bluuebunny/crossref_metadata_2025_split huggingface dataset:
Surgical Management of Perforated Peptic Ulcer: A Comparative Meta-analysis of Laparoscopic Versus Open Surgery
Authors: Salman Mohamed AbdAlla , Issa Mohamed , Salman Ahmed , Tourky Mohamed , Elewa Ahmed , Alrahawy Mahmoud , Shetty Neehar , Elsherbiney Mohammed , Elhaj Mujahid Gasemelseed Fadlallah , Shaaban Hossam El-Din 
Published: August 2022

Background:
Despite the widescale success of proton pump inhibitors to reducing the incidence of peptic ulcer disease, perforated peptic ulcer (PPU) remains a significant cause of severe complications and death. The implementation of open or surgical repair of PPU should be guided by reliable guidelines which are based on current systematic evidence.

Objectives:
To assess the comparative efficacy and safety of laparoscopic and open repair of PPU.

Methods:
A systematic review and meta-analysis was conducted based on retrospective, prospective cohort studies, and randomized clinical trials. Duration of surgery and postoperative complications and death were collected from eligible studies, and the outcomes were pooled using mean differences (MD) or relative risks (RRs) for numerical and binary outcomes, respectively. The estimated variance was expressed as 95% confidence intervals (95% CIs).

Results:
Forty-five studies were included (8456 patients, 56.08% underwent open repair, 6 prospective studies, 7 randomized clinical trials, and 32 retrospective studies). Compared with open repair, laparoscopic surgeries were associated with longer operative times (MD=8.36, 95% CI, 0.49-16.22), shorter hospital stay (MD=−2.74, 95% CI, −3.70 to−1.79), a higher risk of suture leakage (RR=1.91, 95% CI, 1.04-3.49) and lower risks of mortality (RR=0.57, 95% CI, 0.47-0.70), septic shock (RR=0.69, 95% CI, 0.49-0.98), renal failure (RR=0.38, 95% CI, 0.18-0.79), and wound infection (RR=0.26, 95% CI, 0.19-0.37).

Conclusion:
Laparoscopic repair of PPU showed promising safety outcomes; however, future well-designed randomized studies are warranted to reduce the observed performance bias and possible selection bias in individual studies.
Burden of Colovesical Fistula and Changing Treatment Pathways: A Systematic Literature Review
Authors: Froiio Caterina , Bernardi Daniele , Asti Emanuele , Bonavina Giulia , Conti Andrea , Carmignani Luca , Bonavina Luigi 
Published: August 2022

Purpose:
Colovesical fistula (CVF) is a rare complication of sigmoid diverticulitis causing significant morbidity and quality of life impairment. Aim of this study was to analyze contemporary literature data to appraise the current standard of care and changes of treatment algorithms over time.

Materials and Methods:
A systematic review of the literature on surgical management of CVF was conducted through PUBMED, EMBASE, and COCHRANE databases, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement guidelines.

Results:
Fourteen papers published between 2014 and 2020 and including 1061 patients were analyzed. One-stage colonic resection with primary anastomosis, with or without loop ileostomy, was the most common surgical procedure. A laparoscopic or robotic approach was attempted in 39.5% of patients, and conversion rate to open surgery was 7.8%. Clavien-Dindo grade ≥3 complication rate, 30-day mortality, and recurrence rate were 7.4%, 1.5%, and 0.5%, respectively.

Conclusions:
Minimally invasive sigmoidectomy with primary anastomosis is safe and should be the first-choice approach for CVF. Bladder repair is not necessary after a negative intraoperative leak test. A standardized perioperative care can improve clinical outcomes and reduce the length of hospital stay and the duration of Foley catheterization.
Tranexamic Acid in Pediatric Hemorrhagic Trauma
Authors: Borgman Matthew A. , Nishijima Daniel K. 
Published: August 2022

Abstract
There is strong evidence in adult literature that tranexamic acid (TXA) given within three hours from injury is associated with improved outcomes. The evidence for TXA use in injured children is limited to retrospective studies and one prospective observational trial. Two studies in combat settings and one prospective civilian US study have found association with improved mortality. These studies indicate the need for a randomized controlled trial to evaluate the efficacy of TXA in injured children and to clarify appropriate timing, dose and patient selection. Additional research is also necessary to evaluate trauma induced coagulopathy in children. Recent studies have identified three distinct fibrinolytic phenotypes following trauma (hyperfibrinolysis, physiologic fibrinolysis, and fibrinolytic shutdown) which can be identified with viscohemostatic assays (VHA). Whether VHA can appropriately identify children that may benefit or be harmed by TXA is also unknown.

Level of evidence
Level II
Chemical reprogramming ameliorates cellular hallmarks of aging and extends lifespan
Authors: Schoenfeldt Lucas , Paine Patrick T. , Kamaludeen M. Nibrasul H. , Phelps Grace B. , Mrabti Calida , Perez Kevin , Ocampo Alejandro 
Published: August 2022

ABSTRACTThe dedifferentiation of somatic cells into a pluripotent state by cellular reprogramming coincides with a reversal of age-associated molecular hallmarks. Although transcription factor induced cellular reprogramming has been shown to ameliorate these aging phenotypes in human cells and extend health and lifespan in mice, translational applications of this approach are still limited. More recently, chemical reprogramming via small molecule cocktails have demonstrated a similar ability to induce pluripotency in vitro, however, its potential impact on aging is unknown. Here, we demonstrated that partial chemical reprogramming is able to improve key drivers of aging including genomic instability and epigenetic alterations in aged human cells. Moreover, we identified an optimized combination of two reprogramming molecules sufficient to induce the amelioration of additional aging phenotypes including cellular senescence and oxidative stress. Importantly, in vivo application of this two-chemical combination significantly extendedC. eleganslifespan. Together, these data demonstrate that improvement of key drivers of aging and lifespan extension is possible via chemical induced partial reprogramming, opening a path towards future translational applications.
Thinking outside the CaaX-box: an unusual reversible prenylation on ALDH9A1
Authors: Suazo Kiall F. , Schey Garrett L. , Auger Shelby A. , Li Ling , Distefano Mark 
Published: August 2022

AbstractProtein lipidation is a post-translational modification that confers hydrophobicity on protein substrates to control their cellular localization, mediate protein trafficking, and regulate protein function. In particular, protein prenylation is a C-terminal modification on proteins bearing canonical prenylation motifs catalyzed by prenyltransferases. Such types of proteins have been of interest owing to their potential association with various diseases. Chemical proteomic approaches have been pursued over the last decade to define prenylated proteomes (prenylome) and probe their responses to perturbations in various cellular systems. Here, we describe the discovery of prenylation of a non-canonical prenylated protein, ALDH9A1, which lacks any apparent prenylation motif. This enzyme was initially identified through chemical proteomic profiling of prenylomes in various cell lines. Metabolic labeling with an isoprenoid probe using overexpressed ALDH9A1 reveals that this enzyme can be prenylated inside cells but does not respond to inhibition by prenyltransferase inhibitors. Site-directed mutagenesis of the key residues involved in ALDH9A1 activity indicate that the catalytic C288 bears the isoprenoid modification likely through an NAD+-dependent mechanism. Furthermore, the isoprenoid modification is also susceptible to hydrolysis, indicating a reversible modification. We hypothesize that this modification originates from endogenous farnesal or geranygeranial, the established degradation products of prenylated proteins and results in a thioester form that accumulates. This novel reversible prenoyl modification on ALDH9A1 expands the current paradigm on protein prenylation by illustrating a potentially new type of protein-lipid modification that may also serve as a novel mechanism for controlling enzyme function.
The two-component system YesMN promotes pneumococcal host-to-host transmission, and regulates genes involved in zinc homeostasis
Authors: Zafar M. Ammar , Costa-Terryl Alicia , Young Taylor M. 
Published: August 2022

AbstractThe ability to sense and respond rapidly to the dynamic environment of the upper respiratory tract (URT) makes Streptococcus pneumoniae (Spn) a highly successful human pathogen. Two-component systems (TCS) of Spn sense and respond to multiple signals it encounters allowing Spn to adapt and thrive in various host sites. Spn TCS have been implicated in their ability to promote pneumococcal colonization of the URT and virulence. As the disease state can be a dead-end for a pathogen, we considered whether TCS would contribute to pneumococcal transmission. Herein, we determined the role of YesMN, an understudied TCS of Spn, and observe that YesMN contributes towards pneumococcal shedding and transmission but is not essential for colonization. The YesMN regulon includes genes involved in zinc homeostasis and glycan metabolism, which are upregulated during reduced zinc availability in a YesMN dependent fashion. Thus, we identify the YesMN regulon and the molecular signals it senses that lead to the activation of genes involved in zinc homeostasis and glycan metabolism. Furthermore, in contract to Spn mono-infection, we demonstrate that YesMN is critical for high pneumococcal density in the URT during influenza A (IAV) coinfection. We attribute reduced colonization of the yesMN mutant due to increased association with and clearance by the mucus covering the URT epithelial surface. Thus, our results highlight the dynamic interactions that occur between Spn and IAV in the URT, and the role that TCS play in modulation of these interactions.
Paternal obesity alters the sperm epigenome and is associated with changes in the placental transcriptome and cellular composition
Authors: Pépin Anne-Sophie , Jazwiec Patrycja A. , Dumeaux Vanessa , Sloboda Deborah M. , Kimmins Sarah 
Published: August 2022

SummaryPaternal obesity has been implicated in adult-onset metabolic disease in offspring. However, the molecular mechanisms driving these paternal effects and the developmental processes involved remain poorly understood. One underexplored possibility is the role of paternally driven gene expression in placenta function. To address this, we investigated paternal high-fat diet-induced obesity in relation to sperm epigenetic signatures, the placenta transcriptome and cellular composition. C57BL6/J males were fed either a control or high-fat diet for 10 weeks beginning at 6 weeks of age. Males were timed-mated with control-fed C57BL6/J females to generate pregnancies, followed by collection of sperm, and placentas at embryonic day (E)14.5. Chromatin immunoprecipitation targeting histone H3 lysine 4 tri-methylation (H3K4me3) followed by sequencing (ChIP-seq) was performed on sperm to define obesity-associated changes in enrichment. Paternal obesity corresponded with altered sperm H3K4me3 enrichment at imprinted genes, and at promoters of genes involved in metabolism and development. Notably, sperm altered H3K4me3 was localized at placental enhancers and genes implicated in placental development and function. Bulk RNA-sequencing on placentas detected paternal obesity-induced sex-specific changes in gene expression associated with hypoxic processes such as angiogenesis, nutrient transport and imprinted genes. Paternal obesity was also linked to placenta development; specifically, a deconvolution analysis revealed altered trophoblast cell lineage specification. These findings implicate paternal obesity-effects on placenta development and function as one mechanism underlying offspring metabolic disease.Summary sentencePaternal obesity impacts the sperm epigenome at genes implicated in placenta development and is associated with an altered placenta transcriptome and trophoblast cell lineage specification.
The reproductive status of the host determines the tolerance and resistance toMycobacterium marinuminfection inDrosophila melanogaster
Authors: Arch Marta , Vidal Maria , Fuentes Esther , Abat Anmaw Shite , Cardona Pere Joan 
Published: August 2022

AbstractBoth the sex and the reproductive status of the host have a major impact on the regulation of the immune response against infection. Due thatDrosophila melanogasterhas become a powerful model for study such interactions, we wanted to understand whether the sex or the reproductive status has an impact on the tolerance or resistance of the host to the in the model of systemicMycobacterium marinuminfection. We measured gene expression by RT-qPCR of immune genes,diptericinanddrosomycin, as well as host survival and the bacillary load at time of death. We also assessed the impact of metabolic (by expression ofupd3andimpl2) and hormonal (byecRexpression) regulation in the protection against infection. Data showed that resistance increased in actively mating males and females, and also in mated females while reducing the tolerance to infection. The data also suggest the Toll and IMD pathways determine tolerance and resistance, respectively, while basal levels ofecRfavors the stimulation of the IMD pathway. A time related role has been found forupd3expression, linked to the increase or decrease in the mycobacterial load at the beginning and at the end of the infection, respectively. Finally,impl2expression has been related to the increase of resistance only in non-actively mating males. The results obtained allows further interpretation of the results when assessing the differences between sexes and highlights the role of the reproductive status inD. melanogasterto face infections, since our data demonstrated their importance to determine resistance and tolerance againstM. marinuminfection.
Lithography-less, frugal and long-term diffusion-based static gradient generating microfluidic device for high-throughput drug testing
Authors: Bachal Ketaki , Yadav Shital , Gandhi Prasanna , Majumder Abhijit 
Published: August 2022

AbstractDrug testing is a vital step in identification of the potential efficacy of any new/existing drug and/or combinations of drugs. The conventional methods of testing the efficacy of new drugs using multi-well plates are time consuming, prone to evaporation loss and manual error. Microfluidic devices with automated generation of concentration gradient provide a promising alternative. The implementation of such microfluidic devices is still limited owing to the additional expertise and facilities required to fabricate and run these devices. Conventional microfluidic devices also need pumps, tubings, valves, and other accessories, making them bulky and nonportable. To address these problems, we have developed a method for fabricating microfluidic structures using a nonconventional technique by exploiting the Saffman-Taylor instability in lifted Hele-Shaw cell. Multi-channel structure molds with varying dimensions were fabricated by shaping ceramic polymer slurry and retaining the shape. Further using the mold thus made, polydimethyl siloxane (PDMS) devices offering static, stable, diffusion-based gradient were casted using soft lithography. We have demonstrated with COMSOL simulation, as well as using Fluorescein isothiocyanate (FITC), a fluorescent dye, that the concentration gradient can be generated in this device, which remains stable for at least 5 days. Using this multichannel device, in vitro drug efficacy was validated with two drugs namely-Temozolomide (TMZ) and Curcumin, one FDA approved and one under research, on glioblastoma cells (U87MG). The resulting IC50 values were consistent with those reported in literature. We have also demonstrated the possibility of conducting molecular assays post-drug testing in the device by microtubule staining after curcumin treatment on cervical cancer cells (HeLa). In summary, we have demonstrated a i) user-friendly, ii) portable, static drug testing platform that iii) does not require further accessories and can create iv) a stable gradient for long duration. Such a device can reduce the time, manual errors, fabrication and running expenditure, and resources to a great extent in drug testing.Abstract Figure
Structural basis of how the BIRC6/SMAC complex regulates apoptosis and autophagy
Authors: Ehrmann Julian F. , Grabarczyk Daniel B. , Heinke Maria , Deszcz Luiza , Kurzbauer Robert , Hudecz Otto , Shulkina Alexandra , Gogova Rebeca , Meinhart Anton , Versteeg Gijs A. , Clausen Tim 
Published: August 2022

SummaryInhibitor of apoptosis proteins (IAPs) bind to pro-apoptotic proteases, keeping them inactive and preventing cell death. BIRC6 is an exceptionally large, multidomain IAP that inhibits its targets by means of its atypical ubiquitin ligase activity and in addition, functions as an inhibitor of autophagy by depleting LC3B. Little is known of the mechanisms by which BIRC6 interacts with its targets and fulfills these two roles. Here, we determined the cryo-EM structure of BIRC6 alone and in complex with two mitochondrial pro-apoptotic proteins, HTRA2 and SMAC. We show BIRC6 is an antiparallel homodimer that forms a crescent shape that arcs around a spacious cavity. The cavity is surrounded by binding sites for client proteins, where they interact with the flexible UBC domain that mediates ubiquitin ligation. Functional data reveal that multivalent binding of SMAC in the central cavity obstructs substrate binding, impeding ubiquitination of both autophagy and apoptotic target proteins. Together our data reveal the molecular mechanisms of how SMAC specifically binds and inhibits BIRC6 to promote apoptosis, and how this regulatory mechanism also extends to autophagy substrates. The interaction sites are hot spots of cancer and atrophy mutations, highlighting the importance of carefully balancing the interplay between BIRC6 and SMAC.
Positional cues underlie cell fate specification during branching morphogenesis of the embryonic mammary epithelium
Authors: Carabaña Claudia , Sun Wenjie , Perkins Meghan , Kapoor Varun , Journot Robin , Hartani Fatima , Faraldo Marisa M. , Lloyd-Lewis Bethan , Fre Silvia 
Published: August 2022

AbstractHow cells coordinate morphogenetic cues and fate specification during development is a fundamental question at the basis of tissue formation. Lineage tracing studies have demonstrated that many stratified epithelia, including the mammary gland, first arise from multipotent stem cells, which are progressively replaced by distinct pools of unipotent progenitors that maintain tissue homeostasis postnatally. The lack of specific markers for early fate specification in the mammary gland has prevented the delineation of the features and spatial localization of lineage-committed progenitors that co-exist with multipotent stem cells (MaSCs) during tissue development. Here, using single-cell RNA-sequencing across 4 stages of embryonic development, we reconstructed the differentiation trajectories of multipotent mammary stem cells towards basal and luminal fate. Our data revealed that MaSCs can already be resolved into distinct populations exhibiting lineage commitment at the time coinciding with the first sprouting events of mammary branching morphogenesis (E15.5). By visualizing gene expression across our developmental atlas, we provide novel molecular markers for committed and multipotent MaSCs, and define their spatial distribution within the developing tissue. Furthermore, we show that the mammary embryonic mesenchyme is composed of two spatially-restricted cell populations, representing the sub-epithelial and dermal mesenchyme. Mechanistically, we explored the communication between different subsets of mesenchymal and epithelial cells, using time-lapse analysis of mammary embryonic explant cultures, and reveal that mesenchymal-produced FGF10 accelerates embryonic mammary branching morphogenesis without affecting cell proliferation. Altogether, our data elucidate the spatiotemporal signals underlying lineage specification of multipotent mammary stem cells and uncover the paracrine interactions between epithelial and mesenchymal cells that guide mammary branching morphogenesis.
Treatment history shapes the evolution of complex carbapenem-resistant phenotypes in Klebsiella spp.
Authors: Rosas Natalia C. , Wilksch Jonathan J. , Barber Jake , Li Jiahui , Wang Yanan , Sun Zhewei , Rocker Andrea , Webb Chaille , Perlaza-Jiménez Laura , Stubenrauch Christopher , Vijaykrishna Dhanasekaran , Song Jiangning , Taiaroa George , Davies Mark , Strugnell Richard A. , Bao Qiyu , Zhou Tieli , McDonald Michael J. , Lithgow Trevor 
Published: August 2022

ABSTRACTAntibiotic resistance is driven by selection, but how a bacterial strain’s evolutionary history shapes drug-resistance remains an open question. Here we reconstruct the genetic and evolutionary mechanisms of carbapenem resistance in a clinical isolate of Klebsiella. A combination of short and long read sequencing, machine learning, genetic and enzymatic analyses established that this carbapenem-resistant strain carries no carbapenemase-encoding genes. Genetic reconstruction of the resistance phenotype confirmed that two distinct genetic loci are necessary for the strain to acquire carbapenem resistance. Experimental evolution of the carbapenem-resistant strains in growth conditions without the antibiotic revealed that both loci confer a significant cost, and are readily lost by de novo mutation resulting in the rapid evolution of a carbapenem-sensitive phenotype. Thus, historical contingency - a patient’s treatment history - can shape the evolution of antibiotic resistance and suggests that the strategic combinations of antibiotics could direct the evolution of low-fitness, drug-resistant genotypes.
Impact on S. aureus and E. coli membranes of treatment with chlorhexidine and alcohol solutions: insights from molecular simulations and nuclear magnetic resonance
Authors: Waller Callum , Marzinek Jan , McBurnie Eilish , Bond Peter J , Williamson Philip T. F. , Khalid Syma 
Published: August 2022

ABSTRACTMembranes form the first line of defence of bacteria against potentially harmful molecules in the surrounding environment. Understanding the protective properties of these membranes represents an important step towards development of targeted anti-bacterial agents such as sanitizers. Use of propanol, isopropanol and chlorhexidine can significantly decrease the threat imposed by bacteria in the face of growing anti-bacterial resistance via mechanisms that include membrane disruption. Here we have employed molecular dynamics simulations and nuclear magnetic resonance to explore the impact of chlorhexidine and alcohol on the S. aureus cell membrane, as well as the E. coli inner and outer membranes. We identify how sanitizer components partition into these bacterial membranes, and show that chlorhexidine is instrumental in this process.