bluuebunny/crossref_metadata_2025_split huggingface dataset:
The SapM phosphatase can arrest phagosome maturation in an ESX-1 independent manner in
Mycobacterium tuberculosis
and BCG
Authors: Xander Christian , Rajagopalan Saranathan , Jacobs William R. , Braunstein Miriam 
Published: June 2024

ABSTRACT

Mycobacterium tuberculosis
(
Mtb
) is an intracellular pathogen that survives and grows in macrophages. A mechanism used by
Mtb
to achieve intracellular survival is to secrete effector molecules that arrest the normal process of phagosome maturation. Through phagosome maturation arrest (PMA),
Mtb
remains in an early phagosome and avoids delivery to degradative phagolysosomes. One PMA effector of
Mtb
is the secreted SapM phosphatase. Because the host target of SapM, phosphatidylinositol-3-phosphate (PI
3
P), is located on the cytosolic face of the phagosome, SapM needs to not only be released by the mycobacteria but also travel out of the phagosome to carry out its function. To date, the only mechanism known for
Mtb
molecules to leave the phagosome is phagosome permeabilization by the ESX-1 secretion system. To understand this step of SapM function in PMA, we generated identical in-frame
sapM
mutants in both the attenuated
Mycobacterium bovis
bacille Calmette-Guérin (BCG) vaccine strain, which lacks the ESX-1 system, and
Mtb
. Characterization of these mutants demonstrated that SapM is required for PMA in BCG and
Mtb
. Further, by establishing a role for SapM in PMA in BCG, and subsequently in a
Mtb
mutant lacking the ESX-1 system, we demonstrated that the role of SapM does not require ESX-1. We further determined that ESX-2 or ESX-4 is also not required for SapM to function in PMA. These results indicate that SapM is a secreted effector of PMA in both BCG and
Mtb
, and that it can function independent of the known mechanism for
Mtb
molecules to leave the phagosome.
Molecular profiling of visible polypoid and invisible conventional intestinal-type low-grade dysplasia in patients with idiopathic inflammatory bowel disease
Authors: Christakis Alexander , Nowak Jonathan , Hamilton Matthew J , Goldblum John R , Parrack Paige , Lindeman Neal I , Odze Robert , Patil Deepa T 
Published: June 2024

AimsLittle is known about the molecular features of visible polyps with low-grade intestinal-type dysplasia in patients with inflammatory bowel disease (IBD). To better understand their origins and biological potential, we sought to genomically profile these lesions and compare them with invisible low-grade dysplasia and sporadic adenomas from non-IBD patients.Methods22 polyps within areas of colitis, 13 polyps outside areas of colitis, 10 foci of invisible dysplasia from patients with IBD and 6 sporadic tubular adenomas from non-IBD patients were analysed using the OncoPanel assay.ResultsPolyps arising in areas of colitis showed a greater spectrum of mutations, includingAPC,KRAS,FBXW7,TP53,ARID1AandTCF7L2. Polyps outside colitis and non-IBD sporadic adenomas showed a limited mutational profile, withAPCandCTNNB1mutations. Invisible dysplasia was characterised byTP53,CTNNB1andKRASalterations. Compared with dysplastic polyps, none of the invisible dysplastic foci showedAPCalterations (73%—within colitis; p=0.0001, 92%—outside colitis; p<0.0001, 83%—sporadic adenomas; p=0.001).TP53mutations were significantly higher in invisible dysplasia (50%) compared with polyps within colitis (9%; p=0.02) and outside colitis (8%; p=0.03).ConclusionsMolecular alterations in visible low-grade dysplastic polyps with conventional intestinal-type dysplasia from patients with IBD and sporadic adenomas from non-IBD patients overlap significantly.APCalterations appear to play a major role in the development of visible low-grade dysplastic lesions in patients with IBD, regardless of background colitis. As with IBD-associated colorectal cancers,TP53mutations are an early event in the development of invisible, low-grade conventional intestinal-type dysplasia in patients with IBD.
Social media sensors as early signals of influenza outbreaks at scale
Authors: Martín-Corral David , García-Herranz Manuel , Cebrian Manuel , Moro Esteban 
Published: June 2024

AbstractDetecting early signals of an outbreak in a viral process is challenging due to its exponential nature, yet crucial given the benefits to public health it can provide. If available, the network structure where infection happens can provide rich information about the very early stages of viral outbreaks. For example, more central nodes have been used as social network sensors in biological or informational diffusion processes to detect early contagious outbreaks. We aim to combine both approaches to detect early signals of a biological viral process (influenza-like illness, ILI), using its informational epidemic coverage in public social media. We use a large social media dataset covering three years in a country. We demonstrate that it is possible to use highly central users on social media, more precisely high out-degree users from Twitter, as sensors to detect the early signals of ILI outbreaks in the physical world without monitoring the whole population. We also investigate other behavioral and content features that distinguish those early sensors in social media beyond centrality. While high centrality on Twitter is the most distinctive feature of sensors, they are more likely to talk about local news, language, politics, or government than the rest of the users. Our new approach could detect a better and smaller set of social sensors for epidemic outbreaks and is more operationally efficient and privacy respectful than previous ones, not requiring the collection of vast amounts of data.
Electrochemical and Theoretical Investigations on the Binding of Anticancer Drug Olaparib to Human Serum Albumin
Authors: Keciba Amina , Bakirhan Nurgul K. , Gözde Gündüz Miyase , Doulache Merzak , Saidat Boubakeur , Atici Esen Bellur , Ozkan Sibel A. 
Published: June 2024

This article explores the interaction between Olaparib (OLA), an anticancer drug, and human serum albumin (HSA) on a glassy carbon electrode using cyclic voltammetry and differential pulse voltammetry methods. The study investigates the alterations in the electrochemical behavior of [Fe(CN)6]3–/4– redox pairs in a physiological pH buffer solution due to the OLA-HSA interaction. The electrochemical and kinetic parameters of the redox probe were calculated in the presence of both the drug and protein. Notable variations in these parameters were observed, which can be attributed to the formation of an electro-inactive complex between the protein and drug. The study determined the parameters describing the OLA-HSA complex, including the binding constant and complex stoichiometry. The results revealed the formation of a strong singular drug-albumin complex with a binding constant of 1.12 × 105 M–1. Molecular docking studies supported the experimental findings and provided insights into the binding interactions of OLA with HSA. This study provides valuable insights for future research aimed at enhancing drug delivery systems.
Oncogenic Calreticulin Induces Immune Escape by Stimulating TGFβ Expression and Regulatory T-cell Expansion in the Bone Marrow Microenvironment
Authors: Schmidt Dominik , Endres Cornelia , Hoefflin Rouven , Andrieux Geoffroy , Zwick Melissa , Karantzelis Nikolaos , Staehle Hans F. , Vinnakota Janaki Manoja , Duquesne Sandra , Mozaffari Jovein Miriam , Pfeifer Dietmar , Becker Heiko , Blazar Bruce R. , Zähringer Alexander , Duyster Justus , Brummer Tilman , Boerries Melanie , Baumeister Julian , Shoumariyeh Khalid , Li Juan , Green Anthony R. , Heidel Florian H. , Tirosh Itay , Pahl Heike L. , Leimkühler Nils , Köhler Natalie , de Toledo Marcelo A.S. , Koschmieder Steffen , Zeiser Robert 
Published: June 2024

Abstract
Increasing evidence supports the interplay between oncogenic mutations and immune escape mechanisms. Strategies to counteract the immune escape mediated by oncogenic signaling could provide improved therapeutic options for patients with various malignancies. As mutant calreticulin (CALR) is a common driver of myeloproliferative neoplasms (MPN), we analyzed the impact of oncogenic CALRdel52 on the bone marrow (BM) microenvironment in MPN. Single-cell RNA sequencing revealed that CALRdel52 led to the expansion of TGFβ1-producing erythroid progenitor cells and promoted the expansion of FoxP3+ regulatory T cells (Treg) in a murine MPN model. Treatment with an anti-TGFβ antibody improved mouse survival and increased the glycolytic activity in CD4+ and CD8+ T cells in vivo, whereas T-cell depletion abrogated the protective effects conferred by neutralizing TGFβ. TGFβ1 reduced perforin and TNFα production by T cells in vitro. TGFβ1 production by CALRdel52 cells was dependent on JAK1/2, PI3K, and ERK activity, which activated the transcription factor Sp1 to induce TGFβ1 expression. In four independent patient cohorts, TGFβ1 expression was increased in the BM of patients with MPN compared with healthy individuals, and the BM of patients with MPN contained a higher frequency of Treg compared with healthy individuals. Together, this study identified an ERK/Sp1/TGFβ1 axis in CALRdel52 MPNs as a mechanism of immunosuppression that can be targeted to elicit T-cell–mediated cytotoxicity.
Significance: Targeting the mutant calreticulin/TGFβ1 axis increases T-cell activity and glycolytic capacity, providing the rationale for conducting clinical trials on TGFβ antagonists as an immunotherapeutic strategy in patients with myeloproliferative neoplasms.
High Gastric Cancer Mortality and Years of Life Lost in Nicaragua: A Population-Based Study 1997 to 2012
Authors: Peña-Galo Edgar M. , Palacios-Navarro Guillermo , Pastora-Membreño Javier , Torres-Herman Tatiana , Norwood Dalton A. , Montalvan-Sanchez Eleazar E. , Beasley Timothy , Bravo Luis E. , Morgan Douglas R. 
Published: June 2024

Abstract

Background:
Gastric adenocarcinoma is the fourth leading cause of cancer-related mortality and leading infection-associated cancer. Gastric adenocarcinoma has striking geographic variability, with high incidence in East Asia and mountainous Latin America. Reliable cancer data and population-based cancer registries are lacking for the majority of low- and middle-income countries, including the Central American Four region (CA-4, Nicaragua, El Salvador, Honduras, and Guatemala).

Methods:
Mortality data for Nicaragua were obtained from the highly rated Ministry of Health death registry. All the patients were diagnosed with gastric cancer between 1997 and 2012 (ICD-10 codes, C16.0–C16.9) and death due to any cause were included in the study. Data on variables such as sex, age (stratified by 5-year age groups), municipality, urban/rural, altitude, and year of death were analyzed.

Results:
A total of 3,886 stomach cancer deaths were reported in Nicaragua between 1997 and 2012, of which 2,214 (56.9%) were male. The age-standardized mortality rates were 13.1 and 8.7 per 100,000 habitants for males and females, respectively, and without significant change during the study period (annual percentage change = −0.7, P = 0.2). An average of 17.9 years were lost per death, accounting for 67,964 years of life lost (YLL).

Conclusions:
The burden of gastric cancer mortality is high in Nicaragua with a significantly elevated age-standardized mortality rate, YYL, and average YLL.

Impact:
The projected increase in mortality portends the double cancer burden in northern Central America, with persistent infection-associated cancers and growing transition cancers (e.g., breast and colon cancers), which has implications for cancer control in Mesoamerica and US Latino populations.
See related commentary by Riquelme and Abnet, p. 1550
Biomarker-Driven Personalized Immunoprevention: Toward More Efficient Clinical Trials?
Authors: Yendamuri Sai , Dragnev Konstantin H. 
Published: June 2024

AbstractIn this secondary analysis of specimens from the CANTOS trial, the investigators find that patients with clonal hematopoiesis mutations, particularly in the TET2 gene, predict a benefit of decreased cancer risk with the administration of the anti-IL1β agent canakinumab. Despite small numbers and the need for prospective validation, the findings are exciting as they demonstrate the potential for personalized chemoprevention approaches. Such personalized approaches can potentially enhance the feasibility of cancer prevention trials.See related article by Woo et al., p. 429
RNA-encoded Interleukin 2 with Extended Bioavailability Amplifies RNA Vaccine–Induced Antitumor T-cell Immunity
Authors: Peters Daniel , Kranz Lena M. , Eisel David , Diken Mustafa , Kreiter Sebastian , Türeci Özlem , Sahin Ugur , Vormehr Mathias 
Published: June 2024

Abstract
Interleukin 2 (IL-2) is a crucial cytokine in T-cell immunity, with a promising potential in cancer vaccines. However, therapeutic application of IL-2 is hampered by its short half-life and substantial toxicity. This study reports preclinical characterization of a mouse serum albumin–IL-2 fusion protein (Alb–IL2) encoded on nucleoside-modified RNA that is delivered via a nanoparticle formulation (Alb–IL2 RNA-NP) mediating prolonged cytokine availability. Alb–IL2 RNA-NP was combined with RNA-lipoplex (RNA-LPX) vaccines to evaluate its effect on the expansion of vaccine-induced antigen specific T-cell immunity. In mice dosed with Alb–IL2 RNA-NP, translated protein was shown to be systemically available up to 2 days, with an albumin-dependent preferred presence in the tumor and tumor-draining lymph node. Alb–IL2 RNA-NP administration prolonged serum availability of the cytokine compared with murine recombinant IL-2. In combination with RNA-LPX vaccines, Alb-IL2 RNA-NP administration highly increased the expansion of RNA-LPX vaccine–induced CD8+ T cells in the spleen and blood. The combination enhanced and sustained the fraction of IL-2 receptor (IL-2R) α-positive antigen-specific CD8+ T cells and ameliorated the functional capacity of the CD8+ T-cell population. Alb–IL2 RNA-NP strongly improved the antitumor activity and survival of concomitant RNA-LPX vaccination and PD-L1 blockade in a subcutaneous mouse tumor model. The favorable pharmacokinetic properties of Alb–IL2 RNA-NP render it an attractive modality for rationally designed combination immunotherapy. RNA vaccines that induce tumor-specific T-cell immunity for Alb–IL2 RNA-NP to further amplify are particularly attractive combination partners.
Projected Impact of Nonpharmacologic Management of Stage 1 Hypertension Among Lower-Risk US Adults
Authors: Sims Kendra D. , Wei Pengxiao Carol , Penko Joanne M. , Hennessy Susan , Coxson Pamela G. , Mukand Nita H. , Bellows Brandon K. , Kazi Dhruv S. , Zhang Yiyi , Boylan Ross , Moran Andrew E. , Bibbins-Domingo Kirsten 
Published: June 2024

BACKGROUND:
The 2017 American College of Cardiology/American Heart Association blood pressure guideline classified 31 million US adults as having stage 1 hypertension and recommended clinicians provide counseling on behavioral change to the low-risk portion of this group. However, nationwide reductions in cardiovascular disease (CVD) and associated health care expenditures achievable by nonpharmacologic therapy remain unquantified.

METHODS:
We simulated interventions on a target population of US adults aged 35 to 64 years, identified from the 2015–2018 National Health and Nutrition Examination Survey, with low-risk stage 1 systolic hypertension: that is, untreated systolic blood pressure 130 to 139 mm Hg with diastolic BP <90 mm Hg; no history of CVD, diabetes, or chronic kidney disease; and a low 10-year risk of CVD. We used meta-analyses and trials to estimate the effects of population-level behavior modification on systolic blood pressure. We assessed the extent to which restricting intervention to those in regular contact with clinicians might prevent the delivery of nonpharmacologic therapy.

RESULTS:
Controlling systolic blood pressure to <130 mm Hg among the 8.8 million low-risk US adults with stage 1 hypertension could prevent 26 100 CVD events, avoid 2900 deaths, and save $1.7 billion in total direct health care costs over 10 years. Adoption of the Dietary Approaches to Stop Hypertension diet could prevent 28 000 CVD events. Other nonpharmacologic interventions could avert between 3800 and 19 500 CVD events. However, only 51% of men and 75% of women regularly interacted with clinicians for counseling opportunities.

CONCLUSIONS:
Among low-risk adults with stage 1 hypertension, substantial benefits to cardiovascular health could be achieved through public policy that promotes the adoption of nonpharmacologic therapy.
Age-related unstable transient states and imbalanced activation proportion of brain networks in people with autism spectrum disorder: A resting-state fMRI study using coactivation pattern analyses
Authors: Zhang Yunge , Lin Lin , Zhou Dongyue , Song Yang , Stein Abigail , Zhou Shuqin , Xu Huashuai , Zhao Wei , Cong Fengyu , Sun Jin , Li Huanjie , Du Fei 
Published: June 2024

Abstract
The atypical static brain functions related to the executive control network (ECN), default mode network (DMN), and salience network (SN) in people with autism spectrum disorder (ASD) has been widely reported. However, their transient functions in ASD are not clear. We aim to identify transient network states (TNSs) using coactivation pattern (CAP) analysis to characterize the age-related atypical transient functions in ASD. CAP analysis was performed on a resting-state fMRI dataset (78 ASD and 78 healthy control (CON) juveniles, 54 ASD and 54 CON adults). Six TNSs were divided into the DMN-TNSs, ECN-TNSs, and SN-TNSs. The DMN-TNSs were major states with the highest stability and proportion, and the ECN-TNSs and SN-TNSs were minor states. Age-related abnormalities on spatial stability and TNS proportion were found in ASD. The spatial stability of DMN-TNSs was found increasing with age in CON, but was not found in ASD. A lower proportion of DMN-TNSs was found in ASD compared with CON of the same age, and ASD juveniles had a higher proportion of SN-TNSs while ASD adults had a higher proportion of ECN-TNSs. The abnormalities on spatial stability and TNS proportion were related to social deficits. Our results provided new evidence for atypical transient brain functions in people with ASD.
A generative model of the connectome with dynamic axon growth
Authors: Liu Yuanzhe , Seguin Caio , Betzel Richard F. , Han Daniel , Akarca Danyal , Di Biase Maria A. , Zalesky Andrew 
Published: June 2024

Abstract
Connectome generative models, otherwise known as generative network models, provide insight into the wiring principles underpinning brain network organization. While these models can approximate numerous statistical properties of empirical networks, they typically fail to explicitly characterize an important contributor to brain organization—axonal growth. Emulating the chemoaffinity-guided axonal growth, we provide a novel generative model in which axons dynamically steer the direction of propagation based on distance-dependent chemoattractive forces acting on their growth cones. This simple dynamic growth mechanism, despite being solely geometry-dependent, is shown to generate axonal fiber bundles with brain-like geometry and features of complex network architecture consistent with the human brain, including lognormally distributed connectivity weights, scale-free nodal degrees, small-worldness, and modularity. We demonstrate that our model parameters can be fitted to individual connectomes, enabling connectome dimensionality reduction and comparison of parameters between groups. Our work offers an opportunity to bridge studies of axon guidance and connectome development, providing new avenues for understanding neural development from a computational perspective.
Aerobic Exercise Improves Heart Rate Variability After an Implantable Cardioverter Defibrillator (ICD)
Authors: Dougherty Cynthia M. , Cordoza Makayla , Wang Di , Alsoyan Afnan Hamad , Stein Phyllis K. , Burr Robert L. 
Published: June 2024

Purpose: The purpose of the study was to determine the effect of moderately strenuous aerobic exercise training on heart rate variability (HRV) and heart rate turbulence (HRT) in patients with an implantable cardioverter defibrillator (ICD). Methods: Patients were randomized to a 24-week home-based aerobic exercise (EX) training program ( n = 84) or to usual care (UC) ( n = 76). All subjects underwent 24-h Holter monitoring at baseline, 8 and 24 weeks. Generalized estimating equations were used to test the effects of exercise on HRV and HRT outcomes. Results: The study group was comprised of n = 160 patients (124 M, 36 F, age 54.9 ± 12.2 years) with an ICD for primary (43%) or secondary prevention (57%). Compared to UC, EX was associated with a significant improvement in parasympathetic HRV for root mean square of successive differences (rMSSD; p = .05) at 8 weeks and global HRV for standard deviation of all normal (N-N) intervals (SDNN; p = .05) and standard deviation of 5-min averages N-N intervals (SDANN; p = .03) at 24 weeks. When stratified by adherence, those who were ≥80% adherent (minutes/week) had significant improvements in parasympathetic HRV (rMSSD, pNN50) and global HRV (SDNN, SDANN) at 8 weeks, and a further significant improvement in global HRV (SDNN, SDANN, SDNN index) at 24 weeks. Neither HRT nor ventricular ectopy changed with exercise training. Conclusion: Moderately strenuous aerobic exercise improved parasympathetic and global HRV indices following an ICD, with greater adherence associated with greater improvements. Clinical trial registration Clinicaltrials.gov: NCT 00522340.
Odontogenic Maxillary Sinusitis Microbiology Compared With Chronic Rhinosinusitis: A Meta-Analysis
Authors: Lu Chang , Zhao Yue , Qin Yicheng , Zhang Xi , Yang Xiaozhe , Zhao Yan , Wang Xiangdong , Lin Jiang 
Published: June 2024

Background Subtypes of sinusitis have different symptoms and prognoses due to different pathogens. Odontogenic maxillary sinusitis (OMS) mainly occurs unilaterally and is different from chronic rhinosinusitis (CRS) usually occurring bilaterally in terms of clinical characteristics. However, comprehensive microbiological comparisons between OMS and CRS have never been systematically conducted and most comparisons are methodologically biased. This study aims to provide a comprehensive analysis of the microbiology associated with OMS and CRS through a meta-analysis approach in order to provide evidence for differential diagnosis of OMS and CRS from a microbiological perspective. Methods The databases PubMed and CNKI were searched from their inception to July 2023. A random-effects model was employed to derive the pooled prevalence estimates of the identified bacterial species or genera. Results The 17 represented studies included 6 concerning OMS, 12 concerning CRS, and 4 concerning normal sinus, yielding 191, 610, and 92 samples, respectively. Though not statistically significant, the prevalence of Peptostreptococcus and Prevotella was generally higher in OMS compared to CRS. Notably, Fusobacterium was identified as the only genus with a significantly higher prevalence in OMS compared to CRS. Conclusion Fusobacterium was significantly more prevalent in OMS compared with CRS, while Staphylococcus aureus was more prevalent in CRS than in OMS. Such differences in bacterial profile may partly explain the distinct pathology observed and contribute to the development of novel strategies for diagnosis and therapeutic interventions in OMS.