by pathogens for infection. In this review, we highlight the role of phosphoinositides in plant-pathogen interaction and the implication of this remarkable convergence in the battle against plant diseases.

Genomics-assisted genetics of complex regions from chickpea chromosome 4 reveals two candidate genes for Ascochyta blight resistance.

Ascochyta blight (AB) disease caused by the fungus Ascochyta rabiei is a major threat to global chickpea production. Molecular breeding for improved AB resistance requires the identification of robust fine-mapped QTLs/candidate genes and associated markers. Earlier, we identified three QTLs (qABR4.1, qABR4.2, and qABR4.3) for AB resistance on chickpea chromosome 4 by employing multiple quantitative trait loci sequencing strategy on an intra-specific (FLIP84-92C x PI359075) and an inter-specific (FLIP84-92C x PI599072) crosses derived recombinant inbred lines. Here, we report the identification of AB resistance providing candidate genes under the fine mapped qABR4.2 and qABR4.3 genomic region by combining genetic mapping, haplotype block inheritance, and expression analysis. The qABR4.2 region was narrowed down from 5.94 Mb to ∼800 kb. Among 34 predicted gene models, a secreted class III peroxidase encoding gene showed higher expression in AB-resistant parent after A. rabiei conidia inoculation. Under qABR4.3, we identified a frame-shift mutation in a cyclic nucleotide-gated channel CaCNGC1 gene leading to the truncated N-terminal domain in resistant accession of chickpea. The extended N-terminal domain of CaCNGC1 interacts with chickpea calmodulin. Thus, our analysis has revealed narrowed genomic regions and their associated polymorphic markers, namely CaNIP43 and CaCNGCPD1. These co-dominant markers significantly associate with AB resistance on qABR4.2 and qABR4.3 regions. Our genetic analysis revealed that the presence of AB-resistant alleles at two major QTLs (qABR4.1 and qABR4.2) together provide AB resistance in the field while minor QTL qABR4.3 determines the degree of resistance. The identified candidate genes and their diagnostic markers will assist in the biotechnological advancement and introgression of AB resistance into locally adapted chickpea varieties used by farmers.

A small cysteine-rich fungal effector, BsCE66 is essential for the virulence of Bipolaris sorokiniana on wheat plants.

The Spot Blotch (SB) caused by hemibiotrophic fungal pathogen Bipolaris sorokiniana is one of the most devastating wheat diseases leading to 15-100% crop loss. However, the biology of Triticum-Bipolaris interactions and host immunity modulation by secreted effector proteins remain underexplored. Here, we identified a total of 692 secretory proteins including 186 predicted effectors encoded by B. sorokiniana genome. Gene Ontology categorization showed that these proteins belong to cellular, metabolic and signaling processes, and exhibit catalytic and binding activities. Further, we functionally characterized a cysteine-rich, B. sorokiniana Candidate Effector 66 (BsCE66) that was induced at 24-96 hpi during host colonization. The Δbsce66 mutant did not show vegetative growth defects or stress sensitivity compared to wild-type, but developed drastically reduced necrotic lesions upon infection in wheat plants. The loss-of-virulence phenotype was rescued upon complementing the Δbsce66 mutant with BsCE66 gene. Moreover, BsCE66 does not form homodimer and conserved cysteine residues form intra-molecular disulphide bonds. BsCE66 localizes to the host nucleus and cytosol, and triggers a strong oxidative burst and cell death in Nicotiana benthamiana. Overall, our findings demonstrate that BsCE66 is a key virulence factor that is necessary for host immunity modulation and SB disease progression. These findings would significantly improve our understanding of Triticum-Bipolaris interactions and assist in the development of SB resistant wheat varieties.

The nuclear effector ArPEC25 from the necrotrophic fungus Ascochyta rabiei targets the chickpea transcription factor CaßLIM1a and negatively modulates lignin biosynthesis, increasing host susceptibility.

Fungal pathogens deploy a barrage of secreted effectors to subvert host immunity, often by evading, disrupting, or altering key components of transcription, defense signaling, and metabolic pathways. However, the underlying mechanisms of effectors and their host targets are largely unexplored in necrotrophic fungal pathogens. Here, we describe the effector protein Ascochyta rabiei PEXEL-like Effector Candidate 25 (ArPEC25), which is secreted by the necrotroph A. rabiei, the causal agent of Ascochyta blight disease in chickpea (Cicer arietinum), and is indispensable for virulence. After entering host cells, ArPEC25 localizes to the nucleus and targets the host LIM transcription factor CaßLIM1a. CaßLIM1a is a transcriptional regulator of CaPAL1, which encodes phenylalanine ammonia lyase (PAL), the regulatory, gatekeeping enzyme of the phenylpropanoid pathway. ArPEC25 inhibits the transactivation of CaßLIM1a by interfering with its DNA-binding ability, resulting in negative regulation of the phenylpropanoid pathway and decreased levels of intermediates of lignin biosynthesis, thereby suppressing lignin production. Our findings illustrate the role of fungal effectors in enhancing virulence by targeting a key defense pathway that leads to the biosynthesis of various secondary metabolites and antifungal compounds. This study provides a template for the study of less explored necrotrophic effectors and their host target functions.

Progress in bioactive surface coatings on biodegradable Mg alloys: A critical review towards clinical translation.

Mg and its alloys evince strong candidature for biodegradable bone implants, cardiovascular stents, and wound closing devices. However, their rapid degradation rate causes premature implant failure, constraining clinical applications. Bio-functional surface coatings have emerged as the most competent strategy to fulfill the diverse clinical requirements, besides yielding effective corrosion resistance. This article reviews the progress of biodegradable and advanced surface coatings on Mg alloys investigated in recent years, aiming to build up a comprehensive knowledge framework of coating techniques, processing parameters, performance measures in terms of corrosion resistance, adhesion strength, and biocompatibility. Recently developed conversion and deposition type surface coatings are thoroughly discussed by reporting their essential therapeutic responses like osteogenesis, angiogenesis, cytocompatibility, hemocompatibility, anti-bacterial, and controlled drug release towards in-vitro and in-vivo study models. The challenges associated with metallic, ceramic and polymeric coatings along with merits and demerits of various coatings have been illustrated. The use of multilayered hybrid coating comprising a unique combination of organic and inorganic components has been emphasized with future perspectives to obtain diverse bio-functionalities in a facile single coating system for orthopedic implant applications.

ß-blockers as the First Line of Treatment for Hypertension Management.

ß-adrenergic blocker group of medicines has been traditionally used to control high blood pressure since propranolol was discovered by Sir James Black almost 50 years ago. They were the drug of choice in hypertension (HTN) associated with ischemic heart disease, tachyarrhythmias including atrial fibrillation (AF), and anxiety. Congestive cardiac failure was a relative contraindication, but with major advances in science, it became an absolute indication. However, with the advent of newer antihypertensives, especially calcium channel blocker (CCBs) and renin-angiotensin-aldosterone inhibitors, comparative studies were done, and depending on the outcomes of these trials, ß-blockers (BBs) were downgraded to fourth or fifth-line therapy, except in the conditions mentioned above, along with HTN in pregnancy. But clinicians never rejected BBs as important antihypertensives, as evidenced by various real-world data. Also, many investigators found the unfairness of the trial designs where BBs were poor performers. The fact that all BBs are not similar, and differ widely in various properties, added to the question of downgrading all BBs on the basis of trials mostly with atenolol, which is also used once daily. Moreover, trials like ASCOT could not show the reduction of most of the events after long-term follow-up with the use of newer antihypertensives. Added to the issue is the fact that the majority of the trials used BBs with diuretics, and selecting BBs as the sole nonperformer appears to be unjustified and illogical. The recent European Society of HTN (ESH) guideline reemphasized the fact that all the five major classes of antihypertensives, including BBs, can be used as first-line medicine and also can be used interchangeably. Moreover, apart from the traditional indications of BBs, this guideline listed nineteen other conditions, including high heart rate (HR), chronic obstructive pulmonary disease (COPD), and obstructive sleep apnoea, as the conditions where BBs are preferred agents as antihypertensive. So, the life history of BBs in HTN has completed a full cycle, and they are ready now for prime time again. How to cite this article: Ray S, Saboo B, Joshi S, et al. ß-blockers as the First Line of Treatment for Hypertension Management. J Assoc Physicians India 2023;71(9):95-100.

Identification and assessment of stress and associated stressors among veterinary students in India using a cross-sectional questionnaire survey.

Background: Veterinary education, is a rigorous professional training program, which exposes students to significant academic and non-academic pressures. The identification of stressors and stress levels among veterinary students mighty help the designing and implementation of coping strategies to protect the students' mental health. Methods: A 44-item based cross-sectional questionnaire survey was prepared and disseminated among veterinary students in India to identify the stressors responsible, measure the amount of stress, and relate stress to characteristics like gender, degree year, and family income. A total of n = 611 veterinary students across 14 states including 27 colleges/universities participated in the study. The collected data was evaluated for sampling adequacy, construct validity, and reliability using a set of statistical tests. Results: The analysis revealed high sampling adequacy with a KMO value of 0.957 and a highly significant anti-image correlation (p < 0.001). The principal component analysis generated six factors or subscales which effectively explained 51.98% of the variance in the data, depicting high construct validity. The Cronbach's alpha value of 0.957 revealed high internal consistency for the questionnaire. Analysis revealed more than 94% of pupils under stress, with levels ranging from moderate to severe. Academic-related stressor (95.58%) was the leading cause of overall stress in the present study followed by inter- and intrapersonal and career related-stressors (93.12%) and exams and evaluation-related stressor (90.99%). In comparison to male students, female students reported significantly higher levels of overall stress, academic stress, and intrapersonal and interpersonal stress (p < 0.001) using Chi-square. The students from lower-income families experienced significantly higher overall stress as well as stress due to family responsibilities (p < 0.001). The first-year undergraduate students reported significantly higher (p < 0.001) stress due to family responsibilities-related stressors whereas second-year students due to social activities-related stressors. The hierarchal regression model predicted that gender, family income, academic-related stressors, inter- and intrapersonal and career-related stressors, and social activities-related stressors can be employed to evaluate overall stress among students, as they ensured the maximum variance in the data (p < 0.001). Conclusions: To the best of our knowledge, this is the first Indian study to identify stressors, quantify associated stress and predict major attributes to be targeted in future studies for veterinary students.

Development of a cold target recoil ion momentum spectrometer and a projectile charge state analyzer setup to study electron transfer processes in highly charged ion-atom/molecule collisions.

We report the development and performance of a cold target recoil ion momentum spectrometer (COLTRIMS) setup at TIFR, which is built to study various atomic and molecular processes involving the interaction of slow, highly charged ions from an electron cyclotron resonance based ion accelerator. We give a detailed description of the experimental setup, as well as report some initial results on the electron-capture process in collisions of Ar8+ ions with helium and carbon monoxide targets. Here, we present the longitudinal momentum transfer and the sub-shell resolved Q-value spectrum in the case of 2, 4, and 6 keV/u Ar8+ beams in collision with helium. A longitudinal momentum resolution of 0.27 a.u. is achieved in the present system. We also report the state-selective scattering angle distributions for all the collision systems under investigation. We further discuss the fragmentation of the CO2+ molecular ions for different electron capture channels for the 5 keV/u Ar8+ beam. The combination of the COLTRIMS, along with the beam cleaner, the electrostatic deflectors, and the charge state analyzer, is shown to have certain advantages.

Postoperative Recovery Time in Inguinal Herniotomy Under Ilioinguinal/Iliohypogastric Block and Sedation Versus General Anesthesia: A Retrospective Propensity-Score Matched Study.

Background Associated advantages of ilioinguinal/iliohypogastric block and sedation versus general anesthesia (GA) for inguinal hernia repair have not been reported. The use of regional anesthesia (RA) is advantageous during the COVID-19 pandemic as it eliminates the need for airway manipulation.This study aimed to determine the association between postoperative recovery time when ilioinguinal/iliohypogastric block and sedation were utilized for inguinal hernia versus GA. Method This single-center retrospective study used multivariable logistic regression to model the anesthetic modality as a function of age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) physical status, major comorbidities to generate a propensity score for each patient for matching. Results After screening 295 patients, 80 patients each in the general and regional anesthesia groups were matched.RA was associated with a 35.6 minutes (95% CI: -46.6 to -25.0) shorter total postoperative recovery time when compared to GA without the increased preoperative time and adverse outcomes. Conclusions Inguinal hernia repair, when performed under ilioinguinal/iliohypogastric block and sedation, was associated with reduced postoperative recovery time. This can be advantageous during the time of the COVID-19 pandemic to reduce the risk of aerosol generation and shorten hospital stay. Future research can focus on establishing a causal relationship.

Identification of a Novel Pseudo-Natural Product Type IV IDO1 Inhibitor Chemotype.

Natural product (NP)-inspired design principles provide invaluable guidance for bioactive compound discovery. Pseudo-natural products (PNPs) are de novo combinations of NP fragments to target biologically relevant chemical space not covered by NPs. We describe the design and synthesis of apoxidoles, a novel pseudo-NP class, whereby indole- and tetrahydropyridine fragments are linked in monopodal connectivity not found in nature. Apoxidoles are efficiently accessible by an enantioselective [4+2] annulation reaction. Biological evaluation revealed that apoxidoles define a new potent type IV inhibitor chemotype of indoleamine 2,3-dioxygenase 1 (IDO1), a heme-containing enzyme considered a target for the treatment of neurodegeneration, autoimmunity and cancer. Apoxidoles target apo-IDO1, prevent heme binding and induce unique amino acid positioning as revealed by crystal structure analysis. Novel type IV apo-IDO1 inhibitors are in high demand, and apoxidoles may provide new opportunities for chemical biology and medicinal chemistry research.

A Global Transcriptome and Co-expression Analysis Reveals Robust Host Defense Pathway Reprogramming and Identifies Key Regulators of Early Phases of Cicer-Ascochyta Interactions.

Ascochyta blight (AB) caused by the filamentous fungus Ascochyta rabiei is a major threat to global chickpea production. The mechanisms underlying chickpea response to A. rabiei remain elusive to date. Here, we investigated the comparative transcriptional dynamics of AB-resistant and -susceptible chickpea genotypes upon A. rabiei infection, to understand the early host defense response. Our findings revealed that AB-resistant plants underwent rapid and extensive transcriptional reprogramming compared with a susceptible host. At the early stage (24 h postinoculation [hpi]), mainly cell-wall remodeling and secondary metabolite pathways were highly activated, while differentially expressed genes related to signaling components, such as protein kinases, transcription factors, and hormonal pathways, show a remarkable upsurge at 72 hpi, especially in the resistant genotype. Notably, our data suggest an imperative role of jasmonic acid, ethylene, and abscisic acid signaling in providing immunity against A. rabiei. Furthermore, gene co-expression networks and modules corroborated the importance of cell-wall remodeling, signal transduction, and phytohormone pathways. Hub genes such as MYB14, PRE6, and MADS-SOC1 discovered in these modules might be the master regulators governing chickpea immunity. Overall, we not only provide novel insights for comprehensive understanding of immune signaling components mediating AB resistance and susceptibility at early Cicer-Ascochyta interactions but, also, offer a valuable resource for developing AB-resistant chickpea. [Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Ascochyta rabiei: A threat to global chickpea production.

The necrotrophic fungus Ascochyta rabiei causes Ascochyta blight (AB) disease in chickpea. A. rabiei infects all aerial parts of the plant, which results in severe yield loss. At present, AB disease occurs in most chickpea-growing countries. Globally increased incidences of A. rabiei infection and the emergence of new aggressive isolates directed the interest of researchers toward understanding the evolution of pathogenic determinants in this fungus. In this review, we summarize the molecular and genetic studies of the pathogen along with approaches that are helping in combating the disease. Possible areas of future research are also suggested. TAXONOMY: kingdom Mycota, phylum Ascomycota, class Dothideomycetes, subclass Coelomycetes, order Pleosporales, family Didymellaceae, genus Ascochyta, species rabiei. PRIMARY HOST: A. rabiei survives primarily on Cicer species. DISEASE SYMPTOMS: A. rabiei infects aboveground parts of the plant including leaves, petioles, stems, pods, and seeds. The disease symptoms first appear as watersoaked lesions on the leaves and stems, which turn brown or dark brown. Early symptoms include small circular necrotic lesions visible on the leaves and oval brown lesions on the stem. At later stages of infection, the lesions may girdle the stem and the region above the girdle falls off. The disease severity increases at the reproductive stage and rounded lesions with concentric rings, due to asexual structures called pycnidia, appear on leaves, stems, and pods. The infected pod becomes blighted and often results in shrivelled and infected seeds. DISEASE MANAGEMENT STRATEGIES: Crop failures may be avoided by judicious practices of integrated disease management based on the use of resistant or tolerant cultivars and growing chickpea in areas where conditions are least favourable for AB disease development. Use of healthy seeds free of A. rabiei, seed treatments with fungicides, and proper destruction of diseased stubbles can also reduce the fungal inoculum load. Crop rotation with nonhost crops is critical for controlling the disease. Planting moderately resistant cultivars and prudent application of fungicides is also a way to combat AB disease. However, the scarcity of AB-resistant accessions and the continuous evolution of the pathogen challenges the disease management process. USEFUL WEBSITES: https://www.ndsu.edu/pubweb/pulse-info/resourcespdf/Ascochyta%20blight%20of%20chickpea.pdf https://saskpulse.com/files/newsletters/180531_ascochyta_in_chickpeas-compressed.pdf http://www.pulseaus.com.au/growing-pulses/bmp/chickpea/ascochyta-blight http://agriculture.vic.gov.au/agriculture/pests-diseases-and-weeds/plant-diseases/grains-pulses-and-cereals/ascochyta-blight-of-chickpea http://www.croppro.com.au/crop_disease_manual/ch05s02.php https://www.northernpulse.com/uploads/resources/722/handout-chickpeaascochyta-nov13-2011.pdf http://oar.icrisat.org/184/1/24_2010_IB_no_82_Host_Plant https://www.crop.bayer.com.au/find-crop-solutions/by-pest/diseases/ascochyta-blight.

Broadening the horizon of crop research: a decade of advancements in plant molecular genetics to divulge phenotype governing genes.

MAIN CONCLUSION: Advancements in sequencing, genotyping, and computational technologies during the last decade (2011-2020) enabled new forward-genetic approaches, which subdue the impediments of precise gene mapping in varied crops. The modern crop improvement programs rely heavily on two major steps-trait-associated QTL/gene/marker's identification and molecular breeding. Thus, it is vital for basic and translational crop research to identify genomic regions that govern the phenotype of interest. Until the advent of next-generation sequencing, the forward-genetic techniques were laborious and time-consuming. Over the last 10 years, advancements in the area of genome assembly, genotyping, large-scale data analysis, and statistical algorithms have led faster identification of genomic variations regulating the complex agronomic traits and pathogen resistance. In this review, we describe the latest developments in genome sequencing and genotyping along with a comprehensive evaluation of the last 10-year headways in forward-genetic techniques that have shifted the focus of plant research from model plants to diverse crops. We have classified the available molecular genetic methods under bulk-segregant analysis-based (QTL-seq, GradedPool-Seq, QTG-Seq, Exome QTL-seq, and RapMap), target sequence enrichment-based (RenSeq, AgRenSeq, and TACCA), and mutation-based groups (MutMap, NIKS algorithm, MutRenSeq, MutChromSeq), alongside improvements in classical mapping and genome-wide association analyses. Newer methods for outcrossing, heterozygous, and polyploid plant genetics have also been discussed. The use of k-mers has enriched the nature of genetic variants which can be utilized to identify the phenotype-causing genes, independent of reference genomes. We envisage that the recent methods discussed herein will expand the repertoire of useful alleles and help in developing high-yielding and climate-resilient crops.

2B-Alert Web 2.0, an Open-Access Tool for Predicting Alertness and Optimizing the Benefits of Caffeine: Utility Study.

BACKGROUND: One-third of the US population experiences sleep loss, with the potential to impair physical and cognitive performance, reduce productivity, and imperil safety during work and daily activities. Computer-based fatigue-management systems with the ability to predict the effects of sleep schedules on alertness and identify safe and effective caffeine interventions that maximize its stimulating benefits could help mitigate cognitive impairment due to limited sleep. To provide these capabilities to broad communities, we previously released 2B-Alert Web, a publicly available tool for predicting the average alertness level of a group of individuals as a function of time of day, sleep history, and caffeine consumption. OBJECTIVE: In this study, we aim to enhance the capability of the 2B-Alert Web tool by providing the means for it to automatically recommend safe and effective caffeine interventions (time and dose) that lead to optimal alertness levels at user-specified times under any sleep-loss condition. METHODS: We incorporated a recently developed caffeine-optimization algorithm into the predictive models of the original 2B-Alert Web tool, allowing the system to search for and identify viable caffeine interventions that result in user-specified alertness levels at desired times of the day. To assess the potential benefits of this new capability, we simulated four sleep-deprivation conditions (sustained operations, restricted sleep with morning or evening shift, and night shift with daytime sleep) and compared the alertness levels resulting from the algorithm's recommendations with those based on the US Army caffeine-countermeasure guidelines. In addition, we enhanced the usability of the tool by adopting a drag-and-drop graphical interface for the creation of sleep and caffeine schedules. RESULTS: For the 4 simulated conditions, the 2B-Alert Web-proposed interventions increased mean alertness by 36% to 94% and decreased peak alertness impairment by 31% to 71% while using equivalent or smaller doses of caffeine as the corresponding US Army guidelines. CONCLUSIONS: The enhanced capability of this evidence-based, publicly available tool increases the efficiency by which diverse communities of users can identify safe and effective caffeine interventions to mitigate the effects of sleep loss in the design of research studies and work and rest schedules.

Wearables Detect Malaria Early in a Controlled Human-Infection Study.

OBJECTIVE: Observational studies on the use of commercially available wearable devices for infection detection lack the rigor of controlled clinical studies, where time of exposure and onset of infection are exactly known. Towards that end, we carried out a feasibility study using a commercial smartwatch for monitoring heart rate, skin temperature, and body acceleration on subjects as they underwent a controlled human malaria infection (CHMI) challenge. METHODS: Ten subjects underwent CHMI and were asked to wear the smartwatch for at least 12 hours/day from 2 weeks pre-challenge to 4 weeks post-challenge. Using these data, we developed 2B-Healthy, a Bayesian-based infection-prediction algorithm that estimates a probability of infection. We also collected data from eight control subjects for 4 weeks to assess the false-positive rate of 2B-Healthy. RESULTS: Nine of 10 CHMI subjects developed parasitemia, with an average time to parasitemia of 12 days. 2B-Healthy detected infection in seven of nine subjects (78% sensitivity), where in six subjects it detected infection 6 days before parasitemia (on average). In the eight control subjects, we obtained a false-positive rate of 6%/week. CONCLUSION: The 2B-Healthy algorithm was able to reliably detect infection prior to the onset of symptoms using data collected from a commercial smartwatch in a controlled human infection study. SIGNIFICANCE: Our findings demonstrate the feasibility of wearables as a screening tool to provide early warning of infection and support further research on the use of the 2B-Healthy algorithm as the basis for a wearable infection-detection platform.