Southern California University of Health Sciences

This review highlights the emerging relevance of meningeal lymphatic vessels (MLVs) in the context of ischemic stroke, challenging the conventional view of a privileged immunological central nervous system. MLVs facilitate immunological surveillance by modulating the entry of peripheral immune cells into the meningeal compartment, a process not impeded by the blood–brain barrier. In ischemic stroke, these vessels play a crucial role in the neuroinflammatory cascade, contributing to immune responses by draining antigens and signals to cervical lymph nodes. Their involvement extends to potential contributions to resolving ischemia-induced cerebral edema, impacting fluid homeostasis. The dynamic interaction among MLVs, neuroinflammation, and fluid dynamics suggests promising therapeutic approaches. Targeting these vessels for immunomodulation, fluid drainage, and preserving blood–brain barrier integrity emerges as an innovative approach to improve ischemic stroke outcomes. However, successful clinical translation awaits further exploration of the therapeutic potential of these vessels. The multifaceted contributions of MLVs provide a compelling rationale for ongoing research, aiming to fully harness their therapeutic impact in ischemic stroke management.

The present study assessed the impact of modafinil (MD) on memory function and oxidative damage in the brains of naive rats. Wistar rats were administered either a single dose or repeated doses (over 30 days) of water or MD (75, 150, or 300 mg/kg) via gavage. The novel object recognition (NOR), open-field habituation (OFH), and inhibitory avoidance task (IA) tested the animals’ memory. Furthermore, the oxidative and nitrosative stress markers (4-hydroxynonenal [4-HNE], 8-isoprostane [8-ISO], 3-nitrotyrosine [3-nitro], superoxide dismutase [SOD], and catalase [CAT]) were assessed in the frontal cortex, hippocampus and striatum of the rats. The acute administration of MD did not affect any memory measures or oxidative stress parameters evaluated in this study. In contrast, chronic MD administration at a dose of 300 mg/kg decreased memory related to habituation and recognition. In addition, chronic administration of this drug increased oxidative lipid damage, evaluated through 8-ISO and 4-HNE. These findings suggest a potential link between chronic MD use, memory impairment, and oxidative stress in the brains of rats, emphasizing the importance of further research in this area.

The aim of this study was to evaluate long-term inflammatory, biochemical and behavioral parameters in adult male and female Wistar rats submitted to a model of high-fat and high fructose diet and sepsis. In the study we used 8-month-old male and female rats. High-fat and high fructose diet was provided for 4 months, and sepsis was induced shortly afterwards. Behavioral tests were performed at 10, 30 and 60 days after sepsis induction, at 30- and 60-days metabolic parameters, leptin and cytokines (prefrontal cortex and hippocampus) were determined. High-fat and high-fructose diet was able to induce glucose intolerance. Sepsis favored anxious behavior at 10 days after sepsis, remaining at 30 days and with apparent improvement at 60 days in females and maintenance of behavior in males. Cognitive damage was observed both at 30 and 60 days in animals from both groups. Plasma metabolic parameters were elevated only males exposed to a high-fat high-fructose diet and submitted to CLP only at 30 days. Long-term brain inflammation was not consistently affected both by sex and high-fat and high fructose diet.The relationship between high-fat and high fructose diet, gender and sepsis is still contradictory, as are the mechanisms involved in this paradox. Models and analyses need to be standardized in order to better understand how this event occurs.

Background Despite advancements in surgical techniques, interventional procedures, novel pharmacotherapies, and other contemporary treatments, patients after coronary artery bypass graft surgery (CABG) remain at risk for graft failure and progression of native vessel disease progression. Consequently, secondary revascularization is often required. Methods This is a retrospective observational study evaluating the incidence, trends, and predictors of revascularization after CABG surgery. Results Of 2,476 patients followed in this post-CABG study, 1458 patients received dual antiplatelet therapy (DAPT) compared to 1005 patients received aspirin monotherapy (AMT). The overall incidence of revascularization was significantly higher in the DAPT group (14.54%, 212 out of 1458) compared to the AMT group (7.07%, 71 out of 1005), with an odds ratio (OR) of 2.24 (95% CI: 1.69–2.97, p < 0.001). 770 patients who received DAPT for six months or more after surgery were compared in sub-analysis and were noted to have significantly higher incidence of revascularization compared to AMT (22.08% vs. 6.96%; OR = 3.157, 95% CI: 2.734–4.940; p < 0.001). The binary regression model revealed that younger patients ( hazard ratio (HR) = 0.964, 95% CI: 0.95–0.97; p < 0.001), diabetics (HR = 1.50, 95% CI: 1.12-2.00, p = 0.007), patients who had fewer internal mammary artery grafts (HR = 0.54, 95% CI: 0.36–0.81, p = 0.003), and patients receiving DAPT of any duration after CABG (HR = 3.47, 95% CI: 2.55–4.72, p < 0.001) were more likely to receive revascularization after CABG. The model, comprising these four predictors, was able to explain 12.8% of the variance in post-CABG revascularization (Nagelkerke R² = 0.128; p < 0.001). The survival rates were 96.5% for the DAPT group and 92.0% for AMT (odds ratio (OR) = 0.421, 95% confidence interval (95% CI): 0.269–0.658; p < 0.001). Conclusion Diabetes mellitus, younger age, fewer Internal mammary artery grafts, and the use of DAPT after CABG were strong predictors of the need for secondary revascularization.

Background Immigrants are the largest subgroup living with chronic hepatitis B (HBV) infection in the United States. It is not well understood how immigration and associated social and cultural factors impact adherence to HBV monitoring. Methods We conducted a multicentre multilingual survey among foreign‐born adults with chronic HBV between 7/2021 and 4/2023. Participants were surveyed regarding (1) immigration factors, (2) acculturation and language preferences, (3) social determinants of health and (4) HBV‐related clinical factors. The primary outcome was optimal adherence, defined as 100% of the time with at least annual testing of HBV DNA, ALT and ultrasound while under care. Logistic regression was used to examine survey factors associated with the outcome. Results Two hundred and seventy‐four foreign‐born patients with HBV (median 57 years, 57% male) from 32 birth countries were included. Thirteen per cent had immigrated within the past 10 years, and 62% were US citizens. Nearly all (92%) reported seeing a specialist for HBV, with 72% currently on treatment. 44% of participants had optimal adherence to monitoring over a median of 6 years (2–7) under care. Factors associated with more optimal adherence on multivariate testing included non‐English survey language (OR 2.32, 95% CI 1.15–4.66), non‐US citizens (OR 2.05, 95% CI 1.01–4.15) and higher education (college vs. high school or less: OR 2.39, 95% CI 1.09–5.24). Medicare insurance (vs. private) was associated with less optimal adherence (OR 0.42, 95% CI 0.19–0.94). Conclusion Adherence to long‐term monitoring is suboptimal among a diverse cohort of immigrants with chronic HBV. More efforts to engage and retain immigrants in care are needed.

Importance There is limited evidence on the comparative effectiveness of different exercise modalities, such as yoga and strengthening exercises, for managing knee osteoarthritis (OA). Objective To compare the effectiveness of yoga vs strengthening exercise for reducing knee pain over 12 weeks in patients with knee OA. Design, Setting, and Participants This single-center, assessor-blinded (for nonpatient-reported outcomes), parallel-arm, active-controlled, superiority randomized clinical trial included adults aged 40 years or older with knee OA and knee pain levels of 40 or higher on a 100-mm visual analog scale (VAS) in Southern Tasmania, Australia. Participants were recruited from April 2021 to June 2022, and follow-up was completed in December 2022. Data were analyzed from May 2023 to July 2024. Interventions Participants were randomized 1:1 to the yoga and strengthening exercise groups. Both groups attended 2 supervised and 1 home-based session per week for 12 weeks followed by 3 unsupervised home-based sessions per week for weeks 13 to 24. Main Outcomes and Measures The primary outcome was the between-group difference in VAS score over 12 weeks assessed using a range of 0 (no pain) to 100 (worst possible pain) with a prespecified noninferiority margin of 10 mm. Secondary outcomes included knee pain over 24 weeks; Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) knee pain, function, and stiffness; patient global assessment; Osteoarthritis Research Society International–Outcome Measures in Rheumatology Clinical Trials response; physical performance measures; leg muscle strength; health-related quality of life assessed via the Assessment of Quality of Life–8 Dimensions (AQol-8D) utility score; depression assessed with the Patient Health Questionnaire–9; and neuropathic pain assessment over 12 and 24 weeks. Analyses were based on the intention-to-treat principle. Results In total, 117 participants were randomized to the yoga (n = 58) or strengthening exercise (n = 59) program. Baseline characteristics of the participants were similar, with a mean (SD) age of 62.5 (8.3) years, and 85 participants (72.6%) were female. The mean (SD) baseline VAS knee pain score of 53.8 (16.0) indicated moderate knee pain. Over 12 weeks, the between-group mean difference in VAS knee pain change was −1.1 mm (95% CI, −7.8 to 5.7 mm), which was not statistically significant but remained within the prespecified noninferiority margin. Of 27 secondary outcomes assessed over 12 and 24 weeks, 7 were statistically significant in favor of yoga. The yoga group showed modestly greater improvements than the strengthening exercise group (between-group differences) over 24 weeks for WOMAC pain (−44.5 mm [95% CI, −70.7 to −18.3 mm]), WOMAC function (−139 mm [95% CI, −228.3 to −49.7 mm]), WOMAC stiffness (−17.6 mm [95% CI, −30.9 to −4.3 mm]), patient global assessment (−7.6 mm [95% CI, −15.1 to −0.2 mm]), and 40-m fast-paced walk test (1.8 [95% CI, 0.4-3.2]). In addition, the yoga group had a modestly greater improvement than the strengthening exercise for depression at 12 weeks (between-group difference in PHQ-9 score, −1.1 [95% CI, −1.9 to −0.2]) and quality of life at 24 weeks (between-group difference in AQoL-8D score, 0.04 [95% CI, 0.0 to 0.07]). Adverse events were similar in both groups and mild. Conclusion and relevance In this randomized clinical trial, yoga did not significantly reduce knee pain compared with strengthening exercises. However, yoga was found to be noninferior to strengthening exercises, suggesting that integrating yoga as an alternative or complementary exercise option in clinical practice may help in managing knee OA. Trial registration ANZCTR.org Identifier: ACTRN12621000066886 .

Neonatal hypoxic-ischemic (HI) injury is a critical condition associated with significant acute brain damage and long-term neurological impairments. Growing evidence highlights the role of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome, a key multiprotein complex driving neuroinflammation, in the progression of neonatal HI brain injury. Activation of the NLRP3 inflammasome triggers the release of pro-inflammatory cytokines, including interleukin-1 beta (IL-1β), which plays a pivotal role in exacerbating brain damage. This article examines current research to better understand the relationship between neonatal HI, NLRP3 inflammasome activation, and neuroinflammatory process. Furthermore, it emphasizes the therapeutic potential of targeting this pathway, proposing its modulation as a promising neuroprotective strategy to reduce neuroinflammation and improve outcomes in affected neonates.

The human spastizin (spastic paraplegia 15, SPG15) and spatacsin (spastic paraplegia 11, SPG11) complex is involved in the formation of lysosomes, and mutations in these two proteins are linked with hereditary autosomal-recessive spastic paraplegia. SPG11–SPG15 can cooperate with the fifth adaptor protein complex (AP5) involved in membrane sorting of late endosomes. We employed cryogenic-electron microscopy and in silico predictions to investigate the structural assemblies of the SPG11–SPG15 and AP5–SPG11–SPG15 complexes. The W-shaped SPG11–SPG15 intertwined in a head-to-head fashion, and the N-terminal region of SPG11 is required for AP5 complex interaction and assembly. The AP5 complex is in a super-open conformation. Our findings reveal that the AP5–SPG11–SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro. These studies provide insights into the structure and function of the spastic paraplegia AP5–SPG11–SPG15 complex, which is essential for the initiation of autolysosome tubulation.

Background Robotic-assisted and laparoscopic techniques are widely used for inguinal hernia repair. While robotic-assisted transabdominal preperitoneal (rTAPP) repair is believed to offer ergonomic advantages for surgeons, there is limited evidence comparing its ergonomic impact to conventional laparoscopic TAPP (cTAPP) repair. This study aims to assess the ergonomic strain on surgeons during these procedures using subjective and objective measures. Methods This crossover observational study involved four experienced hernia surgeons who performed two procedures using each technique. Ergonomic strain was evaluated through self-reported perceived exertion (using the Borg scale), surface electromyography (sEMG) of select muscle groups, and posture analysis using rapid upper limb assessment (RULA) scores derived from kinematic data collected via Xsens Awinda. Statistical comparisons were conducted using the Wilcoxon rank-sum test, with adjustments for multiple comparisons. Results Subjectively, surgeons perceived rTAPP as less physically demanding, with lower postoperative perceived exertion scores (median 1.5 vs. 3.0, p < 0.01). Objective measurements showed higher static muscle activity in the left erector spinae and median activity in the right trapezius during rTAPP (p = 0.016), but overall ergonomic strain, as indicated by RULA scores, was similar across modalities. Median RULA scores for both techniques were 3, and no significant differences were observed in work posture scores. Despite these findings, discomfort during cTAPP was more frequently reported, with surgeons citing the neck, shoulders, and lower back as affected areas. Conclusion While rTAPP was subjectively perceived as less physically demanding, objective metrics did not corroborate these perceptions, showing comparable ergonomic strain between techniques. These findings highlight a complex relationship between subjective and objective ergonomic measures and suggest a need for further research, incorporating broader assessments of cognitive and physical loads, to optimize surgeon ergonomics in minimally invasive procedures. Graphical abstract

Aim To examine how patients experience day surgery. Design Systematic review using Thomas and Harden's framework for synthesis and analysed through Ricoeur's theory of interpretation. Methods and Data Sources Systematic searches in MEDLINE, CINAHL and EMBASE (September 2023) identified qualitative studies focusing on patients' lived experiences with day surgery (defined as < 24‐h hospital stay). Studies were required to provide qualitative data on patient experiences and be published in English or Scandinavian languages. Forward and backward citation searches were also conducted in Scopus. Results Thirty‐four studies met the inclusion criteria. The analysis revealed four key themes: (1) ‘Perceptions of the day surgery concept shape patient expectations’; (2) ‘Navigating expectation and reality: Surprises and challenges in day surgery’; (3) ‘Navigating through postoperative recovery: Feelings of responsibility and insecurity following day surgery’; and (4) ‘The vital role of support from both family and professionals during recovery after day surgery’. Conclusion Patients' expectations of day surgery strongly influence their overall experience, while the complex self‐care demands of postoperative recovery underscore the need for robust support systems involving families and healthcare professionals. Implications for Patient Care This review highlights the importance of thorough preoperative counselling and ongoing support for patients' complex postoperative self‐care. These findings suggest that improved patient‐centred care and targeted support could enhance recovery outcomes in day surgery pathways. Impact Problem addressed: The study explores the often‐overlooked challenges that patients face with postoperative self‐care following day surgery. Main findings: Expectations of day surgery as ‘minor’ often conflict with patients' emotional and physical self‐care needs, revealing a need for comprehensive support. Research impact: Insights from this review can inform patient‐centred care practices in day surgery settings globally, underscoring the critical role of family and professional support. Patient or Public Contribution No patient or public contribution. Trial Registration Registered with PROSPERO: CRD42023414310

Background Cisplatin, etoposide, and bleomycin (PEb) have been the standard of care for patients with germ cell tumors (GCT). In the 1990s, an intergroup trial (POG9049/CCG8882) randomized patients with high‐risk GCT, as defined by the 1990 criteria, to high‐dose (HDPEb) versus standard‐dose PEb. HDPEb resulted in improved event‐free survival (EFS), but no difference in overall survival (OS), thus standard‐dose PEb has remained the standard of care. Subsequently, the Malignant Germ Cell International Consortium (MaGIC) updated the risk stratification for pediatric and adolescent patients with GCT. Currently, patients are categorized as intermediate or poor risk if they are ≥11 years of age with Stage IV ovarian GCT, or testicular, mediastinal, or retroperitoneal GCT with intermediate or poor prognosis using the International Germ Cell Consensus Classification criteria. Methods We re‐analyzed data from the POG9049/CCG8882 trial using the updated MaGIC risk stratification to determine whether HDPEb improved outcomes over PEb in patients with intermediate/poor‐risk GCTs. Results Among 299 patients in the trial, 57 patients (48 males, nine females) met the inclusion criteria for this analysis. There were no statistically significant differences in 5‐year EFS (0.72 vs. 0.70, p ‐value = 0.82) or OS (0.76 vs. 0.74, p ‐value = 0.91) among patients treated with HDPEb versus PEb, respectively. Also, of note patients with mediastinal primaries had significantly worse 5‐year EFS (0.51 vs. 0.83, p ‐value = 0.0062) and OS (0.49 vs. 0.89, p ‐value = 0.0013) compared to other sites, with no difference in outcome between HDPEb and PEb. Conclusions Treatment with HDPEb did not improve outcomes for intermediate/poor‐risk GCT patients compared to standard‐dose PEb.

Background Glioblastoma (GBM) patients frequently develop resistance to temozolomide (TMZ), the standard chemotherapy. While targeting cancer metabolism shows promise, the relationship between metabolic perturbation and drug resistance remains poorly understood. Methods We performed high-throughput CRISPR interference screens in GBM cells to identify genes modulating TMZ sensitivity. Findings were validated using multiple GBM cell lines, patient-derived glioma stem cells, and clinical data. Molecular mechanisms were investigated through transcriptome analysis, metabolic profiling, and functional assays. Results We identified phosphoglycerate kinase 1 (PGK1) as a key determinant of TMZ sensitivity. Paradoxically, while PGK1 inhibition suppressed tumor growth, it enhanced TMZ resistance by inducing metabolic stress. This activated AMPK and HIF-1α pathways, leading to enhanced DNA damage repair through 53BP1. PGK1 expression levels correlated with TMZ sensitivity across multiple GBM models and patient samples. Conclusions Our study reveals an unexpected link between metabolic stress and chemoresistance, demonstrating how metabolic adaptation can promote therapeutic resistance. These findings caution against single-agent metabolic targeting and suggest PGK1 as a potential biomarker for TMZ response in GBM.

The aging process results in structural, functional, and immunological changes in the brain, which contribute to cognitive decline and increase vulnerability to neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and stroke-related complications. Aging leads to cognitive changes and also affect executive functions. Additionally, it causes neurogenic and neurochemical alterations, such as a decline in dopamine and acetylcholine levels, which also impact cognitive performance. The chronic inflammation caused by aging contributes to the impairment of the blood–brain barrier (BBB), contributing to the infiltration of immune cells and exacerbating neuronal damage. Therefore, rejuvenating therapies such as heterochronic parabiosis, cerebrospinal fluid (CSF) administration, plasma, platelet-rich plasma (PRP), and stem cell therapy have shown potential to reverse these changes, offering new perspectives in the treatment of age-related neurological diseases. This review focuses on highlighting the effects of rejuvenating interventions on neuroinflammation and the BBB.

Introduction: Complementary and integrative health (CIH) therapies are gaining recognition. However, their utilization within the diverse All of Us (AoU) research program remains unexplored. Methods: A cross-sectional study of AoU electronic health record and survey data compared characteristics of adult CIH users and nonusers. General linear models estimated factors associated with CIH. Results: A total of 3171 participants were CIH users (chiropractic or osteopathic manipulation, acupuncture, dietary modification, massage); they were more likely White and less likely Black with higher education versus nonusers. Education, insurance, sex, and race were associated with individual CIH modalities. Conclusion: Low utilization was observed, and several factors associated with CIH were identified. Further research is needed to address data gaps.

Background While coronary artery bypass grafting (CABG) surgery is effective in reducing the risk of myocardial infarction and subsequent cardiac events by improving myocardial perfusion, the risk of sudden cardiac death (SCD) remains notable. Methods This retrospective observational study evaluated the efficacy of dual antiplatelet therapy (DAPT) in preventing sudden cardiac death (SCD) among patients undergoing CABG surgery at a major U.S. cardiac center (2012–2015). Data was manually extracted from electronic medical records between 23/04/2017 to 30/03/ 2018 and verified for accuracy, with patients categorized into DAPT or aspirin monotherapy groups based on discharge prescriptions. Results Of 2,476 patients followed in this post-CABG study, the analysis included 1,005 patients who received aspirin monotherapy (AMT) and 1,458 patients who received dual antiplatelet therapy (DAPT). AMT group had a significantly higher incidence of SCD compared to those on DAPT (3.1% vs 0.8%; OR = 3.831, 95% CI: 1.961–7.519; p < 0.001). The binary regression model indicated that a higher BMI was associated with an increased risk of SCD (HR = 1.064, 95% CI: 1.012–1.118, p = 0.014). However, patients prescribed P2Y12 antagonists (HR = 0.285, 95% CI: 0.135–0.603, p < 0.001), those with a GFR > 60 ml/min (HR = 0.314, 95% CI: 0.158–0.624, p < 0.001), and those with a higher ejection fraction (HR = 0.962, 95% CI: 0.939–0.986, p = 0.002) were less likely to experience SCD following CABG. A 1 kg/m2 increase in BMI is associated with a 6.4% increase in the risk of SCD. Morbidly obese patients with BMI > 35 were more likely to have experienced SCD than those with BMI < 35 (HR = 2.400, 95% CI: 1.204–4,787; p = 0.013). Similarly, patients with EF > 40% had decreased incidence of SCD compared to those with EF < 40% (HR 0.347, 95% CI:0.158–0.763; p = 0.008). Patients on AMT had higher all-cause (OR = 2.136, 95% CI 1.502–3.038; p < 0.001) and CV mortality (OR = 3.731, 95% CI 2.233–6.235; p < 0.001) but had lower incidence of major bleeding (by drop in hemoglobin criteria) (OR = 0.704, 95% CI: 0.595–0.833; p < 0.001) compared to the DAPT group. Conclusion DAPT prescription after CABG improves survival and lowers risk of sudden cardiac death.

Chitinase-3 like-protein-1 (CHI3L1) is a protein involved in various pathological conditions, including infectious, allergic, metabolic, cardiovascular, and neurological diseases. In the central nervous system, glial cells, especially activated astrocytes, are the primary sources of CHI3L1 synthesis and secretion. In neurodegenerative diseases, such as Alzheimer's disease, elevated levels of CHI3L1 are correlated with greater cognitive decline and neuroinflammation. Regarding stroke, CHI3L1 is a relevant biomarker associated with an increased risk of adverse events and mortality, particularly in patients with elevated levels following the onset of symptoms. Overall, the presence of CHI3L1 may reflect disease severity and aid in predicting outcomes. This narrative review explores the potential role of CHI3L1 in neurological diseases, with an emphasis on stroke, and it may contribute to guiding the development of effective inhibitors, which could be an attractive therapeutic approach for treating this condition.

Dysfunctions in the immune system and alterations in the microbiome composition following SARS-CoV-2 infection contribute to persistent neurological issues observed in long COVID-19 survivors. We hypothesize that alterations in the gut microbiome composition and peripheral inflammatory profile following COVID-19 may play pivotal roles in behavior changes among individuals experiencing long-term illness. This cross-sectional study included a sample of post-COVID-19 and non-COVID-19 subjects. We assessed the presence of psychiatric conditions utilizing standardized diagnostic criteria, Hamilton Rating Scale for Anxiety (HAM-A), Hamilton Rating Scale for Depression (HAM-D), Biological Rhythms in Neuropsychiatry Assessment Interview (BRIAN), and Functional Assessment Short Test (FAST). Plasma samples were analyzed to examine lipid and inflammatory profiles. Fecal samples were evaluated by 16S rRNA sequencing to identify the gut microbiome composition. Noteworthy findings include a significant increase in the myeloid progenitor inhibitory factor 1 (MPIF-1), interleukin (IL)-17, and triglyceride among post-COVID-19 individuals. While α-diversity in the gut microbiome composition showed no significant differences, β-diversity demonstrated a notable distinction between the healthy control and post-COVID-19 groups. Post-COVID-19 individuals exhibited a decreased abundance of phylum, class, and order of Verrucomicrobia, family, and genus of Akkermansia, a short-chain fatty acid producer and microbial group significantly associated with intestinal barrier homeostasis and the amelioration of metabolic diseases. No difference was found between the behavioral and clinical data. In post-COVID-19 individuals, there were elevated IL-17 and MPIF-1 levels, compared to non-COVID-19 individuals. Additionally, there were notable alterations in gut microbiome composition, as evidenced by changes in β-diversity and a decrease of Verrucomicrobia, family, and Akkermansia genus abundance.

The mechanistic target of rapamycin (mTOR) pathway plays a critical role in cell growth and metabolic homeostasis. The ribosomal protein S6 kinases S6K1 and S6K2 are the major effectors of the mTOR pathway key to translation efficiency, but the underlying regulatory mechanisms remain largely unclear. In this study, we searched for mTOR regulators and found that the splicing factor SRRM2 modulates the levels of S6K1 and S6K2, thereby activating the mTOR-S6K pathway. Interestingly, SRRM2 facilitates the expression of S6K2 by modulating alternative splicing, and enhances the stability of the S6K1 protein by regulating the E3 ubiquitin ligase WWP2. Moreover, SRRM2 is highly expressed in colorectal cancer (CRC) tissues and is associated with a poor prognosis. SRRM2 promotes CRC growth in vitro and in vivo. Combined, these data reveal an oncogenic role of SRRM2 in CRC through activating the mTOR-S6K pathway by two different approaches, further suggesting SRRM2 as a potential therapeutic target for CRC.

Ayurveda, an ancient holistic medicinal system, has sustained its relevance over millennia and continues to be practised extensively in India. However, challenges persist in clinical expertise among Ayurvedic practitioners, often due to limited clinical exposure during their academic journey. The Ayurveda Clinical E-Learning Portal (AyurCeL) aims to bridge the gap in clinical expertise among Ayurvedic practitioners by providing a digital platform for sharing well-documented clinical case studies. This paper outlines the objectives, architecture, and comprehensive modules of AyurCeL, emphasizing its role in facilitating continuous clinical learning and improving the quality of Ayurvedic practice. AyurCeL offers a multi-faceted approach to learning, featuring a clinical case repository, Ayurveda case report preprint archive and post-publication review tool. By merging traditional insights with contemporary technology, AyurCeL not only preserves Ayurveda's profound legacy but also enhances its relevance and reach in today's medical landscape.