ERK3 is involved in regulating cardiac fibroblast function.

ERK3/MAPK6 activates MAP kinase-activated protein kinase (MK)-5 in selected cell types. Male MK5 haplodeficient mice show reduced hypertrophy and attenuated increase in Col1a1 mRNA in response to increased cardiac afterload. In addition, MK5 deficiency impairs cardiac fibroblast function. This study determined the effect of reduced ERK3 on cardiac hypertrophy following transverse aortic constriction (TAC) and fibroblast biology in male mice. Three weeks post-surgery, ERK3, but not ERK4 or p38α, co-immunoprecipitated with MK5 from both sham and TAC heart lysates. The increase in left ventricular mass and myocyte diameter was lower in TAC-ERK3+/- than TAC-ERK3+/+ hearts, whereas ERK3 haploinsufficiency did not alter systolic or diastolic function. Furthermore, the TAC-induced increase in Col1a1 mRNA abundance was diminished in ERK3+/- hearts. ERK3 immunoreactivity was detected in atrial and ventricular fibroblasts but not myocytes. In both quiescent fibroblasts and "activated" myofibroblasts isolated from adult mouse heart, siRNA-mediated knockdown of ERK3 reduced the TGF-ß-induced increase in Col1a1 mRNA. In addition, intracellular type 1 collagen immunoreactivity was reduced following ERK3 depletion in quiescent fibroblasts but not myofibroblasts. Finally, knocking down ERK3 impaired motility in both atrial and ventricular myofibroblasts. These results suggest that ERK3 plays an important role in multiple aspects of cardiac fibroblast biology.

COVID-19 Predictors of Morbidity and Mortality.

Background and objectives There are multiple factors and comorbid conditions that can impact the outcomes of COVID-19. This study aimed to assess how patients with certain comorbidities and risk factors were affected by COVID-19. Methodology This retrospective study involved 578 inpatients who presented to the emergency room (ER) due to COVID-19 infection, diagnosed with COVID-19 between 2020 and 2021. This research takes note of COVID-19 severity, particularly in individuals with comorbidities such as chronic obstructive pulmonary disease (COPD), diabetes mellitus (DM), chronic kidney disease (CKD), coronary artery disease (CAD), and hypertension. Results A two-sample t-test found that age was a significant factor affecting hospital length of stay (LOS) and mortality. An ANOVA analysis of race, DM, and CAD showed a significant effect on LOS (p-values = 0.005, 0.01, and 0.01, respectively) but not on mortality and intubation. White patients had an increased LOS compared to other ethnicities. CKD and hypertension significantly affect mortality and LOS. However, COPD did significantly influence all three variables: mortality, intubation, and LOS (p-values = 0.005, 0.013, and 0.01, respectively). A multiple ANOVA test showed that COPD, hypertension, and CKD had a significant effect on mortality, intubation, and LOS (p-values = 0.014, 0.004, and 0.01, respectively). DM showed weaker significance on mortality, intubation, and LOS (p-value = 0.108). Conclusions Patients with all three comorbid conditions (COPD, hypertension, and CKD) had increased length of stay, intubation, and mortality; thus, appropriate measures including close observation and early intervention may be necessary to prevent mortality in these patients.

Cervicomedullary Compression in Achondroplasia: A Feared Complication and an Unforeseen Risk Factor of Posterior Circulation Stroke.

Achondroplasia is an autosomal dominant disorder with defect in the ossification of the cartilage of long bones. Many bony abnormalities constitute its clinical features, with craniovertebral junction (CVJ) anomalies being one of most common issues which need to be addressed at the earliest. CVJ anomalies in individuals may cause neurovascular compression, which may warrant an early surgery to prevent catastrophic complications. Posterior circulation strokes secondary to CVJ anomalies are well known. We hereby present an unusual case of posterior circulation stroke in an achondroplastic dwarf who presented to our tertiary care centre. Prospective case study. The present case adds to the existing literature about one of the preventable causes of fatal posterior circulation strokes in the young. A high index of suspicion for neurovascular compression at the foramen magnum and early initiation of treatment in achondroplastic young individuals may have gratifying results.

NKX2-5 regulates vessel remodeling in scleroderma-associated pulmonary arterial hypertension.

NKX2-5 is a member of the homeobox-containing transcription factors critical in regulating tissue differentiation in development. Here, we report a role for NKX2-5 in vascular smooth muscle cell phenotypic modulation in vitro and in vascular remodeling in vivo. NKX2-5 is upregulated in scleroderma patients with pulmonary arterial hypertension. Suppression of NKX2-5 expression in smooth muscle cells halted vascular smooth muscle proliferation and migration, enhanced contractility, and blocked the expression of extracellular matrix genes. Conversely, overexpression of NKX2-5 suppressed the expression of contractile genes (ACTA2, TAGLN, CNN1) and enhanced the expression of matrix genes (COL1) in vascular smooth muscle cells. In vivo, conditional deletion of NKX2-5 attenuated blood vessel remodeling and halted the progression to hypertension in a mouse chronic hypoxia model. This study revealed that signals related to injury such as serum and low confluence, which induce NKX2-5 expression in cultured cells, is potentiated by TGF-ß and further enhanced by hypoxia. The effect of TGF-ß was sensitive to ERK5 and PI3K inhibition. Our data suggest a pivotal role for NKX2-5 in the phenotypic modulation of smooth muscle cells during pathological vascular remodeling and provide proof of concept for therapeutic targeting of NKX2-5 in vasculopathies.

Pulmonary hypertension in newly diagnosed obstructive sleep apnea-chronic obstructive pulmonary disease overlap syndrome patients attending a tertiary care centre-a cross-sectional analysis.

INTRODUCTION: Overlap syndrome is the association of obstructive sleep apnea (OSA) with chronic obstructive pulmonary disorder and with other chronic respiratory diseases. Patients with overlap syndrome have a worse prognosis compared with chronic obstructive pulmonary disorder or OSA alone. Additionally, patients with combined chronic obstructive pulmonary disorder and OSA are more likely to develop pulmonary hypertension and right heart failure much earlier than those without overlap. AIM: To assess the occurrence of pulmonary hypertension (PH) in newly diagnosed OSA-chronic obstructive pulmonary disorder overlap syndrome patients attending a tertiary care centre. MATERIALS AND METHODS: This cross-sectional study was conducted at Department of Pulmonary Medicine, Government Medical College, Kozhikode, Kerala, South India, among patients with OSA above 40 years of age who were proactively evaluated to pick out those with undiagnosed overlap. A period of 6 months after getting ethical clearance from June 2018 was selected as the study period. Among patients with symptoms suggestive of OSA above 40 years of age who gave the informed consent were enrolled after screening with Standard Sleep questionnaires (Berlin questionnaire, STOP BANG and Epworth Sleepiness Scale). Enrolled patients underwent routine spirometry and sleep study using the standard Level 1 overnight polysomnography (Level1 OPSG). Patients were classified in to two groups as OSA patients (group I), having an apnea hypopnea index (AHI) > 5/hr alone and the second group as those OSA patients (group II), with an obstructive spirometry pattern who were the overlap group. Arterial blood gas analysis (a sample of radial arterial blood was drawn with the patient awake and supine, and was analyzed for pH, PaCO2 and PaO2) and echocardiography (ECHO) of the two groups were compared as a non-invasive method to assess pulmonary artery hypertension and results were analyzed in a systematic manner. RESULTS: Among the 84 patients enrolled, 16.7% had overlap syndrome and the rest had OSA alone. Statistically significant higher mean weight and BMI for those with overlap syndrome compared to the OSA group were observed. Mean FVC (forced vital capacity), FEV1 (forced expiratory volume 1 s), and FEV1/FVC were lower in those with overlap syndrome compared to OSA group. The mean values of ABG parameters revealed higher PaCO2 and lower PaO2 among the group with overlap syndrome which were statistically significant. However, there was no significant difference in resting room air SaO2 value between the two groups. The mean values of sleep duration and efficiency were significantly lower in those with overlap syndrome with a p value < 0.001. The mean value of arousal and REM (rapid eye movement) sleep percentage were significantly higher among those with overlap syndrome (p < 0.001). Mean value of NREM (non-rapid eye movement) sleep percentage was lower among the group with overlap syndrome compared with the OSA group, and this difference was statistically significant. The mean AHI value of the overlap syndrome group was 39.79 ± 7.54 and this was significantly higher than the OSA group (p < 0.004). Among the 14 patients who had ECHO evidence of pulmonary hypertension, 9 (64.3%) belonged to the overlap group which shows that they are a highly vulnerable group for developing pulmonary hypertension (PH) and requires early detection and more rigorous treatment. CONCLUSION: This study confirms that OSA patients with modest daytime level of hypoxemia and mild-moderate chronic airflow limitation have a high prevalence of PH. Chronic airway obstruction may be asymptomatic in some subjects and this stresses the necessity of pulmonary function test in OSA.

Childhood engagement in cognitively stimulating activities moderates relationships between brain structure and cognitive function in adulthood.

Greater engagement in cognitively stimulating activities (CSA) during adulthood has been shown to protect against neurocognitive decline, but no studies have investigated whether CSA during childhood protects against effects of brain changes on cognition later in life. The current study tested the moderating role of childhood CSA in the relationships between brain structure and cognitive performance during adulthood. At baseline (N=250) and 5-year follow-up (N=204) healthy adults aged 20-80 underwent MRI to assess four structural brain measures and completed neuropsychological tests to measure three cognitive domains. Participants were categorized into low and high childhood CSA based on self-report questionnaires. Results of multivariable linear regressions analyzing interactions between CSA, brain structure, and cognition showed that higher childhood CSA was associated with a weaker relationship between cortical thickness and memory at baseline, and attenuated the effects of change in cortical thickness and brain volume on decline in processing speed over time. These findings suggest higher CSA during childhood may mitigate the effects of brain structure changes on cognitive function later in life.

Comprehensive Risk Assessment of Infection Induced by SARS-CoV-2.

The pandemic COVID-19 (coronavirus disease 2019) is caused by the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), which devastated the global economy and healthcare system. The infection caused an unforeseen rise in COVID-19 patients and increased the mortality rate globally. This study gives an overall idea about host-pathogen interaction, immune responses to COVID-19, recovery status of infection, targeted organs and complications associated, and comparison of post-infection immunity in convalescent subjects and non-infected individuals. The emergence of the variants and episodes of COVID-19 infections made the situation worsen. The timely introduction of vaccines and precautionary measures helped control the infection's severity. Later, the population that recovered from COVID-19 grew significantly. However, understanding the impact of healthcare issues resulting after infection is paramount for improving an individual's health status. It is now recognised that COVID-19 infection affects multiple organs and exhibits a broad range of clinical manifestations. So, post COVID-19 infection creates a high risk in individuals with already prevailing health complications. The identification of post-COVID-19-related health issues and their appropriate management is of greater importance to improving patient's quality of life. The persistence, sequelae and other medical complications that normally last from weeks to months after the recovery of the initial infection are involved with COVID-19. A multi-disciplinary approach is necessary for the development of preventive measures, techniques for rehabilitation and strategies for clinical management when it comes to long-term care.

Diffusion Restriction in Bilateral Thalami: Beyond Artery of Percheron Infarct.

Background: Bilateral thalamic infarction, especially the medial thalamus, has been characteristically described in the artery of Percheron (AOP) affection. However, bilateral thalamic restriction has been described in many entities beyond the AOP infarction. Objective: Here we describe a case series (three cases) with infection as an etiology for bilateral thalamic lesions in the topographic distribution of the AOP from a tertiary care center in tropical India. Materials and Methods: : Case series during a 1-year period collecting cases with bilateral thalamic diffusion restriction on MRI who did not have thalamic infarcts and their outcomes. Results: : Bilateral thalamic lesion can occur in both bacterial and viral infections such as tuberculosis, dengue, and SARS-COV-2. Thus, we intend to add infections as one of the etiologies in the ever-expanding list of conditions that produce bilateral thalamic restriction. Conclusions: All the acute symmetric thalamic lesions are not always secondary to vascular insult. Accurate assessment and prompt diagnosis can prevent unnecessary delays in treatment. To our knowledge, this is the first case series in the literature that throws light on the bilateral thalamic lesions in the topographic distribution of the AOP secondary to infections in a tropical country like India.

Mitigation of Fibrosis after Myocardial Infarction in Rats by Using a Porcine Cholecyst Extracellular Matrix.

Fibrosis that occurs after nonfatal myocardial infarction (MI) is an irreversible reparative cardiac tissue remodeling process characterized by progressive deposition of highly cross-linked type I collagen. No currently available therapeutic strategy prevents or reverses MI-associated fibrotic scarring of myocardium. In this study, we used an epicardial graft prepared of porcine cholecystic extracellular matrix to treat experimental nonfatal MI in rats. Graft-assisted healing was characterized by reduced fibrosis, with scanty deposition of type I collagen. Histologically, the tissue response was associated with a favorable regenerative reaction predominated by CD4-positive helper T lymphocytes, enhanced angiogenesis, and infiltration of proliferating cells. These observations indicate that porcine cholecystic extracellular matrix delayed the fibrotic reaction and support its use as a potential biomaterial for mitigating fibrosis after MI. Delaying the progression of cardiac tissue remodeling may widen the therapeutic window for management of scarring after MI.

Microfluidic devices for the detection of disease-specific proteins and other macromolecules, disease modelling and drug development: A review.

Microfluidics is a revolutionary technology that has promising applications in the biomedical field.Integrating microfluidic technology with the traditional assays unravels the innumerable possibilities for translational biomedical research. Microfluidics has the potential to build up a novel platform for diagnosis and therapy through precise manipulation of fluids and enhanced throughput functions. The developments in microfluidics-based devices for diagnostics have evolved in the last decade and have been established for their rapid, effective, accurate and economic advantages. The efficiency and sensitivity of such devices to detect disease-specific macromolecules like proteins and nucleic acids have made crucial impacts in disease diagnosis. The disease modelling using microfluidic systems provides a more prominent replication of the in vivo microenvironment and can be a better alternative for the existing disease models. These models can replicate critical microphysiology like the dynamic microenvironment, cellular interactions, and biophysical and biochemical cues. Microfluidics also provides a promising system for high throughput drug screening and delivery applications. However, microfluidics-based diagnostics still encounter related challenges in the reliability, real-time monitoring and reproducibility that circumvents this technology from being impacted in the healthcare industry. This review highlights the recent microfluidics developments for modelling and diagnosing common diseases, including cancer, neurological, cardiovascular, respiratory and autoimmune disorders, and its applications in drug development.

A baseline study of microplastic pollution in a Southern Indian Estuary.

Knowledge on the processes controlling the vertical distribution of microplastics (MPs) in estuaries is less. This research was carried out to determine the MP distribution in the surface, middle, and bottom layers of the Udyavara River Estuary in southwest India. The mean (± standard deviation) concentrations were 320.83 (± 98.30), 514.55 (± 352.16), and 755.03 (± 400.96) particles/m3, respectively. Fibres, films, and fragments dominated, and 57 % of the MPs had a size range of 0.3-1 mm, while 43 % had a size of 1-5 mm. The main polymers were high-density polyethylene and polyethylene terephthalate. A positive correlation (r = 0.421, p = 0.0205, n = 30) exists between the MPs and salinity, suggesting that the MPs are held by dense saline waters. The mean pollution load index value was 2.25 indicating severe pollution. Microplastic pollution is due to harbour, fishing, industrial activities, the effects of southwest monsoon rain, and tidal currents.

Leisure activity engagement across adulthood predicts cognitive change after five years: Do gender and age matter?

OBJECTIVE: To examine the association between leisure activity (LA) frequency and cognitive trajectories over 5 years across adulthood, and whether gender and age moderate these associations. METHOD: A total of 234 cognitively healthy adults (21-80 years) completed a LA questionnaire at baseline and neuropsychological measures at baseline and after 5 years. Latent change score analysis was applied to generate latent variables estimating changes in different cognitive domains. For a secondary analysis, LA components' scores were calculated, reflecting cognitive-intellectual, social, and physical activities. Regression analysis examined the association between baseline LA and cognitive change, and potential moderation of gender and age. In addition, we tested the influence of cortical gray matter thickness on the results. RESULTS: We found that higher LA engagement was associated with slower cognitive decline for reasoning, speed, and memory, as well as better vocabulary across two time points. Regarding LA components, higher Social-LA and Intellectual-LA predicted slower rates of cognitive decline across different domains, while Physical-LA was not associated with cognitive change. Gender, but not age, moderated some of the associations observed. Our results remained the same after controlling for cortical gray matter thickness. CONCLUSIONS: We demonstrated a protective effect of LA engagement on cognitive trajectories over 5 years, independent from demographics and a measure of brain health. The effects were in part moderated by gender, but not age. Results should be replicated in larger and more diverse samples. Our findings support cognitive reserve hypothesis and have implications for future reserve-enhancing interventions.

Mycobacterium tuberculosis KasA as a drug target: Structure-based inhibitor design.

Recent studies have reported the ß-ketoacyl-acyl carrier protein KasA as a druggable target for Mycobacterium tuberculosis. This review summarizes the current status of major classes of KasA inhibitors with an emphasis on significant contributions from structure-based design methods leveraging X-ray crystal structures of KasA alone and in complex with inhibitors. The issues addressed within each inhibitor class are discussed while detailing the characterized interactions with KasA and structure-activity relationships. A critical analysis of these findings should lay the foundation for new KasA inhibitors to study the basic biology of M. tuberculosis and to form the basis of new antitubercular molecules of clinical significance with activity against drug-sensitive and drug-resistant infections.

Diet moderates the effect of resting state functional connectivity on cognitive function.

Past research suggests modifiable lifestyle factors impact structural and functional measures of brain health, as well as cognitive performance, but no study to date has tested the effect of diet on resting state functional connectivity (rsFC), and its relationship with cognition. The current study tested whether Mediterranean diet (MeDi) moderates the associations between internetwork rsFC and cognitive function. 201 cognitively intact adults 20-80 years old underwent resting state fMRI to measure rsFC among 10 networks, and completed 12 cognitive tasks assessing perceptual speed, fluid reasoning, episodic memory, and vocabulary. Food frequency questionnaires were used to categorize participants into low, moderate, and high MeDi adherence groups. Multivariable linear regressions were used to test associations between MeDi group, task performance, and internetwork rsFC. MeDi group moderated the relationship between rsFC and fluid reasoning for nine of the 10 functional networks' connectivity to all others: higher internetwork rsFC predicted lower fluid reasoning performance in the low MeDi adherence group, but not in moderate and high MeDi groups. Results suggest healthy diet may support cognitive ability despite differences in large-scale network connectivity at rest. Further research is warranted to understand how diet impacts neural processes underlying cognitive function over time.

Rapid microwave hydrothermal processed spinel Co3O4nanospheres infused N-doped graphene nanosheets for high-performance battery.

Spinel Co3O4nanospheres have been synthesized by the microwave-assisted hydrothermal method. The N-doped graphene nanosheets (NGN) were synthesized using Hummer's method. The prepared spinel Co3O4and NGN were mixed under certain proportions using an ultrasonication process and treated with microwave radiation to prepare a novel spinel Co3O4nanospheres infused NGN. The synthesized samples were characterized by x-ray diffraction, Raman spectroscopy, Zetasizer, scanning electron microscope/transmission electron microscopy and x-ray photoelectron spectroscopy for identifying crystal structure and phase, particle size, and the morphology of the nanostructure and the elemental configuration, respectively. The prepared spinel Co3O4/NGN were used as anode material and lithium metal as a reference electrode to fabricate half cell using Swagelok cell components. The electrochemical properties were studied and found to exhibit a larger specific capacity of 575 mAh g-1compared to traditional graphite electrodes, after 100 cycles under 0.1 C rate with a coulombic efficiency of ≈100%. The good electrochemical properties ascribe to the distinctive surface morphological nanostructures of nanoporous nanospheres of spinel Co3O4nanospheres and nanosheets of N-doped graphene that reduce the lithium-ion diffusion pathway. The developed anode material would be a potential electrode for lithium ion battery applications.