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The world is increasingly changing, with climate change, pandemics, and wars becoming key factors. The recent pandemic devastated the tourism industry, leading to a sudden collapse of the global tourism economy. Historically disastrous situations are well known for their impact on innovations and technological advances. Therefore, in light of the idea that disasters can act as catalyst for innovation and transformation, the researchers attempted to conceptualise new strategies in destination development and management from a perspective of tourism destination resilience. The findings contribute to research and policy-making and culminate in identifying six dimensions, namely technology and digitalisation, business model innovation, partnerships and coordination, tourist behaviour, domestic tourism, and sustainability, that illuminate innovative and transformative tendencies in tourism resilience. The study's outcomes offer comprehensive knowledge for policymakers, business planners, and students describing the use of innovative ideas and resilience strategies to adapt to and counter sudden disasters and adopt transformational shifts in business.

Abstract The intricate network of protein-chaperone interactions is crucial for maintaining cellular function. Recent discoveries have unveiled the existence of specialized chaperone assemblies, known as epichaperomes, which serve as scaffolding platforms that orchestrate the reconfiguration of protein-protein interaction networks, thereby enhancing cellular adaptability and proliferation. This study explores the structural and regulatory aspects of epichaperomes, with a particular focus on the role of post-translational modifications (PTMs) in their formation and function. A key finding is the identification of specific PTMs on HSP90, particularly at residues Ser226 and Ser255 within an intrinsically disordered region, as critical determinants of epichaperome assembly. Our data demonstrate that phosphorylation of these serine residues enhances HSP90’s interactions with other chaperones and co-chaperones, creating a microenvironment conducive to epichaperome formation. Moreover, we establish a direct link between epichaperome function and cellular physiology, particularly in contexts where robust proliferation and adaptive behavior are essential, such as in cancer and pluripotent stem cell maintenance. These findings not only provide mechanistic insights but also hold promise for the development of novel therapeutic strategies targeting chaperone assemblies in diseases characterized by epichaperome dysregulation, thereby bridging the gap between fundamental research and precision medicine.

Influenza causes significant morbidity, hospitalizations, and mortality due to lower respiratory tract infections in India. This paper reviews the current evidence regarding influenza epidemiology, the need for vaccination, immunogenicity, and efficacy of available vaccines and provides recommendations for influenza vaccination for adults by the Indian Association of Preventive and Social Medicine (IAPSM). The risk group among adults includes people with chronic disease, the elderly, immunocompromised individuals, pregnant women, travelers, and healthcare workers. Influenza activity is affected by seasons, humidity, and latitude, leading to variability in influenza peaks in different regions of India. The most effective preventive intervention against influenza is vaccination. Current influenza vaccines have good safety profiles, vaccine efficacy, and acceptable cost-effectiveness. As the virus mutates, the vaccine composition should follow WHO recommendations for the current influenza season. Introducing readily available, conventional, and less expensive trivalent influenza vaccines under the national program can achieve maximum impact on the adult population and potentially prevent future outbreaks and pandemics. IAPSM recommends considering routine use of IIV for all individuals above 60 years, adults with comorbidities, and pregnant women in India. The program managers should consider the pattern of influenza seasonality in a particular region. Influenza surveillance conducted through a structured network of laboratories in India has the potential to provide information about circulating strains, morbidity, and mortality. IAPSM emphasizes conducting community-based studies regarding influenza’s burden, vaccine efficacy, timing of vaccination, and cost-effectiveness among Indian adults to generate evidence.

Typhoid is a major public health concern in India, particularly among those dwelling in urban slums with poor sanitation. The disease caused by Salmonella enterica serovar Typhi spread majorly through contaminated food and water. The economic burden of the disease is catastrophic and affects both families and the government making a strong case for including typhoid vaccines in the national immunization schedule. The World Health Organization has prequalified several vaccines and has recommended their use in endemic areas. While there is robust evidence for vaccination of children from India and other LMICs, the case for adult vaccination remains less clear. The Indian Association of Preventive and Social Medicine acknowledges the necessity to adopt a widespread typhoid immunization program, along with other preventive strategies, especially in the vulnerable pockets. IAPSM recommends focusing on newer-generation Typhoid Conjugate Vaccines (TCVs), which provide long-lasting and superior immunological benefits, and are effective across all ages including adults. IAPSM suggests routine use of Typbar-TCV™ for adults up to 45 years old in India. The organization also highlights the necessity for post-marketing surveillance of these vaccines, to monitor the long-term safety and effectiveness of various vaccines in different communities. IAPSM encourages members to take front-line efforts in their community health service areas, and finally appeals for the development of vaccines to cover a more extensive range of Salmonella infections so that control over typhoid can be strengthened.

Background: Full-thickness rectal prolapse remains a challenging pathology to correct surgically with significant recurrence rates. Among perineal approaches, the proctosigmoidectomy with levatorplasty, commonly referred to as the Altemeier procedure is frequently performed. The addition of levatorplasty has been postulated to improve recurrence rates, however, its efficacy varies across studies. The aim of this study was to systematically review recurrence rates following proctosigmoidectomy with levatorplasty, and to meta-analyze pooled data comparing recurrence rates between proctosigmoidectomy with and without a levatorplasty. Methods: A search of EMBASE, OVID Medline, and CENTRAL was performed from database inception to October 2021 aimed at identifying studies investigating recurrences of rectal prolapse following proctosigmoidectomy with levatorplasty. Primary endpoint was recurrence of rectal prolapse. Articles that did not report this endpoint or did not evaluate proctosigmoidectomy with levatorplasty were excluded. A pairwise meta-analysis was performed using Mantel-Haenszel random effects. Results: From 200 citations, 14 primary studies met inclusion criteria. A total of 620 patients (88.9% female, mean age: 71 years) underwent proctosigmoidectomy with levatorplasty, and 117 without levatorplasty. Of the patients undergoing levatorplasty, 86 (13.8%) experienced a recurrence. Mean follow up was 46 months. Meta-analysis comparing recurrence rates between proctosigmoidectomy with and without levatorplasty demonstrated no significant difference (RR 0.80, 0.92, 95% CI 0.32–2.59, P = 0.87, I2 = 77%). Narrative review of postoperative quality of life metrics demonstrated decreased incontinence with levatorplasty as measured by Wexner and ICIQ-SIF scores. Discussion: The addition of a levatorplasty does not significantly reduce the risk of recurrent rectal prolapse after proctosigmoidectomy, however it may improve postoperative continence.

Abstract Amplification of sea surface temperature (SST) seasonality in response to global warming is a robust feature in climate model projections but season‐dependent regional disparities in this amplification and the associated mechanisms are not well addressed. Here, by analyzing large ensemble simulations using Community Earth System Model version 2, we investigate detailed spatiotemporal characteristics of the amplification of SST seasonality focusing on the North Pacific and North Atlantic, where robust changes are projected to emerge around 2050 under SSP3‐7.0 scenario. Our results indicate that atmosphere‐ocean coupled processes shape regional changes in SST seasonality differently between warm (MAMJJAS) and cold seasons (ONDJF). During the warm season, the projected warming tendency is mainly due to increased net surface heat flux and weakening of vertical mixing. On the other hand, in the cold season, the projected cooling tendency is driven by strengthened vertical mixing over the North Pacific associated with the northward shift of storm tracks but weakened horizontal advection and mixing due to changes in ocean currents over the North Atlantic.

Abstract Systems-level assessments of protein-protein interaction (PPI) network dysfunctions are currently out-of-reach because approaches enabling proteome-wide identification, analysis, and modulation of context-specific PPI changes in native (unengineered) cells and tissues are lacking. Herein, we take advantage of chemical binders of maladaptive scaffolding structures termed epichaperomes and develop an epichaperome-based ‘omics platform, epichaperomics, to identify PPI alterations in disease. We provide multiple lines of evidence, at both biochemical and functional levels, demonstrating the importance of these probes to identify and study PPI network dysfunctions and provide mechanistically and therapeutically relevant proteome-wide insights. As proof-of-principle, we derive systems-level insight into PPI dysfunctions of cancer cells which enabled the discovery of a context-dependent mechanism by which cancer cells enhance the fitness of mitotic protein networks. Importantly, our systems levels analyses support the use of epichaperome chemical binders as therapeutic strategies aimed at normalizing PPI networks.

Neurodegenerative disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), represent debilitating conditions with complex, poorly understood pathologies. Epichaperomes, pathologic protein assemblies nucleated on key chaperones, have emerged as critical players in the molecular dysfunction underlying these disorders. In this study, we introduce the synthesis and characterization of clickable epichaperome probes, PU-TCO, positive control, and PU-NTCO, negative control. Through comprehensive in vitro assays and cell-based investigations, we establish the specificity of the PU-TCO probe for epichaperomes. Furthermore, we demonstrate the efficacy of PU-TCO in detecting epichaperomes in brain tissue with a cellular resolution, underscoring its potential as a valuable tool for dissecting single-cell responses in neurodegenerative diseases. This clickable probe is therefore poised to address a critical need in the field, offering unprecedented precision and versatility in studying epichaperomes and opening avenues for novel insights into their role in disease pathology.

Strong negative climatological air-sea interactions effectively damp warming over the eastern Indian Ocean, resulting in weakening of the winds therein. This, in turn, changes the strength of ocean currents, which is considered as the primary mechanism responsible for modulating warming patterns.

Background: India accounted for 6% of global burden of malaria with 95% population residing in malaria endemic areas. However, Punjab is in the malaria elimination phase with annual parasite incidence (API)

Glycosylation, a prevalent post-translational modification, plays a pivotal role in regulating intricate cellular processes by covalently attaching glycans to macromolecules. Dysregulated glycosylation is linked to a spectrum of diseases, encompassing cancer, neurodegenerative disorders, congenital disorders, infections, and inflammation. This review delves into the intricate interplay between glycosylation and protein conformation, with a specific focus on the profound impact of N-glycans on the selection of distinct protein conformations characterized by distinct interactomes—namely, protein assemblies—under normal and pathological conditions across various diseases. We begin by examining the spike protein of the SARS virus, illustrating how N-glycans regulate the infectivity of pathogenic agents. Subsequently, we utilize the prion protein and the chaperone glucose-regulated protein 94 as examples, exploring instances where N-glycosylation transforms physiological protein structures into disease-associated forms. Unraveling these connections provides valuable insights into potential therapeutic avenues and a deeper comprehension of the molecular intricacies that underlie disease conditions. This exploration of glycosylation’s influence on protein conformation effectively bridges the gap between the glycome and disease, offering a comprehensive perspective on the therapeutic implications of targeting conformational mutants and their pathologic assemblies in various diseases. The goal is to unravel the nuances of these post-translational modifications, shedding light on how they contribute to the intricate interplay between protein conformation, assembly, and disease.

The observed sea ice concentration (SIC) over the Arctic has receded substantially in recent decades, and future model projections predict a seasonally ice-free Arctic in the second half of this century. Nevertheless, the impact of the Pacific on Arctic sea ice projections has yet to receive much attention. Observations show that summertime Arctic SIC growth events are related to the weakening of the Aleutian low and cooling events over the equatorial Pacific, and vice versa. We demonstrate that under various Coupled Model Intercomparison Project Phase 6 projections, the models in which the impact of El Niño-driven SIC loss is significantly higher than the La Niña-related SIC growth tend to turn seasonally ice-free by about 10–20 years ahead of the ensemble mean under high-emission future scenarios. We show how the non-linear impact of the El Niño Southern Oscillation (ENSO) on Arctic SIC resulted in a faster decline of summertime sea ice. The ENSO-related SIC changes in the multi-model ensemble mean of Arctic SIC are considerably lower than the internal variability and anthropogenic-driven changes. However, the asymmetric interannual ENSO effects over several decades and the resultant changes in surface heat fluxes over the Arctic lead to significant differences in the timing of sea ice extinction. Our results suggest that climate models must capture the realistic tropical Pacific–Arctic teleconnection to better predict the long-term evolution of the Arctic climate.

Abstract The weakening of zonal atmospheric circulation, a widely accepted projection of climate change in response to global warming, features a weakening of the Indian Ocean Walker circulation (IWC), with an anomalous ascending motion over the western and anomalous descending motion over the eastern Indian Ocean. The projected IWC weakening has previously been attributed to slower warming in the east than the west, that is, to a positive Indian Ocean Dipole (IOD)-like warming pattern. However, such a warming pattern can also be induced by IWC weakening. As a result, the cause-and-effect relationship cannot be easily determined, and the projected change is poorly constrained and highly uncertain. Here, using a suite of coupled climate model simulations under a high-emission scenario, we find that the IWC slowdown is accompanied by not only a positive IOD-like warming pattern but also anomalous meridional circulation that is associated with anomalous descending motion over the eastern Indian Ocean. We further show that the anomalous local meridional circulation is closely linked to enhanced land-sea thermal contrast and is unlikely to result from the positive IOD-like warming pattern, suggesting that the IWC weakening is in part driven by the anomalous local meridional circulation. Our findings underscore the important role of local meridional circulation changes in modulating future IWC changes.

Background: In December 2020, over 500 residents of Eluru City were hospitalised with seizures and sudden loss of consciousness (LOC) resembling the neurotoxic effects of organochlorine poisoning after a flooding event during the last week of November 2020. We described the epidemiological investigation of outbreak and identified risk factors. Methods: We performed descriptive analysis followed by 1:1 unmatched case-control study. Cases were identified through house-to-house search and review of medical records at district hospital. A case defined as sudden onset LOC or new-onset seizures in an Eluru resident aged ≥1 year, December 1–15, 2020 and a control as absence of neurological symptoms in a person aged ≥1 year selected randomly from same administrative division of the case. We compared cases and controls for possible risk factors and calculated adjusted odds ratio (aOR) with 95% confidence interval (CI). Biological and environmental samples were tested for contaminants. Results: We identified 545 cases (56% males), including one death. Seizures were reported in 491 (90%) cases. Median age was 27 years (interquartile range: 17–37 years) and 480 (88%) cases resided in urban area. Cases were clustered in administrative divisions supplied by municipal water reservoirs. Cases were more likely than controls to use municipal water as primary source of drinking water (aOR = 4.6, 95% CI = 1.6–13.0). High levels (average: 14.6 mg/l) of organochlorine compounds were detected in all municipal water samples (acceptable limit:

Joshi, Gomes et al. employ a chemical modulation approach of the cellular interactome to a hyperconnectivity state and show association with the increased response of pancreatic cancer cell lines to specific drugs, including those that target the MAPK-pathways and PI3K-mTOR pathway. To achieve this, the authors employ chemical modulation of the interactome via epichaperome inhibition with the small molecule PU-H71.

Let R be a commutative ring with identity. The zero-divisor graph of R denoted by is an undirected graph where is the set of non-zero zero-divisors of R and there is an edge between the vertices z1 and z2 in if A set of vertices S resolves a graph G if every vertex is uniquely determined by its vector of distances to the vertices in S. The metric dimension of G is the minimum cardinality of a resolving set of G. If we remove any vertex in a resolving set, then the resulting set is also a resolving set, called the fault-tolerant resolving set, and its minimum cardinality is called the fault-tolerant metric dimension. In this article, we study the fault-tolerant metric dimension for where R = and Furthermore, we obtain some results regarding the line graph of and the zero-divisor graph of a Cartesian product of fields.

Drugs with a long residence time at their target sites are often more efficacious in disease treatment. The mechanism, however, behind prolonged retention at the site of action is often difficult to understand for non-covalent agents. In this context, we focus on epichaperome agents, such as zelavespib and icapamespib, which maintain target binding for days despite rapid plasma clearance, minimal retention in non-diseased tissues, and rapid metabolism. They have shown significant therapeutic value in cancer and neurodegenerative diseases by disassembling epichaperomes, which are assemblies of tightly bound chaperones and other factors that serve as scaffolding platforms to pathologically rewire protein–protein interactions. To investigate their impact on epichaperomes in vivo, we conducted pharmacokinetic and target occupancy measurements for zelavespib and monitored epichaperome assemblies biochemically in a mouse model. Our findings provide evidence of the intricate mechanism through which zelavespib modulates epichaperomes in vivo. Initially, zelavespib becomes trapped when epichaperomes bound, a mechanism that results in epichaperome disassembly, with no change in the expression level of epichaperome constituents. We propose that the initial trapping stage of epichaperomes is a main contributing factor to the extended on-target residence time observed for this agent in clinical settings. Zelavespib’s residence time in tumors seems to be dictated by target disassembly kinetics rather than by frank drug–target unbinding kinetics. The off-rate of zelavespib from epichaperomes is, therefore, much slower than anticipated from the recorded tumor pharmacokinetic profile or as determined in vitro using diluted systems. This research sheds light on the underlying processes that make epichaperome agents effective in the treatment of certain diseases.

Here, the authors show structural, biochemical, and functional insights into the discovery of epichaperome‐ directed chemical probes for use in central nervous system diseases. Probes emerging from this work have translated to human clinical studies in Alzheimer’s disease and cancer.

Graph invariants provide an amazing tool to analyze the abstract structures of graphs. Metric dimension and edge metric dimension as graph invariants have numerous applications, among them are robot navigation, pharmaceutical chemistry, etc. In this article, we compute the metric and edge metric dimension of two classes of windmill graphs such as French windmill graph and Dutch windmill graph, and also certain generalizations of these graphs.

E-learning is the most promising venture in the entire world. During the COVID-19 lockdown, e-learning is successfully providing potential information to the students and researchers. In developing nations like India, with limited resources, e-learning tools and platforms provide a chance to make education available to middle and low income households. This paper gives insights about three different online services, namely Google Classroom, Zoom, and Microsoft Teams being used by three different educational institutions. We aim to analyze the efficiency and acceptability of e-learning tools among Indian students during the COVID-19 lockdown. The paper also aims to evaluate the impact of e-learning on the environment and public health during COVID-19 lockdown. It is found that e-learning has potential to reduce carbon emissions, which has beneficial impact on the environment. However, the mental health is impacted as e-learning may lead to self-isolation and reduction in academic achievements that may lead to anxiety and mental depression. Due to usage of electronic devices for learning, the eyes and neck muscles may be put in strain, having deleterious effects on physical health.

Abstract The epichaperome is a new cancer target composed of hyperconnected networks of chaperome members that facilitate cell survival. Cancers with an altered chaperone configuration may be susceptible to epichaperome inhibitors. We developed a flow cytometry-based assay for evaluation and monitoring of epichaperome abundance at the single cell level, with the goal of prospectively identifying patients likely to respond to epichaperome inhibitors, to measure target engagement, and dependency during treatment. As proof of principle, we describe a patient with an unclassified myeloproliferative neoplasm harboring a novel PML-SYK fusion, who progressed to acute myeloid leukemia despite chemotherapy and allogeneic stem cell transplant. The leukemia was identified as having high epichaperome abundance. We obtained compassionate access to an investigational epichaperome inhibitor, PU-H71. After 16 doses, the patient achieved durable complete remission. These encouraging results suggest that further investigation of epichaperome inhibitors in patients with abundant baseline epichaperome levels is warranted.

Summary: Epichaperomes are disease-associated pathologic scaffolds composed of tightly bound chaperones and co-chaperones. They provide opportunities for precision medicine where aberrant protein-protein interaction networks, rather than a single protein, are detected and targeted. This protocol describes the synthesis and characterization of two 124I-labeled epichaperome probes, [124I]-PU-H71 and [124I]-PU-AD, both which have translated to clinical studies. It shows specific steps in the use of these reagents to image and quantify epichaperome-positivity in tumor bearing mice through positron emission tomography.For complete details on the use and execution of this protocol, please refer to Bolaender et al. (2021), Inda et al. (2020), and Pillarsetty et al. (2019).

India has been on a steady march to address malnutrition in the last decade. The nutrition community has worked on building consensus on key actions, implementation platforms were put in place and financing for nutrition slowly increased. Under the strong leadership of the Prime Minister, a revolutionary program to address malnutrition was launched in 2018. As actions under the mission accelerated, the COVID-19 pandemic arrived in early 2020. Affecting health systems, food systems, nutrition programs, social safety nets, and the economy, the pandemic has the potential to exacerbate the challenge of malnutrition in multiple ways. India can mitigate some of the possible ways in which COVID-19 will affect malnutrition but will require strong leadership and continued commitment, adaptation of the national nutrition mission, strengthening of the social safety net and innovative evidence-based data to take informed decisions, implement them and ensure feedback to take necessary corrective action. In this article, we outline some challenges and key areas for action. We conclude that India's nutrition journey is too important to be derailed by a crisis like COVID-19. This is a clarion call for the nutrition community in India to rally strongly to support continued attention to malnutrition in all its forms, to generate relevant evidence, and to support and engage all of society to urgently and adequately address malnutrition in the context of the COVID-19 pandemic. We have come too far to turn back now.

Abstract Restoration of a 3D face from the mesh image is highly demanded in computer vision applications. 3D face restoration is a challenging task due to the variation of expression, poses, intrinsic geometries, and textures. The proposed technique consists of two main components, namely face restoration and recognition. A novel three‐dimensional (3D) landmark‐based face restoration method is proposed. 3D facial landmarks are used in the face recognition technique. It uses the principle of reflection and mid‐face plane for the restoration of facial landmarks. By using the restored 3D face, a deep learning‐based face recognition system is developed. It utilizes the concept of deep features from variational autoencoders. Further, these deep feature embeddings are trained using triplet loss training to increase the distance between embeddings of different persons and decreasing the distance between embeddings of the same person. These trained embeddings are used in support vector machine for prediction. The proposed framework is compared with recently developed face recognition techniques in terms of computational time. The proposed technique is able to recognize the person's face with better accuracy than the existing methods. Further, ablation studies are conducted to test the robustness of the proposed technique.

Background: In Punjab, first COVID-19 case was detected on March 5, 2020 followed by multiple clusters. Understanding the epidemiology of reported COVID-19 cases helps decision makers in planning future responses. We described the epidemiological patterns, laboratory surveillance and contact tracing of COVID-19 cases in Punjab. Methods: We analysed state's COVID-19 data from March–May 2020 to describe time, place and person distribution. We analysed the laboratory surveillance and contact tracing reports to calculate frequency of testing, sample positivity rate (PR) and contacts traced per case. Findings: A total of 2256 cases were reported from March–May 2020 (attack rate 75 cases/million and case fatality rate 2%). Attack rate was higher among males (81 cases/million males) and maximum affected age group was 60–69 years (164∙5 cases/million). Five of 22 districts reported almost half cases in May's first week. Mortality rate was highest among individuals >60 years (six deaths/million) and males (two deaths/million males). Of 45 deaths, 41 reported comorbidities [(hypertension (42%), diabetes (40%)]. COVID-19 testing increased from 46 samples/day (PR: 2%) in March's first week to 4000 samples/day (PR: 2∙5%) by May's end (2752 tests/million). Amritsar conducted 2035 tests/million (highest PR: 6∙5%) while Barnala conducted 4158 tests/million (lowest PR: 1%). For 2256 cases, 19,432 contacts were traced (nine contacts/case) with 11% positivity rate. Interpretation: COVID-19 in Punjab mostly affected males, >60 years of age and individuals with comorbid conditions. Many districts with less testing and contact tracing had higher positivity rate. We recommended to implement and ensure adequate testing and contact tracing in all the districts of Punjab.

Sentiment analysis of news headlines is an important factor that investors consider when making investing decisions. We claim that the sentiment analysis of financial news headlines impacts stock market values. Hence financial news headline data are collected along with the stock market investment data for a period of time. Using Valence Aware Dictionary and Sentiment Reasoning (VADER) for sentiment analysis, the correlation between the stock market values and sentiments in news headlines is established. In our experiments, the data on stock market prices are collected from Yahoo Finance and Kaggle. Financial news headlines are collected from the Wall Street Journal, Washington Post, and Business-Standard website. To cope with such a massive volume of data and extract useful information, various embedding methods, such as Bag-of-words (BoW) and Term Frequency-Inverse Document Frequency (TF-IDF), are employed. These are then fed into machine learning models such as Naive Bayes and XGBoost as well as deep learning models such as Convolutional Neural Network (CNN) and Long Short-Term Memory (LSTM). Various natural language processing, andmachine and deep learning algorithms are considered in our study to achieve the desired outcomes and to attain superior accuracy than the current state-of-the-art. Our experimental study has shown that CNN (80.86%) and LSTM (84%) are the best performing models in relation to machine learning models, such as Support Vector Machine (SVM) (50.3%), Random Forest (67.93%), and Naive Bayes (59.79%). Moreover, two novel methods, BERT and RoBERTa, were applied with the expectation of better performance than all the other models, and they did exceptionally well by achieving an accuracy of 90% and 88%, respectively.

Summary: Stresses associated with disease may pathologically remodel the proteome by both increasing interaction strength and altering interaction partners, resulting in proteome-wide connectivity dysfunctions. Chaperones play an important role in these alterations, but how these changes are executed remains largely unknown. Our study unveils a specific N-glycosylation pattern used by a chaperone, Glucose-regulated protein 94 (GRP94), to alter its conformational fitness and stabilize a state most permissive for stable interactions with proteins at the plasma membrane. This “protein assembly mutation’ remodels protein networks and properties of the cell. We show in cells, human specimens, and mouse xenografts that proteome connectivity is restorable by inhibition of the N-glycosylated GRP94 variant. In summary, we provide biochemical evidence for stressor-induced chaperone-mediated protein mis-assemblies and demonstrate how these alterations are actionable in disease.

Tubal ligation (TL) is an effective and common method of fertility control. In the year 2009, over 24,000 were performed in Canada alone. Migration of Filshie clips used during TL is estimated to occur in 25% of all patients; 0.1-0.6% of these patients subsequently experience symptoms or extrusion of the clip from anatomical sites such as the anus, vagina, urethra, or abdominal wall. Migrated clips may present as chronic groin sinus, perianal sepsis, or chronic abdominal pain. These symptoms can occur as early as 6 weeks or as late as 21 years after application. We present the case of a 49-year-old female with a 3.5-year history of intermittent dull nonradiating left upper quadrant (LUQ) pain lasting on average 2-3 days. There were no other associated symptoms, and the longest pain-free period was 4 days. Her past medical history includes COPD, GERD, IBS, and depression. Current medications are only remarkable for Symbicort. Pertinent past surgical history includes laparoscopic tubal ligation with Filshie clips in 1999, followed by a vaginal hysterectomy in 2013. Migrated tubal ligation clip was noted on an abdominal X-ray. The patient was then referred for surgical management. Subsequent CT scan confirmed a solitary clip present adjacent to the left lobe of the liver. No other abnormalities were reported. Patient underwent laparoscopy for removal of the clip, which was identified to be underneath the left lobe of the liver embedded in the gastrohepatic omentum. Please see the video link provided. Postoperative pathology report confirmed the presence of a Filshie clip. Patient reported complete resolution of her LUQ pain at a 5-week and 3.5-month follow-up. This case shows that although symptomatic clip migration is a rare phenomenon, it should be given special consideration in women with unexplained chronic abdominal pain and a history of TL. Additionally, removal of clip can provide resolution of symptoms.

The Indo-Pacific warm pool (IPWP) is enclosed by a 28 °C isotherm and plays a vital role in controlling atmospheric circulations. However, the effects of changes in regional warm pool sea surface temperatures (SSTs) remain unexplored. We divided the IPWP into the Indian and Pacific sectors and distinguished their responses to natural variability and global warming. Furthermore, we examined the impacts of the interannual variability (IAV) in warm pool SST on the tropical Hadley, Walker, and monsoon circulations. The Hadley circulation was affected by warm pool SST warming, i.e., warmer SSTs over the warm pool strengthened the upward branch of Hadley circulation, whereas the downward branch was respectively weakened and strengthened in the Northern and Southern Hemispheres. Walker circulation was strengthened (weakened) in the warming (natural) mode. Consequently, the Walker circulation is weakened since the natural variability of warm pool SST plays a more dominant role rather than the warming trend of SSTs over the warm pool. Furthermore, our analysis displays that warm pool warming has little impact on the monsoon circulation. Our findings highlight the different roles of the IAV of warm pool regions in each tropical circulation as part of the warming trend and natural variability.

Background: Schizophrenia, a severe psychological disorder, shows symptoms such as hallucinations and delusions. In addition, patients with schizophrenia often exhibit a deficit in working memory which adversely impacts the attentiveness and the behavioral characteristics of a person. Although several clinical efforts have already been made to study working memory deficit in schizophrenia, in this paper, we investigate the applicability of a machine learning approach for identification of the brain regions that get affected by schizophrenia leading to the dysfunction of the working memory. Methods: We propose a novel scheme for identification of the affected brain regions from functional magnetic resonance imaging data by deploying group independent component analysis in conjunction with feature extraction based on statistical measures, followed by sequential forward feature selection. The features that show highest accuracy during the classification between healthy and schizophrenia subjects are selected. Results: This study reveals several brain regions like cerebellum, inferior temporal gyrus, superior temporal gyrus, superior frontal gyrus, insula, and amygdala that have been reported in the existing literature, thus validating the proposed approach. We are also able to identify some functional changes in the brain regions, such as Heschl gyrus and the vermian area, which have not been reported in the literature involving working memory studies amongst schizophrenia patients. Conclusions: As our study confirms the results obtained in earlier studies, in addition to pointing out some brain regions not reported in earlier studies, the findings are likely to serve as a cue for clinical investigation, leading to better medical intervention.

The fungal pathogen Candida albicans causes lethal systemic infections in humans. To better define how pathogens resist oxidative attack by the immune system, we examined a family of four Flavodoxin-Like Proteins (FLPs) in C. albicans. In agreement with previous studies showing that FLPs in bacteria and plants act as NAD(P)H quinone oxidoreductases, a C. albicans quadruple mutant lacking all four FLPs (pst1Δ, pst2Δ, pst3Δ, ycp4Δ) was more sensitive to benzoquinone. Interestingly, the quadruple mutant was also more sensitive to a variety of oxidants. Quinone reductase activity confers important antioxidant effects because resistance to oxidation was restored in the quadruple mutant by expressing either Escherichia coli wrbA or mammalian NQO1, two distinct types of quinone reductases. FLPs were detected at the plasma membrane in C. albicans, and the quadruple mutant was more sensitive to linolenic acid, a polyunsaturated fatty acid that can auto-oxidize and promote lipid peroxidation. These observations suggested that FLPs reduce ubiquinone (coenzyme Q), enabling it to serve as an antioxidant in the membrane. In support of this, a C. albicans coq3Δ mutant that fails to synthesize ubiquinone was also highly sensitive to oxidative stress. FLPs are critical for survival in the host, as the quadruple mutant was avirulent in a mouse model of systemic candidiasis under conditions where infection with wild type C. albicans was lethal. The quadruple mutant cells initially grew well in kidneys, the major site of C. albicans growth in mice, but then declined after the influx of neutrophils and by day 4 post-infection 33% of the mice cleared the infection. Thus, FLPs and ubiquinone are important new antioxidant mechanisms that are critical for fungal virulence. The potential of FLPs as novel targets for antifungal therapy is further underscored by their absence in mammalian cells.