bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting PI3Kα increases the efficacy of anti‐PD‐1 antibody in cervical cancer
Authors: Jiang Wei , Ouyang Xueyan , Li Chunyan , Long Yixiu , Chen Wei , Ji Zhaodong , Shen Xuxia , Xiang Libing , Yang Huijuan 
Published: July 2023

AbstractTargeting programmed death 1(PD‐1) has been approved for relapsed cervical cancer with unsatisfactory clinical efficacy. This study aims to analyse the impact of PI3K pathway activation on tumour immune microenvironment and evaluates the immune sensitization effect by PI3K inhibition in cervical cancer. The effect of PIK3CA mutation on PD‐L1 expression and CD8+ T cells differentiation was determined in cervical cancer tissues. Luciferase and ChIP‐qPCR/PCR assays were used to determine the transcriptional regulation of PD‐L1 by PIK3CA‐E545K. The effects of PI3K inhibitor treatment on immune environment in vitro and in vivo were evaluated by RNA sequencing (RNA‐seq) and flow cytometry. The efficacy of PI3K inhibitor and anti‐PD‐1 therapy was assessed in cell‐derived xenografts (CDX) and patients‐derived xenografts (PDX). PD‐L1 overexpression is more frequently observed in elder women with squamous cervical carcinoma. It predicts longer progress‐free survival and overall survival. PIK3CA mutation results in increased mRNA and protein levels of PD‐L1, the repression of CD8+ T cell differentiation in cervical cancer. Here, we report a case that continuous pembrolizumab monotherapy treatment induced complete remission of a recurrent cervical cancer patient with systemic metastasis and PIK3CA‐E545K mutation, implying that PIK3CA mutation is potentially a biomarker for pembrolizumab treatment in cervical cancer. Specifically, this mutation promotes the expression of PD‐L1 by upregulating the transcription factor IRF1. PI3Kα‐specific inhibitor markedly activates immune microenvironment by regulating the PD‐1/L1‐related pathways and promoting CD8+ T cell differentiation and proliferation in Caski‐CDXs with PIK3CA‐E545K mutation. PI3Kα inhibitor significantly enhances the anti‐tumour efficacy of PD‐1 blockade in CDXs and PDXs. PIK3CA mutations may predict the response of cervical cancer to PD‐1 blockade. The efficacy of PI3Kα inhibitors combined with PD‐1 antibodies is promising in cervical cancer and warrants additional clinical and mechanistic investigations.
Trans‐2,3‐enoyl‐CoA reductase‐like‐related catecholaminergic polymorphic ventricular tachycardia with regular ventricular tachycardia and response to flecainide
Authors: Ebrahim Mohammad A. , Alkhabbaz Ali A. , Albash Buthaina , AlSayegh Ali H. , Webster Gregory 
Published: July 2023

AbstractIntroductionWe describe a unique case of TECRL‐CPVT presented with cardiac arrest.MethodsPost resuscitation, the patient developed regular ventricular tachycardia featuring a left purkinje system morphology.ResultsThere was clear suppression of arrhythmia with the addition of flecainide and isolated ventricular ectopy causing secondary T‐wave changes.ConclusionA high index of suspicion was required to eventually make the diagnosis through whole exome sequencing.
Living, quiescent Lactobacillus plantarum Lp90 probiotic, delivered topically to full thickness tissues in vitro via a just‐add‐water cream delivery system, stimulates the expression of elastin protein
Authors: Gruber James V. , Holtz Robert 
Published: July 2023

AbstractIntroductionDelivering living probiotics to the skin can be challenging as most water‐containing cosmetic products require preservatives to maintain product stability. A recently introduced powdered technology [Stratabiosys™, Vantage Personal Care] allows for quiescent probiotic powders to be stored for extended periods of time. The powders can then be reconstituted to creams at the point of use by adding water and mixing and were examined in vitro on reconstructed human full thickness tissues to see if the probiotic had any influence of several important biomolecules expressed in the skin.Materials and MethodsA probiotic powder containing 200 M CFU/gram of living quiescent Lactobacillus plantarum Lp90 was reconstituted to a cream by adding ultrapure water and gently mixing the components at room temperature to quickly produce a cream. The resulting cream was tested topically on Epiderm® Full Thickness Tissues by treating the tissues for 24 h, removing the cream with a PBS rinse and then repeating the treatment for another 24 h. The resulting tissues were examined for four strategically important skin biomolecules including Type 1A collagen, elastin, filaggrin and hyaluronic acid. The probiotic‐containing powder was tested against untreated tissues and powders not containing probiotics and powders containing measured amounts of one of two cryoprotectants known to be used to maintain the integrity of the quiescent probiotics during drying of the quiescent probiotic powders.ResultsIt was found that topical treatment on Epiderm® tissues with creams containing 2 M (1%), 4 M (2%) and 6 M (3%) CFU/gram prepared from a base powder containing 200 M CFU/gram of Lactobacillus plantarum Lp90 stimulated elastin expression in a dose dependent fashion. There was no effect on the other biomolecules examined in the studies. In addition, it was found that creams made from powders containing only the known cryoprotectants, not bacteria, had no influence on elastin expression.ConclusionThe results of this study demonstrate that topical delivery of probiotics is possible from powders containing quiescent probiotic powders converted to creams just prior to application to the tissues. In the case of a powder containing Lactobacillus plantarum Lp90, topical application significantly increased expression of elastin in the skin replicants after 48 h of exposure to the cream made with the probiotic. The elastin‐stimulating effects are not coming from the oligosaccharide cryoprotectants used to maintain the probiotic powders in their quiescent, dried state. The results indicate that it is the living Lactobacillus plantarum probiotic that is stimulating the elastin expression in the skin tissues.
Pharmacokinetics and tolerability of multiple‐day oral dosing of mycophenolate mofetil in healthy horses
Authors: Bello Kaitlyn , Lorch Gwendolen , Kim Kyeongmin , Toribio Ramiro E. , Yan Liwei , Xie Zhiliang , Hill Kasey , Phelps Mitch 
Published: July 2023

AbstractBackgroundAdditional efficacious immunomodulatory treatment is needed for the management of immune‐mediated disease in horses. Mycophenolate mofetil (MMF) is an immunosuppressive drug that warrants assessment as a viable therapeutic agent for horses.Hypothesis/ObjectivesTo evaluate the pharmacokinetics (PK) of multiple‐day oral dosing of MMF in healthy horses and to determine the tolerability of this dosing regimen.AnimalsSix healthy Standardbred mares.MethodsHorses received MMF 10 mg/kg PO q12h for 7 days in the fed state. Serial sampling was performed over 12 hours on Days 1 and 7 with trough samples collected every 24 hours, immediately before morning drug administration. Noncompartmental PK analyses were performed to determine primary PK parameters, followed by calculation of geometric means and coefficients of variation. A CBC, serum biochemical profile, physical examination, and fecal scoring were used to assess dose tolerability.ResultsSeven days of treatment resulted in a mycophenolic acid (MPA) area under the curve (AUC0‐12) of 12 594 h × ng/mL (8567‐19 488 h × ng/mL) and terminal half‐life (T1/2) of 11.3 hours (7.5‐15.9 hours), yielding minor metabolite accumulation in all horses treated. Salmonellosis was detected in the feces of 2 horses by Day 7, and all horses developed myelosuppression, hyperbilirubinemia, hyporexia, decreased gastrointestinal motility, and decreased fecal output by the seventh day of treatment.Conclusion and Clinical ImportanceAdministration of MMF at 10 mg/kg PO q12h resulted in hematologic and clinical toxicity within 1 week of treatment. A decreased MMF dose, frequency, or both is needed to avoid colic. Drug monitoring should include frequent hemograms, serum biochemical profiles, and strict biosecurity protocols.
Evidence that OLE RNA is a component of a major stress‐responsive ribonucleoprotein particle in extremophilic bacteria
Authors: Breaker Ronald R. , Harris Kimberly A. , Lyon Seth E. , Wencker Freya D. R. , Fernando Chrishan M. 
Published: July 2023

AbstractOLE RNA is a ~600‐nucleotide noncoding RNA present in many Gram‐positive bacteria that thrive mostly in extreme environments, including elevated temperature, salt, and pH conditions. The precise biochemical functions of this highly conserved RNA remain unknown, but it forms a ribonucleoprotein (RNP) complex that localizes to cell membranes. Genetic disruption of the RNA or its essential protein partners causes reduced cell growth under various stress conditions. These phenotypes include sensitivity to short‐chain alcohols, cold intolerance, reduced growth on sub‐optimal carbon sources, and intolerance of even modest concentrations of Mg2+. Thus, many bacterial species appear to employ OLE RNA as a component of an intricate RNP apparatus to monitor fundamental cellular processes and make physiological and metabolic adaptations. Herein we hypothesize that the OLE RNP complex is functionally equivalent to the eukaryotic TOR complexes, which integrate signals from various diverse pathways to coordinate processes central to cell growth, replication, and survival.
Burden of blindness and vision loss in China over the past 30 years: findings and predictions based on the Global Burden of Disease Study 2019
Authors: Jiang Bo , Yao Qingying , Yuan Xianbin , Liu Gaoqin , Lu Peirong 
Published: July 2023

AimsTo investigate the burden of blindness and vision loss (BVL) in China over the past 30 years according to year, age and sex, and to estimate future predictions.MethodsWe analysed the years lived with disability (YLDs), number of cases, age-standardised YLD rates (ASYRs) and age-standardised prevalence rates (ASPRs) of BVL in China from 1990 to 2019. We focused on changes over time using estimated annual percentage changes (EAPCs). Additionally, we used the Bayesian age-period-cohort model to predict the BVL burden from 2020 to 2030.ResultsThe number of YLDs and prevalent cases due to BVL increased from 2.57 (95% uncertainty interval (UI) 1.74 to 3.72) and 90.76 million (95% UI 72.21 to 111.92) in 1990 to 5.42 (95% UI 3.61 to 8.02) and 211.67 million (95% UI 168.21 to 259.66) in 2019, respectively. The BVL ASYRs and ASPRs showed a decreasing trend, with EAPCs of −0.13 (95% CI −0.28 to 0.02) and −0.11 (95% CI −0.19 to −0.04), respectively. The elderly and female populations had a higher BVL burden. The numbers of YLDs and cases due to BVL are projected to continue rising to 7.74 and 279.49 million in 2030, respectively. The ASYRs and ASPRs also showed increasing trends.ConclusionWhile rates of BVL in China have decreased, there has been a notable increase in the number of YLDs and new cases over the past 30 years. Projections suggest that the burden of BVL will continue to rise over the next 11 years. To address this challenge, appropriate policies must be implemented.
Lifelong differences in cancer incidence and mortality between subgroups of similar socioeconomic status in the Royal Norwegian Navy
Authors: Strand Leif Aage , Rudvin Inger , Martinsen Jan Ivar , Fadum Elin Anita , Grimsrud Tom K 
Published: July 2023

ObjectivesIn a previous cohort study of 28 300 Navy servicemen, vessel crews showed higher cancer incidence and mortality than did land-based personnel. We have extended the follow-up to look for changes in cancer risk, and to explore temporal trends in cancer incidence and cancer mortality during more than six decades of follow-up.MethodsCancer incidence and total cancer mortality were compared with the general population by calculating standardised ratios (standardised incidence ratios (SIRs), standardised mortality ratios) for the entire follow-up, with temporal trends through seven consecutive 10-year time spans from individual entry to follow-up. Rates were compared between the subgroups using Poisson regression, expressed as rate ratios (RRs).ResultsCancer incidence in Navy servicemen suggested a healthy soldier effect limited to the first three decades of follow-up and confined to land-based personnel. Overall, vessel crews showed 13% higher cancer incidence and 36% higher cancer mortality than other Navy servicemen. Some of the differences may be explained by a higher risk in vessel crews of cancers known to have less than 25% 5-year relative survival (RR=1.71), such as cancers of the lung, liver, pancreas and mesothelioma.ConclusionThrough most of the observation time, vessel crews had an overall cancer SIR that was higher than that of land-based personnel. Much of this excess involved cancers with a generally poor prognosis, linked to lifestyle and work environment. The contrasts in cancer incidence and mortality between the two subgroups of Navy servicemen persisted through more than six decades.
Near-optimal Lower Bounds on Quantifier Depth and Weisfeiler–Leman Refinement Steps
Authors: Berkholz Christoph , Nordström Jakob 
Published: July 2023

We prove near-optimal tradeoffs for quantifier depth (also called quantifier rank) versus number of variables in first-order logic by exhibiting pairs of
n
-element structures that can be distinguished by a
k
-variable first-order sentence but where every such sentence requires quantifier depth at least
n

Ω (
k
/log
k
)

. Our tradeoffs also apply to first-order counting logic and, by the known connection to the
k
-dimensional Weisfeiler–Leman algorithm, imply near-optimal lower bounds on the number of refinement iterations.

A key component in our proof is the hardness condensation technique introduced by Razborov in the context of proof complexity. We apply this method to reduce the domain size of relational structures while maintaining the minimal quantifier depth needed to distinguish them in finite variable logics.
Radiotherapy-Induced Neurocognitive Impairment Is Driven by Heightened Apoptotic Priming in Early Life and Prevented by Blocking BAX
Authors: Singh Rumani , Yu Stacey , Osman Marwa , Inde Zintis , Fraser Cameron , Cleveland Abigail H. , Almanzar Nicole , Lim Chuan Bian , Joshi Gaurav N. , Spetz Johan , Qin Xingping , Toprani Sneh M. , Nagel Zachary , Hocking Matthew C. , Cormack Robert A. , Yock Torunn I. , Miller Jeffrey W. , Yuan Zhi-Min , Gershon Timothy , Sarosiek Kristopher A. 
Published: July 2023

AbstractAlthough external beam radiotherapy (xRT) is commonly used to treat central nervous system (CNS) tumors in patients of all ages, young children treated with xRT frequently experience life-altering and dose-limiting neurocognitive impairment (NI) while adults do not. The lack of understanding of mechanisms responsible for these differences has impeded the development of neuroprotective treatments. Using a newly developed mouse model of xRT-induced NI, we found that neurocognitive function is impaired by ionizing radiation in a dose- and age-dependent manner, with the youngest animals being most affected. Histologic analysis revealed xRT-driven neuronal degeneration and cell death in neurogenic brain regions in young animals but not adults. BH3 profiling showed that neural stem and progenitor cells, neurons, and astrocytes in young mice are highly primed for apoptosis, rendering them hypersensitive to genotoxic damage. Analysis of single-cell RNA sequencing data revealed that neural cell vulnerability stems from heightened expression of proapoptotic genes including BAX, which is associated with developmental and mitogenic signaling by MYC. xRT induced apoptosis in primed neural cells by triggering a p53- and PUMA-initiated, proapoptotic feedback loop requiring cleavage of BID and culminating in BAX oligomerization and caspase activation. Notably, loss of BAX protected against apoptosis induced by proapoptotic signaling in vitro and prevented xRT-induced apoptosis in neural cells in vivo as well as neurocognitive sequelae. On the basis of these findings, preventing xRT-induced apoptosis specifically in immature neural cells by blocking BAX, BIM, or BID via direct or upstream mechanisms is expected to ameliorate NI in pediatric patients with CNS tumor.Significance:Age- and differentiation-dependent apoptotic priming plays a pivotal role in driving radiotherapy-induced neurocognitive impairment and can be targeted for neuroprotection in pediatric patients.
Two Types of Mid-High-Latitude Intraseasonal Oscillations in the Southern Hemisphere during Austral Summer
Authors: Xu Qinghan , Yang Shuangyan 
Published: July 2023

Abstract
Using NCEP–NCAR reanalysis data, the atmospheric intraseasonal oscillation (ISO) over the mid-high latitudes in the Southern Hemisphere during austral summer is studied. Two types of 10–30-day eastward- and westward-propagating ISO at mid-high latitudes are extracted by extended empirical orthogonal functions. The analysis of wave activity flux reveals that the energy sources of the eastward-propagating wave train are in the southwest Pacific and southern Indian Ocean, and the westward-propagating wave train is over the east coast of South America. The diagnosis of geopotential height tendency shows that the zonal gradient of ISO relative vorticity guided by mean zonal wind plays a major role in the eastward propagation of the wave train, while the meridional gradient of mean relative vorticity and geostrophic vorticity guided by ISO meridional wind plays a major role in the westward propagation of the wave train. Energy analysis shows that the amplitude enhancement over the South Pacific is due to the ISO disturbance gaining energy from the mean flow. The eastward-propagating ISO obtains energy from the mean flow through kinetic and potential energy conversion, while the westward-propagating ISO cannot obtain energy through potential energy conversion. The surface air temperature and precipitation in South America are affected by the circulation and propagation corresponding to both types of ISO. The useful forecasting skills by the subseasonal-to-seasonal forecasting project for eastward- and westward-propagating types can reach to 17 days, while the potential forecasting skills improve to 20 and 19 days, respectively.

Significance Statement
The intraseasonal oscillation (ISO) has important effects on regional weather and climate, and we focus on the ISO over mid-high latitudes in the Southern Hemisphere, which has been paid little attention. We reveal two leading types of the mid-high-latitude ISO during austral summer, namely, the eastward- and westward-propagating types. Also, the characteristics and effects of the two types are explored. To understand their dynamical process, the geopotential height tendency and energy conversion are diagnosed. It is also found that the two ISO types can be predicted up to 17 days in advance by the subseasonal-to-seasonal project, which may provide guidance for the extended-range forecasts.
Elimination Games: The Global Rise of Military Reality TV and the Shaping of the Citizen Subject
Authors: Kaempf Sebastian , Stahl Roger 
Published: July 2023

The past decade has seen the global growth of military-style reality television programming. These programmes, produced by militaries themselves or through collaboration with the entertainment sector, have proven to be an effective and increasingly powerful public relations conduit. Our article offers a theoretical treatment of reality television, both the aesthetic modes by which it invites the viewing subject as well as the political economy of its use in public relations. These dimensions are explored through two case studies. First, we focus on the genesis of military-style reality TV in the United States, where, after 9/11, the US military seized on the genre to pioneer and field-test various themes in response to public exigency as the occupations of Afghanistan and Iraq drew on. Second, we analyse the German military as both a latecomer and innovator to these new public relations endeavours. By reading the generic and aesthetic strategies in both cases, we argue that the genre’s public relations function goes beyond the immediate task of recruitment to cultivate civic participation in militaristic fantasies through a mediasphere rife with invitations to ‘go soldier’. Military reality TV, we argue, represents the militarization of civic identity and the gradual displacement of values from deliberative to authoritarian, cosmopolitan to nationalistic and diplomatic to combative. Jeux éliminatoires : L’essor mondial de la télé-réalité militaire et la formation du citoyen sujet
Multi-therapeutic and Biomolecular Exploration of Andrographolide against Bacterial-induced Oxidative and Inflammatory Damages
Authors: Alnoman Maryam M. 
Published: July 2023

Aim/Background Oxidative and inflammatory damage induced by bacterial infections has been attributed as a more concerning health issue raised by health professionals and researchers due to large antibiotic drug resistance. Natural products and their derived medicines play an immense role in fighting pathogenic micro-organisms. Considering these factors, the study is aimed at exploring the biological effect of andrographolide against gram-positive and negative bacterial strains that induce oxidative and inflammatory onsets using in silico approaches. Materials and Methods In silico docking analysis was conducted using AutoDock Vina to determine the biological interactivity of andrographolide with proteins (catalase (CAT), tumor necrosis factor (TNF-α), and cytochrome P450 VDH mutant T107A with bound Vitamin D3) involved in pathogenesis caused by bacterial infection. Furthermore, absorption, distribution, metabolism and excretion (ADME) analysis was performed to evaluate the pharmacokinetic behavior of andrographolide by assessing several parameters such as lipophilicity, skin permeability, GI absorption, blood-brain barrier (BBB) permeability. Results The results of the study showed that andrographolide exhibited significant interaction with TNF-α with amino acids such as GLN B: 27, ILE B: 136, and ASP B: 45 for site 1 and ASN D: 30, ARG C: 31, and ARG C: 82 for site 2. However, the effect of andrographolide was found to be comparable with that of other proteins. In ADME analysis, the boiled egg plot represents the andrographolide that exists in the white region, which represents a good distribution of andrographolide, while lipophilicity in the form of the consensus logP was found to be 2.3 with high GI-absorption and no BBB permeability. Conclusion The study concludes that andrographolide can be a promising agent against oxidative and inflammatory stress induced by bacterial onsets and may reduce the vitality of several gram-positive and gram-negative bacterial strains.
Selective Partial Agonism of Vasopressin 1a Receptors In Vitro by OCE-205
Authors: Croston Glenn , Cable Edward E. , Toy Jeannine , Tariga Hiroe , Laporte Regent , Harris Geoff , Bukofzer Stan 
Published: July 2023

Objective To test the selectivity and degree of functional agonism of Ocelot Bio’s dual agonist/antagonist molecule, OCE-205, at the vasopressin 1a receptor (V1aR). Methods Cells expressing human (h) or rat V1a, V1b, V2, or oxytocin receptors (OTR) were incubated with varying concentrations of OCE-205 or with arginine vasopressin (AVP), and responses were measured with fluorescence or reporter gene assays. In addition, human resistance arteries were exposed to increasing concentrations of OCE-205, and the resulting contractility was measured. Results The mean efficacy of OCE-205 at hV1aR was 39% of the maximal possible effect (MPE), with a mean EC50 of 0.71 nM. Above 1 nM OCE-205, the percent maximal possible effect (%MPE) plateaued. The EC50 was much higher at hV1bR (134 nM), hV2R (420 nM), and OTR (6.9 nM), indicating selectivity for hV1aR. Results at rat receptors were similar. OCE-205 produced 40.0% of maximal depolarization-induced contraction, demonstrating functional partial agonism. Conclusion The dual agonist/antagonist structure of OCE-205 thus allows it to act as a highly selective partial agonist at vasopressin V1aR at therapeutically relevant concentrations.