Miracle-dz/UniFAR-FTUs huggingface dataset:
Evaluation of High Cholesterol and Risk of Dementia and Cognitive Decline in Older Adults Using Individual Patient Meta-Analysis

Introduction: Although increased cholesterol level has been acknowledged as a risk factor for dementia, evidence synthesis based on published data has yielded mixed results. This is especially relevant in older adults where individual studies report non-linear relationships between cholesterol and cognition and, in some cases, find higher cholesterol associated with a lower risk of subsequent cognitive decline or dementia. Prior evidence synthesis based on published results has not allowed us to focus on older adults or to standardize analyses across studies. Given our ageing population, an increased risk of dementia in older adults, and the need for proportionate treatment in this age group, an individual participant data (IPD) meta-analysis is timely. Method: We combined data from 8 studies and over 21,000 participants aged 60 years and over in a 2-stage IPD to examine the relationship between total, high-density, and low-density lipoprotein (HDL and LDL) cholesterol and subsequent incident dementia or cognitive decline, with the latter categorized using a reliable change index method. Results: Meta-analyses found no relationship between total, HDL, or LDL cholesterol (per millimoles per litre increase) and risk of cognitive decline in this older adult group averaging 76 years of age. For total cholesterol and cognitive decline: odds ratio (OR) 0.93 (95% confidence interval [CI] 0.86: 1.01) and for incident dementia: OR 1.01 [95% CI 0.89: 1.13]. This was not altered by rerunning the analyses separately for statin users and non-users or by the presence of an APOE e4 allele. Conclusion: There were no clear consistent relationships between cholesterol and cognitive decline or dementia in this older adult group, nor was there evidence of effect modification by statin use. Further work is needed in younger populations to understand the role of cholesterol across the life-course and to identify any relevant intervention points. This is especially important if modification of cholesterol is to be further evaluated for its potential influence on risk of cognitive decline or dementia.
Longitudinal relationship between intramuscular adipose tissue of the quadriceps and activities of daily living in older inpatients

The longitudinal relationship between intramuscular adipose tissue of the quadriceps and activities of daily living (ADL) in older inpatients remains unclear. This study aimed to examine whether decrease of intramuscular adipose tissue of the quadriceps in older inpatients is related to the recovery of ADL than increase of muscle mass.
BDTX-1535 Goes After Osimertinib Resistance.

According to a preclinical report, the investigational tyrosine kinase inhibitor BDTX-1535 may mitigate resistance to osimertinib, the standard of care for EGFR-mutant non-small cell lung cancer. It could also potentially treat central nervous system metastases, having shown preclinical efficacy in glioblastoma.
Virtual Reality Treatment Displaying the Missing Leg Improves Phantom Limb Pain: A Small Clinical Trial

Background Phantom limb pain (PLP) is a common and in some cases debilitating consequence of upper- or lower-limb amputation for which current treatments are inadequate. Objective This small clinical trial tested whether game-like interactions with immersive VR activities can reduce PLP in subjects with transtibial lower-limb amputation. Methods Seven participants attended 5–7 sessions in which they engaged in a visually immersive virtual reality experience that did not require leg movements (Cool! TM), followed by 10–12 sessions of targeted lower-limb VR treatment consisting of custom games requiring leg movement. In the latter condition, they controlled an avatar with 2 intact legs viewed in a head-mounted display (HTC Vive TM). A motion-tracking system mounted on the intact and residual limbs controlled the movements of both virtual extremities independently. Results All participants except one experienced a reduction of pain immediately after VR sessions, and their pre session pain levels also decreased over the course of the study. At a group level, PLP decreased by 28% after the treatment that did not include leg movements and 39.6% after the games requiring leg motions. Both treatments were successful in reducing PLP. Conclusions This VR intervention appears to be an efficacious treatment for PLP in subjects with lower-limb amputation.
Local Delivery of Senolytic Drug Inhibits Intervertebral Disc Degeneration and Restores Intervertebral Disc Structure

Intervertebral disc (IVD) degeneration (IVDD) is a leading cause of chronic low back pain. There is a strong clinical demand for more effective treatments for IVDD as conventional treatments provide only symptomatic relief rather than arresting IVDD progression. This study shows that senolytic therapy with local drug delivery can inhibit IVDD and restore IVD integrity. ABT263, a senolytic drug, is loaded in poly(lactic‐co‐glycolic acid) nanoparticles (PLGA‐ABT) and intradiscally administered into injury‐induced IVDD rat models. The single intradiscal injection of PLGA‐ABT may enable local delivery of the drug to avascular IVD, prevention of potential systemic toxicity caused by systemic administration of senolytic drug, and morbidity caused by repetitive injections of free drug into the IVD. The strategy results in the selective elimination of senescent cells from the degenerative IVD, reduces expressions of pro‐inflammatory cytokines and matrix proteases in the IVD, inhibits progression of IVDD, and even restores the IVD structure. This study demonstrates for the first time that local delivery of senolytic drug can effectively treat senescence‐associated IVDD. This approach can be extended to treat other types of senescence‐associated degenerative diseases.
Deep Brain Stimulation for Preclinical and Prodromal Alzheimer’s Disease: Integrating Beneficence, Non-Maleficence, and Autonomy Considerations Through Responsible Innovation

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Use of PD-1 Inhibitors in the Treatment of Advanced Basal Cell Carcinoma

minimal discomfort with MMS. The reported discomfort level withMMS was similar to teeth cleaning, mammogram, and prostate examination. This confirms previous studies’ findings thatMMS is a well-tolerated procedure. Our study demonstrated higher rates of patient discomfort with liquid nitrogen therapy compared withMMS, which may be due to multiple reasons, including the lack of anesthetic, limited counseling, and less postprocedural follow-up. One possibility for lower reported discomfort with colonoscopy is the fact that patients commonly undergo conscious sedation or general anesthesia with this procedure. Another important aspect that our study highlights is the high patient satisfaction scores with MMS, with 97% of our patients reporting that they would have no hesitations undergoing another MMS. Discomfort also did not appear to be affected by surgical or patient factors, suggesting a high tolerability of the procedure across a variety of populations. Limitations of this study include relatively small sample size, recall bias, and loss to follow-up. Being able to compare MMS with other common procedures during preoperative counseling may help the physician to better connect with their patients, set reasonable expectations, and ultimately help improve their experience. References 1. Reeder VJ, Gustafson CJ, Mireku K, Davis SA, et al. Trends in Mohs surgery from 1995 to 2010: an analysis of nationally representative data. Dermatol Surg 2015;41:397–403. 2. Connolly SM, Baker DR, Coldiron BM, FazioMJ, et al. AAD/ACMS/ ASDSA/ASMS 2012 appropriate use criteria for Mohs micrographic surgery: a report of the AmericanAcademy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery. J Am Acad Dermatol 2012;67:531–50. Erratum in: J Am Acad Dermatol 2015; 72:748. 3. Limthongkul B, Samie F,Humphreys TR. Assessment of postoperative pain after Mohs micrographic surgery. Dermatol Surg 2013;39: 857–63.
The widespread presence of a family of fish virulence plasmids in Vibrio vulnificus stresses its relevance as a zoonotic pathogen linked to fish farms

ABSTRACT Vibrio vulnificus is a pathogen of public health concern that causes either primary septicemia after ingestion of raw shellfish or secondary septicemia after wound exposure to seawater. In consequence, shellfish and seawater are considered its main reservoirs. However, there is one aspect of its biology that is systematically overlooked: its association with fish in its natural environment. This association led in 1975 to the emergence of a zoonotic clade within phylogenetic lineage 2 following successive outbreaks of vibriosis in farmed eels. Although this clade is now worldwide distributed, no new zoonotic clades were subsequently reported. In this work, we have performed phylogenetic, genomic and functional studies to show that other zoonotic clades are in fact present in 4 of the 5 lineages of the species. Further, we associate these clades, most of them previously but incompletely described, with the acquisition of a family of fish virulence plasmids containing genes essential for resistance to the immune system of certain teleosts of interest in aquaculture. Consequently, our results provide several pieces of evidence about the importance of this species as a zoonotic agent linked to fish farms, as well as on the relevance of these artificial environments acting as drivers that accelerate the evolution of the species.
Evidence from simulation studies for selective constraints on the codon usage of the Angiosperm psbA gene

The codon usage of the Angiosperm psbA gene is atypical for flowering plant chloroplast genes but similar to the codon usage observed in highly expressed plastid genes from some other Plantae, particularly Chlorobionta, lineages. The pattern of codon bias in these genes is suggestive of selection for a set of translationally optimal codons but the degree of bias towards these optimal codons is much weaker in the flowering plant psbA gene than in high expression plastid genes from lineages such as certain green algal groups. Two scenarios have been proposed to explain these observations. One is that the flowering plant psbA gene is currently under weak selective constraints for translation efficiency, the other is that there are no current selective constraints and we are observing the remnants of an ancestral codon adaptation that is decaying under mutational pressure. We test these two models using simulations studies that incorporate the context-dependent mutational properties of plant chloroplast DNA. We first reconstruct ancestral sequences and then simulate their evolution in the absence of selection on codon usage by using mutation dynamics estimated from intergenic regions. The results show that psbA has a significantly higher level of codon adaptation than expected while other chloroplast genes are within the range predicted by the simulations. These results suggest that there have been selective constraints on the codon usage of the flowering plant psbA gene during Angiosperm evolution.
Cardiovascular and renal effects of novel nonpeptide nociceptin opioid peptide receptor agonists

Partial agonists of the nociceptin opioid peptide (NOP) receptor have potential therapeutic use as antihypertensive and water diuretics (aquaretics). To date, peptide NOP receptor ligands have failed to progress in clinical trials due to poor pharmacokinetics and adverse effects. Nonpeptide, small‐molecule NOP receptor ligands may be more suitable as therapeutic agents. This study investigated the cardiovascular and renal responses produced by the novel nonpeptide NOP agonists AT‐403, AT‐090, AT‐127, and AT‐039.
Luteal expression of factors involved in the metabolism and sensitivity to oestrogens in the dog during pregnancy and in non‐pregnant cycle

Abstract The canine corpus luteum (CL) is the main source of reproductive steroids during dioestrus in the dog and remains active even in the absence of pregnancy (non‐pregnant dioestrus, physiological pseudopregnancy). Whereas the biological effects of 17β‐oestradiol (E2) in the canine CL remain unclear, the transcriptional availability of oestrogen receptors, ESR1 and ESR2, as well as other modulators of local availability of E2, for example, HSD17B7 (converts oestrone into oestradiol), SULT1E1 (inactivates E2 binding capacity to its own receptors through sulphonation) and STS (reverts E2 sulphonation), were previously detected in the CL of non‐pregnant bitches. The aim of the present work was to evaluate the mRNA amounts of these factors involved in luteal sensitivity and metabolism of E2 in the canine CL during the course of non‐pregnant dioestrus (days 10, 20, 30, 40, 50 and 60 post‐ovulation, n = 5/group) and at different stages of pregnancy (n = 4‐6/group): pre‐implantation (days 8–12), post‐implantation (days 18–25), mid‐gestation (days 35–40) and prepartum luteolysis. During pregnancy, the availability of ESR1, HSD17B7, SULT1E1 and STS decreased from mid‐pregnancy to prepartum luteolysis. The main findings during non‐pregnant dioestrus were as follows: increased ESR2:ESR1 ratio on days 40 and 50 after ovulation, decreasing during luteal regression (day 60); increased STS at day 30 when SULT1E1 levels decreased; increased availability of SULT1E1 transcripts during luteal regression; and decreased amounts of HSD17B7 mRNA in early dioestrus, increasing towards later stages. These results suggest that E2 signalling and biologically active local concentrations could diverge in response to time and pregnancy status of the bitch.
Combined Treatment of 6-Gingerol Analog and Tobramycin for Inhibiting Pseudomonas aeruginosa Infections

Pseudomonas aeruginosa is a pathogen that causes various infectious diseases through quorum-sensing regulation. Although antibiotics are mainly used to treat P. aeruginosa infections, they cause the emergence of resistant bacteria in humans. ABSTRACT Pseudomonas aeruginosa is a ubiquitous human pathogen that causes severe infections. Although antibiotics, such as tobramycin, are currently used for infection therapy, their antibacterial activity has resulted in the emergence of multiple antibiotic-resistant bacteria. The 6-gingerol analog, a structural derivative of the main component of ginger, is a quorum sensing (QS) inhibitor. However, it has a lower biofilm inhibitory activity than antibiotics and the possibility to cause toxicity in humans. Therefore, novel and more effective approaches for decreasing dosing concentration and increasing biofilm inhibitory activity are required to alleviate P. aeruginosa infections. In this study, a 6-gingerol analog was combined with tobramycin to treat P. aeruginosa infections. The combined treatment of 6-gingerol analog and tobramycin showed strong inhibitory activities on biofilm formation and the production of QS-related virulence factors of P. aeruginosa compared to single treatments. Furthermore, the combined treatment alleviated the infectivity of P. aeruginosa in an insect model using Tenebrio molitor larvae without inducing any cytotoxic effects in human lung epithelial cells. The 6-gingerol analog showed these inhibitory activities at much lower concentrations when used in combination with tobramycin. Adjuvant effects were observed through increased QS-disrupting processes rather than through antibacterial action. In particular, improved RhlR inactivation by this combination is a possible target for therapeutic development in LasR-independent chronic infections. Therefore, the combined treatment of 6-gingerol analog and tobramycin may be considered an effective method for treating P. aeruginosa infections. IMPORTANCE Pseudomonas aeruginosa is a pathogen that causes various infectious diseases through quorum-sensing regulation. Although antibiotics are mainly used to treat P. aeruginosa infections, they cause the emergence of resistant bacteria in humans. To compensate for the disadvantages of antibiotics and increase their effectiveness, natural products were used in combination with antibiotics in this study. We discovered that combined treatment with 6-gingerol analog from naturally-derived ginger substances and tobramycin resulted in more effective reductions of biofilm formation and virulence factor production in P. aeruginosa than single treatments. Our findings support the notion that when 6-gingerol analog is combined with tobramycin, the effects of the analog can be exerted at much lower concentrations. Furthermore, its improved LasR-independent RhlR inactivation may serve as a key target for therapeutic development in chronic infections. Therefore, the combined treatment of 6-gingerol analog and tobramycin is suggested as a novel alternative for treating P. aeruginosa infections.
Role of internalin proteins in the pathogenesis of Listeria monocytogenes

Listeria monocytogenes is a food‐borne bacterium that causes gastroenteritis, meningitis, or abortion. L. monocytogenes induces its internalization (entry) into human cells and either spreads laterally in tissues or transcytoses to traverse anatomical barriers. In this review, we discuss mechanisms by which five structurally related proteins of the “internalin” family of L. monocytogenes (InlA, InlB, InlC, InlF, and InlP) interact with distinct host receptors to promote infection of human cells and/or crossing of the intestinal, blood–brain, or placental barriers. We focus on recent results demonstrating that the internalin proteins InlA, InlB, and InlC exploit exocytic pathways to stimulate transcytosis, entry, or cell‐to‐cell spread, respectively. We also discuss evidence that InlA‐mediated transcytosis contributes to traversal of the intestinal barrier, whereas InlF promotes entry into endothelial cells to breach the blood–brain barrier. InlB also facilitates the crossing of the blood–brain barrier, but does so by extending the longevity of infected monocytes that may subsequently act as a “Trojan horse” to transfer bacteria to the brain. InlA, InlB, and InlP each contribute to fetoplacental infection by targeting syncytiotrophoblast or cytotrophoblast layers of the placenta. This work highlights the diverse functions of internalins and the complex mechanisms by which these structurally related proteins contribute to disease.
IL-33 activates group 2 innate lymphoid cell expansion and modulates endometriosis

Chronic inflammation and localized alterations in immune cell function are suspected to contribute to the progression of endometriosis and its associated symptoms. In particular, the alarmin IL-33 is elevated in the plasma, peritoneal fluid, and endometriotic lesions from patients with endometriosis; however, the exact role of IL-33 in the pathophysiology of endometriosis is not well understood. In this study, we demonstrate, in both humans and a murine model, that IL-33 contributes to the expansion of group 2 innate lymphoid cells (ILC2s), and this IL-33–induced ILC2 expansion modulates the endometriosis lesion microenvironment. Importantly, we show that IL-33 drives hallmarks of severe endometriosis, including elevated inflammation, lesion proliferation, and fibrosis, and that this IL-33–induced aggravation is mediated by ILC2s. Finally, we demonstrate the functionality of IL-33 neutralization as a promising and potentially novel therapeutic avenue for treating the debilitating symptoms of endometriosis.
E2F transcription factor 1 is involved in the phenotypic modulation of esophageal squamous cell carcinoma cells via microRNA-375

ABSTRACT E2F family of transcription factors modulates multiple cellular functions associated with cell cycle and apoptosis. Here, we focused on the relevance of E2F1 to esophageal squamous cell carcinoma (ESCC) and identification of E2F1-mediated network in this study. Query of Gene Expression Omnibus database revealed that E2F1 was the core gene that was upregulated in ESCC. E2F1 downregulation inhibited ESCC cell activity. microRNA (miR)-375 was confirmed to be a downstream target of E2F1. E2F1 bound to miR-375 promoter and inhibited miR-375 transcription. Moreover, miR-375 inhibitor mitigated the repressive impacts of si-E2F1 on ESCC cells in part. Further study showed that sestrin 3 (SESN3) could interact with miR-375, and its knockdown annulled the stimulative effect of miR-375 inhibitor on ESCC development. Finally, E2F1 and SESN3 downregulation inhibited the phosphatidylinositol 3 kinase (PI3K)/AKT pathway activity in cells, while miR-375 inhibitor promoted PI3K/AKT pathway activation. These findings suggest that E2F1 inhibited miR-375 expression and promoted SESN3 expression to activate the PI3K/AKT pathway in ESCC.