Miracle-dz/UniFAR-FTUs huggingface dataset:
Targeting mitochondrial responses to intra-articular fracture to prevent posttraumatic osteoarthritis

Inhibiting mitochondrial oxidant production after surgical fixation of an intra-articular fracture prevents osteoarthritis in a porcine model. Osteoarthritis—A mitochondrial malady Articular cartilage—the smooth, avascular tissue that covers the bones in joints—can be damaged by traumatic injury, which can lead to osteoarthritis. In response to injury, chondrocytes ramp up mitochondrial activity, producing reactive oxygen species that can cause further tissue damage and cell death. Coleman and colleagues treated intra-articular fractures in a porcine model with an antioxidant or an inhibitor of the mitochondrial electron transport chain. Regulating mitochondrial metabolism prevented osteoarthritis. This work suggests that the mighty mitochondrion is a therapeutic target for posttraumatic osteoarthritis. We tested whether inhibiting mechanically responsive articular chondrocyte mitochondria after severe traumatic injury and preventing oxidative damage represent a viable paradigm for posttraumatic osteoarthritis (PTOA) prevention. We used a porcine hock intra-articular fracture (IAF) model well suited to human-like surgical techniques and with excellent anatomic similarities to human ankles. After IAF, amobarbital or N-acetylcysteine (NAC) was injected to inhibit chondrocyte electron transport or downstream oxidative stress, respectively. Effects were confirmed via spectrophotometric enzyme assays or glutathione/glutathione disulfide assays and immunohistochemical measures of oxidative stress. Amobarbital or NAC delivered after IAF provided substantial protection against PTOA at 6 months, including maintenance of proteoglycan content, decreased histological disease scores, and normalized chondrocyte metabolic function. These data support the therapeutic potential of targeting chondrocyte metabolism after injury and suggest a strong role for mitochondria in mediating PTOA.
ALK is a therapeutic target for lethal sepsis

FDA-approved ALK-inhibiting drugs protect mice against sepsis through attenuating STING signaling activation in innate immune cells. Taking the STING out of sepsis Despite the existence of antibiotic therapy, sepsis is associated with a high mortality rate. Zeng et al. screened a library of kinase inhibitors to identify drugs that targeted the STING (stimulator of interferon genes) pathway, which was up-regulated in mononuclear cells from patients with sepsis. The authors found that STING is activated by anaplastic lymphoma kinase (ALK), which interacts with epidermal growth factor receptor and signals through downstream serine-threonine protein kinase AKT. Inhibiting ALK-STING signaling genetically or with oral drug treatment improved survival in mouse models of sepsis and endotoxemia. The ALK-STING pathway could be a useful target for drug development for sepsis. Sepsis, a life-threatening organ dysfunction caused by infection, is a major public health concern with limited therapeutic options. We provide evidence to support a role for anaplastic lymphoma kinase (ALK), a tumor-associated receptor tyrosine kinase, in the regulation of innate immunity during lethal sepsis. The genetic disruption of ALK expression diminishes the stimulator of interferon genes (STING)–mediated host immune response to cyclic dinucleotides in monocytes and macrophages. Mechanistically, ALK directly interacts with epidermal growth factor receptor (EGFR) to trigger serine-threonine protein kinase AKT phosphorylation and activate interferon regulatory factor 3 (IRF3) and nuclear factor κB (NF-κB) signaling pathways, enabling STING-dependent rigorous inflammatory responses. Moreover, pharmacological or genetic inhibition of the ALK-STING pathway confers protection against lethal endotoxemia and sepsis in mice. The ALK pathway is up-regulated in patients with sepsis. These findings uncover a key role for ALK in modulating the inflammatory signaling pathway and shed light on the development of ALK-targeting therapeutics for lethal systemic inflammatory disorders.
Correlation Between Body Temperature and Survival Rate in Patients With Hospital-Acquired Bacteremia

Background: Fever is a complex and major sign of a patient’s acute response to infection. However, analysis of the risks and benefits associated with the change in body temperature of an infected host remains controversial. Objective: To examine the relationship between the intensity of the change in body temperature and the mortality of patients with hospital-acquired bacteremia. Design: A prospective observational study. Method: Subjects were hospitalized adult patients who developed clinical signs of infection 48 hr or more after admission and had documented bacterial growth in blood culture. The maximum body temperature (maxTe) during the early period of infection measurements (i.e., the day before, the day of, and 2 days after the day of blood culture) was used to indicate the intensity of the body temperature response. Patients were categorized as discharged alive or died in hospital. Cox regression analysis was employed to analyze the data. Results: The cohort consisted of 502 subjects. The mean maxTe of subjects was 38.6°C, and 14.9% had a maxTe lower than 38.0°C. The in-hospital mortality rate was 18.9%. The highest in-hospital mortality was found in subjects with a maxTe lower than 38°C (30.7%). Multivariate Cox regression analysis determined that the maxTe and the severity of comorbidity are the two variables associated with in-hospital mortality. Conclusions: Lack of a robust febrile response may be associated with greater risk of mortality in patients with bacteremia. Clinicians must be vigilant in identifying patients at risk for a blunted febrile response to bacteremia for more intensive monitoring.
Blood Lipids: A Shortcut From Hostility to Chd?

The present article describes the associations between hostility and serum lipids in Coronary Artery Disease (CAD) patients. A sample of 212 male coronary patients was used of which 127 recently suffered a Myocardial Infarction (MI), and 85 had undergone either a Coronary Artery Bypass Grafting (CABG) or a Percutaneous Transluminal Coronary Angioplasty (PTCA). Total Cholesterol (TC), High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL) and triglyceride concentrations were measured as well as four hostility factors: ‘Negative Affectivity’ (NA), ‘Anger-In’ (AI), ‘Anger-Out’ (AO) and Coping, i.e. behaviors to control feelings of anger and anxiety. The results indicated that the effects of hostility on lipids were mediated by various factors such as body weight in relation to body length (BMI), Socio-Economic Status (SES), Left Ventricle Ejection Fraction (LVEF) and Age. In subgroups of highly exhausted patients or of patients scoring high on the Type A Behavior Pattern (TABP), however, more direct (unilinear) associations between lipids and hostility were found. The findings of the present study confirm the rather weak association between hostility and blood lipids found elsewhere. Furthermore, a low level of triglycerides was consistently associated with low AO, be it again in interaction with BMI (AO × BMI), both in the group of non-MI patients and in the total sample for those patients who score high on vital exhaustion and/or TABP. This finding provides an extra argument against the popular notion of the healthfulness under all circumstances of anger expression. Until now the exact role of triglycerides as a function of anger/hostility has been under-explored. This issue merits further attention in future research.
Targeting extracellular matrix stiffness to attenuate disease: From molecular mechanisms to clinical trials

Targeting extracellular matrix stiffness holds clinical potential to attenuate pathological progression in the emerging field of mechanomedicine. Tissues stiffen during aging and during the pathological progression of cancer, fibrosis, and cardiovascular disease. Extracellular matrix stiffness is emerging as a prominent mechanical cue that precedes disease and drives its progression by altering cellular behaviors. Targeting extracellular matrix mechanics, by preventing or reversing tissue stiffening or interrupting the cellular response, is a therapeutic approach with clinical potential. Major drivers of changes to the mechanical properties of the extracellular matrix include phenotypically converted myofibroblasts, transforming growth factor β (TGFβ), and matrix cross-linking. Potential pharmacological interventions to overcome extracellular matrix stiffening are emerging clinically. Aside from targeting stiffening directly, alternative approaches to mitigate the effects of increased matrix stiffness aim to identify and inhibit the downstream cellular response to matrix stiffness. Therapeutic interventions that target tissue stiffening are discussed in the context of their limitations, preclinical drug development efforts, and clinical trials.
Probiotic strains detect and suppress cholera in mice

A probiotic intervention with Lactococcus lactis strains provides colonization resistance and in vivo detection of cholera in mice. Designer bugs as drugs The endemic persistence and outbreaks of Vibrio cholerae indicate a need for new methods of control; in this issue, two groups investigated the potential of engineered bacteria to mediate cholera resistance in animal models. Mao et al. discovered that lactic acid production by the probiotic Lactococcus lactis rendered the infant mouse gut hostile to V. cholerae and engineered L. lactis to detect breakthrough infection. Hubbard et al. extensively modified a contemporary V. cholerae strain for a live oral vaccine, which resulted in an attenuated strain that could protect infant rabbits from V. cholerae challenge within 24 hours of vaccine administration, indicating the protective effects were not dependent on adaptive immunity. These papers showcase innovative approaches to tackling cholera. Microbiota-modulating interventions are an emerging strategy to promote gastrointestinal homeostasis. Yet, their use in the detection, prevention, and treatment of acute infections remains underexplored. We report the basis of a probiotic-based strategy to promote colonization resistance and point-of-need diagnosis of cholera, an acute diarrheal disease caused by the pathogen Vibrio cholerae. Oral administration of Lactococcus lactis, a common dietary fermentative bacterium, reduced intestinal V. cholerae burden and improved survival in infected infant mice through the production of lactic acid. Furthermore, we engineered an L. lactis strain that specifically detects quorum-sensing signals of V. cholerae in the gut and triggers expression of an enzymatic reporter that is readily detected in fecal samples. We postulate that preventive dietary interventions with fermented foods containing natural and engineered L. lactis strains may hinder cholera progression and improve disease surveillance in populations at risk of cholera outbreaks.
Platelet microparticles sustain autophagy-associated activation of neutrophils in systemic sclerosis

Platelet microparticles from patients with systemic sclerosis prompt endothelial cell activation, neutrophil recruitment, and lung fibrosis. Platelets nurture neutrophil damage Systemic sclerosis, or scleroderma, is a complicated inflammatory fibrotic disease involving multiple organs. Different immune cells contribute to the pathology of systemic sclerosis. Maugeri et al. investigated mechanisms that could contribute to endothelial damage in patients. They observed that activated platelets from patients produced microparticles that induced neutrophil activation, including autophagy and neutrophil extracellular trap production. These microparticles expressed the damage-associated molecular pattern HMGB1, and accordingly, an HMGB1 inhibitor prevented this neutrophil activiation. Inhibiting microparticles to interrupt this platelet-neutrophil axis may be helpful to prevent endothelial damage, thereby disrupting disease pathogenesis. Endothelial cell damage and platelet activation contribute to sustained vasculopathy, which is a key clinical characteristic of systemic sclerosis (SSc), also known as scleroderma. Microparticles released from activated platelets in the blood of SSc patients (SSc-microparticles) are abundant and express the damage-associated molecular pattern (DAMP) HMGB1. SSc-microparticles interacted with neutrophils in vitro and in immunocompromised mice and promoted neutrophil autophagy, which was characterized by mobilization of their granule content, enhanced proteolytic activity, prolonged survival, and generation of neutrophil extracellular traps (NETs). Neutrophils migrated within the mouse lung, with collagen accumulation in the interstitial space and the release of soluble E-selectin by the vascular endothelium. Microparticle-neutrophil interaction, neutrophil autophagy and survival, and generation of NETs abated in the presence of BoxA, a competitive inhibitor of HMGB1. Consistent with these results, neutrophils in the blood of SSc patients were autophagic and NET by-products were abundant. Our findings implicate neutrophils in SSc vasculopathy and suggest that platelet-derived, microparticle-associated HMGB1 may be a potential indicator of disease and target for novel therapeutics.
Measuring Light at Night and Melatonin Levels in Shift Workers: A Review of the Literature

Shift work, especially that involving rotating and night shifts, is associated with an increased risk of diseases, including cancer. Attempts to explain the association between shift work and cancer in particular have focused on the processes of melatonin production and suppression. One hypothesis postulates that exposure to light at night (LAN) suppresses melatonin, whose production is known to slow the development of cancerous cells, while another proposes that circadian disruption associated with shift work, and not just LAN, increases health risks. This review focuses on six studies that employed quantitative measurement of LAN and melatonin levels to assess cancer risks in shift workers. These studies were identified via searching the PubMed database for peer-reviewed, English-language articles examining the links between shift work, LAN, and disease using the terms light at night, circadian disruption, health, risk, cancer, shift work, or rotating shift. While the results indicate a growing consensus on the relationship between disease risks (particularly cancer) and circadian disruption associated with shift work, the establishment of a direct link between LAN and disease has been impeded by contradictory studies and a lack of consistent, quantitative methods for measuring LAN in the research to date. Better protocols for assessing personal LAN exposure are required, particularly those employing calibrated devices that measure and sample exposure to workplace light conditions, to accurately assess LAN’s effects on the circadian system and disease. Other methodologies, such as measuring circadian disruption and melatonin levels in the field, may also help to resolve discrepancies in the findings.
Impact of fatty infiltration of the teres minor muscle on the outcome of reverse total shoulder arthroplasty.

BACKGROUND Reports have demonstrated that reverse shoulder arthroplasty restores overhead elevation but fails to restore active external rotation. The teres minor muscle-tendon unit contributes to active external rotation, and its deficiency may impair the clinical outcome. It was therefore the purpose of this study to evaluate the influence of fatty infiltration of the teres minor muscle on the clinical outcome after reverse total shoulder replacement. METHODS Forty-two shoulders in forty-two patients (average age, seventy-one years) with painful cuff tear arthropathy or an irreparable rotator cuff deficiency with pseudoparesis were treated with a reverse Delta-III shoulder arthroplasty and followed clinically for a minimum of twenty-four months. Preoperatively, fatty infiltration of the teres minor was assessed, according to the grading system of Goutallier et al., with use of magnetic resonance imaging. The effect of teres minor fatty infiltration on the subjective and objective outcomes of the reverse shoulder arthroplasty was evaluated. RESULTS The thirty shoulders with stage-0, 1, or 2 fatty infiltration of the teres minor muscle (group 1) had a significantly better ultimate Constant score, a significantly better subjective shoulder value, and significantly greater preoperative-to-postoperative improvement than the twelve shoulders with stage-3 or 4 fatty infiltration (group 2). In group 1 the relative Constant score increased by an average of 41% and the subjective shoulder value increased by an average of 44%, whereas in group 2 the respective increases were 32% (p = 0.033) and 25% (p = 0.018). Group 1 had an average increase of 6.2 points in the score for extremity positioning, whereas group 2 gained only 5.3 points (p = 0.033). Group 1 had a net gain of 9 degrees of external rotation with the arm at the side compared with an average net loss of 7 degrees in group 2 (p < 0.001). CONCLUSIONS Stage-3 or 4 fatty infiltration of the teres minor compromises the clinical outcome of reverse shoulder arthroplasty for the treatment of irreparable rotator cuff tears.
Dialysis arteriovenous access monitoring and surveillance according to the 2017 Spanish Guidelines

The Spanish Multidisciplinary Group on Vascular Access (GEMAV), which includes experts from the five scientific societies involved (nephrology (S.E.N.), vascular surgery (SEACV), interventional radiology (SERAM-SERVEI), infectious diseases (SEIMC), and nephrology nursing (SEDEN)), along with the methodological support of the Iberoamerican Cochrane Centre, has developed the Spanish Clinical Guidelines on Vascular Access for Hemodialysis. This article summarizes the main issues from the guideline’s chapter entitled “Monitoring and surveillance of arteriovenous access. ” We will analyze the current evidence on conflicting topics such as the value of the flow-based screening methods for the arteriovenous access surveillance or the role of Doppler ultrasound as the imaging exploration to confirm suspected stenosis. In addition, the concept of significant stenosis and the criteria to perform the elective intervention for stenosis were reviewed. The adoption of these guidelines will hopefully translate into a reduced risk of thrombosis and increased patency rates for both arteriovenous fistulas and grafts.
Neutrophils cause obstruction of eyelid sebaceous glands in inflammatory eye disease in mice

Neutrophils obstruct the meibomian gland in a mouse model of inflammatory eye disease and correlate with disease severity in patients with meibomian gland dysfunction. Inflammatory obstruction in the eye Obstruction of eyelid glands called meibomian glands (MGs) is a risk factor for developing chronic inflammation of the eyelids. The function of these glands is to secrete oils onto the surface of the eye. The etiology of MG obstruction is not completely understood. Now, Reyes et al. have discovered that polymorphonuclear neutrophils (PMNs) promoted MG obstruction in a mouse model of inflammatory eye disease. Furthermore, PMNs were increased in tears of patients with MG obstruction, and PMN number correlated with the severity of the obstruction. The data suggest that PMNs might contribute to the etiology of MG obstruction in inflammatory eyelid disease. Meibomian glands (MGs) are sebaceous glands of the eyelid margin that secrete lipids needed to avert tear evaporation and to help maintain ocular surface homeostasis. Obstruction of MGs or other forms of MG dysfunction can promote chronic diseases of the ocular surface. Although chronic eyelid inflammation, such as allergic eye disease, is an associated risk factor for obstructive MG dysfunction, it is not clear whether inflammatory processes contribute to the pathophysiology of MG obstruction. We show that polymorphonuclear neutrophils (PMNs) promoted MG obstruction in a chronic inflammatory model of allergic eye disease in mice. Analysis of leukocytes in tears of patients with MG dysfunction showed an increase in PMN numbers compared to healthy subjects. Moreover, PMN numbers in tears positively correlated with clinical severity of MG dysfunction. Our findings point to a role for PMNs in the pathogenesis and progression of MG dysfunction.
The human naive B cell repertoire contains distinct subclasses for a germline-targeting HIV-1 vaccine immunogen

Inspection of the naive B cell repertoire specific for an HIV vaccine immunogen provides actionable information for human vaccine design and advancement. Learning from naive B cells Despite decades of intensive research, HIV vaccines are unable to generate broadly neutralizing antibodies that are likely necessary for protection. One vaccine candidate, eOD-GT8, was designed to bait naive B cells that may be capable of producing antibodies similar to VRC01, a potent CD4-binding site–targeting antibody with breadth. Havenar-Daughton et al. inspected the potential of human naive B cells to recognize eOD-GT8, and isolated B cells that used similar genes as those used to make VRC01. They also observed B cells with immunoglobulin genes similar to those used in other types of broadly neutralizing antibodies, some with a more conventional maturation path than VRC01. Their results suggest that vaccination of humans with eOD-GT8 has the potential to eventually induce CD4-binding site broadly neutralizing antibodies, which would be a major step forward in HIV vaccines. Traditional vaccine development to prevent some of the worst current pandemic diseases has been unsuccessful so far. Germline-targeting immunogens have potential to prime protective antibodies (Abs) via more targeted immune responses. Success of germline-targeting vaccines in humans will depend on the composition of the human naive B cell repertoire, including the frequencies and affinities of epitope-specific B cells. However, the human naive B cell repertoire remains largely undefined. Assessment of antigen-specific human naive B cells among hundreds of millions of B cells from multiple donors may be used as pre–phase 1 ex vivo human testing to potentially forecast B cell and Ab responses to new vaccine designs. VRC01 is an HIV broadly neutralizing Ab (bnAb) against the envelope CD4-binding site (CD4bs). We characterized naive human B cells recognizing eOD-GT8, a germline-targeting HIV-1 vaccine candidate immunogen designed to prime VRC01-class Abs. Several distinct subclasses of VRC01-class naive B cells were identified, sharing sequence characteristics with inferred precursors of known bnAbs VRC01, VRC23, PCIN63, and N6. Multiple naive B cell clones exactly matched mature VRC01-class bnAb L-CDR3 sequences. Non–VRC01-class B cells were also characterized, revealing recurrent public light chain sequences. Unexpectedly, we also identified naive B cells related to the IOMA-class CD4bs bnAb. These different subclasses within the human repertoire had strong initial affinities (KD) to the immunogen, up to 13 nM, and represent encouraging indications that multiple independent pathways may exist for vaccine-elicited VRC01-class bnAb development in most individuals. The frequencies of these distinct eOD-GT8 B cell specificities give insights into antigen-specific compositional features of the human naive B cell repertoire and provide actionable information for vaccine design and advancement.