bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nutritional Support for the Trauma and Emergency General Surgery Patient: What You Need to Know
Authors: Hartwell Jennifer L. , Evans David C. , Martin Matthew J. 
Published: February 2024

ABSTRACT
Decades of research have provided insight into the benefits of nutritional optimization in the elective surgical patient. Patients who are nutritionally prepared for surgery enjoy reduced length of hospital and intensive care unit stays and suffer fewer complications. In the Trauma and Emergency General Surgery (EGS) patient populations, we are not afforded the pre-operative period of optimization and patients often suffer longer lengths of hospital stay, discharge to nonhome destinations, and higher infectious and mortality rates. Nonetheless, ongoing research in this vulnerable and time critical diagnosis population has revealed significant outcomes benefits with the meticulous nutritional support of these patients. However, it is important to note that optimal nutritional support in this challenging patient population is not simply a matter of “feeding more and feeding earlier”. In this review, we will address assessing nutritional needs, the provision of optimal nutrition, the timing and route of nutrition, monitoring outcomes, and discuss the management of nutrition in the complex trauma and EGS patient.

LEVEL OF EVIDENCE
Level V, literature synthesis and expert opinion
Chemical genetics inC. elegansidentifies anticancer mycotoxins chaetocin and chetomin as potent inducers of a nuclear metal homeostasis response
Authors: Abraham Elijah , Athapaththu A. M. Gihan K. , Atanasova Kalina R. , Chen Qi-Yin , Corcoran Taylor J. , Piloto Juan , Wu Cheng-Wei , Ratnayake Ranjala , Luesch Hendrik , Choe Keith P. 
Published: February 2024

ABSTRACTC. elegans numr-1/2(nuclear-localizedmetal-responsive) is an identical gene pair encoding a nuclear protein previously shown to be activated by cadmium and disruption of the integrator RNA metabolism complex. We took a chemical genetic approach to further characterize regulation of this novel metal response by screening 41,716 compounds and extracts fornumr-1p::GFPactivation. The most potent activator was chaetocin, a fungal 3,6-epidithiodiketopiperazine (ETP) with promising anticancer activity. Chaetocin activatesnumr-1/2strongly in the alimentary canal but is distinct from metal exposure because it represses canonical cadmium-responsive metallothionine genes. Chaetocin has diverse targets in cancer cells including thioredoxin reductase, histone lysine methyltransferase, and acetyltransferase p300/CBP; further work is needed to identify the mechanism inC. elegansas genetic disruption and RNAi screening of homologs did not inducenumr-1/2in the alimentary canal and chaetocin did not affect markers of integrator dysfunction. We demonstrate that disulfides in chaetocin and chetomin, a dimeric ETP analog, are required to inducenumr-1/2.ETP monomer gliotoxin, despite possessing a disulfide linkage, had almost no effect onnumr-1/2, suggesting a dimer requirement. Chetomin inhibitsC. elegansgrowth at low micromolar levels and loss ofnumr-1/2increases sensitivity;C. elegansand Chaetomiaceae fungi inhabit similar environments raising the possibility thatnumr-1/2functions as a defense mechanism. There is no direct ortholog ofnumr-1/2in humans, but RNAseq suggests that chaetocin affects expression of cellular processes linked to stress response and metal homeostasis in colorectal cancer cells. Our results reveal interactions between metal response gene regulation and ETPs and identify a potential mechanism of resistance to this versatile class of preclinical compounds.
Neurovascular mitochondrial susceptibility impacts blood-brain barrier function and behavior
Authors: Crockett A. M. , Kebir H. , Vélez Colόn M. C. , Iascone D. M. , Cielieski B. , Rossano A. , Sehgal A. , Anderson S. A. , Alvarez J. I. 
Published: February 2024

AbstractMaintenance of blood-brain barrier (BBB) integrity is critical to optimal brain function, and its impairment has been linked to multiple neurological disorders. A notable feature of the BBB is its elevated mitochondrial content compared to peripheral endothelial cells, although the functional implications of this phenomenon remain unknown. Here we studied BBB mitochondrial function in the context of the 22q11.2 deletion syndrome (22qDS), a condition associated with a highly increased risk for neuropsychiatric disease. As the 22q11.2 deletion includes 6 mitochondrial genes, and because we have previously identified BBB impairment in 22qDS, we addressed the hypothesis that mitochondrial deficits contribute to BBB dysfunction and impact behavior in this condition. We report mitochondrial impairment in human induced pluripotent stem cell (iPSC)-derived BBB endothelial cells from 22qDS patients, and in BBB endothelial cells from a mouse model of 22qDS. Remarkably, treatment to improve mitochondrial function attenuates mitochondrial deficits and enhances BBB function in both the iPSC and mouse 22qDS models. This treatment also corrected social memory in the mouse model, a deficit previously associated with BBB dysfunction. As BBB integrity correlated with social memory performance, together our findings suggest that mitochondrial dysfunction in the BBB influences barrier integrity and behavior in 22qDS.
A tale of too many trees: a conundrum for phylogenetic regression
Authors: Adams Richard , Lozano Jenniffer Roa , Duncan Mataya , Green Jack , Assis Raquel , DeGiorgio Michael 
Published: February 2024

AbstractJust exactly which tree(s) should we assume when testing evolutionary hypotheses? This question has plagued comparative biologists for decades. Given a perfectly estimated tree (if this is even possible in practice), we seldom know with certainty whether such a tree is truly best (or even adequate) to represent the evolutionary history of our studied traits. Regardless of our certainty, choosing a tree is required for all phylogenetic comparative methods. Yet, phylogenetic conflict and error are ubiquitous in modern comparative biology, and we are still learning about their dangers when testing evolutionary hypotheses. Here we investigated the consequences of gene tree-species tree mismatch for phylogenetic regression in the presence of incomplete lineage sorting. Our simulation experiments reveal excessively high false positive rates for mismatched phylogenetic regression with both small and large trees, simple and complex traits, and known and estimated phylogenies. In some cases, we find evidence of a directionality of error: incorrectly assuming a species tree for traits that evolved according to a gene tree sometimes fares worse than the opposite. To explore difficult yet realistic regression scenarios, we also used estimated rather than known trees to conduct case studies, as well as an expansive gene expression dataset to investigate an arguably best-case scenario in which one may have a better chance to match tree with trait. Though never meant to be a panacea for all that may ail phylogenetic comparative methods, we found promise in the application of a robust estimator as a potential, albeit imperfect, solution to some issues raised by tree mismatch, perhaps offering a path forward. Collectively, our results emphasize the importance of careful study design for comparative methods, highlighting the need to fully appreciate the role of adequate phylogenetic modeling for testing evolutionary hypotheses.
Alveolar macrophages play a key role in tolerance to ozone
Authors: Smith Gregory J. , Nalesnik Morgan , Immormino Robert M. , Simon Jeremy M. , Harkema Jack R. , Mock Jason R. , Moran Timothy P. , Kelada Samir N. P. 
Published: February 2024

ABSTRACTAcute exposure to ozone (O3) causes pulmonary inflammation and injury in humans and animal models. In rodents, acute O3-induced inflammation and injury can be mitigated by pre-exposure to relatively low concentration O3, a phenomenon referred to as tolerance. While tolerance was described long ago, the underlying mechanisms are not known, though upregulation of antioxidants has been proposed. To identify new mechanisms for O3tolerance, we generated a mouse model in which female C57BL6/NJ mice were pre-exposed to filtered air (FA) or 0.8 ppm O3for four days (4 hours/day), then challenged with 2 ppm O3(3 hours) 2 days later, and phenotyped for airway inflammation and injury 6 or 24 hours thereafter. As expected, pre-exposure to O3resulted in significantly reduced airway inflammation and injury at 24 hours, as well as reduced induction of antioxidant genes. Like previous studies in rats, tolerance was associated with changes in the frequency and proliferation of alveolar epithelial cells, but was not associated with upregulation of antioxidants, CCSP (SCGB1A1), or mucus. We found that alveolar macrophages (AMs) play a critical role in tolerance, as depletion of AMs using clodronate in mice pre-exposed to O3restored many responses to acute O3challenge. Further, AMs of O3tolerized mice exhibited decreased expression of genes involved in cellular signaling via Toll-like receptors, MYD88, and NF-kB, and proinflammatory cytokine production. We conclude that O3tolerance is highly, but not exclusively, dependent on AMs, and that further studies investigating how repeated O3exposure induces hypo-responsiveness in AMs are warranted.
Alterations in genes associated with cytosolic RNA sensing in whole blood are associated with coronary microvascular disease in SLE
Authors: Huo Lihong , Montano Erica , Tumurkhuu Gantseg , Bose Moumita , Berman Daniel S. , Wallace Daniel , Wei Janet , Ishimori Mariko , Merz C. Noel Bairey , Jefferies Caroline 
Published: February 2024

AbstractObjectiveTo investigate whether gene signatures discriminate systemic lupus erythematosus (SLE) patients with coronary microvascular dysfunction (CMD) from those without and whether any signaling pathway is linked to the underlying pathobiology of SLE CMD.MethodsThis study collected whole blood RNA samples from female subjects aged 37 to 57, comprising 11 SLE patients (4 SLE-CMD, 7 SLE-non-CMD) and 10 HC. Total RNA was then used for library preparation and sequencing. Differential gene expression analysis was performed to identify gene signatures associated with CMD in SLE patients using DEseq2 v1.42.0. Gene Set Enrichment Analysis were performed by ClusterProfiler v4.10.0 and pathfindR v2.3.1.ResultsRNA-seq analysis revealed 143 differentially expressed (DE) genes between the SLE and HC groups. GO analysis indicated associations with virus defense and interferon signaling in SLE. 14 DE genes were identified from comparison between SLE-CMD and SLE-non-CMD with adjusted parameters (padj < 0.1). Notably, SLE-CMD exhibited elevated levels of genes associated with RNA sensing, while downregulated genes in SLE-non-CMD were associated with blood coagulation and cell-cell junction. Further investigation highlighted differences in IFN signaling and ADP-ribosylation pathways between SLE-CMD and SLE-non-CMD, suggesting distinct molecular mechanisms underlying vascular changes in CMD and reduced left ventricular function in non-CMD.ConclusionOur study identified a unique gene signature in SLE-CMD compared to the HC group, highlighting the significant involvement of type 1 interferon, RIG-I family proteins, and chronic inflammation in the progression of SLE-CMD. The intricate relationship between SLE-CMD and these factors underscores their probable role in initiating and advancing SLE-CMD.
A Mathematical Framework for Comparison of Intermittent versus Continuous Adaptive Chemotherapy Dosing in Cancer
Authors: McGehee Cordelia , Mori Yoichiro 
Published: February 2024

AbstractChemotherapy resistance in cancer remains a barrier to curative therapy in advanced disease. Dosing of chemotherapy is often chosen based on the maximum tolerated dosing principle; drugs that are more toxic to normal tissue are typically given in on-off cycles, whereas those with little toxicity are dosed daily. When intra-tumoral cell-cell competition between sensitive and resistant cells drives chemotherapy resistance development, it has been proposed that adaptive chemotherapy dosing regimens, whereby a drug is given intermittently at a fixed dose or continuously at a variable dose based on tumor size, may lengthen progression free survival over traditional dosing [1]. Indeed, in mathematical models using modified Lotka Volterra systems to study dose timing, rapid competitive release of the resistant population and tumor outgrowth is apparent when cytotoxic chemotherapy is maximally dosed [2]. This effect is ameliorated with continuous (dose modulation) or intermittent (dose skipping) adaptive therapy in mathematical models and experimentally, however, direct comparison between these two modalities has been limited. Here, we develop a mathematical framework to formally analyze intermittent adaptive therapy in the context of bang-bang control theory. We prove that continuous adaptive therapy is superior to intermittent adaptive therapy in its robustness to uncertainty in initial conditions, time to disease progression, and cumulative toxicity. We additionally show that under certain conditions, resistant population extinction is possible under adaptive therapy or fixed-dose continuous therapy. Here, continuous fixed-dose therapy is more robust to uncertainty in initial conditions than adaptive therapy, suggesting an advantage of traditional dosing paradigms.Significance StatementIntra-tumoral cell-cell competition between drug resistant and drug sensitive cancer cells is hypothesized to drive resistance development after chemotherapy administration in certain cancers. Optimization of chemotherapy delivery through dose or schedule adaptation based on tumor parameters (adaptive therapy) has been hypothesized to utilize chemotherapy sensitive cells to compete with chemotherapy resistant cells and delay tumor outgrowth. Here, we develop an analytical framework to compare two alternative adaptive therapy approaches: dose modulation (continuous) and schedule modulation (intermittent). Through direct analytical comparison, we demonstrate that continuous adaptive therapy is superior to intermittent adaptive therapy across physiologically relevant metrics. Furthermore, in parameters spaces where resistant population extinction is feasible, traditional fixed-dose therapy at a low dose may carry additional benefits over adaptive therapy.
Tetrameric INTS6-SOSS1 complex facilitates DNA:RNA hybrid autoregulation at double-strand breaks
Authors: Long Qilin , Ajit Kamal , Sedova Katerina , Haluza Vojtech , Stefl Richard , Dokaneheifard Sadat , Beckedorff Felipe , Valencia Monica G , Sebesta Marek , Shiekhattar Ramin , Gullerova Monika 
Published: February 2024

AbstractDNA double strand breaks (DSBs) represent a lethal form of DNA damage that can trigger cell death and initiate oncogenesis. The activity of RNA polymerase II (RNAPII) at the break site is required for efficient DSB repair. However, the regulatory mechanisms governing the transcription cycle at DSBs are not well understood. Here, we show that Integrator complex subunit 6 (INTS6) associates with the trimeric SOSS1 (comprising INTS3, INIP, and hSSB1) to form a tetrameric SOSS1 complex following DNA damage. INTS6 binds to DNA:RNA hybrids and plays a crucial role in Protein Phosphatase 2 (PP2A) recruitment to DSBs, facilitating the dephosphorylation of RNAPII. Furthermore, INTS6 prevents the accumulation of damage-induced RNA transcripts (DARTs) and the stabilization of DNA:RNA hybrids at DSB sites. INTS6 interacts with, and promotes the recruitment of Senataxin (SETX) to DSBs, facilitating the resolution of DNA:RNA hybrids/R-loops. Our results underscore the significance of the SOSS1 complex in the autoregulation of DNA:RNA dynamics and the promotion of efficient DNA repair.
Estimating Propulsion Kinetics in Absence of a Direct Measurement of the Anterior Component of Ground Reaction Force
Authors: Cohen Hannah N. , Vasquez Miguel , Sergi Fabrizio 
Published: February 2024

AbstractAnterior ground reaction force (AGRF) is a common measurement of walking function in post-stroke individuals. It is typically measured using multi-axis force-plates which are not always found in robotic research labs. Here we present a comparison of models using kinematic and kinetic metrics of propulsion to estimate AGRF.Nine models using measurements of maximum vertical ground reaction force (maxVGRF), vertical ground reaction force at peak AGRF (aVGRF), maximum trailing limb angle (maxTLA), trailing limb angle at peak AGRF (aTLA) and stride length (SL) were used to predict different metrics of propulsion kinetics, including maximum AGRF (maxAGRF), propulsive impulse (PI), maximum AGRF normalized by body-weight (maxAGRFnorm), and normalized PI (PInorm) from participants at speeds [0.6 1.4] m/s. R2and AICc scores were recorded for each model, and the individual participant R2values for the best single and two-factor models for each outcome were examined.Of the single-factor models, kinematic measurements were the best predictors of the outcome measurements. More specifically, maxAGRF/norm were best predicted by SL (R2= 0.91, 0.82, respectively), and PI/norm were best predicted by maxTLA (R2= 0.84, 0.43, respectively). For the two-factor models, maxAGRFnorm and PInorm were both best predicted by SL and aVGRFnorm, and maxVGRF yeilded the best predictions for maxAGRF and PI. Models predicting maxAGRF/norm better fit individual participants than those predicting PI/norm. These results indicate that maxAGRF can be estimated with reasonable accuracy (R2= 0.92, RMSE of residuals: 1.5% bodyweight, equivalent to a 0.09 m/s increase in velocity) in the absence of a direct measurement of AGRF using both kinematic and kinetic measurements of propulsion.
Human like severe hypertriglyceridemia in a high fat fed chicken model
Authors: Saranya K. , Beniha JG , Deepshikha TK , Shankar Kriti , Vishnu R , Kadiyala Gopi , Saxena Uday 
Published: February 2024

SummaryCardiovascular disease (CVD) is the biggest cause of mortality globally. Controlling the risk factors for CVD such as blood cholesterol and triglycerides is the hallmark of primary prevention of CVD. There are several drugs to control cholesterol that are available but not many approaches to reducing triglycerides safely are available.High blood triglycerides or hypertriglyceridemia in humans is classified as moderate (200-400 mg/dl plasma levels) severe (400-800 mg/dl) and very severe (>800 mg/dl). There are not many appropriate in vivo models to study human like severe hypertriglyceridemia. We show here that high fat fed chickens rapidly and in a sustained manner respond by demonstrating triglyceride levels reminiscent of severe hypertriglyceridemia in humans. Such a model could be useful in better understanding this human disease as well as serve to test new therapies.
STING contributes to pulmonary hypertension by targeting the interferon and BMPR2 signaling through targeting F2RL3
Authors: Deng Lin , Cao Chengrui , Cai Zongye , Wang Ziping , Leng Bin , Chen Zhen , Kong Fanhao , Zhou Zhiyue , He Jun , Nie Xiaowei , Bian Jin-Song 
Published: February 2024

AbstractRational/ObjectivesPulmonary hypertension (PH) is an incurable disease characterized by pulmonary arterial remodeling. Endothelial injury and inflammation are the key triggers of the disease initiation. Recent findings suggest that STING (stimulator of interferon genes) activation plays a critical role in the endothelial dysfunction and interferon signaling. Here, we investigated the involvement of STING in the pathogenesis of PH.MethodsPH patients and rodent PH model samples, Sugen5416/hypoxia (SuHx) PH model, and pulmonary artery endothelial cells (PAECs) were used to evaluate the hypothesis.Measurement and Main ResultsThe cyclic GMP-AMP (cGAS)-STING signaling pathway was activated in the lung tissues from rodent PH models and PH patients, and the TNF-α induced PAECsin vitro. In particular, STING significantly elevated in the endothelial cell in PH disease settings. In SuHx mouse model, genetic knockout or pharmacological inhibition of STING prevented the progression of PH. Functionally, knockdown of STING reduced the proliferation and migration in PAECs. Mechanistically, STING transcriptional regulates its binding partner F2RL3 through STING-NF-κB axis, which activated the interferon signaling and repressed the BMPR2 signaling bothin vitroandin vivo. Further analysis revealed that F2RL3 expression was increased in PH settings and identified negative feedback regulation of F2RL3/BMPR2 signaling. Accordingly, a positive correlation of expression levels between STING and F2RL3/ interferon-stimulated genes (ISGs) was observedin vivo.ConclusionsOur findings suggest that STING activation in PAECs plays a critical role in the pathobiology of PH. Targeting STING may be a promising therapeutic strategy for preventing the development of PH.
Superoxide enters neurons via LRRC8A – containing volume-regulated anion channels
Authors: Harris Kate , Uruk Gokhan , Won Seok Joon , Mai Nguyen , Baxter Paul , Everaerts Katharina , Sah Rajan , Swanson Raymond A. 
Published: February 2024

SummarySuperoxide (O2-) is both an intercellular signaling molecule and a cause of neuronal oxidative stress. Superoxide entry into neurons is thought to be indirect, requiring its dismutation to nonpolar hydrogen peroxide. Here we show instead that superoxide enters neurons directly, via LRRC8A-containing volume-sensitive organic anion channels. In primary cultures, neuronal oxidative stress induced either by NMDA receptor stimulation or exposure to authentic superoxide was blocked by the anion channel blockers DIDS and DCPIB and by LRRC8A gene disruption. In mouse cortex, neuronal oxidative stress induced by either NMDA injection or transient ischemia was likewise blocked by both DCPIB and LRRC8A gene disruption. These findings identify a role for LRRC8A-containing volume-sensitive organic anion channels in neuronal oxidative signaling, stress, and glutamate excitotoxicity.