Transcriptional factors targeting in cancer stem cells for tumor modulation.

Cancer Stem Cells (CSCs) are now considered the primary "seeds" for the onset, development, metastasis, and recurrence of tumors. Despite therapeutic breakthroughs, cancer remains the leading cause of death worldwide. This is because the tumor microenvironment contains a key population of cells known as CSCs, which promote tumor aggression. CSCs are self-renewing cells that aid tumor recurrence by promoting tumor growth and persisting in patients after many traditional cancer treatments. According to reports, numerous transcription factors (TF) play a key role in maintaining CSC pluripotency and its self-renewal property. The understanding of the functions, structures, and interactional dynamics of these transcription factors with DNA has modified the hypothesis, paving the way for novel transcription factor-targeted therapies. These TFs, which are crucial and are required by cancer cells, play a vital function in the etiology of human cancer. Such CSC TFs will help with gene expression profiling, which provides crucial data for predicting the prognosis of patients. To overcome anti-cancer medication resistance and completely eradicate cancer, a potent therapy combining TFs-based CSC targets with traditional chemotherapy may be developed. In order to develop therapies that could eliminate CSCs, we here concentrated on the effect of TFs and other components of signalling pathways on cancer stemness.

Nanomedicine as potential cancer therapy via targeting dysregulated transcription factors.

Cancer as a disease possess quite complicated pathophysiological implications and is among the prominent causes of morbidity and mortality on global scales. Anti-cancer chemotherapy, surgery, and radiation therapy are some of the present-day conventional treatment options. However, these therapeutic paradigms own several retreats, including lack of specificity, non-targeted toxicological implications, inefficient drug delivery to targeted cells, and emergence of cancer resistance, ultimately causing ineffective cancer management. Owing to the advanced and better biophysical characteristic features and potentiality for the tailoring and customizations and in several fashions, nanotechnology can entirely transubstantiate the cancer identification and its managements. Additionally, nanotechnology also renders several answers to present-day mainstream limitations springing-up in anti-cancer therapeutics. Nanocarriers, owing to their outstanding physicochemical features including but not limited to their particle size, surface morphological features viz. shape etc., have been employed in nanomedicinal platforms for targeting various transcription factors leading to worthy pharmacological outcomes. This transcription targeting activates the wide array of cellular and molecular events like antioxidant enzyme-induction, apoptotic cell death, cell-cycle arrest etc. These outcomes are obtained after the activation or inactivation of several transcription factors and cellular pathways. Further, nanoformulations have been precisely calibrated and functionalized with peculiar targeting groups for improving their efficiency to deliver the drug-payload to specified and targeted cancerous cells and tissues. This review undertakes an extensive, across-the-board and all-inclusive approach consisting of various studies encompassing different types of tailored and customized nanoformulations and nanomaterials designed for targeting the transcription factors implicated in the process of carcinogenesis, tumor-maturation, growth and metastasis. Various transcription factors viz. nuclear factor kappa (NF-κB), signal transducer and activators of transcription (STAT), Cmyc and Twist-related protein 1 (TWIST1) along with several types of nanoparticles targeting these transcription factors have been summarized here. A section has also been dedicated to the different types of nanoparticles targeting the hypoxia inducing factors. Efforts have been made to summarize several other transcription factors implicated in various stages of cancer development, growth, progression and invasion, and their targeting with different kinds of nanomedicinal agents.

Insight into the transcription factors regulating Ischemic stroke and glioma in response to shared stimuli.

Cerebral ischemic stroke and glioma are the two leading causes of patient mortality globally. Despite physiological variations, 1 in 10 people who have an ischemic stroke go on to develop brain cancer, most notably gliomas. In addition, glioma treatments have also been shown to increase the risk of ischemic strokes. Stroke occurs more frequently in cancer patients than in the general population, according to traditional literature. Unbelievably, these events share multiple pathways, but the precise mechanism underlying their co-occurrence remains unknown. Transcription factors (TFs), the main components of gene expression programmes, finally determine the fate of cells and homeostasis. Both ischemic stroke and glioma exhibit aberrant expression of a large number of TFs, which are strongly linked to the pathophysiology and progression of both diseases. The precise genomic binding locations of TFs and how TF binding ultimately relates to transcriptional regulation remain elusive despite a strong interest in understanding how TFs regulate gene expression in both stroke and glioma. As a result, the importance of continuing efforts to understand TF-mediated gene regulation is highlighted in this review, along with some of the primary shared events in stroke and glioma.

Sequence variants underlying severe combined immunodeficiency and leukocyte adhesion deficiency type 1 in six consanguineous families.

Inborn errors of immunity (IEI) are defined as genetic disorders affecting the immune system and resulting in diverse clinical signs and symptoms. Despite the lack of diagnosis and unavailability of IEI estimation in the Pakistani population, consanguinity is exacerbating its prevalence. The current study focuses on severe combined immunodeficiency (SCID) and leukocyte adhesion deficiency type 1 (LAD1). SCID is associated with the life-threatening symptoms developing at post-birth. LAD1 is clinically characterized by recurrent bacterial infections related to the skin, mouth, and respiratory tract owing to impaired leukocytes. Herein, in six consanguineous families, flow cytometry was used to evaluate the patient's immune status. Whole-exome sequencing (WES) was then conducted to search for the causative variations in immunodeficiency genes. Sanger sequencing was used to assess the segregation of the variants with the disorder within the families. Sequence analysis revealed five homozygous variants in four different causative genes. This included four novel nonsense variants in CD70 p.(Thr126Profs*33), CD3e p.(Trp151*), IL7R p.(Val138Ilefs*10), and ITGB2 p.(Ser627Valfs*61), and one previously reported in ITGB2 p.(Cys62*). In one of the families, two variants in two different genes, including DNAH6 p.(Tyr2653His) and NIPAL4 p.(Gly121Ser), were detected in an unclassified patient. All the identified variants were found in a homozygous state in the patient but in a heterozygous state in the available parents. The study will facilitate the diagnosis and management of IEI patients.

Unveiling the Therapeutic Potential of Non-Coding RNAs in Stroke-Induced Tissue Regeneration.

Stroke is a major contributor to mortality and impairment on a global scale, with few effective treatments available. Aberrant expression of various non-coding RNAs (ncRNAs) has been identified after stroke onset, impacting neurogenesis, angiogenesis, apoptosis, and autophagy. The roles and mechanisms of ncRNAs hold great promise for future ischemic stroke treatments, as they could modify stroke impact and course on a well-controllable molecular level. Exploring the functions and underlying mechanisms of ncRNAs after stroke has the potential to unveil novel therapeutic targets for the treatment of stroke and may also pave the way toward novel and more precise diagnostic options for stroke and stroke outcomes. This review emphasizes the importance of ncRNAs in the treatment of stroke and their potential as therapeutic targets.

Sticky Floor, Broken Ladder, and Glass Ceiling in Internal Medicine Academic Ranking, Leadership, and Research Productivity.

BACKGROUND: Despite more women entering medicine, substantial gender disparities remain in various medical disciplines. This study explores the extent of these disparities in Canadian academic internal medicine, particularly in academic ranks, leadership positions, and research productivity. DESIGN: Cross-sectional. SUBJECTS: Faculty physicians within internal medicine and subspecialties. MAIN MEASURES: Data on faculty physicians with Medical Doctorate (MD), Doctor of Osteopathic Medicine (DO), or Bachelor of Medicine, Bachelor of Surgery (MBBS) degrees were compiled from 17 internal medicine programs listed in the Canadian Resident Matching Service (CaRMS). Research metrics were obtained using Elsevier's Scopus, and analyses were performed with Stata v14.2. KEY RESULTS: Among 5099 physician faculty members in internal medicine, 34% were women, and 66% were men. Among the faculty members holding leadership positions, 68% were men, and 32% were women. There was a significant difference in h-index between men and women physician faculty members (p ≤ 0.001), with men having a higher research output. Across all academic ranks, men faculty had higher median h-index values: Assistant Professor (12 vs. 9), Associate Professor (20 vs. 16), and Professor (40 vs. 30). Women were underrepresented in the procedural specialties, while only a few internal medicine subspecialties, such as palliative medicine and geriatrics, had a women predominance. CONCLUSIONS: Our study underscores existing gender disparity within academic internal medicine in Canada, aligning with global trends. Women remain disproportionately underrepresented in academic ranks, leadership positions, and research productivity. Addressing these disparities necessitates a systemic and multifaceted approach, encompassing policy reforms, mentorship, and fostering an inclusive work environment.

MCC950 reduces autophagy and improves cognitive function by inhibiting NLRP3-dependent neuroinflammation in a rat model of Alzheimer's disease.

Alzheimer's disease (AD) is the seventh most common cause of mortality and one of the major causes of disability and vulnerability in the elderly. AD is characterized by gradual cognitive deterioration, the buildup of misfolded amyloid beta (Aß) peptide, and the generation of neurofibrillary tangles. Despite enormous scientific progress, there is no effective cure for AD. Thus, exploring new treatment options to stop AD or at least slow down its progress is important. In this study, we investigated the potential therapeutic effects of MCC950 on NLRP3-mediated inflammasome-driven inflammation and autophagy in AD. Rats treated with streptozotocin (STZ) exhibited simultaneous activation of the NLRP3 inflammasome and autophagy, as confirmed by Western blot, immunofluorescence, and co-immunoprecipitation analyses. MCC950, a specific NLRP3 inhibitor, was intraperitoneally administered (50 mg/kg body weight) to rats with AD-like symptoms induced by intracerebroventricular STZ injections (3 mg/kg body weight). MCC950 effectively suppressed STZ-induced cognitive impairment and anxiety by inhibiting NLRP3-dependent neuroinflammation. Moreover, our findings indicate that MCC950 exerts neuroprotective effects by attenuating autophagy in neuronal cells. The inhibiting effects of MCC950 on inflammasome activation and autophagy were reproduced in vitro, provding further mechansistic insights into MCC950 therapeutic action. Our findings suggest that MCC950 impedes the progression of AD and may also improve cognitive function through the mitigation of autophagy and NLRP3 inflammasome inhibition.

Computational Insights into Schottky Barrier Heights: Graphene and Borophene Interfaces with H- and H́-XSi2N4 (X = Mo, W) Monolayers.

The two-dimensional (2D) semiconducting family of XSi2N4 (X = Mo and W), an emergent class of air-stable monolayers, has recently gained attention due to its distinctive structural, mechanical, transport, and optical properties. However, the electrical contact between XSi2N4 and metals remains a mystery. In this study, we inspect the electronic and transport properties, specifically the Schottky barrier height (SBH) and tunneling probability, of XSi2N4-based van der Waals contacts by means of first-principles calculations. Our findings reveal that the electrical contacts of XSi2N4 with metals can serve as the foundation for nanoelectronic devices with ultralow SBHs. We further analyzed the tunneling probability of different metal contacts with XSi2N4. We found that the H-phase XSi2N4/metal contact shows superior tunneling probability compared to that of H́-based metal contacts. Our results suggest that heterostructures at interfaces can potentially enable efficient tunneling barrier modulation in metal contacts, particularly in the case of MoSi2N4/borophene compared to MoSi2N4/graphene and WSi2N4/graphene in transport-efficient electronic devices. Among the studied heterostructures, tunneling efficiency is highest at the H and H́-MoSi2N4/borophene interfaces, with barrier heights of 2.1 and 1.52 eV, respectively, and barrier widths of 1.04 and 0.8 Å. Furthermore, the tunneling probability for these interfaces was identified to be 21.3 and 36.4%, indicating a good efficiency of carrier injection. Thus, our study highlights the potential of MoSi2N4/borophene contact in designing power-efficient Ohmic devices.

Recent Trends in the Incidence of Gastric Cancer in the United States.

BACKGROUND: Gastric cancer (GC) incidence rates overall in the United States have declined over recent decades and are predicted to continue declining. However, there have been mixed recent findings regarding the potential stabilization of rates and potential divergent trends by age group. We used the most recent cancer data for the United States and examined trends in GC between 1992 and 2019, overall and in important subgroups of the population. METHODS: Age-adjusted GC incidence rates and trends in adults 20 years or older were calculated using data from the Surveillance, Epidemiology, and End Results (SEER) 12 program. Secular trends were examined overall and by age group, sex, race/ethnicity, SEER registry, and tumor location. We used joinpoint regression to compute annual percent changes, average annual percent changes, and associated 95% CI. RESULTS: GC rates decreased by 1.23% annually from 1992 to 2019. Despite overall decreases, GC incidence rates increased for age groups below 50 years, predominately driven by noncardia GC (74.3% of all GCs). Cardia GC (26.7% of GC) rates decreased in all age groups except for 80 to 84 years. Overall GC rates decreased for both sexes, all races, and for all SEER registry regions, with the largest decreases occurring in males, Asians and Pacific Islanders, and in Hawaii. Age-period-cohort analysis revealed that birth cohorts before 1940 and after 1980 both had increased rates of GC compared with the reference birth cohort of 1955. CONCLUSION: GC rates overall have continued to decline through 2019, despite increases in the rate of noncardia GC for younger age groups.

Exome sequencing revealed variants in SGCA and SIL1 genes underlying limb girdle muscular dystrophy and Marinesco-Sjögren syndrome patients.

BACKGROUND: Inherited neuromuscular (NMD) and neurodegenerative diseases (NDD) belong to two distinct categories that disturb different components of the nervous system, leading to a variety of different symptoms and clinical manifestations. Both NMD and NDD are a heterogeneous group of genetic conditions. Genetic variations in the SGCA and SIL1 genes have been implicated in causing Limb Girdle Muscular Dystrophy (LGMD), a type of neuromuscular disorder, and Marinesco-Sjögren Syndrome (MSS) which is a neurodegenerative disorder. METHODS: In the present study, we have investigated four patients presenting LGMD and five patients with MSS features. After collecting detailed clinical and family history, necessary laboratory investigations, including estimation of a skeletal muscle marker enzyme serum creatine kinase (CK), nerve conduction study (NCS), electromyography (EMG), echocardiography (Echo), Magnetic resonance imaging (MRI -brain), CT-brain and X-rays were performed. Whole exome followed by Sanger sequencing was employed to search for the disease-causing variants. RESULTS: Physical examination in LGMD patients revealed poor muscle tone and facing difficulty in straightening up from the floor. Clinical history revealed frequent falls and strenuousness in climbing stairs. They started toe-walking in early childhood. Laboratory investigations confirmed elevated CK levels and abnormal NCS and EMG. The MSS patients showed abnormalities in gate and jerking movement, abnormal speech, and strabismus with cataract. MRI-brain showed cerebral atrophy in some MSS patients with elevated CK levels. Whole exome sequencing revealed a nonsense variant [c.C574T, p.(Arg192*)] in the SGCA gene and a frameshift [c.936dupG, p.(Leu313AlaFs*39)] in the SIL1 gene in LGMD and MSS patients, respectively. CONCLUSION: Our study emphasizes the significance of integrating clinical and genetic analyses for precise diagnosis and tailored management strategies in inherited NMD and NDD disorders. To the best of our knowledge, this is the first study documenting SGCA and SIL1 recurrent variants in subcontinent populations with few rare clinical features. The recurrent mutations expanding the global understanding of the mutation's geographic and ethnic distribution and contributing valuable epidemiological data. The study will facilitate genetic counseling for families experiencing similar clinical features, both within Pakistani populations and in other regions.

The efficacy of Linum usitatissimum seeds to inhibit estrogen receptor as a natural therapy for PCOS: An in silico and in vitro analysis.

Polycystic ovarian syndrome (PCOS) is an endocrinological disorder aroused due to hormonal disturbances. It is characterized by anovulation due to an excess of androgen and estrogen hormones, thus leading to the formation of multiple cysts, imposing life-threatening conditions. This manuscript aimed to introduce a natural estrogen receptor (ESR) inhibitors that can provide protection against PCOS. The computational analysis of Linum usitatissimum seeds  compounds against ESR alpha receptor was performed, and the binding affinities of the ligand compounds and receptor proteins were scrutinized. Nine lignin compounds were docked, and the results were compared with that of reference estrogen receptor inhibitors, clomiphene, and tamoxifen. The binding affinity scores for pinoresinol, lariciresinol, secoisolariciresinol, and matairesinol were -10.67, -10.66, -10.91, and -10.60 kcal mol-1 , respectively. These were comparable to the binding affinity score of reference compounds -11.406 kcal mol-1 for clomiphene and -10.666 kcal mol-1 for tamoxifen. Prime MM-GBSA studies showcased that Linum usitatissimum seeds compounds exhibit significant efficacy and efficiency towards receptor protein. Moreover, MD-simulation studies were performed and the results depict that the lignin compounds form stable complexes at 300 K throughout the simulation time. For further clarity, in-vitro experiments were carried out. The results exhibit the decline in cell proliferation in a concentration-dependent manner by extract 1 (ethyl acetate) EX1 and extract 2 (petroleum ether) EX2. Hence, providing evidence regarding the anti-estrogenic activity of the sample extracts. Collectively, these results showed that flax seed can reduce the levels of estrogen, which can induce ovulation and prevent cyst formation, and ultimately can provide protection against PCOS.

Short-term symptomatic outcomes of GERD in patients with gastroparesis after gastric per oral endoscopic pyloromyotomy.

Gastroparesis (Gp) patients often have gastroesophageal reflux disease (GERD). Management of GERD in Gp patients is a challenge. Many studies have shown that gastric peroral endoscopic pyloromyotomy (G-POEM or POP) is moderately effective in reducing nausea and vomiting in patients with Gp. This study aims to determine whether G-POEM can improve GERD in Gp Patients. Patients who underwent G-POEM from July 2021 to October 2022 were enrolled in the study. GERD Health-Related Quality of Life (GERD HRQL) and Reflux Symptom Index (RSI) were used to assess patients' GERD before and after G-POEM. The use of proton pump inhibitors (PPIs) before and after G-POEM were also documented. The Gastroparesis Cardinal Symptom Index (GCSI) was used to assess the severity of Gp before and after G-POEM. A 'Welch two-sample t-test' was used to find differences in GERD HRQL (health-related quality of life) and RSI scores before and after the procedure. Pearson's chi-square test was used to find differences for use of PPI before and after G-POEM. Twenty-three consecutive refractory Gp patients with 30% male (average age 63.2) and 70% female patients (average age 53.9) were enrolled. Of these, 14 had diabetes, 3 had a history of surgery, and 6 had idiopathic Gp. The mean follow-up was 41 days (range 7-61 days). There was a significant decrease in the mean GERD HRQL score from 16.5 to 6.5 after G POEM with a P-value <0.0001 (95% level of significance) and a significant decrease in mean RSI score from 15.3 to 5.2 after G-POEM with P-value <0.0001 (95% level of significance). The proportion of use of PPI before GPOEM was 0.91, and the proportion of PPI use after GPOEM was 0.43 (P = 0.0008). The mean GCSI pre- and post-GPOEM were 3.53 and 1.59, respectively. Eighteen had clinical success in Gp as defined by decreased mean GCSI score greater than 1. In this short-term outcome study, 87% of patients' GERD HRQL scores and RSI scores decreased after G-POEM. These findings indicate that GPOEM not only effectively reduces Gp symptoms but also improves GERD symptoms leading to decreased or more effective use of PPI in these patients. To our knowledge, this is the first study to comprehensively show G-POEM significantly improves GERD. Further studies with a larger patient population and long-term outcomes are needed.

Emerging technology effects on combined agricultural and eco-vermicompost.

This study focused on the waste management of livestock manure and wetland plant residues and their increasing effect on terrestrial and aquatic ecosystems. The benefits of nutrient-rich plants and manures are often overlooked. By conducting a soil column experiment with a fully factorial design, this work found that adding the vermicompost amendments of wetland plants [combination of Canna indica (CiV), Cyperus alternifollius (CaV), Acorus calamus (AcV), and Hydrocotyle vulgaris (HvV) vermicompost] to agricultural wastes affected maize growth throughout its growing season. The results demonstrated that the use of combined AcV and HvV wetland plant-based vermicompost as an organic fertilizer increased the plant total nitrogen (TN: 92% increase) and soil organic matter (SOM: 192% increase) compared with those in control CK. Meanwhile, the combination of CaV with HvV increased the shoot biomass by 3.4 and 4.6 folds compared with that in NPK and CK, respectively. Overall, a new approach for transforming ecological wastes into organic fertilizers was proposed.

Relationship between academic procrastination and self-efficacy amongst dental undergraduate students at a public university in Karachi, Pakistan.

Objective: To compare the procrastination and self-efficacy scores among students with respect to the academic year of dental undergraduate programme, and to assess the relationship between self-efficacy and academic procrastination among the students. METHODS: The descriptive study was conducted at Sindh Institute of Oral Health Sciences, Jinnah Sindh Medical University, Karachi, from January to March 2023, and comprised medical students of either gender from all the 4 academic years. Data was collected using a structured questionnaire whose validity was assessed using a pilot study. Data was analysed using SPSS 18. RESULTS: Of the 136 students, 84(61.8%) were females and 52(38.2%) were males. There were 34(25%) students from the 1st year, 32(23.5%) from 2nd year, 38(28%) from the 3rd year, and 32(23.5%) from the final year. The highest mean score for procrastination was from 3rd year students 67.7±12.8, while the highest mean score for self-efficacy was from 1st year students 30.2±4. There was no significant difference in terms of gender (p>0.05). Procrastination scores had a significant association with the academic year (p=0.016). Conclusion: Procrastination scores were high among the dental students with the highest score from 3rd year students. The academic environment should provide support help the students devise strategies to optimally utilise the available time.

Can preoperative Carbohydrate Antigen 19-9 predict metastatic pancreatic cancer? Results of a systematic review and meta-analysis.

BACKGROUND: To investigate the relationship between preoperative Carbohydrate Antigen19-9(CA19-9)and pancreatic cancer occult metastasis. METHODS: Systematic search of MEDLINE, CENTRAL, Web of Science and bibliographic reference lists were conducted. All comparative observational studies investigating the predictive ability of preoperative CA 19-9 in patients with pancreatic cancer were considered. Mean CA-19-9 value in the pancreatic cancer patients with and without metastasis were evaluated. Best cut-off value of CA 19-9 for metastasis was determined using ROC analysis. RESULTS: Ten comparative observational studies reporting a total of 1431 pancreatic cancer patients with (n = 496) and without (n = 935) metastasis were included. Subsequent meta-analysis demonstrated that mean preoperative CA 19-9 level was significantly higher in patients with metastases compared to those without (MD: 904.4; 95 % CI, 642.08-1166.74, P < 0.0001). The between-study heterogeneity was significant (I2: 99 %, P < 0.00001). ROC analysis yielded a cut-off CA 19-9 level of 336 with a sensitivity and specificity for predicting metastasis of 90 % and 80 %, respectively (AUC = 0.90). CONCLUSIONS: CA 19-9 level is significantly higher in patients with metastatic pancreatic cancer. A preoperative CA 19-9 value of 336 should be considered as an acceptable cut-off value to design prospective studies.

Role of non-coding RNAs in the progression and resistance of cutaneous malignancies and autoimmune diseases.

Skin, the largest organ of human body, is vital for the existence and survival of human beings. Further, developmental and physiological mechanisms associated with cutaneous biology are vital for homeostasis as their deregulations converge towards pathogenesis of a number of skin diseases, including cancer. It has now been well accepted that most of the transcribed human genome lacks protein translational potential and has been termed as non-coding RNAs (nc-RNAs), which includes circular RNA (circRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), micro RNA (miRNA), long noncoding RNA (lncRNA), and piwi-interacting RNA (piRNAs). These nc-RNAs have gained great attention in both preclinical and clinical research as they are critical in most of the regulatory mechanisms of biological homeostasis and disease development by controlling the gene expression at transcriptional, post-transcriptional and epigenetic level. In this review we have illustrated how nc-RNAs are critical in the development and maintenance of cutaneous homeostasis and functioning and also, most importantly, how the dysregulated expression and functioning of nc-RNAs play critical role in the pathogenesis of cutaneous diseases including cancer and the autoimmune skin diseases. Considering the vital role of nc-RNAs in cancer resistance, metastasis and autoimmune diseases, we have also highlighted their role as promising prognostic and therapeutic targets for the cutaneous diseases.

Exploring and targeting potential druggable antimicrobial resistance targets ArgS, SecY, and MurA in Staphylococcus sciuri with TCM inhibitors through a subtractive genomics strategy.

Staphylococcus sciuri (also currently Mammaliicoccus sciuri) are anaerobic facultative and non-motile bacteria that cause significant human pathogenesis such as endocarditis, wound infections, peritonitis, UTI, and septic shock. Methicillin-resistant S. sciuri (MRSS) strains also infects animals that include healthy broilers, cattle, dogs, and pigs. The emergence of MRSS strains thereby poses a serious health threat and thrives the scientific community towards novel treatment options. Herein, we investigated the druggable genome of S. sciuri by employing subtractive genomics that resulted in seven genes/proteins where only three of them were predicted as final targets. Further mining the literature showed that the ArgS (WP_058610923), SecY (WP_058611897), and MurA (WP_058612677) are involved in the multi-drug resistance phenomenon. After constructing and verifying the 3D protein homology models, a screening process was carried out using a library of Traditional Chinese Medicine compounds (consisting of 36,043 compounds). The molecular docking and simulation studies revealed the physicochemical stability parameters of the docked TCM inhibitors in the druggable cavities of each protein target by identifying their druggability potential and maximum hydrogen bonding interactions. The simulated receptor-ligand complexes showed the conformational changes and stability index of the secondary structure elements. The root mean square deviation (RMSD) graph showed fluctuations due to structural changes in the helix-coil-helix and beta-turn-beta changes at specific points where the pattern of the RMSD and root mean square fluctuation (RMSF) (< 1.0 Å) support any major domain shifts within the structural framework of the protein-ligand complex and placement of ligand was well complemented within the binding site. The ß-factor values demonstrated instability at few points while the radius of gyration for structural compactness as a time function for the 100-ns simulation of protein-ligand complexes showed favorable average values and denoted the stability of all complexes. It is assumed that such findings might facilitate researchers to robustly discover and develop effective therapeutics against S. sciuri alongside other enteric infections.

Interactions between diabetic and hypertensive drugs: a pharmacogenetics approach.

Diabetes is known to increase susceptibility to hypertension due to increase in inflammation, oxidative stress, and endothelial dysfunction, leading to vascular stiffness. The polytherapy might lead to several drug-drug interactions (DDIs), which cause certain life-threatening complications such as diabetic nephropathy and hypoglycaemia. So, in this review we focused on drug-drug interactions and impact of genetic factors on drug responses for better disease management. Drug-drug interactions (DDIs) may act either synergistically or antagonistically. For instance, a combination of metformin with angiotensin II receptor antagonist or angiotensin-converting enzyme inhibitors (ACEIs) synergistically improves glucose absorption, whereas the same hypertensive drug combination with sulphonylurea might cause severe hypoglycaemia sometimes. Thiazolidinediones (TDZs) can cause fluid retention and heart failure when taken alone, but a combination of angiotensin II receptor antagonist with TZDs prevents these side effects. Interindividual genetic variation affects the DDI response. We found two prominent genes, GLUT4 and PPAR-γ, which are common targets for most of the drug. So, all of these findings established a connection between drug-drug interaction and genetics, which might be used for effective disease management.

Oxidative Stress-induced Autophagy Compromises Stem Cell Viability.

Stem cell therapies have emerged as a promising treatment strategy for various diseases characterized by ischemic injury such as ischemic stroke. Cell survival after transplantation remains a critical issue. We investigated the impact of oxidative stress, being typically present in ischemically challenged tissue, on human dental pulp stem cells (hDPSC) and human mesenchymal stem cells (hMSC). We used oxygen-glucose deprivation (OGD) to induce oxidative stress in hDPSC and hMSC. OGD-induced generation of O2•- or H2O2 enhanced autophagy by inducing the expression of activating molecule in BECN1-regulated autophagy protein 1 (Ambra1) and Beclin1 in both cell types. However, hDPSC and hMSC pre-conditioning using reactive oxygen species (ROS) scavengers significantly repressed the expression of Ambra1 and Beclin1 and inactivated autophagy. O2•- or H2O2 acted upstream of autophagy, and the mechanism was unidirectional. Furthermore, our findings revealed ROS-p38-Erk1/2 involvement. Pre-treatment with selective inhibitors of p38 and Erk1/2 pathways (SB202190 and PD98059) reversed OGD effects on the expression of Ambra1 and Beclin1, suggesting that these pathways induced oxidative stress-mediated autophagy. SIRT3 depletion was found to be associated with increased oxidative stress and activation of p38 and Erk1/2 MAPKs pathways. Global ROS inhibition by NAC or a combination of polyethylene glycol-superoxide dismutase (PEG-SOD) and polyethylene glycol-catalase (PEG-catalase) further confirmed that O2•- or H2O2 or a combination of both impacts stems cell viability by inducing autophagy. Furthermore, autophagy inhibition by 3-methyladenine (3-MA) significantly improved hDPSC viability. These findings contribute to a better understanding of post-transplantation hDPSC and hMSC death and may deduce strategies to minimize therapeutic cell loss under oxidative stress.

Effect of Averaging Measurements From Multiple MRI Pulse Sequences on Kidney Volume Reproducibility in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Total kidney volume (TKV) is an important biomarker for assessing kidney function, especially for autosomal dominant polycystic kidney disease (ADPKD). However, TKV measurements from a single MRI pulse sequence have limited reproducibility, ± ~5%, similar to ADPKD annual kidney growth rates. PURPOSE: To improve TKV measurement reproducibility on MRI by extending artificial intelligence algorithms to automatically segment kidneys on T1-weighted, T2-weighted, and steady state free precession (SSFP) sequences in axial and coronal planes and averaging measurements. STUDY TYPE: Retrospective training, prospective testing. SUBJECTS: Three hundred ninety-seven patients (356 with ADPKD, 41 without), 75% for training and 25% for validation, 40 ADPKD patients for testing and 17 ADPKD patients for assessing reproducibility. FIELD STRENGTH/SEQUENCE: T2-weighted single-shot fast spin echo (T2), SSFP, and T1-weighted 3D spoiled gradient echo (T1) at 1.5 and 3T. ASSESSMENT: 2D U-net segmentation algorithm was trained on images from all sequences. Five observers independently measured each kidney volume manually on axial T2 and using model-assisted segmentations on all sequences and image plane orientations for two MRI exams in two sessions separated by 1-3 weeks to assess reproducibility. Manual and model-assisted segmentation times were recorded. STATISTICAL TESTS: Bland-Altman, Schapiro-Wilk (normality assessment), Pearson's chi-squared (categorical variables); Dice similarity coefficient, interclass correlation coefficient, and concordance correlation coefficient for analyzing TKV reproducibility. P-value < 0.05 was considered statistically significant. RESULTS: In 17 ADPKD subjects, model-assisted segmentations of axial T2 images were significantly faster than manual segmentations (2:49 minute vs. 11:34 minute), with no significant absolute percent difference in TKV (5.9% vs. 5.3%, P = 0.88) between scans 1 and 2. Absolute percent differences between the two scans for model-assisted segmentations on other sequences were 5.5% (axial T1), 4.5% (axial SSFP), 4.1% (coronal SSFP), and 3.2% (coronal T2). Averaging measurements from all five model-assisted segmentations significantly reduced absolute percent difference to 2.5%, further improving to 2.1% after excluding an outlier. DATA CONCLUSION: Measuring TKV on multiple MRI pulse sequences in coronal and axial planes is practical with deep learning model-assisted segmentations and can improve TKV measurement reproducibility more than 2-fold in ADPKD. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.