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Drought alone causes more annual loss in crop yield than all pathogens combined. To adapt to moisture gradients in soil, plants alter their physiology, modify root growth and architecture, and close stomata on their aboveground segments. These tissue-specific responses modify the flux of cellular signals, resulting in early flowering or stunted growth and, often, reduced yield. Physiological and molecular analyses of the model plant Arabidopsis thaliana have identified phytohormone signaling as key for regulating the response to drought or water insufficiency. Here we discuss how engineering hormone signaling in specific cells and cellular domains can facilitate improved plant responses to drought. We explore current knowledge and future questions central to the quest to produce high-yield, drought-resistant crops.

Mycobacterium tuberculosis can adapt to changing environments by non-heritable mechanisms. Frame-shifting insertions and deletions (indels) may also participate in adaptation through gene disruption, which could be reversed by secondary introduction of a frame-restoring indel. We present ScarTrek, a program that scans genomic data for indels, including those that together disrupt and restore a gene’s reading frame, producing “frame-shift scars” suggestive of reversible gene inactivation. We use ScarTrek to analyze 5977 clinical M. tuberculosis isolates. We show that indel frequency inversely correlates with genomic linguistic complexity and varies with gene-position and gene-essentiality. Using ScarTrek, we detect 74 unique frame-shift scars in 48 genes, with a 3.74% population-level incidence of unique scar events. We find multiple scars in the ESX-1 gene cluster. Six scars show evidence of convergent evolution while the rest shared a common ancestor. Our results suggest that sequential indels are a mechanism for reversible gene silencing and adaptation in M. tuberculosis . Bacterial adaptation through frame-shifting insertions and deletions (indels) could be reversed by secondary introduction of a frame-restoring indel. Here, the authors develop ScarTrek, a program that scans genomic data for different indels, and analyze 5977 clinical M. tuberculosis isolates for indel frequency.

Glucose (Glc) plays a fundamental role in regulating lateral root (LR) development as well as LR emergence. In this study, we show that brassinosteroid (BR) signaling works downstream of Glc in controlling LR production/emergence in Arabidopsis (Arabidopsis thaliana) seedlings. Glc and BR can promote LR emergence at lower concentrations, while at higher concentrations, both have an inhibitory effect. The BR biosynthesis and perception mutants showed highly reduced numbers of emerged LRs at all the Glc concentrations tested. BR signaling works downstream of Glc signaling in regulating LR production, as in theglucose insensitive2-1brassinosteroid insensitive1double mutant, Glc-induced LR production/emergence was severely reduced. Differential auxin distribution via the influx carriers AUXIN RESISTANT1/LIKE AUXIN RESISTANT1-3 and the efflux carrier PIN-FORMED2 plays a central role in controlling LR production in response to Glc and BR. Auxin signaling components AUXIN RESISTANT2,3 and SOLITARY ROOT act downstream of Glc and BR. AUXIN RESPONSE FACTOR7/19 work farther downstream and control LR production by regulating the expression ofLATERAL ORGAN BOUNDARIES-DOMAIN29andEXPANSIN17genes. Increasing light flux could also mimic the Glc effect on LR production/emergence. However, increased light flux could not affect LR production in those BR and auxin signaling mutants that were defective for Glc-induced LR production. Altogether, our study suggests that, under natural environmental conditions, modulation of endogenous sugar levels can manipulate root architecture for optimized development by altering its nutrient/water uptake as well as its anchorage capacity.

Background While assisted reproductive technologies (ART) have helped many people experiencing infertility become pregnant, the ART process can take a psychological toll. This study examined whether and how perceived stress- and depression-related symptoms vary among individuals at different stages of the infertility and ART process, and whether ART-specific stressors and emotional support are associated with mental health symptomatology. Methods Data were collected using an online REDCap survey administered between July 2021 and March 2022. The survey was administered to 240 participants who had experienced infertility, including those who had not yet accessed ART, those undergoing ART but who were not yet pregnant, those currently pregnant through ART, and those who had given birth in the last year through ART. Each participant completed the Cohen Perceived Stress Scale (range 0–40) and the Edinburgh Depression Scale (range 0–30). Participants who had undergone ART were asked about their experience of ART-specific stressors and how helpful partner and provider support had been during the ART process. Survey data were analyzed using ANOVA and multivariate linear regressions. Results 88% of participants reported medium or high levels of perceived stress, and 43.8% of respondents showed probable indications of depression. Perceived stress and depression symptoms were significantly higher for individuals currently undergoing, but not yet pregnant from, ART treatments. These effect sizes were substantial; for example, depression scores in this group were five points higher than among currently pregnant individuals and nine points higher than among postpartum individuals. For the subset of participants who had used or were currently undergoing ART ( N  = 221), perceived social stigma and the physical and time demands of ART were significantly associated with higher stress and depression symptoms, while partner emotional support was associated with lower perceived stress. Conclusions The ART process exacerbates perceived stress and depression symptoms among individuals experiencing infertility. Given the potential long-term impacts on both parent and child wellbeing, clinicians and policymaking groups, including the American Society for Reproductive Medicine (ASRM), should consider making access to mental health services a standard of care during infertility treatment.

The seminal discovery of paclitaxel from endophytic fungus Taxomyces andreanae was a milestone in recognizing the immense potential of endophytic fungi as prolific producers of bioactive secondary metabolites of use in medicine, agriculture, and food industries. Following the discovery of paclitaxel, the research community has intensified efforts to harness endophytic fungi as putative producers of lead molecules with anticancer, anti-inflammatory, antimicrobial, antioxidant, cardio-protective, and immunomodulatory properties. Endophytic fungi have been a valuable source of bioactive compounds over the last three decades. Compounds such as taxol, podophyllotoxin, huperzine, camptothecin, and resveratrol have been effectively isolated and characterized after extraction from endophytic fungi. These findings have expanded the applications of endophytic fungi in medicine and related fields. In the present review, we systematically compile and analyze several important compounds derived from endophytic fungi, encompassing the period from 2011 to 2022. Our systematic approach focuses on elucidating the origins of endophytic fungi, exploring the structural diversity and biological activities exhibited by these compounds, and giving special emphasis to the pharmacological activities and mechanism of action of certain compounds. We highlight the tremendous potential of endophytic fungi as alternate sources of bioactive metabolites, with implications for combating major global diseases. This underscores the significant role that fungi can play in the discovery and development of novel therapeutic agents that address the challenges posed by prevalent diseases worldwide.

Little is known about the physiology of latent Mycobacterium tuberculosis infection. We studied the mutational rates of 24 index tuberculosis (TB) cases and their latently infected household contacts who developed active TB up to 5.25 years later, as an indication of bacterial physiological state and possible generation times during latent TB infection in humans. Here we report that the rate of new mutations in the M. tuberculosis genome decline dramatically after two years of latent infection (two-sided p < 0.001, assuming an 18 h generation time equal to log phase M. tuberculosis , with latency period modeled as a continuous variable). Alternatively, assuming a fixed mutation rate, the generation time increases over the latency duration. Mutations indicative of oxidative stress do not increase with increasing latency duration suggesting a lack of host or bacterial derived mutational stress. These results suggest that M. tuberculosis enters a quiescent state during latency, decreasing the risk for mutational drug resistance and increasing generation time, but potentially increasing bacterial tolerance to drugs that target actively growing bacteria. Here, Colangeli et al. use a human household contact cohort to measure the rate of mutation and evolution of Mycobacterium tuberculosis strains and find that long term latency is characterized by reduced mutation rates compared to latency in the first year, coinciding with clinical risk of developing active TB.

Formation of functional skeletal tissues requires highly organized steps of mesenchymal progenitor cell differentiation. The dental follicle (DF) surrounding the developing tooth harbors mesenchymal progenitor cells for various differentiated cells constituting the tooth root–bone interface and coordinates tooth eruption in a manner dependent on signaling by parathyroid hormone-related peptide (PTHrP) and the PTH/PTHrP receptor (PPR). However, the identity of mesenchymal progenitor cells in the DF and how they are regulated by PTHrP-PPR signaling remain unknown. Here, we show that the PTHrP-PPR autocrine signal maintains physiological cell fates of DF mesenchymal progenitor cells to establish the functional periodontal attachment apparatus and orchestrates tooth eruption. A single-cell RNA-seq analysis revealed cellular heterogeneity of PTHrP⁺ cells, wherein PTHrP⁺ DF subpopulations abundantly express PPR. Cell lineage analysis using tamoxifen-inducible PTHrP-creER mice revealed that PTHrP⁺ DF cells differentiate into cementoblasts on the acellular cementum, periodontal ligament cells, and alveolar cryptal bone osteoblasts during tooth root formation. PPR deficiency induced a cell fate shift of PTHrP⁺ DF mesenchymal progenitor cells to nonphysiological cementoblast-like cells precociously forming the cellular cementum on the root surface associated with up-regulation of Mef2c and matrix proteins, resulting in loss of the proper periodontal attachment apparatus and primary failure of tooth eruption, closely resembling human genetic conditions caused by PPR mutations. These findings reveal a unique mechanism whereby proper cell fates of mesenchymal progenitor cells are tightly maintained by an autocrine system mediated by PTHrP-PPR signaling to achieve functional formation of skeletal tissues.

With the commitment of the national government to provide universal healthcare at cheap and affordable prices in India, public healthcare services are being strengthened in India. However, there is dearth of cost data for provision of health services through public system like primary & community health centres. In this study, we aim to bridge this gap in evidence by assessing the total annual and per capita cost of delivering the package of health services at PHC and CHC level. Secondly, we determined the per capita cost of delivering specific health services like cost per antenatal care visit, per institutional delivery, per outpatient consultation, per bed-day hospitalization etc. We undertook economic costing of fourteen public health facilities (seven PHCs and CHCs each) in three North-Indian states viz., Haryana, Himachal Pradesh and Punjab. Bottom-up costing method was adopted for collection of data on all resources spent on delivery of health services in selected health facilities. Analysis was undertaken using a health system perspective. The joint costs like human resource, capital, and equipment were apportioned as per the time value spent on a particular service. Capital costs were discounted and annualized over the estimated life of the item. Mean annual costs and unit costs were estimated along with their 95% confidence intervals using bootstrap methodology. The overall annual cost of delivering services through public sector primary and community health facilities in three states of north India were INR 8.8 million (95% CI: 7,365,630-10,294,065) and INR 26.9 million (95% CI: 22,225,159.3-32,290,099.6), respectively. Human resources accounted for more than 50% of the overall costs at both the level of PHCs and CHCs. Per capita per year costs for provision of complete package of preventive, curative and promotive services at PHC and CHC were INR 170.8 (95% CI: 131.6-208.3) and INR162.1 (95% CI: 112-219.1), respectively. The study estimates can be used for financial planning of scaling up of similar health services in the urban areas under the aegis of National Health Mission. The estimates would be also useful in undertaking equity analysis and full economic evaluations of the health systems.

Improving hypertension management is a national priority that can decrease morbidity and mortality. Evidence-based hypertension management guidelines advocate self-measured BP (SMBP), but widespread implementation of SMBP is lacking. The purpose of this study was to describe the perspective of primary care physicians (PCPs) on SMBP to identify the barriers and facilitators for implementing SMBP. We collected data from PCPs from a large health system using semi-structured interviews based on the Theoretical Domains Framework (TDF). Responses were recorded, transcribed, and qualitatively analyzed into three overarching TDF domains based on the Behavior Change Wheel (BCW): 1) Motivation 2) Opportunity and 3) Capabilities. The sample size was based on theme saturation. All 17 participating PCPs believed that SMBP is a useful, but underutilized tool. Although individual practices varied, most physicians felt that the increased data points from SMBP allowed for better hypertension management. Most felt that overcoming existing barriers would be difficult, but identified several facilitators: physician support of SMBP, the possibility of having other trained health professionals to assist with SMBP and patient education; improving patient engagement and empowerment with SMBP, and the interest of the health system in using technology to improve hypertension management. PCPs believe that SMBP can improve hypertension management. There are numerous barriers and facilitators for implementing SMBP. Successful implementation in clinical practice will require implementation strategies targeted at increasing patient acceptability and reducing physician workload. This may need a radical change in the current methods of managing hypertension.

Epistatic interactions between residues determine a protein's adaptability and shape its evolutionary trajectory. When a protein experiences a changed environment, it is under strong selection to find a peak in the new fitness landscape. It has been shown that strong selection increases epistatic interactions as well as the ruggedness of the fitness landscape, but little is known about how the epistatic interactions change under selection in the long-term evolution of a protein. Here we analyze the evolution of epistasis in the protease of the human immunodeficiency virus type 1 (HIV-1) using protease sequences collected for almost a decade from both treated and untreated patients, to understand how epistasis changes and how those changes impact the long-term evolvability of a protein. We use an information-theoretic proxy for epistasis that quantifies the co-variation between sites, and show that positive information is a necessary (but not sufficient) condition that detects epistasis in most cases. We analyze the \"fossils\" of the evolutionary trajectories of the protein contained in the sequence data, and show that epistasis continues to enrich under strong selection, but not for proteins whose environment is unchanged. The increase in epistasis compensates for the information loss due to sequence variability brought about by treatment, and facilitates adaptation in the increasingly rugged fitness landscape of treatment. While epistasis is thought to enhance evolvability via valley-crossing early-on in adaptation, it can hinder adaptation later when the landscape has turned rugged. However, we find no evidence that the HIV-1 protease has reached its potential for evolution after 9 years of adapting to a drug environment that itself is constantly changing. We suggest that the mechanism of encoding new information into pairwise interactions is central to protein evolution not just in HIV-1 protease, but for any protein adapting to a changing environment.