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Isopropyl alcohol (IPA) is widely used in industrial and home-cleaning products, easily available to general public and inexpensive: intoxications can occur unintentionally, in suicide attempts or by alcohol abusers as a substitute for ethanol. Symptoms involve the gastrointestinal tract, central nervous system and at high doses cardiovascular manifestations may appear. Ketonemia, ketonuria without hyperglicemia or acidosis and elevated osmol gap are common laboratory findings. Mortality and morbidity is low, but some fatal cases have been reported in patients in deep coma and especially those with hypotension. We present a life-threatening intoxication, with deep coma and hypotension, treated successfully with hemodialysis. Whether hemodialysis must always be performed is a controversial question. Our opinion is hemodialysis is not needed, even in life-threatening situations. Arguments about this opinion are presented.

In recent years, the integration of single‐cell multi‐omics data has provided a more comprehensive understanding of cell functions and internal regulatory mechanisms from a non‐single omics perspective, but it still suffers many challenges, such as omics‐variance, sparsity, cell heterogeneity, and confounding factors. As it is known, the cell cycle is regarded as a confounder when analyzing other factors in single‐cell RNA‐seq data, but it is not clear how it will work on the integrated single‐cell multi‐omics data. Here, a cell cycle‐aware network (CCAN) is developed to remove cell cycle effects from the integrated single‐cell multi‐omics data while keeping the cell type‐specific variations. This is the first computational model to study the cell‐cycle effects in the integration of single‐cell multi‐omics data. Validations on several benchmark datasets show the outstanding performance of CCAN in a variety of downstream analyses and applications, including removing cell cycle effects and batch effects of scRNA‐seq datasets from different protocols, integrating paired and unpaired scRNA‐seq and scATAC‐seq data, accurately transferring cell type labels from scRNA‐seq to scATAC‐seq data, and characterizing the differentiation process from hematopoietic stem cells to different lineages in the integration of differentiation data. [ABSTRACT FROM AUTHOR]

Background: The observational Frailty in European Emergency Departments (FEED) study found 40% of older people attending for care to be living with frailty. Older people with frailty have poorer outcomes from emergency care. Current best practice calls for early identification of frailty and holistic multidisciplinary assessment. This survey of FEED sites explores variations in frailty-attuned service definitions and provision. Methods: This cross-sectional survey included study sites across Europe identified through snowball recruitment. Site co-ordinators (healthcare professionals in emergency and geriatric care) were surveyed online using Microsoft Forms. Items covered department and hospital capacity, frailty and delirium identification methods, staffing, and frailty-focused healthcare services in the ED. Descriptive statistics were reported. Results: A total of 68 sites from 17 countries participated. Emergency departments had median 30 (IQR 21–53) trolley spaces. Most defined "older people" by age 65+ (64%) or 75+ (25%). Frailty screening was used at 69% of sites and mandated at 38%. Night-time staffing was lower compared to day-time for nursing (10 [IQR 8–14] vs. 14 [IQR 10–18]) and physicians (5 [IQR 3–8] vs. 10 [IQR 7–15]). Most sites had provision for ED frailty specialist services by day, but these services were rarely available at night. Sites mostly had accessible facilities; however, hot meals were rarely available at night (18%). Conclusion: This survey demonstrated variability in case definitions, screening practices, and frailty-attuned service provision. There is no unanimous definition for older age, and while the Clinical Frailty Scale was commonly used, this was rarely mandated or captured in electronic records. Frailty services were often unavailable overnight. Appreciation of the variation in frailty service models could inform operational configuration and workforce development. [ABSTRACT FROM AUTHOR]

Immunotherapy, particularly immune checkpoint blockade (ICB) therapies, has revolutionized oncology. However, it encounters challenges such as inadequate drug accumulation and limited efficacy against "cold" tumors characterized by lack of T cell infiltration and immunosuppressive microenvironments. Here, a controlled antibody production and releasing nanoparticle (CAPRN) is introduced, designed to augment ICB efficacy by facilitating tumor-targeted antibody production and inducing photodynamic cell death. CAPRN achieves tumor-specific accumulation via pH-responsive PEG detachment, enabling efficient intracellular gene delivery encoding anti-PD-L1 antibody. Laser-induced photodynamic therapy (PDT) not only triggers cancer cell death but also facilitates targeted antibody release from dying tumor cells. CAPRN demonstrates significant anti-tumor efficacy, attributed to multiple effects including enhanced antibody release, dendritic cell (DC) maturation, and T cell activation. Moreover, CAPRN exhibits substantial tumor suppression in both primary and bilateral tumor models, accompanied by activated T cell infiltration and enhanced immune responses. This study presents a novel strategy for priming robust immunotherapy, offering targeted antibody release through laser-assisted photodynamic nanoparticles., (© 2025 Wiley‐VCH GmbH.)

Objective: Falls are a leading cause for ED presentations among older adults. Existing secondary falls prevention interventions have not been shown to decrease fall-related ED re-presentation, indicating a need to better understand contributing factors. Our aim was to evaluate risk factors for fall re-presentations among the older patient population presenting to the ED., Methods: This is a single-centre case-control study. Cases were patients aged ≥65 years with two falls-related ED presentations within 6 months. Age- and sex-matched controls had a corresponding index, but no subsequent ED fall presentation. Data collected included falls risk factors and clinical features of the index presentation. Univariate and multivariate analyses were conducted to assess the relationship between potential exposures and fall re-presentation., Results: A total of 300 patients (mean age 83.8 years) were studied. On univariate analysis, factors significantly associated with ED fall re-presentation included increasing multimorbidity (P < 0.0001), increasing number of medications (P < 0.0001) and residing in residential aged care facility (RACF) (odds ratio [OR] 3.06, P < 0.001). No factors remained significant on multivariate analysis. Post-hoc analyses for the RACF subgroup showed that psychotropic medication use (OR 1.65, P = 0.04) and prior fall within 12 months (OR 2.68, P < 0.001) were significantly associated with re-presentation. Initial presentation with serious musculoskeletal injury was a significant protective factor (OR 0.21, P = 0.02)., Conclusion: The present study failed to identify factors independently associated with ED fall re-presentation, suggesting that the factors are complex and inter-related. Two high-risk populations were identified - those from RACF and those initially presenting with falls not resulting in serious injury., (© 2024 The Author(s). Emergency Medicine Australasia published by John Wiley & Sons Australia, Ltd on behalf of Australasian College for Emergency Medicine.)

Cardiovascular disorders (CVDs) are a major global health concern, but their underlying molecular mechanisms are not fully understood. Recent research highlights the role of long noncoding RNAs (lncRNAs), particularly ANRIL, in cardiovascular development and disease. ANRIL, located in the human genome's 9p21 region, significantly regulates cardiovascular pathogenesis. It controls nearby tumor suppressor genes CDKN2A/B through epigenetic pathways, influencing cell growth and senescence. ANRIL interacts with epigenetic modifiers, leading to altered histone modifications and gene expression changes. It also acts as a transcriptional regulator, impacting key genes in CVD development. ANRIL's involvement in cardiovascular epigenetic regulation suggests potential therapeutic strategies. Manipulating ANRIL and its associated epigenetic modifiers could offer new approaches to managing CVDs and preventing their progression. Dysregulation of ANRIL has been linked to various cardiovascular conditions, including coronary artery disease, atherosclerosis, ischemic stroke, and myocardial infarction. This abstract provides insights from recent research, emphasizing ANRIL's significance in the epigenetic landscape of cardiovascular disorders. By shedding light on ANRIL's role in cellular processes and disease development, the abstract highlights its potential as a therapeutic target for addressing CVDs., (© 2024 Wiley Periodicals LLC.)

Background: While multidimensional and interdisciplinary assessment of older adult patients improves their short-term outcomes after evaluation in the emergency department (ED), this assessment is time-consuming and ill-suited for the busy environment. Thus, identifying patients who will benefit from this strategy is challenging. Therefore, this study aimed to identify older adult patients suitable for a different ED approach as well as independent variables associated with poor short-term clinical outcomes. Methods: We included all patients =65 years attending 52 EDs in Spain over 7 days. Sociodemographic, comorbidity, and baseline functional status data were collected. The outcomes were 30-day mortality, re-presentation, hospital readmission, and the composite of all outcomes. Results: During the study among 96,014 patients evaluated in the ED, we included 23,338 patients =65 years--mean age, 78.4±8.1 years; 12,626 (54.1%) women. During follow-up, 5,776 patients (24.75%) had poor outcomes after evaluation in the ED: 1,140 (4.88%) died, 4,640 (20.51) returned to the ED, and 1,739 (7.69%) were readmitted 30 days after discharge following the index visit. A model including male sex, age =75 years, arrival by ambulance, Charlson Comorbidity Index =3, and functional impairment had a C-index of 0.81 (95% confidence interval, 0.80-0.82) for 30-day mortality. Conclusion: Male sex, age =75 years, arrival by ambulance, functional impairment, or severe comorbidity are features of patients who could benefit from approaches in the ED different from the common triage to improve the poor short-term outcomes of this population. [ABSTRACT FROM AUTHOR]

Objective: This study was to investigate the differences between young older adults with and without vision impairment on neuropsychological and psychiatric outcomes following falls during the past year and to identify predictors of cognitive decline or mental distress., Methods: A secondary analysis of 668 young older Chinese adults aged 65 ∼ 79 years old with a history of falls was conducted from the cross-sectional survey data in the 2018 wave of the Chinese Longitudinal Health Longevity Survey (CLHLS)., Results: Participants with vision impairment scored significantly higher on anxiety and depression and lower on cognitive function and SWB than those without vision impairment. And vision impairment was a significant predictor of adverse outcomes for all four neuropsychological and psychiatric measures., Conclusion: Neurocognitive deficits, psychological problems, and decreased self-sufficiency are quite common among community-dwelling older adults with visual impairment who have a history of falls within a year., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The aging process is accompanied by a continuous decline of the cardiac system, disrupting the homeostatic regulation of cells, organs, and systems. Aging increases the prevalence of cardiovascular diseases, thus heart failure and mortality. Understanding the cardiac aging process is of pivotal importance once it allows us to design strategies to prevent age-related cardiac events and increasing the quality of live in the elderly. In this review we provide an overview of the cardiac aging process focus on the following topics: cardiac structural and functional modifications; cellular mechanisms of cardiac dysfunction in the aging; genetics and epigenetics in the development of cardiac diseases; and aging heart and response to the exercise. [ABSTRACT FROM AUTHOR]

Fatigue is the most commonly reported and debilitating extraglandular symptom of primary Sjögren′s syndrome (pSS). Fatigue and exertional intolerance are hallmark symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We aimed to characterize fatigue and further symptoms among pSS patients and to determine whether there is a symptom overlap in pSS and ME/CFS. In 19 patients with pSS, we assessed pSS symptom severity and disease activity via questionnaires as well as the Canadian Consensus Criteria (CCC) for ME/CFS. Hand grip strength (HGS) and levels of α1-, α2-, β1-, β2-, M3- and M4-receptor-autoantibodies were measured. A subgroup of pSS patients exhibited severe fatigue and had higher severity of pain (p = 0.045), depression (p = 0.021) and sleep disturbances (p = 0.020) compared to those with less fatigue. Four of eighteen pSS patients fulfilled the CCC. HGS parameters strongly correlated with fatigue severity (p < 0.05), but strength fully recovered one hour after exertion in contrast to ME/CFS. Levels of β1-, β2- and M4-receptor-autoantibodies were elevated and correlated significantly with disease activity assessed by the ESSDAI (p < 0.05), but not fatigue severity. Only a minor subgroup of pSS patients fulfills the CCC, and post exertional malaise (PEM) is atypical, as it is primarily triggered by mental/emotional but not physical exertion. HGS assessment is an objective measure to assess overall fatigue severity. [ABSTRACT FROM AUTHOR]

Abdominal aortic aneurysm (AAA) is a severe vascular disease and a major public health issue with an unmet medical need for therapy. This disease is featured by a progressive dilation of the abdominal aorta, boosted by atherosclerosis, ageing, and smoking as major risk factors. Aneurysm growth increases the risk of aortic rupture, a life-threatening emergency with high mortality rates. Despite the increasing progress in our knowledge about the etiopathology of AAA, an effective pharmacological treatment against this disorder remains elusive and surgical repair is still the unique available therapeutic approach for high-risk patients. Meanwhile, there is nomedical alternative for patients with small aneurysms but close surveillance. Clinical trials assessing the efficacy of antihypertensive agents, statins, doxycycline, or anti-platelet drugs, among others, failed to demonstrate a clear benefit limiting AAA growth, while data from ongoing clinical trials addressing the benefit of metformin on aneurysm progression are eagerly awaited. Recent preclinical studies have postulated new therapeutic targets and pharmacological strategies paving the way for the implementation of future clinical studies exploring these novel therapeutic strategies. This review summarises some of the most relevant clinical and preclinical studies in search of new therapeutic approaches for AAA. [ABSTRACT FROM AUTHOR]

(1) Background: Non-Hodgkin Lymphoma is a neoplasm that can significantly compromise the immune system, but timely assessment can change the patient outcome. In cancer, the activation of the immune system could lead to the secretion of autoantibodies. (2) Methods: A retrospective cohort study was performed from 2017 to 2019 in patients with Non-Hodgkin Lymphoma diagnosed with a biopsy. (3) Results: We included 39 patients who were newly diagnosed, untreated, and without any autoimmune disease previously reported. Thirty patients had the presence of autoantibodies (antiphospholipid antibodies, anti-cytoplasmic neutrophils antibodies, antinuclear antibodies), and nine were without autoantibodies. There were no statistical differences among groups regarding clinical, demographic, staging, and prognosis characteristics. Also, there were no differences in the outcomes of the patients after finishing chemotherapy and one year after initiating treatment. (4) Conclusions: Further investigations must be conducted regarding an extended panel of autoantibodies because the panel of autoantibodies in this study did not show a relationship between the presence and the clinical outcome of the patients. [ABSTRACT FROM AUTHOR]

Although the curative effect of hematological malignancies has been improved in recent years, relapse or drug resistance of hematological malignancies will eventually recur. Furthermore, the microenvironment disorder is an important mechanism in the pathogenesis of hematological malignancies. Immunogenic cell death (ICD) is a unique mechanism of regulated cell death (RCD) that triggers an intact antigen‐specific adaptive immune response by firing a set of danger signals or damage‐associated molecular patterns (DAMPs), which is an immunotherapeutic modality with the potential for the treatment of hematological malignancies. This review summarizes the existing knowledge about the induction of ICD in hematological malignancies and the current research on combining ICD inducers with other treatment strategies for hematological malignancies. [ABSTRACT FROM AUTHOR]

Alpha-2-macroglobulin (A2M) is a protease inhibitor that regulates extracellular matrix (ECM) stability and turnover. Here, we show that A2M is expressed by endothelial cells (ECs) from human eye choroid. We demonstrate that retinal pigment epithelium (RPE)-conditioned medium induces A2M expression specifically in ECs. Experiments using chemical inhibitors, blocking antibodies, and recombinant proteins revealed a key role of VEGF-A in RPE-mediated A2M induction in ECs. Furthermore, incubation of ECs with RPE-conditioned medium reduces matrix metalloproteinase-2 gelatinase activity of culture supernatants, which is partially restored after A2M knockdown in ECs. We propose that dysfunctional RPE or choroidal blood vessels, as observed in retinal diseases such as age-related macular degeneration, may disrupt the crosstalk mechanism we describe here leading to alterations in the homeostasis of choroidal ECM, Bruch's membrane and visual function. [ABSTRACT FROM AUTHOR]

Background: Primary Sjögren Syndrome is a rare autoimmune systemic disease characterized by impaired secretory functions of the exocrine gland. One of the main clinical features is dry mouth and subsequent oral diseases, which are also found in patients with Sicca. This leads to a marked deterioration in the quality of life and the patient's search for information and solutions. Many patients turn to patients' associations that offer moments of sharing to their members, especially through online discussion forums. Today, these forums represent quality material for a sociological or biomedical analysis of patients' concerns, as close as possible to their daily lives. Our objective is to analyze the concerns of patients with SS or Sicca regarding their dry mouth especially dental care. Methods: In this cross-sectional observation study, a quantitative analysis of the Mouth-Nose online forum discussion of the French Association of Patients with Gougerot-Sjögren's Syndromes and Dryness have been performed. After reading and re-reading, initial request themes, topics, and subtopics were established and coding was performed. Then, the 885 threads were classified depending the initial request, pragma-linguistic indices and the main topic discussed in the thread. After identifying the threads dealing with dental care, we looked at which types of care were most discussed and classified the discussions according to whether or not the patient was satisfied with their care at the dentist. Results: The majority of the initial requests are posts for experiences sharing and/or advice. The topic of "dental care" is one of the main concerns of the forum users. Among the threads that concern dental care, requests to share experience with implants are in the majority. Finally, the majority of the posts on dental care relate to care in private dental practice, deals with dental implants and prevention and resulted mainly in patient satisfaction. Conclusions: Analysis of the forum reveals importance of patient concerns about prevention, and care costs due to implant treatment, which add to disease burden. Most of messages relate favorable experiences with their dentists, which is in line with the approach of sharing experiences and support characteristic of a forum. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) and heart failure (HF) are two chronic disorders that affect millions worldwide. Hyperglycemia can induce excessive generation of highly reactive free radicals that promote oxidative stress and further exacerbate diabetes progression and its complications. Vascular dysfunction and damage to cellular proteins, membrane lipids and nucleic acids can stem from overproduction and/or insufficient removal of free radicals. The aim of this article is to review the literature regarding the use of antidiabetic drugs and their role in glycemic control in patients with heart failure and oxidative stress. Metformin exerts a minor benefit to these patients. Thiazolidinediones are not recommended in diabetic patients, as they increase the risk of HF. There is a lack of robust evidence on the use of meglinitides and acarbose. Insulin and dipeptidyl peptidase-4 (DPP-4) inhibitors may have a neutral cardiovascular effect on diabetic patients. The majority of current research focuses on sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists. SGLT2 inhibitors induce positive cardiovascular effects in diabetic patients, leading to a reduction in cardiovascular mortality and HF hospitalization. GLP-1 receptor agonists may also be used in HF patients, but in the case of chronic kidney disease, SLGT2 inhibitors should be preferred. [ABSTRACT FROM AUTHOR]

Human immune deficiency virus (HIV) infection in the brain leads to chronic neuroinflammation due to the production of pro-inflammatory cytokines, which in turn promotes HIV transcription in infected microglial cells. However, powerful counteracting silencing mechanisms in microglial cells result in the rapid shutdown of HIV expression after viral reactivation to limit neuronal damage. Here we investigated whether the Nerve Growth Factor IB-like nuclear receptor Nurr1 (NR4A2), which is a repressor of inflammation in the brain, acts directly to restrict HIV expression. HIV silencing following activation by TNF-α, or a variety of toll-like receptor (TLR) agonists, in both immortalized human microglial cells (hμglia) and induced pluripotent stem cells (iPSC)-derived human microglial cells (iMG) was enhanced by Nurr1 agonists. Similarly, overexpression of Nurr1 led to viral suppression, while conversely, knock down (KD) of endogenous Nurr1 blocked HIV silencing. The effect of Nurr1 on HIV silencing is direct: Nurr1 binds directly to the specific consensus binding sites in the U3 region of the HIV LTR and mutation of the Nurr1 DNA binding domain blocked its ability to suppress HIV-1 transcription. Chromatin immunoprecipitation (ChIP) assays also showed that after Nurr1 binding to the LTR, the CoREST/HDAC1/G9a/EZH2 transcription repressor complex is recruited to the HIV provirus. Finally, transcriptomic studies demonstrated that in addition to repressing HIV transcription, Nurr1 also downregulated numerous cellular genes involved in inflammation, cell cycle, and metabolism, further promoting HIV latency and microglial homoeostasis. Nurr1 therefore plays a pivotal role in modulating the cycles of proviral reactivation by potentiating the subsequent proviral transcriptional shutdown. These data highlight the therapeutic potential of Nurr1 agonists for inducing HIV silencing and microglial homeostasis and ultimately for the amelioration of the neuroinflammation associated with HIV-associated neurocognitive disorders (HAND). Author summary: HIV enters the brain almost immediately after infection where it infects perivascular macrophages, microglia and, to a much lesser extent, astrocytes. In previous work using an immortalized human microglial cell model, we observed that integrated HIV constantly underwent cycles of reactivation and subsequent re-silencing. We now show that HIV shutdown after proviral reactivation is mediated by the Nurr1 nuclear receptor. Both the functional activation of Nurr1 by specific agonists, and the over expression of Nurr1, resulted in rapid silencing of activated HIV in microglial cells. Nurr1 not only repressed HIV expression but also selectively down regulated genes involved in microglial homeostasis and inflammation. Thus, Nurr1 is pivotal for HIV silencing and repression of inflammation in the brain and is a promising therapeutic target for the treatment of HAND. [ABSTRACT FROM AUTHOR]

Sjögren's syndrome (SS) is a systemic chronic autoimmune disorder characterized by lymphoplasmacytic infiltration of salivary glands (SGs) and lacrimal glands, causing glandular damage. The disease shows a combination of dryness symptoms found in the oral cavity, pharynx, larynx, and vagina, representing a systemic disease. Recent advances link chronic inflammation with SG fibrosis, based on a molecular mechanism pointing to the epithelial to mesenchymal transition (EMT). The continued activation of inflammatory-dependent fibrosis is highly detrimental and a common final pathway of numerous disease states. The important question of whether and how fibrosis contributes to SS pathogenesis is currently intensely debated. Here, we collect the recent findings on EMT-dependent fibrosis in SS SGs and explore clinical evidence of multi-organ fibrosis in SS to highlight potential avenues for therapeutic investigation. [ABSTRACT FROM AUTHOR]

Low energy constants (LECs) of heavy-hadron chiral perturbation theory (HH χ PT) for low lying bottom mesons are computed. The available data for J P = 0 - , 1 - , 0 + and 1 + of bottom mesons are used to analyze the mass formulae of low lying bottom mesons having low energy constants up to one-loop corrections. The decay widths of bottom mesons ( J P = 0 + and 1 + ) are analyzed to constraint the couplings. These coupling constants are used to fix the one-loop corrections in the mass formulae. The masses and couplings are then used to find LECs from mass formulae. The behavior of tree level masses are studied by changing LECs. This study has improved over the infinite number of sets of LECs for low lying bottom meson masses in HH χ PT. [ABSTRACT FROM AUTHOR]

Purpose: To investigate salivary gland ultrasonography (SGUS) findings in primary Sjögren's syndrome (pSS) patients positive for the anti-centromere antibody (ACA) and compare these with those in ACA-negative pSS patients. Methods: We analyzed demographic, clinical, laboratory, and SGUS data of pSS patients who fulfilled the 2002 American-European Consensus Group classification criteria for pSS. SGUS findings of four major salivary glands (bilateral parotid and submandibular glands) were scored in five categories and compared between ACA-positive and ACA-negative pSS patients. Linear regression analysis was performed to elucidate the factors associated with SGUS score. Results: In total, 121 pSS patients were enrolled (19, ACA-positive). The ACA-positive patients were older (67.0 vs 58.0 years, P = 0.028), whereas anti-Ro/SSA and anti-La/SSB positivity was more prevalent in the ACA-negative group (89.2% vs 21.1%, P < 0.001, and 47.1% vs 10.5%, P = 0.007, respectively). The total SGUS and hypoechoic area scores were lower in ACA-positive patients (16.0 vs 23.0, P = 0.027, and 4.0 vs 7.0, P = 0.004, respectively). In univariate regression analysis, being positive for unstimulated salivary flow rate (USFR < 1.5 ml/15 min), anti-Ro/SSA, and rheumatoid factor were positively associated whereas ACA positivity was negatively associated with the SGUS score. In multivariate regression analysis, being positive for USFR, anti-Ro/SSA, and rheumatoid factor showed significant association with the SGUS score. Conclusions: ACA-positive pSS patients showed a lower SGUS score than ACA-negative patients, which was especially prominent in the hypoechoic area component. [ABSTRACT FROM AUTHOR]

Bacillus Calmette-Guerin (BCG) is an attenuated bacterial vaccine used to protect against Mycobacterium tuberculosis (Mtb) in regions where infections are highly prevalent. BCG is currently delivered by the intradermal route, but alternative routes of administration are of great interest, including intrapulmonary delivery to more closely mimic respiratory Mtb infection. In this study, mice subjected to pulmonary delivery of green fluorescent protein– tagged strains of virulent (Mtb) and attenuated (BCG) mycobacteria were studied to better characterize infected lung cell subsets. Profound differences in dissemination patterns were detected between Mtb and BCG, with a strong tendency of Mtb to disseminate from alveolar macrophages (AMs) to other myeloid subsets, mainly neutrophils and recruited macrophages. BCG mostly remained in AMs, which promoted their activation. These preactivated macrophages were highly efficient in containing Mtb bacilli upon challenge and disrupting early bacterial dissemination, which suggests a potential mechanism of protection associated with pulmonary BCG vaccination. Respiratory BCG also protected mice against a lethal Streptococcus pneumoniae challenge, suggesting that BCG-induced innate activation could confer heterologous protection against respiratory pathogens different from Mtb. BCG drove long-term activation of AMs, even after vaccine clearance, and these AMs reacted efficiently upon subsequent challenge. These results suggest the generation of a trained innate memory-like response in AMs induced by pulmonary BCG vaccination. [ABSTRACT FROM AUTHOR]

We investigated the microstructure of the iron selenide superconductor (K0.7Na0.3)Fe2-ySe2 with a Tc=32K and a near 100% Meissner screening volume fraction. Topography and electron transport properties were studied using electron microscopy and ultra-high vacuum scanning tunneling microscopy (STM) techniques. Room temperature STM measurements reliably identify spatial variations of the local electronic properties of this material. The studied crystals consist of continuous regions with significantly different shapes of current-voltage curves reflecting different electronic transport properties of these regions. Fitting of the local current-voltage curves with the Simmons model for metal-dielectric-metal structure confirmed a phase separation in the sample to a metal and semiconducting phases. The observed regions have dimensions in the range of several tenths of a micrometer and indicate a phase separation in the sample. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is an acute inflammatory process arises from a wide range of lung insults. A major cause of ALI is dysfunction of the pulmonary vascular endothelial barrier but the mechanisms involved are incompletely understood. The therapeutic potential of histone deacetylase (HDAC) inhibitors for the treatment of cardiovascular and inflammatory diseases is increasingly apparent, but the mechanisms by which HDACs regulate pulmonary vascular barrier function remain to be resolved. We found that specific Class IIa HDACs inhibitor, TMP269, significantly attenuated the lipopolysaccharide (LPS)‐induced human lung microvascular endothelial cells (HLMVEC) barrier compromise in vitro and improved vascular barrier integrity and lung function in murine model of ALI in vivo. TMP269 decreased LPS‐induced myosin light chain phosphorylation suggesting the role for Class IIa HDACs in LPS‐induced cytoskeleton reorganization. TMP269 did not affect microtubule structure and tubulin acetylation in contrast to the HDAC6‐specific inhibitor, Tubastatin A suggesting that Class IIa HDACs and HDAC6 (Class IIb) regulate endothelial cytoskeleton and permeability via different mechanisms. Furthermore, LPS increased the expression of ArgBP2 which has recently been attributed to HDAC‐mediated activation of Rho. Depletion of ArgBP2 abolished the ability of LPS to disrupt barrier function in HLMVEC and both TMP269 and Tubastatin A decreased the level of ArgBP2 expression after LPS stimulation suggesting that both Class IIa and IIb HDACs regulate endothelial permeability via ArgBP2‐dependent mechanism. Collectively, our data strongly suggest that Class IIa HDACs are involved in LPS‐induced ALI in vitro and in vivo via specific mechanism which involved contractile responses, but not microtubule reorganization. [ABSTRACT FROM AUTHOR]

Immunogenic cell death (ICD) is a vital component of therapeutically induced anti‐tumor immunity. An iridium(III) complex (Ir1), containing an N,N‐bis(2‐chloroethyl)‐azane derivate, as an endoplasmic reticulum‐localized ICD inducer for non‐small cell lung cancer (NSCLC) is reported. The characteristic discharge of damage‐associated molecular patterns (DAMPs), that is, cell surface exposure of calreticulin (CRT), extracellular exclusion of high mobility group box 1 (HMGB1), and ATP, were generated by Ir1 in A549 lung cancer cells, accompanied by an increase in endoplasmic reticulum stress and reactive oxygen species (ROS). The vaccination of immunocompetent mice with Ir1‐treated dying cells elicited an antitumor CD8+ T cell response and Foxp3+ T cell depletion, which eventually resulted in long‐acting anti‐tumor immunity by the activation of ICD in lung cancer cells. Ir1 is the first Ir‐based complex that is capable of developing an immunomodulatory response by immunogenic cell death. [ABSTRACT FROM AUTHOR]