Shatavarin-IV rescues the Di (2-ethylhexyl) phthalate (DEHP) induced oxidative stress in rat granulosa cells in vitro.

Studies provide notable evidence that oxidative stress (OS) mediated reactive oxygen species (ROS) disturb reproductive health. We have shown in our previous publication that exposure of Di-(2-ethylhexyl) phthalate (DEHP), induces OS mediated ROS generation which inhibits steroid synthesis. In the present study, we demonstrated the ameliorative/protective effects of one of the steroidal saponins, i.e., Shatavarin-IV, isolated from the roots of Asparagus racemosus against DEHP induced OS in rat granulosa cells. Granulosa cells were exposed with DEHP alone (400µM), Shatavarin-IV alone (8µg/ml), and a combination of DEHP + Shatavarin-IV (400µM + 8µg/ml) in vitro for 24 hrs. Intracellular ROS, OS/hypoxia, mitochondrial membrane potential, steroid-responsive genes expression were analyzed. The results revealed that the effective dose of DEHP (400µg) significantly increased OS compared to the control by increasing ROS levels, mitochondrial membrane potential, and ß-galactosidase activity with a higher level of apoptotic genes (Bax, Caspase-3) expression at mRNA level. Further, DEHP significantly (p<0.05) reduced mRNA expression of steroidogenic responsive genes (StAR, CYP17A1 and CYP19A1) in granulosa cells treated with above combination compared to control. Interestingly, co-treatment of DEHP + Shatavarin-IV significantly suppressed the DEHP induced OS, ROS, ß-galactosidase levels and enhanced steroidogeneic and apoptotic gene expression activities, which suggests that Shatavarin-IV rescued DEHP-induced changes that may useful for the prevention of DEHP- induced reproductive toxicity.

Immature platelet fraction in patients diagnosed with COVID-19.

BACKGROUND: The recent pandemic caused by the newly identified virus, SARS-Cov-2 is associated with thromboembolic events. Patients infected with COVID-19 have been found to have thrombocytopenia. A decrease in platelet count may be caused by increased destruction and consumption of platelets or by decreased production of platelets in the bone marrow. Immature platelet fraction (IPF) is a new platelet parameter that is an indicator for peripheral destruction and consumption of platelets. OBJECTIVES: To assess the immature platelet fraction (IPF) in patients infected with COVID-19. MATERIALS AND METHODS: The present study is a retrospective study where secondary data obtained from previous laboratory records of COVID-positive patients admitted at a tertiary care hospital in Delhi from 4 January to 4 February 2022 was analyzed. Sixty-eight COVID-positive patients were included. Platelet parameters included from the automated hematology analyzer Mindray were platelet count, mean platelet volume (MPV), immature platelet fraction (IPF), and platelet large cell ratio (P-LCR). Data was analyzed using SPSS Version 25. A P value less than 0.05 was considered statistically significant. RESULTS: In the present study mild thrombocytopenia was noted in 40% of the patients infected with COVID-19 admitted to the hospital. The median platelet count in these patients was found to be 91,000/mm3 (64,000-1,31,000). Low platelet count was associated with a significantly higher IPF, MPV, PDW, P-LCR, and a significantly lower PCT as compared to patients infected with COVID-19 with normal platelet count. There was a significant increase in IPF with a decrease in platelet count (P value < 0.05). A significant increase in IPF was noted with an increase in MPV and P-LCR (P value < 0.05). INTERPRETATION AND CONCLUSION: The present study suggests that thrombocytopenia in patients infected with COVID-19 may probably be due to peripheral destruction and consumption of platelets.

Impact of Patient Education Formats on Treatment Adherence and Denture Hygiene in Edentulous Patients: A Comparative Study.

BACKGROUND Effective communication and patient education are important in geriatric dental care. Memory decline complicates patient adherence. This study aimed to compare verbal, audio, and video patient education material (PEM) and adherence to dental prosthetic management in edentulous patients. MATERIAL AND METHODS 90 completely/partially edentulous patients (aged 40 to 70 years), were divided (simple random) into three groups (Gp) of 30 each . A total of 68 instructions were organized into 9 learning categories. For GpVi, a 20 minute video was shot using a Sony camera (PD170), with two actors depicting related PEM information. Patients were recalled after 1 day and 7days, to recall the PEM instructions. A Denture plaque Index (DPI) determined the efficiency of the instructions at both time intervals. Frequencies, means and standard deviations were derived for each group and then compared using Chi square, paired and unpaired t test and a Neuman-Keul post hoc pairwise test. All significant differences were kept at probability t value of ≤0.05. RESULTS PEM instructions related to patient individuality, proper tongue position and miscellaneous showed poor patient recall. At 1 day interval, audio was found to have better recall than video and verbal in 5 PEM instruction categories. At 7 day interval, video showed better recall than other two groups (P≤0.05). Despite improvements in patients recall, DPI revealed better denture hygiene maintenance in patients receiving instructions through video format (P≤0.05). CONCLUSIONS For all categories, no single media was considered to be sufficient, audio produced early better recall while video influenced long term recall and better denture hygiene maintenance.

Mental health markers and protective factors in students with symptoms of physical pain across WEIRD and non-WEIRD samples - a network analysis.

BACKGROUND: Studies conducted in Western societies have identified variables associated with chronic pain, but few have done so across cultures. Our study aimed to clarify the relationship between specific mental health markers (i.e., depression, anxiety, posttraumatic stress disorder [PTSD], perceived stress) as well as specific protective factors (i.e., social support and self-efficacy) related to physical pain among university students across non-WEIRD and WEIRD samples. METHOD: A total of 188 university students (131 women and 57 men) were included in the study. We used network analysis to ascertain mental health markers especially central to the experience of physical pain. RESULTS: No statistically significant difference was found between mental health markers (i.e., depression, anxiety, perceived stress, and PTSD) and protective factors (i.e., social support and self-efficacy) associated with physical pain symptoms for Swiss students versus Indian students (M = 0.325, p = .11). In addition, networks for Swiss versus Indian students did not differ in global strength (S = 0.29, p = .803). Anxiety was the most central mental health marker, and social support was the most important protective factor related to physical pain in both countries. However, for Swiss students, perceived stress, and for Indian students, PTSD symptoms were central mental health markers related to physical pain. CONCLUSION: Our results identify factors that may serve as important treatment targets for pain interventions among students of both countries before it becomes chronic.

Karanjin, A Promising Bioactive Compound Possessing Anti-cancer Activity against Experimental Model of Non-small Cell Lung Cancer Cells.

AIMS: The aim of this study is to isolate the Millettia pinnata (Karanj) leaf extract for pure compound with anticancer properties and to study the molecular target of the isolates in non-small cell lung cancer cell lines. BACKGROUND: In our earlier research Millettia pinnata leaf extract has demonstrated potential anticancer activities. Thus, in pursuit of the bioactive compounds, the most potential active extract from our previous study was purified. Furthermore, the anticancer properties of the isolated compound karanjin was studied and aimed for apoptosis and restraining growth. METHODS: A novel method was developed through column chromatography for isolation and purification of the compound karanjin from leaf chloroform extract. The purified component was then characterised using FTIR, mass spectrometry, and NMR. An MTT-based cytotoxicity assay was used to analyse cell cytotoxicity, whereas fluorescence staining was used for apoptosis and reactive oxygen species inhibition quantification. Furthermore, the real-time PCR assay was used to determine the molecular mechanism of action in cells causing cytotoxicity induced by karanjin dosing. RESULTS: The anticancer activity of karanjin in A549 cell line exhibited prominent activity revealing IC50 value of 4.85 µM. Conferring the predicted molecular pathway study, karanjin restrains the proliferation of cancer cells through apoptosis, which is controlled by extrinsic pathway proteins FAS/FADD/Caspases 8/3/9. Downregulation of KRAS and dependent gene expression also stopped cell proliferation. CONCLUSION: Karanjin has been identified as a compound with potential effect in non-small cell lung cancer cells. Molecular mechanism for apoptosis and inhibition of reactive oxygen species induced through H2O2 were observed, concluding karanjin have medicinal and antioxidant properties.

New drug discovery of cardiac anti-arrhythmic drugs: insights in animal models.

Cardiac rhythm regulated by micro-macroscopic structures of heart. Pacemaker abnormalities or disruptions in electrical conduction, lead to arrhythmic disorders may be benign, typical, threatening, ultimately fatal, occurs in clinical practice, patients on digitalis, anaesthesia or acute myocardial infarction. Both traditional and genetic animal models are: In-vitro: Isolated ventricular Myocytes, Guinea pig papillary muscles, Patch-Clamp Experiments, Porcine Atrial Myocytes, Guinea pig ventricular myocytes, Guinea pig papillary muscle: action potential and refractory period, Langendorff technique, Arrhythmia by acetylcholine or potassium. Acquired arrhythmia disorders: Transverse Aortic Constriction, Myocardial Ischemia, Complete Heart Block and AV Node Ablation, Chronic Tachypacing, Inflammation, Metabolic and Drug-Induced Arrhythmia. In-Vivo: Chemically induced arrhythmia: Aconitine antagonism, Digoxin-induced arrhythmia, Strophanthin/ouabain-induced arrhythmia, Adrenaline-induced arrhythmia, and Calcium-induced arrhythmia. Electrically induced arrhythmia: Ventricular fibrillation electrical threshold, Arrhythmia through programmed electrical stimulation, sudden coronary death in dogs, Exercise ventricular fibrillation. Genetic Arrhythmia: Channelopathies, Calcium Release Deficiency Syndrome, Long QT Syndrome, Short QT Syndrome, Brugada Syndrome. Genetic with Structural Heart Disease: Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia, Dilated Cardiomyopathy, Hypertrophic Cardiomyopathy, Atrial Fibrillation, Sick Sinus Syndrome, Atrioventricular Block, Preexcitation Syndrome. Arrhythmia in Pluripotent Stem Cell Cardiomyocytes. Conclusion: Both traditional and genetic, experimental models of cardiac arrhythmias' characteristics and significance help in development of new antiarrhythmic drugs.

Anxiety, concerns and COVID-19: Cross-country perspectives from families and individuals with neurodevelopmental conditions.

Background: The COVID-19 pandemic had a major impact on the mental health and well-being of children with neurodevelopmental conditions (NDCs) and of their families worldwide. However, there is insufficient evidence to understand how different factors (e.g., individual, family, country, children) have impacted on anxiety levels of families and their children with NDCs developed over time. Methods: We used data from a global survey assessing the experience of 8043 families and their children with NDCs (mean of age (m) = 13.18 years, 37% female) and their typically developing siblings (m = 12.9 years, 45% female) in combination with data from the European Centre for Disease Prevention and Control, the University of Oxford, and the Central Intelligence Agency (CIA) World Factbook, to create a multilevel data set. Using stepwise multilevel modelling, we generated child-, family- and country-related factors that may have contributed to the anxiety levels of children with NDCs, their siblings if they had any, and their parents. All data were reported by parents. Results: Our results suggest that parental anxiety was best explained by family-related factors such as concerns about COVID-19 and illness. Children's anxiety was best explained by child-related factors such as children's concerns about loss of routine, family conflict, and safety in general, as well as concerns about COVID-19. In addition, anxiety levels were linked to the presence of pre-existing anxiety conditions for both children with NDCs and their parents. Conclusions: The present study shows that across the globe there was a raise in anxiety levels for both parents and their children with NDCs because of COVID-19 and that country-level factors had little or no impact on explaining differences in this increase, once family and child factors were considered. Our findings also highlight that certain groups of children with NDCs were at higher risk for anxiety than others and had specific concerns. Together, these results show that anxiety of families and their children with NDCs during the COVID-19 pandemic were predicted by very specific concerns and worries which inform the development of future toolkits and policy. Future studies should investigate how country factors can play a protective role during future crises.

A novel drug-like water-soluble small molecule Focal Adhesion Kinase (FAK) activator promotes intestinal mucosal healing.

Non-steroidal anti-inflammatory drugs (NSAIDs) injure the proximal and distal gut by different mechanisms. While many drugs reduce gastrointestinal injury, no drug directly stimulates mucosal wound healing. Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, induces epithelial sheet migration. We synthesized and evaluated a water-soluble FAK-activating small molecule, M64HCl, with drug-like properties. Monolayer wound closure and Western blots measured migration and FAK phosphorylation in Caco-2 â€‹cells, in vitro kinase assays established FAK activation, and pharmacologic tests assessed drug-like properties. 30 â€‹mg/kg/day M64HCl was administered in two murine small intestine injury models for 4 days. M64HCl (0.1-1000 â€‹nM) dose-dependently increased Caco-2 FAK-Tyr 397 phosphorylation, without activating Pyk2 and accelerated Caco-2 monolayer wound closure. M64HCl dose-responsively activates the FAK kinase domain vs. the non-salt M64, increasing the Vmax of ATP-binding. Pharmacologic tests suggested M64HCl has drug-like properties and is enterally absorbed. M64HCl 25 â€‹mg/kg/day continuous infusion promoted healing of ischemic jejunal ulcers and indomethacin-induced small intestinal injury in C57Bl/6 mice. M64HCl-treated mice exhibited smaller ulcers 4 days after ischemic ulcer induction or indomethacin injury. Renal histology and plasma creatinine were normal. Mild hepatic inflammatory changes and ALT elevation were similar among M64HCl-treated mice and controls. M64HCl was concentrated in kidney and gastrointestinal mucosa and functional nephrectomy studies suggested predominantly urinary excretion. Little toxicity was observed in vitro or in single-dose mouse toxicity studies until >1000x higher than effective concentrations. M64HCl, a water-soluble FAK activator, promotes epithelial restitution and intestinal mucosal healing and may be useful to treat gut mucosal injury.

Implicit angry faces interfere with response inhibition and response adjustment.

Cognitive control enables people to adjust their thoughts and actions according to the current task demands. Response inhibition and response adjustment are two key aspects of cognitive control. Here, we examined how the implicit processing of emotional information influences these two functions with the help of the double-step saccade task. Each trial had either a single target or two sequential targets. Upon a single target onset, participants were required to make a quick saccade, but upon two target onsets, participants were instructed to inhibit their initial saccades and redirect their gaze to the second target. In three experiments, we manipulated the emotional information of the first and second targets. We found that irrelevant emotional information of the first target impaired response inhibition compared to non-emotional information (geometric shapes) of the first target. When non-emotional information (geometric shape) came as the first target, irrelevant angry emotional faces as the second target interfered with both response inhibition and response adjustment compared to irrelevant happy and neutral faces. We explain these results with previous findings that processing faces with irrelevant angry facial expressions take up many attentional resources, leaving fewer resources available for ongoing activities such as response inhibition and response adjustment.

Implementation of a mycobacterial CRISPRi platform in Mycobacterium abscessus and demonstration of the essentiality of ftsZMab.

Mycobacterium abscessus (Mab) is a highly drug-resistant non-tuberculous mycobacterial species that causes debilitating TB-like pulmonary infections. The lack of genetic tools has hampered characterization of its extensive repertoire of virulence factors, antimicrobial resistance mechanisms, and drug targets. In this study, we evaluated the performance of a mycobacterial single plasmid CRISPRi-dCas9 system optimized for M. tuberculosis and M. smegmatis for inducible gene silencing in Mab. The efficacy of CRISPRi-mediated repression of two antibiotic resistance genes (blaMab, whiB7Mab) and two putative essential genes (ftsZMab,topAMab) was determined by measuring mRNA transcript levels and phenotypic outcomes. While our results support the utility of this mycobacterial CRISPRi dCas9Sth1 single-plasmid platform for inducible silencing of specific target genes in Mab, they also highlighted several caveats and nuances that may warrant species-specific optimization for Mab. We observed overall lower levels of gene repression in Mab including variable silencing of different target genes despite use of PAMs of similar predicted strength. In addition, leaky gene repression in the absence of inducer was noted for some genes but not others. Nonetheless, using CRISPRi we demonstrated the silencing of multiple target genes and validated ftsZMab as an essential gene and promising drug target for the first time.

Neuropsychological functions in a pediatric case of partial agenesis of the corpus callosum: Clinical implications.

The corpus callosum (CC) is involved in several cognitive processes and the interhemispheric transfer of information. The current case study investigated neurocognitive and emotional processes in a 7-year-old female with partial agenesis of the corpus callosum, with an absent splenium and posterior body, with comorbid autism and ADHD. We measured cognitive functions, such as response inhibition, error monitoring, attentional disengagement, and attention capture by irrelevant emotional stimuli. We found that response inhibition was intact in the case. When happy faces were used as stop-signals, it interfered with response inhibition compared to angry-face-stop-signals. Similarly, happy faces (relative to angry faces) interfered with error monitoring; irrelevant angry faces captured attention more than happy faces. Attentional disengagement functions were impaired in the case compared to healthy controls. The findings give an insight into the interaction between cognition and emotion in pediatric partial agenesis of the CC, and have important clinical and theoretical implications.

Relationship between behavioral and mood responses to monetary rewards in a sample of Indian students with and without reported pain.

Physical pain has become a major health problem with many university students affected by it worldwide each year. Several studies have examined the prevalence of pain-related impairments in reward processing in Western, Educated, Industrialized, Rich, and Democratic (WEIRD) countries but none of the studies have replicated these findings in a non-western cultural setting. Here, we aimed to investigate the prevalence of physical pain symptoms in a sample of university students in India and replicate our previous study conducted on university students in Switzerland, which showed reduced mood and behavioral responses to reward in students with significant pain symptoms. We grouped students into a sub-clinical (N = 40) and a control group (N = 48) to test the association between pain symptoms and reward processes. We used the Fribourg reward task and the pain sub-scale of the Symptom Checklist (SCL-27-plus) to assess physical symptoms of pain. We found that 45% of the students reported high levels of physical symptoms of pain and interestingly, our ANOVA results did not show any significant interaction between reward and the groups either for mood scores or for outcomes related to performance. These results might yield the first insights that pain-related impairment is not a universal phenomenon and can vary across cultures.

Irrelevant angry faces impair response inhibition, and the go and stop processes share attentional resources.

Response inhibition is a crucial component of executive control, which refers to our ability to suppress responses that are no longer needed or inappropriate. The stop-signal task is a standard tool to assess inhibitory control over actions. Here, we use irrelevant facial expressions (happy, angry, or neutral) as both go and stop-signal to examine competition for shared attentional resources between (a) emotion and inhibition process and (b) go and stop processes. Participants were required to respond to go signals (gender discrimination task: male or female). Occasionally, a stop-signal (face with irrelevant angry, happy, or neutral facial expression) was presented, and participants were required to withhold their motor response. We found that emotion processing (especially angry faces) captures attention away from the task, and the emotionality of the stop signal matters only when the go signal is non-emotional. When the go signal was non-emotional, we found that stop-signal with irrelevant angry facial expressions impaired inhibitory control compared to stop-signal with irrelevant happy and neutral facial expressions. These results indicate that the processing of emotion and inhibition process exploit a shared pool of attentional resources. These results favor an interactive capacity-sharing account of the go and stop processes in models of response inhibition.

Relationship of anemia with COVID-19 deaths: A retrospective cross-sectional study.

Background and Aims: With the second wave of COVID-19, India lost close to three lakh people within the span of a few months. In this study, we aimed to investigate the impact of anemia on the severity of COVID-19 based on the hemoglobin (Hb) concentration of the patients noted at the time of admission to the intensive care unit (ICU), to mark Hb as a prognostic marker of disease severity for the future. Material and Methods: Retrospective data was collected from 784 patients admitted to the COVID adult ICU between March and June 2021. Patients were identified as anemic and non-anemic based on the World Health Organization (WHO) guidelines. Chi-squared test was applied to see the relationship of anemia with the patient deaths. Results: Among the 784 patients, 507 succumbed to COVID-19. Of these, 49.3% had varying degrees of anemia. Significant correlation of anemia with death due to COVID-19 was found in males and females (P = 0.002106 and P = 0.033071, respectively) and in patients without any other comorbidities except anemia (P = 0.002020). This suggests that anemia is independently an important parameter that plays a role in severity of COVID-19. Conclusion: Upon observing a significant correlation between anemia and COVID-19 severity, it can be stated that anemia should be considered as an independent prognostic risk factor for COVID-19 and that hemoglobin can be used for risk stratification in patients under home or hospital care.

Irrelevant positive emotional information facilitates response inhibition only under a high perceptual load.

Response inhibition involves suppressing those responses that are no longer needed. Previous research has separately studied the role of attentional resources and emotional information in response inhibition. Here, we simultaneously manipulate attentional resources and emotional information to investigate the interactive role of emotional information and attentional resources. Attentional resources were manipulated by changing the levels of perceptual load (low and high) of go signals. Emotional information was manipulated by changing the emotional content (irrelevant positive and negative emotional information) of the stop signals. Participants made a go response based on searching for a target letter in conditions of either low perceptual load or high perceptual load. They withheld their response on the presentation of a stop signal. The stop-signal stimulus was selected from two classes: arousal matched positive and negative IAPS images (Experiment 1) and happy, angry, and neutral faces (Experiment 2). The result showed a consistent interaction pattern of perceptual load and emotional information across the two experiments, such that irrelevant positive emotional information consistently improved inhibitory control, albeit only under high load. These results have theoretical implications for understanding the nature of emotional information and their interaction with attentional resources in cognitive control functions.

Leveraging epigenetics to enhance the efficacy of cancer-testis antigen: a potential candidate for immunotherapy.

Ovarian cancer is the most lethal gynecological malignancy in women. The phenotype is characterized by delayed diagnosis, recurrence and drug resistance. Inherent immunogenicity potential, oncogenic function and expression of cancer-testis/germline antigen (CTA) in ovarian cancer render them a potential candidate for immunotherapy. Revolutionary clinical findings indicate that tumor antigen-mediated T-cell and dendritic cell-based immunotherapeutic approaches provide an excellent strategy for targeting tumors. Currently, dendritic cell vaccination for the treatment of B-cell lymphoma and CTA-based T-cell receptor transduced T-cell therapy involving MAGE-A4 and NY-ESO-1 are well documented and shown to be effective. This review highlighted the mechanical aspects of epigenetic drugs that can elicit a CTA-based humoral and cellular immune response and implicate T-cell and dendritic cell-based immunotherapeutic approaches.

Despite substantial advancements in prognosis and diagnostic approaches, epithelial ovarian cancer is still the most lethal gynecological malignancy worldwide. In addition to radiotherapy, chemotherapy, hormonal therapy, and surgery, immunotherapy in the clinical setting is promising. Tumor-restricted expression and strong immunogenic potential make cancer-testis/germline antigen (CTA) a potential candidate for efficient T-cell and dendritic cell-mediated cancer immunotherapy. The expression of CTAs is shown to be modulated by a specific epigenetic fine-tuning mechanism. However, the expression and role of CTA in epithelial ovarian cancer immunotherapy are poorly understood. Therefore, in the current work, the authors thoroughly highlight and explore the possible epigenetic mechanisms associated with CTA expression and their implication in T-cell and dendritic cell-based immunotherapy approaches to ovarian cancer. Understanding such a paradigm is essential to adopting a precision medicine approach for better therapeutic options.

Motivational salience, not valence, modulates time perception.

It has been argued that cognitive processes such as attention and memory are influenced by motivational salience (high or low predictability of an outcome) rather than valance or value (gain or loss). However, whether this holds for subjective time perception remains unclear. To investigate this, a two-phase study was conducted. First, in a value learning task, a set of neutral faces was imbued with different levels of motivational salience (high or low) crossed with two levels of value (gain, loss). Thus, a specific face could acquire, for example, high motivational salience and low value by repeatedly signaling an 80% chance of losing points. Faces with these learned associations were then presented as an oddball for a varying duration (300-700 ms in steps of 50 ms) in a sequence of standard stimuli previously seen but predictive of no outcome (each presented for 500 ms). Participants assessed whether the oddball was longer or shorter than the duration of the standard stimuli. The results show that an oddball associated with a high predictable outcome (80% chance of gain or loss) was perceived to last longer than an oddball associated with a low predictable outcome (20% chance of gain or loss). The present study supports previous studies by showing that a high motivational outcome, rather than valance/value, changes cognitive engagement with a stimulus. Attention may play an essential role in this interaction by modulating subjective expansion of time. (PsycInfo Database Record (c) 2022 APA, all rights reserved).