bluuebunny/crossref_metadata_2025_split huggingface dataset:
The photophysics of protonated cytidine and hemiprotonated cytidine base pair: A computational study
Authors: Martinez‐Fernandez Lara , Improta Roberto 
Published: July 2023

AbstractWe here study the effect that a lowering of the pH has on the excited state processes of cytidine and a cytidine/cytidine pair in solution, by integrating time‐dependent density functional theory and CASSCF/CASPT2 calculations, and including solvent by a mixed discrete/continuum model. Our calculations reproduce the effect of protonation at N3 on the steady‐state infrared and absorption spectra of a protonated cytidine (CH+), and predict that an easily accessible non‐radiative deactivation route exists for the spectroscopic state, explaining its sub‐ps lifetime. Indeed, an extremely small energy barrier separates the minimum of the lowest energy bright state from a crossing region with the ground electronic state, reached by out‐of‐plane motion of the hydrogen substituents of the CC double bond, the so‐called ethylenic conical intersection typical of cytidine and other pyrimidine bases. This deactivation route is operative for the two bases forming an hemiprotonated cytidine base pair, [CH·C]+, the building blocks of I‐motif secondary structures, whereas interbase processes play a minor role. N3 protonation disfavors instead the nπ* transitions, associated with the long‐living components of cytidine photoactivated dynamics.
Highly active antiretroviral therapy discontinuation time is associated with therapeutic failure among human immunodeficiency virus (HIV)‐infected immigrant adults: A cohort study from a Peruvian referral hospital during the Venezuelan exodus
Authors: Rebolledo‐Ponietsky Kirbeliz , Al‐kassab‐Córdova Ali , Lucchetti‐Rodríguez Aldo , Cabieses Baltica , Rodriguez‐Morales Alfonso J. , Mezones‐Holguín Edward 
Published: July 2023

AbstractObjectiveTo evaluate the association between Highly Active Antiretroviral Therapy (HAART) discontinuation time and therapeutic failure (TF) in Venezuelan immigrants with HIV that restart HAART.MethodsWe carried out a retrospective cohort study in a large hospital in Peru. We included Venezuelan immigrants who restarted HAART and were followed over at least 6 months. The primary outcome was TF. Secondary outcomes were immunologic (IF), virologic (VF) and clinical (CF) failures. The exposure variable was HAART discontinuation, categorised as no discontinuation, less than 6 months, and 6 months or more. We applied generalised linear models Poisson family with robust standard errors to calculate crude (cRR) and adjusted (aRR) relative risks by statistical and epidemiological criteria.ResultsWe included 294 patients, 97.2% were males, and the median age was 32 years. Out of all the patients, 32.7% discontinued HAART for less than 6 months, 15.0% discontinued for more than 6 months and the remaining 52.3% did not discontinue. The cumulative incidence of TF was 27.9%, 24.5% in VF, 6.0% in IF and 6.0% in CF. Compared with non‐discontinued HAART patients, the discontinuation for less than 6 months (aRR = 1.98 [95% CI: 1.27–3.09]) and from 6 months to more (aRR = 3.17 [95% CI: 2.02–4.95]) increased the risk of TF. Likewise, treatment discontinuation of up to 6 months (aRR = 2.32 [95% CI: 1.40–3.84]) and from 6 months to more (aRR = 3.93 [95% CI: 2.39–6.45]) increased the risk of VF.ConclusionsHAART discontinuation increases the probability of TF and VF in Venezuelan immigrants.
S2P intramembrane protease RseP degrades small membrane proteins and suppresses the cytotoxicity of intrinsic toxin HokB
Authors: Yokoyama Tatsuhiko , Yamagata Yutaro , Honna Saisei , Mizuno Shinya , Katagiri Shizuka , Oi Rika , Nogi Terukazu , Hizukuri Yohei , Akiyama Yoshinori 
Published: July 2023

ABSTRACT

The site2
-
protease (S2P) family of intramembrane proteases (IMPs) is conserved in all kingdoms of life and cleaves transmembrane proteins within the membrane to regulate and maintain various cellular activities. RseP, an
Escherichia coli
S2P peptidase, is involved in the regulation of gene expression through the regulated cleavage of the two target membrane proteins (RseA and FecR) and in membrane quality control through the proteolytic elimination of remnant signal peptides. RseP is expected to have additional substrates and to be involved in other cellular processes. Recent studies have shown that cells express small membrane proteins (SMPs; single-spanning membrane proteins of approximately 50–100 amino acid residues) with crucial cellular functions. However, little is known about their metabolism, which affects their functions. This study investigated the possible RseP-catalyzed cleavage of
E. coli
SMPs based on the apparent similarity of the sizes and structures of SMPs to those of remnant signal peptides. We screened SMPs cleaved by RseP
in vivo
and
in vitro
and identified 14 SMPs, including HokB, an endogenous toxin that induces persister formation, as potential substrates. We demonstrated that RseP suppresses the cytotoxicity and biological functions of HokB. The identification of several SMPs as novel potential substrates of RseP provides a clue to a comprehensive understanding of the cellular roles of RseP and other S2P peptidases and highlights a novel aspect of the regulation of SMPs.

IMPORTANCE

Membrane proteins play an important role in cell activity and survival. Thus, understanding their dynamics, including proteolytic degradation, is crucial.
E. coli
RseP, an S2P family intramembrane protease, cleaves membrane proteins to regulate gene expression in response to environmental changes and to maintain membrane quality. To identify novel substrates of RseP, we screened small membrane proteins (SMPs), a group of proteins that have recently been shown to have diverse cellular functions, and identified 14 potential substrates. We also showed that RseP suppresses the cytotoxicity of the intrinsic toxin, HokB, an SMP that has been reported to induce persister cell formation, by degrading it. These findings provide new insights into the cellular roles of S2P peptidases and the functional regulation of SMPs.
Predictors and outcomes of pacemaker implantation in patients with cardiac amyloidosis
Authors: Saturi Giulia , De Frutos Fernando , Sguazzotti Maurizio , Gonzalez-Lopez Esther , Nardi Elena , Domínguez Fernando , Ponziani Alberto , Cabrera Eva , Caponetti Angelo Giuseppe , Lozano Sara , Massa Paolo , Cobo-Marcos Marta , Accietto Antonella , Castro-Urda Victor , Giovannetti Alessandro , Toquero Jorge , Gagliardi Christian , Gómez-Bueno Manuel , Rios-Tamayo Rafael , Biagini Elena , Segovia Javier , Galiè Nazzareno , García-Pavía Pablo , Longhi Simone 
Published: July 2023

ObjectiveWe sought to investigate prevalence, incidence and prognostic implications of permanent pacemaker (PPM) implantation in patients with cardiac amyloidosis (CA), thereby identifying the predictors of time to PPM implantation.MethodsSeven hundred eighty-seven patients with CA (602 men, median age 74 years, 571 transthyretin amyloidosis (ATTR), 216 light-chain amyloidosis (AL)) evaluated at two European referral centres were retrospectively included. Clinical, laboratory and instrumental data were analysed. The associations between PPM implantation and mortality, heart failure (HF) or a composite endpoint of mortality, cardiac transplantation and HF were analysed.Results81 (10.3%) patients had a PPM before initial evaluation. Over a median follow-up time of 21.7 months (IQR 9.6–45.2), 81 (10.3%) additional patients (18 with AL (22.2%) and 63 with ATTR (77.8%)) underwent PPM implantation with a median time to implantation of 15.6 months (IQR 4.2–40), complete atrioventricular block was the most common indication (49.4%). Independent predictors of PPM implantation were QRS duration (HR 1.03, 95% CI 1.02 to 1.03, p<0.001) and interventricular septum (IVS) thickness (HR 1.1, 95% CI 1.03 to 1.17, p=0.003). The model to estimate the probability of PPM at 12 months and containing both factors showed a C-statistic of 0.71 and a calibration of slope of 0.98.ConclusionsConduction system disease requiring PPM is a common complication in CA that affects up to 20.6% of patients. QRS duration and IVS thickness are independently associated with PPM implantation. A PPM implantation at 12 months model was devised and validated to identify patients with CA at higher risk of requiring a PPM and who require closer follow-up.
Can CANVAS due toRFC1biallelic expansions present with pure ataxia?
Authors: Hadjivassiliou Marios , Currò Riccardo , Beauchamp Nick , Dominik Natalia , Grunewald Richard A , Shanmugarajah Priya , Zis Panayiotis , Hoggard Nigel , Cortese Andrea 
Published: July 2023

BackgroundBiallelic expansion of AAGGG in the replication factor complex subunit 1 (RFC1) was identified as a major cause of cerebellar ataxia, neuropathy (sensory ganglionopathy, or SG) and vestibular areflexia syndrome (CANVAS). We wanted to clarify ifRFC1expansions can present with pure ataxia and if such expansions could be responsible for some cases where an alternative diagnosis had been made.MethodsWe identified patients with a combination of ataxia and SG and no other cause found, patients where an alternative diagnosis had been made, and patients with pure ataxia. Testing forRFC1expansions was done using established methodology.ResultsAmong 54 patients with otherwise idiopathic sporadic ataxia without SG, none was found to haveRFC1expansions. Among 38 patients with cerebellar ataxia and SG in which all other causes were excluded, 71% hadRFC1expansions. Among 27 patients with cerebellar ataxia and SG diagnosed with coeliac disease or gluten sensitivity, 15% hadRFC1expansions.ConclusionsIsolated cerebellar ataxia without SG makes the diagnosis of CANVAS due toRFC1expansions highly improbable, but CANVAS is frequently the cause of the combination of idiopathic cerebellar ataxia with SG. It is important to screen patients diagnosed with other causes of acquired ataxia and SG as a small percentage were found to haveRFC1expansions.
Risk of secondary progressive multiple sclerosis after early worsening of disability
Authors: Dzau Winston , Sharmin Sifat , Patti Francesco , Izquierdo Guillermo , Eichau Sara , Prat Alexandre , Girard Marc , Duquette Pierre , Onofrj Marco , Lugaresi Alessandra , Ozakbas Serkan , Gerlach Oliver , Boz Cavit , Grammond Pierre , Terzi Murat , Amato Maria Pia , La Spitaleri Daniele , Ramo-Tello Cristina , Maimone Davide , Cartechini Elisabetta , Buzzard Katherine , Skibina Olga , van der Walt Anneke , Butzkueven Helmut , Iuliano Gerardo , Soysal Aysun , Kalincik Tomas 
Published: July 2023

BackgroundWhether progression independent of relapse activity (PIRA) heralds earlier onset of secondary progressive multiple sclerosis (SPMS) and more rapid accumulation of disability during SPMS remains to be determined. We investigated the association between early PIRA, relapse-associated worsening (RAW) of disability and time to SPMS, subsequent disability progression and their response to therapy.MethodsThis observational cohort study included patients with relapsing-remitting multiple sclerosis (RRMS) from the MSBase international registry across 146 centres and 39 countries. Associations between the number of PIRA and RAW during early multiple sclerosis (MS) (the initial 5 years of MS onset) were analysed with respect to: time to SPMS using Cox proportional hazards models adjusted for disease characteristics; and disability progression during SPMS, calculated as the change of Multiple Sclerosis Severity Scores over time, using multivariable linear regression.Results10 692 patients met the inclusion criteria: 3125 (29%) were men and the mean MS onset age was 32.2 years. A higher number of early PIRA (HR=1.50, 95% CI 1.28 to 1.76, p<0.001) and RAW (HR=2.53, 95% CI 2.25 to 2.85, p<0.001) signalled a higher risk of SPMS. A higher proportion of early disease-modifying therapy exposure (per 10%) reduced the effect of early RAW (HR=0.94, 95% CI 0.89 to 1.00, p=0.041) but not PIRA (HR=0.97, 95% CI 0.91 to 1.05, p=0.49) on SPMS risk. No association between early PIRA/RAW and disability progression during SPMS was found.ConclusionsEarly disability increase during RRMS is associated with a greater risk of SPMS but not the rate of disability progression during SPMS. The deterioration associated with early relapses represents a potentially treatable risk factor of SPMS.Trial registration numberAustralian New Zealand Clinical Trials Registry (ACTRN12605000455662).
Monazite–xenotime thermometry: a review of best practices and an example from the Caledonides of northern Scotland
Authors: Mako Calvin A. , Caddick Mark J. , Law Richard D. , Thigpen J. Ryan 
Published: July 2023

Abstract

Monazite–xenotime thermometry is a potentially powerful technique for understanding the evolution of Earth systems. While a rich set of experimental and empirical datasets are available for monazite–xenotime equilibria, five different thermometric calibrations yield significantly different results, making this technique difficult to apply in practice. To clarify best practices for monazite–xenotime thermometry, a compilation of published compositional data for monazite and xenotime with independently determined pressure–temperature conditions is evaluated. For each existing thermometer, we examine how closely estimated temperatures match independent empirical temperatures and consider how best to calculate monazite end-members for each thermometer. Monazite–xenotime thermometry is applied to samples from the Northern Highlands Terrane of northern Scotland, which experienced amphibolite–upper greenschist facies metamorphism and penetrative deformation during the Scandian orogeny. Thermometry data in conjunction with U–Pb dating define relatively slow regional cooling across the Scandian thrust nappes. Thermometry data closely match quartz
c
-axis fabric-based deformation thermometry across the structurally lower nappes, suggesting that monazite and xenotime record the timing and temperature of penetrative deformation and shearing. The data suggest that ductile deformation in the hinterland nappes of the Scandian orogen in Scotland occurred as late as 415–410 Ma.
Galectin-1 Mediates Chronic STING Activation in Tumors to Promote Metastasis through MDSC Recruitment
Authors: Nambiar Dhanya K. , Viswanathan Vignesh , Cao Hongbin , Zhang Weiruo , Guan Li , Chamoli Manish , Holmes Brittany , Kong Christina , Hildebrand Rachel , Koong Amanda Jeanette , von Eyben Rie , Plevritis Sylvia , Li Lingyin , Giaccia Amato , Engleman Edgar , Le Quynh Thu 
Published: July 2023

Abstract

The immune system plays a crucial role in the regulation of metastasis. Tumor cells systemically change immune functions to facilitate metastatic progression. Through this study, we deciphered how tumoral galectin-1 (Gal1) expression shapes the systemic immune environment to promote metastasis in head and neck cancer (HNC). In multiple preclinical models of HNC and lung cancer in immunogenic mice, Gal1 fostered the establishment of a premetastatic niche through polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC), which altered the local microenvironment to support metastatic spread. RNA sequencing of MDSCs from premetastatic lungs in these models demonstrated the role of PMN-MDSCs in collagen and extracellular matrix remodeling in the premetastatic compartment. Gal1 promoted MDSC accumulation in the premetastatic niche through the NF-κB signaling axis, triggering enhanced CXCL2-mediated MDSC migration. Mechanistically, Gal1 sustained NF-κB activation in tumor cells by enhancing stimulator of interferon gene (STING) protein stability, leading to prolonged inflammation-driven MDSC expansion. These findings suggest an unexpected protumoral role of STING activation in metastatic progression and establish Gal1 as an endogenous-positive regulator of STING in advanced-stage cancers.

Significance:
Galectin-1 increases STING stability in cancer cells that activates NF-κB signaling and CXCL2 expression to promote MDSC trafficking, which stimulates the generation of a premetastatic niche and facilitates metastatic progression.
CDK4/6-MEK Inhibition in MPNSTs Causes Plasma Cell Infiltration, Sensitization to PD-L1 Blockade, and Tumor Regression
Authors: Kohlmeyer Jordan L. , Lingo Joshua J. , Kaemmer Courtney A. , Scherer Amanda , Warrier Akshaya , Voigt Ellen , Raygoza Garay Juan A. , McGivney Gavin R. , Brockman Qierra R. , Tang Amy , Calizo Ana , Pollard Kai , Zhang Xiaochun , Hirbe Angela C. , Pratilas Christine A. , Leidinger Mariah , Breheny Patrick , Chimenti Michael S. , Sieren Jessica C. , Monga Varun , Tanas Munir R. , Meyerholz David K. , Darbro Benjamin W. , Dodd Rebecca D. , Quelle Dawn E. 
Published: July 2023

AbstractPurpose:Malignant peripheral nerve sheath tumors (MPNST) are lethal, Ras-driven sarcomas that lack effective therapies. We investigated effects of targeting cyclin-dependent kinases 4 and 6 (CDK4/6), MEK, and/or programmed death-ligand 1 (PD-L1) in preclinical MPNST models.Experimental Design:Patient-matched MPNSTs and precursor lesions were examined by FISH, RNA sequencing, IHC, and Connectivity-Map analyses. Antitumor activity of CDK4/6 and MEK inhibitors was measured in MPNST cell lines, patient-derived xenografts (PDX), and de novo mouse MPNSTs, with the latter used to determine anti–PD-L1 response.Results:Patient tumor analyses identified CDK4/6 and MEK as actionable targets for MPNST therapy. Low-dose combinations of CDK4/6 and MEK inhibitors synergistically reactivated the retinoblastoma (RB1) tumor suppressor, induced cell death, and decreased clonogenic survival of MPNST cells. In immune-deficient mice, dual CDK4/6-MEK inhibition slowed tumor growth in 4 of 5 MPNST PDXs. In immunocompetent mice, combination therapy of de novo MPNSTs caused tumor regression, delayed resistant tumor outgrowth, and improved survival relative to monotherapies. Drug-sensitive tumors that regressed contained plasma cells and increased cytotoxic T cells, whereas drug-resistant tumors adopted an immunosuppressive microenvironment with elevated MHC II-low macrophages and increased tumor cell PD-L1 expression. Excitingly, CDK4/6-MEK inhibition sensitized MPNSTs to anti–PD-L1 immune checkpoint blockade (ICB) with some mice showing complete tumor regression.Conclusions:CDK4/6-MEK inhibition induces a novel plasma cell-associated immune response and extended antitumor activity in MPNSTs, which dramatically enhances anti–PD-L1 therapy. These preclinical findings provide strong rationale for clinical translation of CDK4/6-MEK-ICB targeted therapies in MPNST as they may yield sustained antitumor responses and improved patient outcomes.
LncRNA-Encoded Micropeptide ACLY-BP Drives Lipid Deposition and Cell Proliferation in Clear Cell Renal Cell Carcinoma via Maintenance of ACLY Acetylation
Authors: Zhang Shenghua , Zhang Zheng , Liu Xiaolong , Deng Yibin , Zheng Jian , Deng Jieqiong , Wang Yirong , Guo Binbin , Li Fanrong , Chen Xiaoyue , Pan Yacheng , Wang Jieyu , Lu Jiachun , Wu Siqi , Guo Qiang , Zhou Yifeng 
Published: July 2023

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of lethal kidney cancer. Reprogramming of fatty acid and glucose metabolism resulting in the accumulation of lipids and glycogen in the cytoplasm is a hallmark of ccRCC. Here, we identified a micropeptide ACLY-BP encoded by the GATA3-suppressed LINC00887, which regulated lipid metabolism and promoted cell proliferation and tumor growth in ccRCC. Mechanistically, the ACLY-BP stabilizes the ATP citrate lyase (ACLY) by maintaining ACLY acetylation and preventing ACLY from ubiquitylation and degradation, thereby leading to lipid deposition in ccRCC and promoting cell proliferation. Our results may offer a new clue for the therapeutic approaches and the diagnostic assessment for ccRCC.

Implications:
This study identifies ACLY-BP encoded by LINC00887 as a lipid-related micropeptide that stabilizes ACLY to generate acetyl-CoA, driving lipid deposition and promoting cell proliferation in ccRCC.
TRIM50 Inhibits Gastric Cancer Progression by Regulating the Ubiquitination and Nuclear Translocation of JUP
Authors: Hu Jiajia , Huang Runjie , Liang Chengcai , Wang Yingnan , Wang Min , Chen Yanxing , Wu Chenyi , Zhang Jinling , Liu Zekun , Zhao Qi , Liu Zexian , Wang Feng , Yuan Shuqiang 
Published: July 2023

AbstractGastric cancer is one of the most frequent cancers in the world. Emerging clinical data show that ubiquitination system disruptions are likely involved in carcinoma genesis and progression. However, the precise role of ubiquitin (Ub)-mediated control of oncogene products or tumor suppressors in gastric cancer is unknown. Tripartite motif-containing 50 (TRIM50), an E3 ligase, was discovered by high-output screening of ubiquitination-related genes in tissues from patients with gastric cancer to be among the ubiquitination-related enzymes whose expression was most downregulated in gastric cancer. With two different databases, we verified that TRIM50 expression was lower in tumor tissues relative to normal tissues. TRIM50 also suppressed gastric cancer cell growth and migration in vitro and in vivo. JUP, a transcription factor, was identified as a new TRIM50 ubiquitination target by MS and coimmunoprecipitation experiments. TRIM50 increases JUP K63-linked polyubiquitination mostly at the K57 site. We discovered that the K57 site is critical for JUP nuclear translocation by prediction with the iNuLoC website and further studies. Furthermore, ubiquitination of the K57 site limits JUP nuclear translocation, consequently inhibiting the MYC signaling pathway. These findings identify TRIM50 as a novel coordinator in gastric cancer cells, providing a potential target for the development of new gastric cancer treatment strategies.Implications:TRIM50 regulates gastric cancer tumor progression, and these study suggest TRIM50 as a new cancer target.
Updating the Definition of Cancer
Authors: Brown Joel S. , Amend Sarah R. , Austin Robert H. , Gatenby Robert A. , Hammarlund Emma U. , Pienta Kenneth J. 
Published: July 2023

Abstract
Most definitions of cancer broadly conform to the current NCI definition: “Cancer is a disease in which some of the body's cells grow uncontrollably and spread to other parts of the body.” These definitions tend to describe what cancer “looks like” or “does” but do not describe what cancer “is” or “has become.” While reflecting past insights, current definitions have not kept pace with the understanding that the cancer cell is itself transformed and evolving. We propose a revised definition of cancer: Cancer is a disease of uncontrolled proliferation by transformed cells subject to evolution by natural selection. We believe this definition captures the essence of the majority of previous and current definitions. To the simplest definition of cancer as a disease of uncontrolled proliferation of cells, our definition adds in the adjective “transformed” to capture the many tumorigenic processes that cancer cells adopt to metastasize. To the concept of uncontrolled proliferation of transformed cells, our proposed definition then adds “subject to evolution by natural selection.” The subject to evolution by natural selection modernizes the definition to include the genetic and epigenetic changes that accumulate within a population of cancer cells that lead to the lethal phenotype. Cancer is a disease of uncontrolled proliferation by transformed cells subject to evolution by natural selection.