bluuebunny/crossref_metadata_2025 huggingface dataset:
Control of inflammatory lung injury and repair by metabolic signaling in endothelial cells
Authors: Gould Seth , Herron Ansley , Davis Jonathan , Phillips Mollie , Chakrabarti Mrinmay , Evans Colin E.
Published: October 2024

Purpose of review

Sepsis-induced inflammatory lung injury includes acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). There are currently no effective treatments for ALI/ARDS, but clinical outcomes could be improved by inhibiting lung injury and/or promoting post-sepsis vascular repair. In this review, we describe studies of endothelial cell metabolic pathways in sepsis-induced ALI/ARDS and vascular repair and identify areas of research that deserve attention in future studies. We also describe studies of metabolic interventions that aim to inhibit ALI/ARDS and/or promote post-sepsis vascular repair, including those that target endothelial cell metabolites, endothelial cell metabolic signaling pathways, and endothelial cell metabolism.

Recent findings

Endothelial cells are integral to both the injury and repair phases of ALI/ARDS. During the injury phase of ALI/ARDS, lung endothelial cell survival decreases, and lung endothelial cell-to-endothelial cell (EC-EC) junctions are weakened. During the repair phase after sepsis-induced lung injury, lung endothelial cell proliferation and lung EC-EC junction reannealing occur. These crucial aspects of ALI/ARDS and post-sepsis vascular repair, that is, endothelial cell viability, growth, and junction integrity, are controlled by a myriad of metabolites and metabolic signaling pathways in endothelial cells.

Metabolic signaling pathways in endothelial cells represent a novel class of putative targets for the prevention and treatment of sepsis-induced inflammatory lung injury. Therapies that target metabolic signaling in endothelial cells are currently being explored as potential treatments for sepsis-induced inflammatory lung injury.
Distinct roles of size-defined HDL subpopulations in cardiovascular disease
Authors: Davidson W. Sean , Vaisar Tomas , Heinecke Jay W. , Bornfeldt Karin E.
Published: October 2024

Purpose of review

Doubts about whether high-density lipoprotein-cholesterol (HDL-C) levels are causally related to atherosclerotic cardiovascular disease (CVD) risk have stimulated research on identifying HDL-related metrics that might better reflect its cardioprotective functions. HDL is made up of different types of particles that vary in size, protein and lipid composition, and function. This review focuses on recent findings on the specific roles of HDL subpopulations defined by size in CVD.

Recent findings

Small HDL particles are more effective than larger particles at promoting cellular cholesterol efflux because apolipoprotein A-I on their surface better engages ABCA1 (ATP binding cassette subfamily A member 1). In contrast, large HDL particles bind more effectively to scavenger receptor class B type 1 on endothelial cells, which helps prevent LDL from moving into the artery wall. The specific role of medium-sized HDL particles, the most abundant subpopulation, is still unclear.

HDL is made up of subpopulations of different sizes of particles, with selective functional roles for small and large HDLs. The function of HDL may depend more on the size and composition of its subpopulations than on HDL-C levels. Further research is required to understand how these different HDL subpopulations influence the development of CVD.
Analysis of factors influencing the surgical treatment outcomes of spinal injuries in polytrauma patients
Authors: Sun Xiangyao , Huang Jiang , Wang Weiliang , Gan Limeng , Cao Li , Liu Yuqi , Sun Siyuan , Wang Juyong , Lu Shibao
Published: October 2024

Background:

This study aims to analyze the diagnosis and treatment conditions of polytrauma patients with spinal injuries, to clarify the site of the first surgical intervention, the timing of the surgery, and factors influencing prognosis.

Methods:

This study collected and analyzed data on polytrauma patients with spinal injuries who were treated from January 2017 to January 2023. Data collected primarily included basic patient information, treatment strategy-related information, clinical scoring systems, imaging parameters, and prognosis. The impacts of relevant variables on postoperative survival outcomes were analyzed.

Results:

This study included 60 patients. There was no significant change in the number of patients rated ASIA grade E after 90 days of admission, while there was a significant increase in those rated grade D (P<0.001). Among the groups, patients operated on within less than 12 h had the highest number of ASIA grade A, while those operated on after more than 48 h had the highest number of ASIA grade E (P=0.003). The survival rate of patients who underwent their first spinal surgery between 12 and 48 h was significantly better than those operated earlier than 12 h or later than 48 h (P=0.047). Patients who experienced hemorrhagic shock postsurgery had the lowest survival rate (P<0.001). Only age (P=0.004) and the number of surgeries outside the spine (P=0.033), as covariates, were significantly correlated with patient mortality (R2=0.519).

Conclusions:

Performing spinal surgery too early or too late can adversely affect patient outcomes; the appropriate timing of surgery should be chosen based on the specific characteristics of the patient. In polytrauma patients under emergency conditions, the use of combined surgical treatments should be minimized to prevent the occurrence of a ‘second hit’. Patients who experience hemorrhagic shock have the worst postsurgical survival; targeted treatment should be administered upon hospital admission.
MELAS Presenting as Bilateral Symmetric Occipital and Temporal Cortices Lesions
Authors: Liu Qing , Wang Zhaoxia , Shi Jing , Wang Wenxia , Wen Chao , Zhu Yanping , Chen Xuan , Xing Xiaolian , Su Yangli
Published: October 2024

Introduction:

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode (MELAS) is one of the most common maternally inherited mitochondrial diseases. The stroke-like episode affecting the cortical cortex is the hallmark of MELAS; however, it rarely presents as simultaneously bilateral symmetric cortices lesions.

Case Report:

We reported a case of MELAS in a 46-year-old female patient with bilateral symmetric occipital and internal temporal cortices involvements on brain magnetic resonance imaging (MRI). A literature review of MELAS patients and a retrospective analysis were performed. She had a family history of diabetes. Although she denied a history of diabetes, elevated blood glucose was noted after admission, and diabetes was diagnosed. Laboratory examination revealed elevated lactate acid and creatine kinase levels in blood. Cranial computed tomography (CT) image demonstrated basal ganglia calcification, as well as subtle decreased attenuation in bilateral symmetric occipital and internal temporal cortices. Brain magnetic resonance imaging (MRI) demonstrated symmetric gyriform hyperintensity in bilateral occipital lobes and internal temporal lobes in both grey and white matter on fluid-attenuated inversion recovery (FLAIR) images with restricted diffusion on diffusion weighted images (DWI). A genetic test revealed a point mutation in the mtDNA(3243A > G) by blood examination. Literature review showed that there were 231 eligible patients with MELAS identified from 212 published papers. Symmetric cortical involvements were seen in 15 (6.5%) patients on brain MRI.

Conclusions:

MELAS should be considered as a potential diagnosis in the patients with bilateral symmetric stroke-like cortices lesions.
SS18-SSX Expression and Clinicopathologic Profiles in a Contemporary Cohort of Primary Paratesticular Synovial Sarcoma
Authors: Lobo Anandi , Mishra Sourav K. , Acosta Andres M. , Kaushal Seema , Akgul Mahmut , Williamson Sean R. , Sangoi Ankur R. , Aron Manju , Kandukuri Shivani R. , Shinde Sayali , Sharma Shivani , Jain Ekta , Dhillon Jasreman , Deshwal Akansha , Peddinti Kamal , Jaiswal Sunil , Das Sthiti , Kapoor Rahul , Biswas Ghanashyam , Pradhan Manas R. , Osunkoya Adeboye O. , Pradhan Dinesh , Chakrabarti Indranil , Jha Shilpy , Parwani Anil V. , Shah Rajal B. , Amin Mahul B. , Cheng Liang , Mohanty Sambit K.
Published: October 2024

Synovial sarcoma (SS) is a rare genitourinary malignancy with a specific SS18::SSX 1/2 gene fusion in majority of the instances. The paratesticular location of this neoplasm is extremely rare and only 4 cases are reported in the literature. Herein, we describe the clinicopathologic features and molecular profile of paratesticular SS in the largest case series to date and to the best of our knowledge, and the only series to use novel SS18-SSX antibody for immunohistochemistry. Clinicopathologic, immunohistochemical (IHC), molecular, treatment, and follow-up data of the patients were analyzed. There were 14 patients, ranging from 15 to 47 years (mean: 30 y). The tumor size ranged from 4​​​​​​ to 15 cm. The tumors were unilateral, solid, and homogeneous tan-white with monomorphic spindle cell histology. All 14 tumors expressed SS18-SSX and TLE1 IHC and harbored SS18 rearrangement. In addition, the tumor with multifocal SS18-SSX expression had lower break-apart signals in the FISH assay (38% of the tumor cells; range: 29% to 85%). Radical orchiectomy was performed in all 14 patients and adjuvant chemotherapy was administered in 9 patients. Follow-up was available in 9 patients. The follow-up duration ranged from 5 to 24 months (median=10 mo). Four patients died of metastatic disease (range: 5 to 16 mo) and 2 patients who are alive had metastatic disease at the last follow-up. Based on our experience with the largest series to date and aggregate of the published data, paratesticular SS has a poor prognosis despite aggressive therapy. Owing to its rarity, the differential diagnosis is wide and requires a systematic approach for ruling out key morphologic mimics aided with SS18-SSX IHC and molecular confirmation because this distinction carries important therapeutic and prognostic implications. Due to the excellent concordance of SS18-SSX IHC results with FISH results as observed in our study, we would like to suggest inclusion of SS18-SSX in the diagnostic immunohistochemistry panel of all spindle cell sarcomas where synovial sarcoma is considered as a morphologic differential. SS18-SSX-positive staining may be used as a surrogate for FISH assay in a resource-limited setting where molecular assay is not available. Furthermore, IHC has a fairly shorter turn-around-time, is less complex, and of low cost.
Sex differences in tuberculosis infection and disease among people with HIV
Authors: Chaisson Lelia H. , Durovni Betina , Umar Nasir , Cohn Silvia , Moulton Lawrence H. , Scully Eileen , Cavalcante Solange , Golub Jonathan E. , Chaisson Richard E. , Saraceni Valeria
Published: October 2024

Objectives:

Worldwide, adult men experience an excess burden of tuberculosis (TB) disease compared with women, but few studies have examined sex differences in TB among people with HIV. In this study, we aimed to investigate sex differences in TB infection and disease among people with HIV in Rio de Janeiro, Brazil.

Design:

Analysis of data from a randomized controlled trial and retrospective cohort study.

Methods:

We analyzed data from two studies conducted between 2005 and 2017. The THRio Study (2005–2012) evaluated increasing tuberculin skin testing (TST) and TB preventive therapy (TPT), and Universal ART in Rio study (UnivART; 2010–2017) was a virtual cohort study of people with HIV and TB with data from four national electronic registries.

Results:

Among 4606 people with HIV in THRio, 2992 (65.0%) had a TST placed and read, of whom 312 of 1865 (17%) males and 203 of 1127 (18%) females (P = 0.37) had prevalent TB infection. TB disease incidence was higher among males compared with females overall [IRR 1.33, 95% confidence interval (95% CI) 1.04–1.69], among males compared with females who did not receive TPT [incidence rate ratios (IRR) 1.30, 95% CI 1.01–1.67], and among males compared with females on ART (IRR 1.64, 95% CI 1.17–2.29). Among 54 957 people with HIV in UnivART, TB disease incidence rates were higher among males than females overall (IRR 1.28, 95% CI 1.18–1.39), among males compared with females on ART (IRR 1.58, 95% CI 1.40–1.77), and among males compared with females not on ART (IRR 1.11, 95% CI 0.99–1.25).

Conclusion:

In this medium TB and HIV burden setting, TB disease incidence was higher among males than females with HIV, despite similar prevalence of TB infection.
Biomarkers of microbial translocation and generalized inflammation are associated with frailty among people with HIV
Authors: Ruderman Stephanie A. , Hunt Peter W. , Beck-Engeser Gabriele , Ambayec Gabrielle , Willig Amanda L. , Saag Michael S. , Napravnik Sonia , Cachay Edward , Bamford Laura , Landay Alan , Drumright Lydia N. , Mixson L. Sarah , Whitney Bridget M. , Nance Robin M. , Kitahata Mari M. , Crane Heidi M. , Delaney Joseph A.C. , Hahn Andrew W.
Published: October 2024

Background:

Frailty occurs at higher rates and younger ages among people with HIV (PWH) compared with the general population and is often attributed to chronic inflammation and subsequent immune exhaustion. We assessed how inflammatory biomarkers are associated with frailty among PWH.

Methods:

The Centers for AIDS Research (CFAR) Network of Integrated Clinical Systems (CNICS) cohort is comprised of adult PWH in care at 10 sites, and harmonizes demographic, clinical, and patient-reported outcomes (PRO) data. A panel of 13 inflammatory biomarkers was collected from a subset of virally suppressed PWH once per person between 2010 and 2018. Frailty was measured with a validated PRO phenotype, scored 0–4, from biomarker collection date through July 2022. With adjusted linear mixed models, we estimated longitudinal associations between standard deviation-scaled log2-transformed biomarkers and frailty score.

Results:

Among 273 PWH, most were men (91%), average age at baseline was 45, 42% were non-Hispanic White whereas 35% were non-Hispanic Black, and average follow-up time was 5.5 years. Several biomarkers were associated with higher frailty, including those linked to microbial translocation (sCD14, LBP, KT ratio) and systemic inflammation (CRP, IL-6, suPAR, sTNFR1, sTNFR2). Higher IL-6 was associated with a 0.25-point higher frailty score [95% confidence interval (CI) 0.12–0.39]. Higher sTNFR1 [0.35 (0.13–0.56)], sCD14 [0.21 (0.11–0.31)], and suPAR [0.24 (0.11–0.36)] levels were also associated with higher frailty scores over follow-up.

Conclusion:

Higher levels of biomarkers linked to microbial translocation and systemic inflammation are associated with higher average frailty scores over time in a cohort of virally suppressed PWH, highlighting these pathways as potential interventional targets for mitigating frailty in PWH.
FLUID OVERLOAD MODIFIES HEMODYNAMIC IMPACT OF CONTINUOUS RENAL REPLACEMENT THERAPY: EVIDENCE OF A COVERT CARDIORENAL SYNDROME?
Authors: Thadani Sameer , Lang Anna , Silos Christin , Price Jack , Gelbart Ben , Typpo Katri , Horvat Christopher , Fuhrman Dana Y. , Neumayr Tara , Arikan Ayse Akcan
Published: October 2024

Background: Fluid overload (FO) in critically ill children correlates with higher morbidity and mortality rates. Continuous renal replacement therapy (CRRT) is commonly employed to manage FO. In adults, both FO and CRRT adversely affect myocardial function. It remains unclear if children experience similar cardiovascular effects. Methods: Observational single-center study on children (<18 years) receiving CRRT at Texas Children’s Hospital from 11/2019 to 3/2021. Excluded were those with end-stage renal disease, pacemakers, extracorporeal membrane oxygenation, ventricular assist devices, apheresis, or without an arterial line. Electrocardiometry (ICON Osypka Medical GmbH, Berlin, Germany) which is noninvasive and utilizes bioimpedance, was applied to obtain hemodynamic data over the first 48 h of CRRT. Our aim was to identify how FO >15% affects hemodynamics in children receiving CRRT. Results: Seventeen children, median age 43 months (interquartile range [IQR] 12–124), were included. The median FO at CRRT initiation was 14.4% (2.4%–25.6%), with 9 (53%) patients having FO >15%. Differences were noted in systemic vascular resistance index (1,277 [IQR 1088–1,666] vs. 1,030 [IQR 868–1,181] dynes/s/cm5/m2, P < 0.01), and cardiac index (3.90 [IQR 3.23–4.75] vs. 5.68 [IQR 4.65–6.32] L/min/m2, P < 0.01), with no differences in heart rate or mean arterial pressure between children with and without FO. Conclusion: FO affects the hemodynamic profile of children on CRRT, with those having FO >15% showing higher systemic vascular resistance index and lower cardiac index, despite heart rate and mean arterial pressure remaining unchanged. Our study illustrates the feasibility and utility of electrocardiometry in these patients, suggesting future research employ this technology to further explore the hemodynamic effects of dialysis in children.
ZBTB16 DRIVES VASCULAR CALCIFICATION THROUGH ACCELERATING VSMCS OSTEOBLASTIC TRANSITION IN CHRONIC KIDNEY DISEASE VIA WNT/Β-CATENIN PATHWAY
Authors: Shen Yan , Huang Huaxing , Shen Lianglan , Yao Wubin , Wang Rong , Kang Meizi , Huang Jiashan , Xie Yan , Yang Hongli
Published: October 2024

Chronic kidney disease (CKD)-related vascular calcification (VC) is a common degenerative phenomenon of the vessel wall and its pathological basis is the phenotypic transformation of vascular smooth muscle cells (VSMCs). Zinc finger and BR-C (Broad-Complex), ttk (tramtrack), and bab (bric à brac) (BTB) domain containing 16 (ZBTB16) have been reported to be expressed in the aortic tissues in a rat model of VC. This work is conducted to reveal the functions of ZBTB16 on VC in CKD and to probe its involved reaction mechanisms. In vivo CKD rat models were established by adenine and VSMC calcification were stimulated with high phosphate (Pi) in vitro. Renal function indexes were estimated with relevant assay kits. Renal tissues were histologically examined with hematoxylin and eosin staining. Alizarin red and von kossa staining were used to measure arterial calcification. Reverse transcription-quantitative PCR and western blot were used to detect ZBTB16 expression. Western blot, immunohistochemistry, and immunofluorescence staining were used to detect osteogenic markers and smooth muscle cell markers. Western blot was used to measure the expressions of proteins implicated in Wnt/β-catenin pathway. In the blood samples of CKD patients with VC, aortic tissues of CKD rats, and Pi-treated VSMCs, ZBTB16 expression was significantly increased. ZBTB16 knockdown reduced renal dysfunction, calcium deposition and inhibited VSMCs osteoblast differentiation both in vitro and in vivo. Moreover, silencing with ZBTB16 inactivated Wingless-related integration site (Wnt)/β-catenin pathway. LiCl (Wnt/β-catenin agonist) reversed the protective effects of ZBTB16 knockdown on the calcification and osteoblastic transformation in vitro. Together, ZBTB16 silencing may downregulate Wnt/β-catenin pathway to protect against CKD-associated VC via repressing the osteoblastic transformation of VSMCs.
PREDICTING UNPLANNED TRAUMA INTENSIVE CARE UNIT ADMISSIONS FOR INITIAL NONOPERATIVE, NON-ICU PATIENTS
Authors: Zander Tyler , Kendall Melissa A. , Grimsley Emily A. , Harry Shamir C. , Torikashvili Johnathan V. , Parikh Rajavi , Sujka Joseph , Kuo Paul C.
Published: October 2024

Introduction: Unplanned intensive care unit (ICU) admissions are associated with increased morbidity and mortality. This study uses interpretable machine learning to predict unplanned ICU admissions for initial nonoperative trauma patients admitted to non-ICU locations. Methods: TQIP (2020–2021) was queried for initial nonoperative adult patients admitted to non-ICU locations. Univariable analysis compared patients who required an unplanned ICU admission to those who did not. Using variables that could be known at hospital admission, gradient boosting machines (CatBoost, LightGBM, XGBoost) were trained on 2021 data and tested on 2020 data. SHapley Additive exPlanations (SHAP) were used for interpretation. Results: The cohort had 1,107,822 patients; 1.6% had an unplanned ICU admission. Unplanned ICU admissions were older (71 [58–80] vs. 61 [39–76] years, P < 0.01), had a higher Injury Severity Score (ISS) (9 [8–13] vs. 9 [4–10], P < 0.01), longer length of stay (11 [7–17] vs. 4 [3–6] days, P < 0.01), higher rates of all complications, and most comorbidities and injuries (P < 0.05). All models had an AUC of 0.78 and an F1 score of 0.12, indicating poor performance in predicting the minority class. Mean absolute SHAP values revealed ISS (0.46), age (0.29), and absence of comorbidities (0.16) as most influential in predictions. Dependency plots showed greater SHAP values for greater ISS, age, and presence of comorbidities. Conclusions: Machine learning may outperform prior attempts at predicting the risk of unplanned ICU admissions in trauma patients while identifying unique predictors. Despite this progress, further research is needed to improve predictive performance by addressing class imbalance limitations.
MULTIPLE ORGAN FAILURE FOLLOWING SEVERE BATTLE INJURIES DURING RECENT CONFLICTS: A FRENCH RETROSPECTIVE COHORT STUDY
Authors: Schmitt Johan , Jacques Sébastien Cloé , Herzog Nicolas , Boutonnet Mathieu , Giacardi Christophe , Danguy des Déserts Marc , Martinez Thibault
Published: October 2024

Introduction: Improvements in combat casualty care have increased survival rates, but these patients are at particular risk of developing multiple organ failure (MOF). We investigated the incidence and severity of MOF in a cohort of severe combat casualties. Materials and Methods: This retrospective study included all on-duty French land army war casualties with a severe combat injury requiring intensive care unit admission during 2009–2023. Demographic data, advanced life support interventions, and outcomes were collected. Each organ failure was then analyzed during a 7-day trauma course according to the Sequential Organ Failure Assessment score. Results: Of the 100 patients who met the inclusion criteria, those with persistent MOF at day 4 (MOF group) represented 22% of the total population (median Sequential Organ Failure Assessment score 6.0 [5.3–8.0]). Compared to those without persistent MOF, these patients were more severely injured (median Military Injury Severity Score 38.0 [interquartile range 33.0–56.8] vs. 26.5 [20.0–34.0], P < 0.001) by an explosive mechanism (68.2%) and sustained more traumatic brain injury (40.9% vs. 14.1%, P = 0.013). The MOF group also received significantly more blood units (median 14.0 [8.3–24.8] vs. 6.0 [0.0–12.0], P < 0.001) and massive transfusions (68.2% vs. 32.1%, P = 0.002). Pulmonary and cardiovascular dysfunction were the most frequently observed trauma outcomes. A multivariable logistic regression model showed that MOF persistence at day 4 was significantly associated (odds ratios [95% confidence intervals]) with severe injuries (1.5 [1–2.3], P = 0.042). Conclusion: A high number of severe lesions significantly and independently increased risk of MOF persistence at day 4 after combat-related trauma. These findings are particularly relevant to current and anticipated large-scale combat operations that will challenge battlefield casualty care and evacuation.
EUGENOL RESTRAINS ANGIOTENSIN II-INDUCED DEATH, INFLAMMATION AND FERROPTOSIS OF VASCULAR SMOOTH MUSCLE CELLS BY TARGETING STAT3/HMGB2 AXIS
Authors: Huang Birun , Chen Haiyan , Zhang Xiulan
Published: October 2024

Background: Eugenol has been found to inhibit a variety of disease processes, including abdominal aortic aneurysm (AAA) formation. However, the specific role and the underlying molecular mechanism of Eugenol in AAA progression need to be further revealed. Methods: Vascular smooth muscle cells (VSMCs) were pretreated with Eugenol, followed by treated with Angiotensin II (Ang-II). VSMCs were transfected with HMGB2 siRNA or overexpression vector and treated with Ang-II to confirm the effect of HMGB2 on AAA progression. Cell proliferation and death were determined using cell counting kit 8 assay, 5-ethynyl-2′-deoxyuridine assay, and flow cytometry. Inflammatory factors were examined by ELISA. Fe2+, glutathione, and malondialdehyde levels were tested to evaluate cell ferroptosis. The protein levels of ferroptosis-related markers, high mobility group box 2 (HMGB2), and STAT3 were measured using western blot. Human AAA tissues and normal abdominal aortic tissues were collected to detect HMGB2 mRNA expression by quantitative real-time PCR. The interaction between HMGB2 and STAT3 was confirmed by chromatin immunoprecipitation assay and dual-luciferase reporter assay. Results: Eugenol enhanced VSMCs proliferation, while restrained Ang-II-induced death, inflammation, and ferroptosis. HMGB2 was upregulated in AAA tissues and Ang-II-induced VSMCs, and Eugenol significantly decreased HMGB2 expression. HMGB2 knockdown reduced Ang-II-induced VSMCs death, inflammation, and ferroptosis, Besides, HMGB2 overexpression abolished the effect of Eugenol on Ang-II-induced VSMCs injury. Transcription factor STAT3 bound to HMGB2 promoter region to increase its expression. In addition, Eugenol decreased STAT3 expression to regulate HMGB2. Conclusion: Eugenol could slow down the development of AAA, which might be achieved by regulating STAT3/HMGB2 axis.
Efficacy and safety of double-dose statin monotherapy versus moderate-intensity statin combined with ezetimibe dual therapy in diabetic patients: a systematic review and meta-analysis of randomized controlled trials
Authors: Goyal Aman , Tariq Muhammad Daoud , Jain Hritvik , Shrestha Abhigan Babu , Fatima Laveeza , Riyaz Romana , Yadav Hritik Raj , Safi Darsh , Yasinzai Abdul Qahar K. , Khan Rozi , Sohail Amir Humza , Daoud Mohamed , Sheikh Abu Baker
Published: October 2024

Cardiovascular disease is a leading cause of mortality, especially in individuals with type 2 diabetes mellitus and dyslipidemia. Despite adequate statin therapy, some patients fail to achieve the target low-density lipoprotein-cholesterol levels. Trials have compared doubling the statin dose with the addition of ezetimibe. A systematic literature search was performed using various databases. Forest plots were constructed for pooled analysis with statistical significance set at P < 0.05. Seven trials were included. Monotherapy showed no significant difference compared with dual therapy for low-density lipoprotein-cholesterol levels [mean difference (MD): −5.03; P = 0.37], high-density lipoprotein-cholesterol levels (MD: 0.01; P = 0.95), total cholesterol (MD: −2.38; P = 0.66), and triglycerides (MD: 5.37; P = 0.67) at follow-up compared to baseline. Monotherapy significantly reduced serious clinical adverse events (risk ratio: 0.21; P = 0.04), with no difference in treatment-related adverse effects, discontinuation due to treatment-related or overall adverse events.
The legacy and evolvability of Pere Alberch’s ideas
Authors: Nuño de la Rosa Laura , Müller Gerd B.
Published: October 2024

Pere Alberch played a pivotal role in shaping the field of evolutionary developmental biology during the 1980s and 1990s. Whereas initially his contributions were sidelined by the empirical advancements of the molecular revolution in developmental and evolutionary biology, his theoretical insights have left a lasting impact on the discipline. This article provides a comprehensive review of the legacy and evolvability of Alberch’s ideas in contemporary evo-devo, which included the study of morphogenesis as the proper level of developmental causation, the interplay between developmental constraints and natural selection, the epistemic role of teratologies, the origin of evolutionary novelties and the concept of evolvability.
Detection of butyrate from a Clostridium cluster I (Clostridium sensu stricto) strain, Clostridium tertium, under anaerobic condition
Authors: Miyazaki Mei , Kaneko Nanako , Hardy Nicholas , Iwai Hiroki
Published: October 2024

Lactic acid bacteria and bacillus bifidus are well-known as probiotics used as alternative drugs confronting infectious disease, however, butyric acid (butyrate) bacteria such as Clostridium butyricum are also useful probiotics but little-known in any part of the world. To discover a new bacteria species producing butyrate, we examined the production of organic acid including butyrate in Clostridium tertium and C. butyricum. Protein BLAST (BLASTP) searches on Butyrate kinase (BUK) proteins in the genomes of C. tertium have identified 2 proteins. To confirm their presence in the genome of C. tertium, we detected two buk genes by the polymerase chain reaction (PCR). As phosphotransbutyrylase (ptb), a buk gene adjacent gene, is also present in the announced genome of C. tertium, we confirmed its presence similarly by PCR. Next, we investigated the production of butyrate in C. tertium. Lactic acid (lactate), formic acid (formate), acetic acid (acetate) and butyrate were detected in both thioglycolate medium cultures. Thus, we conclude C. tertium produces butyrate. Our findings provide a new butyrate producing bacterium as a potential probiotic.
Ethylene and epoxyethane metabolism in methanotrophic bacteria: comparative genomics and physiological studies using Methylohalobius crimeensis
Authors: Toppings Noah , Marshall Meghan , Smirnova Angela V. , Sheremet Andriy , Pasala Anthony S. , Nwosu Felix C. , Hepburn Morgan , Lewis Ian , Coleman Nicholas V. , Dunfield Peter F.
Published: October 2024

The genome of the methanotrophic bacterium Methylohalobius crimeensis strain 10Ki contains a gene cluster that encodes a putative coenzyme-M (CoM)-dependent pathway for oxidation of epoxyethane, based on homology to genes in bacteria that grow on ethylene and propylene as sole substrates. An alkene monooxygenase was not detected in the M. crimeensis genome, so epoxyethane is likely produced from co-oxidation of ethylene by the methane monooxygenase enzyme. Similar gene clusters were detected in about 10% of available genomes from aerobic methanotrophic bacteria, primarily strains grown from rice paddies and other wetlands. The sparse occurrence of the gene cluster across distant phylogenetic groups suggests that multiple lateral gene transfer events have occurred in methanotrophs. In support of this, the gene cluster in M. crimeensis was detected within a large genomic island predicted using multiple methods. Growth studies, reverse transcription-quantitative PCR (RT-qPCR) and proteomics were performed to examine the expression of these genes in M. crimeensis. Growth and methane oxidation activity were completely inhibited by the addition of >0.5% (v/v) ethylene to the headspace of cultures, but at 0.125% and below, the inhibition was only partial, and ethylene was gradually oxidized. The etnE gene encoding epoxyalkane:CoM transferase was strongly upregulated in ethylene-exposed cells based on RT-qPCR. Proteomics analysis confirmed that EtnE and nine other proteins encoded in the same gene cluster became much more predominant after cells were exposed to ethylene. The results suggest that ethylene is strongly inhibitory to M. crimeensis, but the bacterium responds to ethylene exposure by expressing an epoxide oxidation system similar to that used by bacteria that grow on alkenes. In the obligate methanotroph M. crimeensis, this system does not facilitate growth on ethylene but likely alleviates toxicity of epoxyethane formed through ethylene co-oxidation by particulate methane monooxygenase. The presence of predicted epoxide detoxification systems in several other wetland methanotrophs suggests that co-oxidation of ambient ethylene presents a stress for methanotrophic bacteria in these environments and that epoxyethane removal has adaptive value.
Super Resolved Single-Cell Spatial Metabolomics from Multimodal Mass Spectrometry Imaging guided by Imaging Mass Cytometry
Authors: Ozturk Efe , Venkataraman Abhijeet , Rivera Moctezuma Felix G. , Coskun Ahmet F.
Published: October 2024

Mass spectrometry imaging (MSI) is a powerful technique for spatially resolved analysis of metabolites and other biomolecules within biological tissues. However, the inherent low spatial resolution of MSI often limits its ability to provide detailed cellular-level information. To address this limitation, we propose a guided super-resolution (GSR) approach that leverages high-resolution Imaging Mass Cytometry (IMC) images to enhance the spatial resolution of low-resolution MSI data. By using these detailed IMC images as guides, we improve the resolution of MSI images, creating high-resolution metabolite maps. This enhancement facilitates more precise analysis of cellular structures and tissue architectures, providing deeper insights into super-resolved spatial metabolomics at the single-cell level.
Establishment and Molecular Characterization of Patient-Derived Organoids for Primary Central Nervous System Lymphoma
Authors: Li Shengjie , Ren Jun , Wu Jianing , Xia Zuguang , Li Yingzhu , Li Chengxun , Cao Wenjun
Published: October 2024

Primary central nervous system lymphoma (PCNSL) exhibits substantial heterogeneity, both intra-tumoral and intertumoral, posing challenges in developing effective treatment methods. Existing in vitro models fail to simulate the inherent microenvironment and the cellular and mutational diversity of native tumors and require a prolonged generation time. To address this concern, we described an organoid culture method for patient-derived PCNSL organoids (CLOs) and evaluated them through extensive molecular characterization. These CLOs accurately mimicked the histological attributes, gene expression landscapes and mutational profiles of their original tumors through rigorous histopathological analysis, RNA sequencing and whole-exome sequencing. Notably, CLOs were generated within 2 weeks, demonstrating rapid development and reliability. Furthermore, therapeutic profiling was performed on three selected CLOs using four standard treatment drugs. High concordance was observed between the drug responses of patients and those observed in the CLOs, with specific sensitivity to ibrutinib and methotrexate and resistance to dexamethasone and rituximab. Taken together, these results emphasize that CLOs can effectively emulate the key characteristics of PCNSL, enhancing the understanding of the genetic landscape of this complex disease. CLOs provide a rapid and reliable platform for exploring individualized treatment strategies, potentially accelerating the transition of research findings to clinical practice.
Genetically Predicted Inflammatory Proteins Mediate the Association Between Gut Microbiota and Preterm Delivery: A Mendelian Randomization Study
Authors: Zhang Min , Chen Xiaodan , Zhang Yan , Huang Jia , Chen Ling
Published: October 2024

Aims

Inflammatory proteins and unique gut microbiota profiles characterize preterm delivery (PTD). Nevertheless, the comprehensive understanding of gut microbiota and inflammatory proteins of PTD remains unclear. This study aimed to investigate the causal relationship between gut microbiota and PTD and identify the inflammatory proteins as potential mediators.

Methods and results

The exposure genome-wide association studies (GWAS) data were sourced from the GWAS Catalog, while the outcome GWAS data were obtained from the Early Growth Genetics (EGG) Consortium. The study used 473 types of gut microbiota, 91 types of inflammatory proteins, and PTD from GWAS. We then performed two-sample Mendelian randomization (TSMR) and bidirectional Mendelian randomization (BDMR) analyses to explore the causal relationships between gut microbiota, inflammatory proteins, and PTD. Additionally, we conducted two-step Mendelian randomization (2SMR) to identify potential mediating inflammatory proteins in this process. MR analysis identified 26 gut microbiota and 6 types of inflammatory proteins causally associated with PTD. Furthermore, there was no strong evidence that genetically predicted PTD affected these gut microbiota and inflammatory proteins. Further, 2SMR analysis revealed that the association between Elusimicrobiaceae and PTD was mediated by the C-C motif chemokine 23 (CCL23), accounting for 5.09% (95%CI; 4.1%-8.7%) of the association. Similarly, the relationship between Thioalkalivibrionaceae and PTD was mediated by the Interleukin-20 receptor subunit alpha (IL-20RA), which accounted for 16.88% (95%CI; 12.77%-20.99%) of the association.

Conclusions

Our results reveal that Elusimicrobiaceae and Thioalkalivibrionaceae were significantly associated with PTD, with mediation occurring via CCL23 and IL-20RA, respectively.

Impact Statement

This study establishes a causal link between specific gut microbiota, inflammatory proteins, and PTD through MR analyses. The findings indicate that targeting the pathways involving Elusimicrobiaceae - CCL23 - PTD and Thioalkalivibrionaceae - IL20RA - PTD may provide promising interventions for preventing and treating PTD.
Alternative transcripts recode human genes to express overlapping, frameshifted microproteins
Authors: Su Haomiao , Katz Samuel G. , Slavoff Sarah A.
Published: October 2024

Overlapping genes were thought to be essentially absent from the human genome until the discovery of abundant, frameshifted internal open reading frames (iORFs) nested within annotated protein coding sequences. However, it is currently unclear how many functional human iORFs exist and how they are expressed. We demonstrate that, in hundreds of cases, alternative transcript variants that bypass the start codon of annotated coding sequences (CDSs) can recode a human gene to express the iORF-encoded microprotein. While many human genes generate such non- coding alternative transcripts, they are poorly annotated. Here we develope a new analysis pipeline enabling the assignment of translated human iORFs to alternative transcripts, and provide long- read sequencing and molecular validation of their expression in dozens of cases. Finally, we demonstrate that a conservedDEDD2iORF switches the function of this gene from pro- to anti- apoptotic. This work thus demonstrates that alternative transcript variants can broadly reprogram human genes to express frameshifted iORFs, revealing new levels of complexity in the human transcriptome and proteome.
The Single-Stranded DNA-Binding Factor SUB1/PC4 Alleviates Replication Stress at Telomeres and is a Vulnerability of ALT Cancer Cells
Authors: Dubois Jean-Christophe , Bonnell Erin , Frion Julie , Zimmer Samuel , Khan Muhammad Riaz , Teplitz Gabriela M. , Casimir Lisa , Méthot Élie , Filion Amélie , Idrissou Mouhamed , Jacques Pierre-Étienne , Wellinger Raymund J. , Maréchal Alexandre
Published: October 2024

Abstract

To achieve replicative immortality, cancer cells must activate telomere maintenance mechanisms. In 10-15% of cancers, this is enabled by recombination-based alternative lengthening of telomeres pathways (ALT). ALT cells display several hallmarks including heterogeneous telomere length, extrachromosomal telomeric repeats and ALT-associated PML bodies. ALT cells also have high telomeric replication stress (RS) enhanced by fork-stalling structures (R-loops, G4s) and altered chromatin states. In ALT cells, telomeric RS promotes telomere elongation but above a certain threshold becomes detrimental to cell survival. Manipulating RS at telomeres has thus been proposed as a therapeutic strategy against ALT cancers.

Through analysis of genome-wide CRISPR fitness screens, we identified ALT-specific vulnerabilities and describe here our characterization of the roles of SUB1, a ssDNA-binding protein, as a novel regulator of telomere stability. SUB1 depletion further increases RS at ALT telomeres, profoundly impairing ALT cell growth without impacting telomerase-positive cancer cells. During RS, SUB1 is recruited to stalled forks and ALT telomeres via its ssDNA-binding domain. This recruitment is potentiated by RPA depletion, suggesting that these factors may compete for ssDNA. The viability of ALT cells and their resilience towards RS also requires ssDNA-binding by SUB1. SUB1 depletion accelerates cell death induced by FANCM depletion, triggering unsustainable levels of telomeric damage specifically in ALT cells. Finally, combining SUB1 depletion with RS-inducing drugs rapidly induces replication catastrophe in ALT cells. Altogether, our work identifies SUB1 as a new ALT susceptibility with important roles in the mitigation of RS at ALT telomeres and suggests new therapeutic strategies for a host of still poorly managed cancers.

SignificanceStatement

Currently, there are few treatment options for ALT cancers with chemotherapy still occupying center stage despite often limited efficacy. ALT cancer cells experience high levels of replication stress at telomeres and its enhancement (e.g. via ATR inhibition) is a promising therapeutic strategy. Sensitivity to ATR inhibition varies amongst ALT cell lines/tumors warranting the development of additional ways to modulate telomeric replication stress. Here we identify SUB1, a single-stranded DNA-binding protein, as a vulnerability of ALT cells. SUB1 localizes to ALT telomeres and mitigates deleterious replication stress. SUB1 depletion synergizes with ATR inhibition and FANCM downregulation suggesting that co-targeting SUB1 with other regulators of replication stress at telomeres may kill ALT cancer cells more effectively.
Nicotine metabolite ratio as an informed biomarker to optimize acupuncture for smoking cessation: randomised controlled trial
Authors: Chen Shu-min , Ji Jia , xin Chai , Li Yang , Wuyuan  , Chang Jin , MiaoZhang  , Liu Zhen-yu , Tan Chao-ren , Yang Jin-sheng , Liu Zhao , Wang Ying-ying
Published: October 2024

Objective

To evaluate the effectiveness of using nicotine metabolite ratio (NMR) as an informed biomarker to optimize acupuncture for smoking cessation.

Methods

This was a prospective, two-arm, open-label randomized controlled trial. Participants were recruited and classified as slow or normal metabolizers based on their NMR values, and were randomly assigned to high-frequency or low-frequency acupuncture groups. Acupuncture sessions were held 3 to 5 times per week for 8 weeks. Minimum behavioral support was provided. The primary outcome was the 12-week continuous abstinence rate assessed by urine cotinine levels. Secondary outcomes included point abstinence, treatment adherence, and adverse reactions.

Results

Between September 2018 and April 2022, 220 participants were included. Among them, 211 (95.9%) were male, and the mean (SD) age was 48.5 (11.6) years. With 0.31 as the NMR cut-off value, 70 (31.8%) were divided as normal metabolizers and 150 (68.2%) as slow metabolizers. The validated 3-month sustained abstinence was 17.3% (19/110) in the high-frequency acupuncture group, which was significantly higher than 8.2% (9/110) in the low-frequency acupuncture group (OR=3.89, 95% CI: 1.36, 8.11). In slow metabolizers, the validated 3-month sustained abstinence rate was 19.0% (15/79) in the high-frequency acupuncture, which was higher than 7.0% (5/71) in low-frequency acupuncture (OR=3.53, 95% CI: 1.03, 6.13). In normal metabolizers, the validated 3-month sustained abstinence rates were 12.9% (4/31) in the high-frequency acupuncture group and 10.3% (4/39) in the low-frequency acupuncture group, with high-frequency acupuncture non-inferior to low-frequency acupuncture (OR=1.11, 95% CI: 0.24, 5.17). Treatment adherence was high in both groups, and adverse reactions were infrequent. No serious adverse events were recorded.

Conclusion

This pioneering study demonstrated that NMR might be used as a biomarker to optimize acupuncture treatments for smoking cessation, particularly among slow metabolizers. This study provides valuable insights into personalized smoking cessation strategies and highlights the potential of integrating acupuncture with other interventions for improved outcomes.

Trial Registration

Chinese Clinical Trials Registry (No.ChiCTR1800018196), Registered 4 September 2018, (chictr.org.cn).
Efficient secretion of a plastic degrading enzyme from the green algaeChlamydomonas reinhardtii
Authors: Molino João Vitor Dutra , Saucedo Barbara , Kang Kalisa , Walsh Chloe , Diaz Crisandra Jade , Tessman Marissa , Mayfield Stephen
Published: October 2024

Plastic pollution has become a global crisis, with microplastics contaminating every environment on the planet, including our food, water, and even our bodies. In response, there is a growing interest in developing plastics that biodegrade naturally, thus avoiding the creation of persistent microplastics. As a mechanism to increase the rate of polyester plastic degradation, we examined the potential of using the green microalgaChlamydomonas reinhardtiifor the expression and secretion of PHL7, an enzyme that breaks down post-consumer polyethylene terephthalate (PET) plastics. We engineeredC. reinhardtiito secrete active PHL7 enzyme and selected strains showing robust expression, by using agar plates containing a polyester polyurethane (PU) dispersion as an efficient screening tool. This method demonstrated the enzyme’s efficacy in degrading ester bond-containing plastics, such as PET and bio-based polyurethanes, and highlights the potential for microalgae to be implemented in environmental biotechnology. The effectiveness of algal-expressed PHL7 in degrading plastics was shown by incubating PET with the supernatant from engineered strains, resulting in substantial plastic degradation, confirmed by mass spectrometry analysis of terephthalic acid (TPA) formation from PET. Our findings demonstrate the feasibility of polyester plastic recycling using microalgae to produce plastic-degrading enzymes. This eco-friendly approach can support global efforts toward eliminating plastic in our environment, and aligns with the pursuit of low-carbon materials, as these engineered algae can also produce plastic monomer precursors. Finally, this data demonstratesC. reinhardtiicapabilities for recombinant enzyme production and secretion, offering a “green” alternative to traditional industrial enzyme production methods.

Graphical Abstract
Automated segmentation of synchrotron-scanned fossils
Authors: During Melanie A. D. , Matelsky Jordan K. , Gustafsson Fredrik K. , Voeten Dennis F. A. E. , Chen Donglei , Wester Brock A. , Körding Konrad P. , Ahlberg Per E. , Schön Thomas B.
Published: October 2024

Computed tomography has revolutionised the study of the internal three-dimensional structure of fossils. Historically, fossils typically spent years in preparation to be freed from the enclosing rock. Now, X-ray and synchrotron tomography reveal structure that is otherwise invisible and data acquisition can be fast. However, manual segmentation of these 3D volumes can still take months to years. This is especially challenging for resource-poor teams, as scanning may be free, but the computing power and (AI-assisted) segmentation software required to handle the resulting large data sets are complex to use and expensive.

Here we present a free, browser-based segmentation tool that reduces computational overhead by splitting volumes into small chunks, allowing processing on low-memory, inexpensive hardware. Our tool also speeds up collaborative ground-truth generation and 3D visualization, all in-browser. We developed and evaluated our pipeline on various open-data scans of differing contrast, resolution, textural complexity, and size. Our tool successfully isolated theThrinaxodonandBroomistegapair from an Early Triassic burrow. It isolated cranial bones from the Cretaceous acipenseriformParapsephurus willybemision both 45.53µm and 13.67µm resolution scanning data. We also isolated bones of the Middle Triassic sauropterygianNothosaurusand a challenging scan of a squamate embryo inside an egg dating back to the Early Cretaceous. Our tool reliably reproduces expert-supervised segmentation at a fraction of the time and cost, offering greater accessibility than existing tools. Beyond the online tool, all our code is open source, enabling contributions from the palaeontology community to further this emerging machine learning ecosystem.