TDP-43 and NEAT long non-coding RNA: Roles in neurodegenerative disease

Understanding and ameliorating neurodegenerative diseases represents a key challenge for supporting the health span of the aging population. Diverse protein aggregates have been implicated in such neurodegenerative disorders, including amyloid-β, α-synuclein, tau, fused in sarcoma (FUS), and transactivation response element (TAR) DNA-binding protein 43 (TDP-43). Recent years have seen significant growth in our mechanistic knowledge of relationships between these proteins and some of the membrane-less nuclear structures that fulfill key roles in the cell function. These include the nucleolus, nuclear speckles, and paraspeckles. The ability of macromolecular protein:RNA complexes to partition these nuclear condensates through biophysical processes that involve liquid–liquid phase separation (LLPS) has also gained attention recently. The paraspeckle, which is scaffolded by the architectural long-non-coding RNA nuclear enriched abundant transcript 1 (NEAT1) plays central roles in RNA processing and metabolism and has been linked dynamically to TDP-43. In this mini-review, we outline essential early and recent insights in relation to TDP-43 proteinopathies. We then appraise the relationships between TDP-43 and NEAT1 in the context of neuronal paraspeckles and neuronal stress. We highlight key areas for investigation based on recent advances in our understanding of how TDP-43 affects neuronal function, especially in relation to messenger ribosomal nucleic acid (mRNA) splicing. Finally, we offer perspectives that should be considered for translational pipelines in order to improve health outcomes for the management of neurodegenerative diseases

MicroRNA-510-3p and Its Gene Network in the Disease Regulation of Preeclampsia: An Insilico Approach

Background: Preeclampsia (PE) is a major health complication for pregnant women that increases the risk of mortality and morbidity. Knowledge of the complex molecular mechanisms associated with PE is incomplete and methods for early diagnosis and treatment options in PE are limited. MicroRNAs (miRNAs) are short non-coding RNAs involved in pathogenesis of various diseases including PE. In our previous studies, we identified a relationship between miR-510-3p and PE. However, the exact molecular mechanisms and genes regulated by miR-510-3p have not been elucidated. Methods: In this study, we employed the bioinformatic tools including miRbase, RNAcomposer, RNAfold, TargetScan, miRDB, miRTarbase to analyze the secondary structure and targets of miR-510-3p from the publicly available databases. We compared the miR-510-3p target genes with PE genes retrieved from the NCBI (National Center for Biotechnology Information) genes database. The miR-510-3p target genes that were involved in PE were further subjected to gene ontology (GO) and Kyoto Encyclopaedia for Genes and Genomes (KEGG) pathway analysis to analyse their biological, molecular and cellular role in PE. STRING, Shiny GO, Cytoscape and Metascape were used for the GO and KEGG analysis. Results and Conclusions: MicroRNA-510-3p had a minimum free energy of –29.10 Kcal and A+U content of 55.4%, suggesting stability and binding affinity towards its targets. Genes that were involved in the positive regulation of angiogenesis were identified, since angiogenesis is an important process in PE. ADAM12, ANGPT2, CHRNA7, DDAH1, ERAP1, FGF2, GRN, HGF, HIF1A, HK2, HMGB1, HMOX1, IL1A, KDR, NRP1, PRKCB, SERPINE1, SIRT1, TGFBR2, THBS1, TLR3, VEGFA, and WNT5A were the miR-510-3p targets involved in the positive regulation of angiogenesis. In conclusion, miR-510-3p is postulated to play an important role in the pathogenesis of PE. Hence, further studies could define miR-510-3p as a novel therapeutic target for PE

Liquid biopsy: Exosomal microRNAs as novel diagnostic and prognostic biomarkers in cancer

Background Detecting cancer at an early stage before clinical manifestation could be an effective strategy to decrease cancer mortality. Thus, identifying liquid biopsy biomarkers with high efficacy could be a promising approach for non-invasive diagnosis of cancer. Main text Liquid biopsies are increasingly used as a supplement to biopsy, as it enables disease progression to be detected months before clinical and radiographic confirmation. Many bodily fluids contain exosomal microRNAs (miRNAs) which could provide a new class of biomarkers for early and minimally invasive cancer diagnosis due to the stability of miRNAs in exosomes. In this review, we mainly focused on the exosomal miRNAs (liquid biopsy) as biomarkers in the diagnosis and prognosis of various cancers. Exosomal miRNAs can be used as diagnostic and prognosis biomarkers that provide unique insights and a more dynamic perspective of the progression and therapeutic responses in various malignancies. Therefore, the development of novel and more sensitive technologies that exploit exosomal miRNAs should be a priority for cancer management

CRISPR/Cas9 and next generation sequencing in the personalized treatment of Cancer

Background: Cancer is caused by a combination of genetic and epigenetic abnormalities. Current cancer therapies are limited due to the complexity of their mechanism, underlining the need for alternative therapeutic approaches. Interestingly, combining the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR/Cas9) system with next-generation sequencing (NGS) has the potential to speed up the identification, validation, and targeting of high-value targets. Main text: Personalized or precision medicine combines genetic information with phenotypic and environmental characteristics to produce healthcare tailored to the individual and eliminates the constraints of “one-size-fits-all” therapy. Precision medicine is now possible thanks to cancer genome sequencing. Having advantages over limited sample requirements and the recent development of biomarkers have made the use of NGS a major leap in personalized medicine. Tumor and cell-free DNA profiling using NGS, proteome and RNA analyses, and a better understanding of immunological systems, are all helping to improve cancer treatment choices. Finally, direct targeting of tumor genes in cancer cells with CRISPR/Cas9 may be achievable, allowing for eliminating genetic changes that lead to tumor growth and metastatic capability. Conclusion: With NGS and CRISPR/Cas9, the goal is no longer to match the treatment for the diagnosed tumor but rather to build a treatment method that fits the tumor exactly. Hence, in this review, we have discussed the potential role of CRISPR/Cas9 and NGS in advancing personalized medicine

Cucumeropsis mannii seed oil ameliorates Bisphenol‐A‐induced adipokines dysfunctions and dyslipidemia

From Wiley via Jisc Publications RouterHistory: received 2022-12-25, rev-recd 2023-01-07, accepted 2023-02-06, pub-electronic 2023-02-18Article version: VoRPublication status: PublishedThis study demonstrated the therapeutic potentials of Cucumeropsis mannii seed oil (CMSO) capable of alleviating BPA‐induced dyslipidemia and adipokine dysfunction. In this study, we evaluated the effects of CMSO on adipokine dysfunctions and dyslipidemia in bisphenol‐A (BPA)‐induced male Wistar rats. Six‐week‐old 36 albino rats of 100–200 g weight were assigned randomly to six groups, which received varied doses of BPA and/or CMSO. The administration of BPA and CMSO was done at the same time for 42 days by oral intubation. The adipokine levels and lipid profile were measured in adipose tissue and plasma using standard methods. BPA induced significant (p < .05) increases in triglycerides, cholesterol, leptin, LDL‐C, and atherogenic and coronary risk indices in adipose tissue and plasma, as well as a decrease in adiponectin and HDL‐C levels in Group II animals. BPA administration significantly (p < .05) elevated Leptin levels and reduced adiponectin levels. BPA plus CMSO reduced triglycerides, cholesterol, leptin, LDL‐C, and atherogenic and coronary risk indices while increasing adiponectin levels and HDL‐C in adipose tissue and plasma (p < .05). The results showed that BPA exposure increased adipose tissue as well as serum levels of the atherogenic index, triglycerides, cholesterol, coronary risk index, LDL‐C, leptin, and body weight with decreased adiponectin levels and HDL‐C. Treatment with CMSO reduced the toxicities caused by BPA in rats by modulating the body weight, adiponectin/leptin levels, and lipid profiles in serum and adipose tissue. This study has shown that CMSO ameliorates BPA‐induced dyslipidemia and adipokine dysfunctions. We suggest for further clinical trial to establish the clinical applications

Patterns of antibiotic use, pathogens, and prediction of mortality in hospitalized neonates and young infants with sepsis: A global neonatal sepsis observational cohort study (NeoOBS).

BACKGROUND: There is limited data on antibiotic treatment in hospitalized neonates in low- and middle-income countries (LMICs). We aimed to describe patterns of antibiotic use, pathogens, and clinical outcomes, and to develop a severity score predicting mortality in neonatal sepsis to inform future clinical trial design. METHODS AND FINDINGS: Hospitalized infants <60 days with clinical sepsis were enrolled during 2018 to 2020 by 19 sites in 11 countries (mainly Asia and Africa). Prospective daily observational data was collected on clinical signs, supportive care, antibiotic treatment, microbiology, and 28-day mortality. Two prediction models were developed for (1) 28-day mortality from baseline variables (baseline NeoSep Severity Score); and (2) daily risk of death on IV antibiotics from daily updated assessments (NeoSep Recovery Score). Multivariable Cox regression models included a randomly selected 85% of infants, with 15% for validation. A total of 3,204 infants were enrolled, with median birth weight of 2,500 g (IQR 1,400 to 3,000) and postnatal age of 5 days (IQR 1 to 15). 206 different empiric antibiotic combinations were started in 3,141 infants, which were structured into 5 groups based on the World Health Organization (WHO) AWaRe classification. Approximately 25.9% (n = 814) of infants started WHO first line regimens (Group 1-Access) and 13.8% (n = 432) started WHO second-line cephalosporins (cefotaxime/ceftriaxone) (Group 2-"Low" Watch). The largest group (34.0%, n = 1,068) started a regimen providing partial extended-spectrum beta-lactamase (ESBL)/pseudomonal coverage (piperacillin-tazobactam, ceftazidime, or fluoroquinolone-based) (Group 3-"Medium" Watch), 18.0% (n = 566) started a carbapenem (Group 4-"High" Watch), and 1.8% (n = 57) a Reserve antibiotic (Group 5, largely colistin-based), and 728/2,880 (25.3%) of initial regimens in Groups 1 to 4 were escalated, mainly to carbapenems, usually for clinical deterioration (n = 480; 65.9%). A total of 564/3,195 infants (17.7%) were blood culture pathogen positive, of whom 62.9% (n = 355) had a gram-negative organism, predominantly Klebsiella pneumoniae (n = 132) or Acinetobacter spp. (n = 72). Both were commonly resistant to WHO-recommended regimens and to carbapenems in 43 (32.6%) and 50 (71.4%) of cases, respectively. MRSA accounted for 33 (61.1%) of 54 Staphylococcus aureus isolates. Overall, 350/3,204 infants died (11.3%; 95% CI 10.2% to 12.5%), 17.7% if blood cultures were positive for pathogens (95% CI 14.7% to 21.1%, n = 99/564). A baseline NeoSep Severity Score had a C-index of 0.76 (0.69 to 0.82) in the validation sample, with mortality of 1.6% (3/189; 95% CI: 0.5% to 4.6%), 11.0% (27/245; 7.7% to 15.6%), and 27.3% (12/44; 16.3% to 41.8%) in low (score 0 to 4), medium (5 to 8), and high (9 to 16) risk groups, respectively, with similar performance across subgroups. A related NeoSep Recovery Score had an area under the receiver operating curve for predicting death the next day between 0.8 and 0.9 over the first week. There was significant variation in outcomes between sites and external validation would strengthen score applicability. CONCLUSION: Antibiotic regimens used in neonatal sepsis commonly diverge from WHO guidelines, and trials of novel empiric regimens are urgently needed in the context of increasing antimicrobial resistance (AMR). The baseline NeoSep Severity Score identifies high mortality risk criteria for trial entry, while the NeoSep Recovery Score can help guide decisions on regimen change. NeoOBS data informed the NeoSep1 antibiotic trial (ISRCTN48721236), which aims to identify novel first- and second-line empiric antibiotic regimens for neonatal sepsis. TRIAL REGISTRATION: ClinicalTrials.gov, (NCT03721302)

Accessing medicines for non-communicable diseases: Patients and health care workers' experiences at public and private health facilities in Uganda.

BACKGROUND:Non-communicable diseases (NCDs) are increasingly prevalent in low- and middle-income countries. Successful management requires consistent access to appropriate medicines. Availability of NCD medicines is generally low, especially in the public sector, however, little is known about other factors affecting access. We explored barriers and facilitators of access to medicines for diabetes and hypertension at public and private health facilities in Uganda. METHODS:We conducted a qualitative descriptive study at six public hospitals and five private health facilities in different regions of Uganda. Data collection included 36 in-depth interviews and 14 focus group discussions (n = 128) among purposively selected adult outpatients with diabetes and/or hypertension and 26 key informant interviews with healthcare workers and patient association leaders. Transcripts were coded and emerging themes identified using the Framework method. RESULTS:Four main themes emerged: Stocking of medicines and supplies, Financial factors, Individual behaviour and attitudes, and Service delivery at health facilities. Stocking of medicines and supplies mainly presented barriers to access at public facilities including frequent stockouts, failure to stock certain medicines and low quality brands often rejected by patients. Financial factors, especially high cost of medicines and limited insurance coverage, were barriers in private facilities. Free service provision was a facilitator at public facilities. Patients' confusion resulting from mixed messages and their preference for herbal treatments were cross-sector barriers. While flexibility in NCD service provision was a facilitator at private facilities, provider burnout and limited operating hours were barriers in public facilities. Patient-driven associations exist at some public facilities and help mitigate inadequate medicine stock. CONCLUSION:Access to NCD medicines in Uganda is influenced by both health system and patient factors. Some factors are sector-specific, while others cross-cutting between public and private sectors. Due to commonalities in barriers, potential strategies for overcoming them may include patient-driven associations, public-private partnerships, and multi-modal health education platforms