bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural and Inflammatory Alterations in the Respiratory Tract Following Chlorine Gas Inhalation in Mice
Authors: Malaviya Rama , Gardner Carol R , Laskin Jeffrey D , Laskin Debra L 
Published: November 2023

Chlorine gas is a cytotoxic pulmonary irritant that causes acute damage to the upper and lower respiratory tract. In the present studies we developed a mouse model of chlorine inhalation exposure to investigate inflammatory mechanisms of lung injury. Spontaneously breathing male C57BL/6 mice were exposed to 325 ppm chlorine for 15 min in whole body chambers. Animals were sacrificed 24 h post‐exposure and bronchoalveolar lavage fluid (BAL) and lung tissue collected. Exposure of mice to chlorine resulted in peribronchial and perivascular edema, hemorrhage and marked congestion in the pulmonary parenchyma. Extensive loss of the epithelium was observed in the large bronchi resulting in denuded bronchial surfaces. This was correlated with increases in BAL cell and protein content, and bronchial epithelial expression of phospho‐histone H2A.X, a marker of double strand DNA breaks, indicating alveolar‐epithelial barrier injury. Chlorine exposure also resulted in increased numbers of lung epithelial cells and macrophages expressing cyclooxygenase and inducible nitric oxide synthase, proteins important in generating mediators involved in inflammatory lung injury. An increase in macrophages expressing Ym‐1+, which are important in wound healing and fibrosis, was also observed. These changes closely resemble the pathogenic response observed in humans following exposure to chlorine. Mechanistic understanding of chlorine toxicity in the respiratory tract will be useful in the identification of efficacious countermeasures for mitigating morbidity following exposure.Support or Funding InformationSupported by NIH Grants U54AR055073, R01ES004738, and P30ES005022.
Inhibitory Role Of BMP4 On The PDGF‐Induced Proliferation And Collagen Synthesis In PASMCs
Authors: Kovacs Laszlo , Cai Pengcheng , Su Yunchao 
Published: November 2023

Pulmonary arterial hypertension (PAH) is a severe lung disease characterized by remodeling of pulmonary vascular walls due to the abnormal vascular smooth muscle cell (VSMC) proliferation and accumulation of extracellular matrix proteins such as collagen. Our recent work shows that platelet‐derived growth factor‐BB (PDGF‐BB) induces cell proliferation and collagen synthesis in pulmonary artery SMC (PASMCs) via extracellular signal–regulated kinases (ERK)‐dependent calpain activation in PAH. The aim of the present study to determine the effect of bone morphogenetic protein 4 (BMP4) on PDGF‐stimulated calpain‐Transforming growth factor beta 1 (TGFβ1) signaling in PASMCs. PASMCs from normal and PAH patients were incubated with PDGF‐BB in the presence and absence of BMP4 for 0.5 to 24 h after which protein levels of collagen‐I, p‐Smad2/3, p‐Smad1/5, p‐ERK and intracellular active TGFβ1, calpain activity and cell proliferation were measured. We found that BMP4 augmented the protein levels of p‐Smad1/5 but did not influence the protein contents of collagen‐I, p‐Smad2/3, p‐ERK, active TGFβ1, and calpain activity in normal PASMCs. However, BMP4 attenuated the PDGF‐induced increases in calpain activity, cell proliferation and protein levels of collagen‐I, p‐Smad2/3, and active TGFβ1 in control cells. The results also showed that BMP4 did not alter the PDGF‐induced increases in p‐ERK or p‐Src. In addition, downregulation of Smad1/5 did not prevent the negative effects of BMP4 on the PDGF‐activated signal pathway. Furthermore, BMP4 increased the PKA activity and blocked the PDGF‐induced decrease in calpain‐2 phosphorylation at Ser369 in normal PASMCs. Inhibition of PKA prevented the inhibitory effects of BMP4 on calpain activation and dephosphorylation of Ser369 induced by PDGF. In addition, PKA activator forskolin recapitulated the inhibitory effect of BMP4 on PDGF‐stimulated calpain activation in normal PASMCs. In contrast, the suppressive effects of BMP4 on PDGF‐induced cell proliferation and collagen synthesis were abrogated in PASMCs from PAH patients. BMP4‐evoked PKA activation was diminished in PASMCs from PAH patients and BMP4 was not able to prevent the PDGF‐induced reduction in S369 phosphorylation and activation of calpain. Collectively, these data demonstrate that BMP4 inhibits PDGF‐induced cell proliferation and collagen synthesis via PKA‐mediated inhibition of calpain‐2 in normal PASMCs. Impairment of the BMP4‐PKA signaling may contribute to elevated calpain activation and pulmonary vascular remodeling in PAH.Support or Funding InformationSupported by FAMRI CIA140083 (YS), Department of Veterans Affairs BX002035 (YS) and AHA 16POST27730023 (LK).
Proteasome activity is required for ribosomal DNA transcription and muscle hypertrophy
Authors: Chandler Paige Nicole , Liu Chang , von Walden Ferdinand , Nader Gustavo A 
Published: November 2023

Skeletal muscle hypertrophy requires enhanced ribosome production, which is mediated by increased transcription of ribosomal DNA (rDNA) genes. Additionally, muscle growth necessitates that protein turnover is finely tuned to ensure a net protein accretion. However, how anabolic and catabolic processes coordinate muscle protein turnover remains to be determined.The objective of this study was to determine the interaction between anabolic and catabolic mechanisms during myotube hypertrophy.Myotubes were stimulated to undergo hypertrophy in the presence of proteolytic inhibitors for the ubiquitin proteasome (UPS, MG‐132), autophagy (ATG, Chloroquine), and caspase systems (CSP, Z‐VAD‐FMK). Inhibition of UPS, but not ATG or CSP, impaired muscle hypertrophy as evidenced by a 68% reduction in protein synthesis rates (p<0.001). Myotube protein content was also impaired by 25%, reflecting the decrease in UPS activity. Because hypertrophy requires increases in rDNA transcription, we considered the possibility that UPS inhibition impaired hypertrophy by disrupting rDNA transcription. Inhibition of UPS by MG‐132 resulted in impaired rDNA transcription, and subsequent analysis revealed that absence of functioning UPS resulted in altered nucleolar morphology in a pattern typical of nucleolar stress.In order to identify potential mediator(s) of nucleolar stress, we determined whether inhibition of the UPS was associated with changes in p53 levels. UPS inhibition caused a significant increase in p53 levels, and direct pharmacological activation of p53 in the presence of a functioning UPS decreased myotube protein content by 25% (p<0.05) and impaired rDNA transcription by 25% (p<0.001).These data indicate that UPS activity impinges in anabolic processes by blocking protein synthesis and rDNA transcription. Furthermore, UPS activity causes nucleolar stress and rDNA transcriptional suppression in a p53‐dependent manner.Support or Funding InformationSupported by the Swedish Research Council (Vetenskapsradet VRK2008‐67X‐20797‐01‐04), The Pennsylvania State University, and The Huck Institute of the Life Sciences.
The role of IP‐10 in Chronic Fatigue Syndrome.
Authors: McArdle Anne , Gusnanto Arief , Earl Kate , Sakellariou George , Lawton Clare , Owens Daniel , Close Graeme , Beadsworth Michael , Dye Louise 
Published: November 2023

Chronic fatigue syndrome (CFS) is a severely debilitating and complex illness of uncertain cause, characterised by prolonged, fatigue triggered by minimal activity. There is evidence that CFS is associated with chronic inflammation. Studies have shown that plasma levels of cytokines are chronically modified in patients with CFS. This study examined physiological, subjective and cognitive factors associated with plasma cytokine concentrations in a cohort of 92 patients compared with age and sex matched healthy controls. A sub‐group of patients and healthy controls (HCs) also underwent more detailed analyses of muscle function, cytokine production and cognitive function. Patients were diagnosed with CFS if they met the Oxford criteria for Chronic Fatigue Syndrome and recommended NICE guidelines. Patients completed a number of validated questionnaires including the Chalder Fatigue Questionnaire (CFQ) which is considered a valid and reliable measure of fatigue in patients with CFS.Patients with CFS demonstrated a characteristic significant reduction in Maximal Voluntary Contraction Force compared with HCs. Data on plasma concentrations of 27 pro‐ and anti‐inflammatory cytokines were analysed using multiple or logistic regression with age and sex which were significant covariates included in each model. CFS was strongly associated with a limited number of cytokines. Diagnosis of CFS was associated with increased plasma contents of MIP‐1a, MIP‐1b and RANTES (p<0.05) and marginally with Eotaxin (p=0.07) when modelled individually. MVC and self‐reported fatigue both showed particularly strong associations with plasma IP‐10 concentrations. Muscle content of IP‐10 mRNA was significantly elevated, suggesting that, at least in part, muscle was a source of this IP‐10 but not the other cytokines. Pairwise associations between MVC and cytokines demonstrated that the reduced MVC seen in patients with CFS was strongly associated with plasma levels of IP‐10, TNF‐α and IL‐5. Further analyses revealed strong correlations between plasma RANTES and eotaxin levels and poorer verbal recall and RTs of patients with CFS. The consistent association of IP‐10 with the physiological features and of RANTES and eotaxin with the cognitive features of CFS provides compelling evidence for a role of these cytokine/chemokines in the physiological and cognitive pathology of CFS. This work was funded by the Medical Research Council.Support or Funding InformationThis work was funded by the Medical Research Council.
MitoQ Supplementation Improves Leg‐Extension Power in Healthy Late Middle‐Aged and Older Adults
Authors: Bispham Nina Z. , Santos‐Parker Jessica R. , Steward Chelsea A.C. , Cuevas Lauren M. , Rosenberg Hannah L. , Murphy Michael P. , Seals Douglas R. , Rossman Matthew J. 
Published: November 2023

Aging is associated with a decline in motor function, which is a primary contributor to diminished functional capacity, increased risk of developing mobility limitations, and clinical disability. Multiple subdomains of motor function are reduced with aging including power, strength, balance, and endurance. Of these, declines in power, as assessed by leg‐extension power, occur earlier and more rapidly with aging. As such, leg‐extension power is one of the strongest predictors of overall physical performance and mobility in older adults. The exact mechanisms underlying age‐related changes in motor function are incompletely understood; however, excessive production of reactive oxygen species by mitochondria (mtROS) may play a role. Accordingly, preclinical data from our laboratory indicate that decreasing mtROS with the mitochondria‐targeted antioxidant MitoQ improves multiple subdomains of motor function in old mice (26–28 months). The purpose of the current study was to translate our preclinical findings to humans by conducting a randomized, placebo‐controlled, crossover clinical trial to assess the efficacy of 6 weeks of oral MitoQ (20 mg/day) vs. placebo supplementation for improving motor function (18 healthy late middle‐aged and older adults, 60–79 yrs). Leg‐extension power assessed at 40% of 1‐repetition maximum was 11% higher with MitoQ supplementation vs. placebo (860±63 vs. 803±71 W, P=0.02). Furthermore, there was an inverse relation between the improvement in leg‐extension power with MitoQ and leg‐extension power assessed under placebo conditions (r=−0.45, P=0.03). Leg strength, balance, endurance, and other subdomains of motor function assessed as part of the NIH toolbox motor battery were not different between conditions (all P>0.05). Aerobic exercise capacity (VO2max) and other participant characteristics were not altered with MitoQ (all P>0.05). Our data demonstrate that 6 weeks of supplementation with MitoQ in healthy late middle‐aged and older adults improves leg‐extension power, a critical determinant of mobility and physical function in this population. Moreover, our data suggest greater improvements in leg‐extension power with MitoQ supplementation in individuals with lower baseline function. Collectively, these data indicate that MitoQ and other therapeutic strategies targeting mtROS may hold promise for improving motor function and reducing the risk of clinical disability with aging.Support or Funding InformationSupported by NIH AG049451, AG053009, AG000279, and an industry contract with MitoQ Limited.
ACOI Surgical Site Infections Management Academy (ACOISSIMA)
Authors: Sartelli Massimo , Cortese Francesco , Scatizzi Marco , Labricciosa Francesco Maria , Bartoli Stefano , Nardacchione Francesco , Sganga Gabriele , Cillara Nicola , Luridiana Gianluigi , Murri Rita , Campli Mario , Catarci Marco , Borghi Felice , Di Marzo Francesco , Siquini Walter , Catena Fausto , Coccolini Federico , Armellino Mariano Fortunato , Baldazzi Gianandrea , Basti Massimo , Ciaccio Giovanni , Bottino Vincenzo , Marini Pierluigi 
Published: November 2023

Background:
Surgical site infections (SSIs) are the most common cause of healthcare-associated infections in surgical patients. Many SSIs may be preventable if simple measures are respected. Despite evidence supporting the effectiveness of evidence-based practices in Infection Prevention and Control, many surgeons fail to implement them.

Methods:
To clarify the key issues in the prevention of SSIs, an expert panel designated by the board of directors of Associazione Chirurghi Ospedalieri Italiani—Italian Surgical Association (ACOI) convened in Rome, Italy, on 16 December 2021, for a consensus conference.

Results:
The expert panel approved 11 evidence-based statements regarding the prevention of SSIs. A article was drafted and reviewed by the expert panel, finally obtaining this document that represents the executive summary of the consensus.

Conclusions:
The document aims to disseminate best practices among Italian surgeons and summarizes the ACOI recommendations for the prevention of SSIs.
The ALIGHIERI survey
Authors: Fransvea Pietro , Botteri Emanuele , Miranda Giuseppe , Pio Evoli Luca , Ortenzi Monica , Giordano Alessio , Argenio Giulio , Sartori Alberto , Azzinnaro Antonio , Marini Pierluigi ,   ACOI Giovani Group
Published: November 2023

Background:
The present survey aimed to provide a comprehensive overview of the Italian scenario concerning general surgery during the first wave coronavirus disease 2019 (COVID-19) outbreak and evaluate the experiences, trends, attitudes, and possible educational outcomes that this emergency brought to light.

Methods:
A 31-item survey was designed and edited by the scientific board of the Associazione Chirurghi Ospedalieri Italiani (ACOI), addressing the impact of the pandemic outbreak on surgical staff and activity during the period from 9 March to 30 May 2020 (phase 1, lockdown period) and addressing the status of surgical activity, staff, and surgery resumption in the period from 1 June to 30 September 2020 (phase 3, restart). The survey was distributed via email and social media to Italian general surgeon working both in COVID-19 and non–COVID-19 hospitals.

Results:
One thousand two hundred and three valid answers were collected for section 1, and 583 for section 2. Fifty percent of the surgery units involved in the study reported that the pandemic had negatively affected their ability to provide surgical assistance. Elective procedures were suppressed for nononcological diseases in 75% of the cases. Seventy-five percent of respondents prioritized oncological surgery over other procedures. During the restart period, the overall surgical activity was resumed entirely only in the 21% of the involved hospital.

Conclusion:
It will be crucial to organize a “recovery plan” t for all the surgical procedures postponed following a spoke-hub model. When “normal circumstances” will be re-established and a clear need for an organization on a national basis to face the subsequent pandemic outbreaks maintaining surgical activity as steady as possible.
ERAS pathway adherence in laparoscopic colorectal surgery
Authors: Pandolfini Lorenzo , Conti Duccio , Ballo Piercarlo , Laessig Romana , Falsetto Alessandro , Paroli Gian Matteo , Genzano Chiara , Cantini Silvio , Pavoni Vittorio , Scatizzi Marco 
Published: November 2023

Background:
The purpose of the study was to analyze the adherence to a newly adopted Enhanced Recovery After Surgery (ERAS) program in a nonspecialized center as well as its impact on postoperative outcomes.

Methods:
All patients who underwent elective colorectal surgery within ERAS protocol in the study period were enrolled. The sample was divided into group 1 (patients with protocol adherence < 85%) and group 2 (patients with protocol adherence > 85%). Clinical outcomes in terms of postoperative complications, readmission, reoperation rates, and length of stay were evaluated in the two groups.

Results:
A total of 150 patients were included in the study. All procedures were performed laparoscopically (99.3%) except for one case. The overall adherence rate to the ERAS protocol components was 88.0 ± 10.5% and the overall length of stay was 5.9 ± 3.3 days. Group 2 (n = 101) experienced lower length of stay than group 1 (n = 49) (P < 0.028). No differences in postoperative complications, readmission, and reoperation rates were observed between the two groups.

Conclusions:
The implementation methods were effective in achieving relevant adherence rate and the newly adopted ERAS program applicable even in nonspecialized centers.
Mgl2+cDC2s coordinate fungal allergic airway type 2, but not type 17, inflammation
Authors: Cook Peter C , Brown Sheila L. , Houlder Emma L. , Baker Syed , Svedberg Freya R. , Howell Gareth , Bertuzzi Margherita , Boon Louis , Konkel Joanne E. , Allen Judith E. , MacDonald Andrew S. 
Published: November 2023

AbstractFungal spores are abundant in the environment and a major cause of asthma. Originally characterised as a type 2 inflammatory disease, allergic airway inflammation that underpins asthma can also involve type 17 inflammation, which can exacerbate disease causing failure of treatments tailored to inhibit type 2 factors. However, the mechanisms that determine the host response to fungi, which can trigger both type 2 and type 17 inflammation in allergic airway disease, remain unclear. We found that CD11c+DCs and CD4+T cells are essential for development of both type 2 and type 17 airway inflammation in mice when repeatedly exposed to inhaled spores. Single cell RNA-sequencing enabled the development of multi-parameter cytometry that identified allergic inflammation dramatically altered the proportion of numerous DC clusters in the lung, but that only two of these (Mgl2+cDC2s and CCR7+DCs) migrated to the dLNs. Targeted removal of several DC subsets revealed that only Mgl2+cDC2 depletion dramatically reduced type 2, but not type 17, anti-fungal allergic airway inflammation. These data highlight distinct DC subsets are potential therapeutic targets for the treatment of pulmonary fungal disease.
Theoretical framework and experimental validation of multiplexed analyte quantification using cross-reactive affinity reagents
Authors: Newman Sharon S. , Hein Linus A. , Adams Alexandra M. , Soh H. Tom 
Published: November 2023

AbstractGold standard immunoassays depend on specific affinity reagents for accurate molecular quantification. Any cross-reactivity of affinity reagents, wherein the reagent non-specifically binds to unintended molecules, can create false positive binding signals and result in inaccurate quantification of analytes. Mitigating cross-reactivity represents one of the greatest challenges in molecular diagnostics, and remains an unsolved problem. To instead overcome the effects of cross-reactivity, we present a mathematical framework that uses generalized binding equations and noise estimation to enable the use of multiple cross-reactive reagents for multiplexed molecular quantification. As a proof-of-concept, we experimentally demonstrate accurate quantification of a small molecule for which no specific affinity reagents are available, even at high concentrations of a cross-reactive molecule. Furthermore, this robust schema yields well-defined bounds of quantification that make it easier to assess the quality of assay results and predicts under which conditions assay performance is likely to break down. This work turns cross-reactive affinity reagents, which were previously a liability, into an asset for achieving accurate quantification of analytes.
Evidence for a role of 5-HT-glutamate co-releasing neurons in acute stress mechanisms
Authors: Gullino L. Sophie , Fuller Cara , Dunn Poppy , Collins Helen M. , El Mestikawy Salah , Sharp Trevor 
Published: November 2023

AbstractThe majority of midbrain 5-hydroxytryptamine (5-HT) neurons express the vesicular glutamate transporter 3 (VGLUT3) and co-release 5-HT and glutamate, but the function of this co-release is unclear. Given the strong links between 5-HT and uncontrollable stress, we used a combination of c-Fos immunocytochemistry and conditional gene knock out in mice to test the hypothesis that glutamate co-releasing 5-HT neurons would be activated by stress and involved in stress coping.Acute, uncontrollable swim stress increased c-Fos immunoreactivity in neurons co-expressing VGLUT3 and the 5-HT marker tryptophan hydroxylase 2 (TPH2) in the dorsal raphe nucleus (DRN). This effect was localised in the ventral DRN subregion and prevented by the antidepressant fluoxetine. In contrast, a more controllable stressor, acute social defeat, had no effect on c-Fos immunoreactivity in VGLUT3-TPH2 co-expressing neurons in the DRN.To test whether activation of glutamate co-releasing 5-HT neurons was causally linked to stress coping, mice with a specific deletion of VGLUT3 in 5-HT neurons were exposed to acute swim stress. Compared to wildtype controls, the mutant mice showed increased climbing behaviour, a measure of active coping. Wildtype mice also showed increased climbing when administered fluoxetine, revealing an interesting parallel between the behavioural effects of genetic loss of VGLUT3 in 5-HT neurons and 5-HT reuptake inhibition.We conclude that 5-HT-glutamate co-releasing neurons are recruited by exposure to uncontrollable stress. Furthermore, natural variation in the balance of 5-HT and glutamate released at the 5-HT synapse may impact on stress susceptibility.