استكشف المجموعة الواسعة من العناوين المتاحة.

Ferroptosis is a mechanism of regulated necrotic cell death characterized by iron-dependent, lipid peroxidation-driven membrane destruction that can be inhibited by glutathione peroxidase 4. Morphologically, it is characterized by cellular, organelle and cytoplasmic swelling and the loss of plasma membrane integrity, with the release of intracellular components. Ferroptosis is triggered in cells with dysregulated iron and thiol redox metabolism, whereby the initial robust but selective accumulation of hydroperoxy polyunsaturated fatty acid-containing phospholipids is further propagated through enzymatic and non-enzymatic secondary mechanisms, leading to formation of oxidatively truncated electrophilic species and their adducts with proteins. Thus, ferroptosis is dependent on the convergence of iron, thiol and lipid metabolic pathways. The kidney is particularly susceptible to redox imbalance. A growing body of evidence has linked ferroptosis to acute kidney injury in the context of diverse stimuli, such as ischaemia-reperfusion, sepsis or toxins, and to chronic kidney disease, suggesting that ferroptosis may represent a novel therapeutic target for kidney disease. However, further work is needed to address gaps in our understanding of the triggers, execution and spreading mechanisms of ferroptosis.

Fluid overload is associated with morbidity and mortality in patients receiving renal replacement therapy (RRT). We aimed to explore whether fluid overload at initiation of RRT was independently associated with mortality and whether changes in cumulative fluid balance during RRT were associated with outcome. We retrospectively analysed the data of patients who were admitted to the multidisciplinary adult intensive care unit (ICU) in a tertiary care centre in the UK between 2012 and 2015 and received continuous RRT (CRRT) for acute kidney injury for at least 24 h. We collected baseline demographics, body mass index (BMI), comorbidities, severity of illness, laboratory parameters at CRRT initiation, daily cumulative fluid balance (FB), daily prescribed FB target, fluid bolus and diuretic administration and outcomes. The day of the lowest cumulative FB during CRRT was identified as nadir FB. Eight hundred twenty patients were analysed (median age 65 years; 49% female). At CRRT initiation, the median cumulative FB was + 1772 ml; 89 patients (10.9%) had a cumulative FB > 10% body weight (BW). Hospital survivors had a significantly lower cumulative FB at CRRT initiation compared to patients who died (1495 versus 2184 ml; p < 0.001). In the 7 days after CRRT initiation, hospital survivors had a significant decline in cumulative FB (mean decrease 473 ml per day, p < 0.001) whilst there was no significant change in cumulative FB in non-survivors (mean decrease 112 ml per day, p = 0.188). Higher severity of illness at CRRT initiation, shorter duration of CRRT, the number of days without a prescribed FB target and need for higher doses of noradrenaline were independent risk factors for not reaching a FB nadir during CRRT. Multivariable analysis showed that older age, lower BMI, higher severity of illness, need for higher doses of noradrenaline and smaller reductions in cumulative FB during CRRT were independent risk factors for ICU and hospital mortality. Cumulative FB at CRRT initiation was not independently associated with mortality. In adult patients receiving CRRT, a decrease in cumulative FB was independently associated with lower mortality. Fluid overload and need for vasopressor support at CRRT initiation were not independently associated with mortality after correction for severity of illness.

Structural variants (SVs) can contribute to oncogenesis through a variety of mechanisms. Despite their importance, the identification of SVs in cancer genomes remains challenging. Here, we present a framework that integrates optical mapping, high-throughput chromosome conformation capture (Hi-C), and whole-genome sequencing to systematically detect SVs in a variety of normal or cancer samples and cell lines. We identify the unique strengths of each method and demonstrate that only integrative approaches can comprehensively identify SVs in the genome. By combining Hi-C and optical mapping, we resolve complex SVs and phase multiple SV events to a single haplotype. Furthermore, we observe widespread structural variation events affecting the functions of noncoding sequences, including the deletion of distal regulatory sequences, alteration of DNA replication timing, and the creation of novel three-dimensional chromatin structural domains. Our results indicate that noncoding SVs may be underappreciated mutational drivers in cancer genomes.

Limitations of existing thrombolytic therapies for acute ischemic stroke have motivated the development of catheter-based approaches that utilize no or low doses of thrombolytic drugs combined with a mechanical action to either dissolve or extract the thrombus. Sonothrombolysis accelerates thrombus dissolution via the application of ultrasound combined with microbubble contrast agents and low doses of thrombolytics to mechanically disrupt the fibrin mesh. In this work, we studied the efficacy of catheter-directed sonothrombolysis in a rat model of ischemic stroke. Microbubbles of 10–20  µ m diameter with a nitrogen gas core and a non-crosslinked albumin shell were produced by a flow-focusing microfluidic device in real time. The microbubbles were dispensed from a catheter located in the internal carotid artery for direct delivery to the thrombus-occluded middle cerebral artery, while ultrasound was administered through the skull and recombinant tissue plasminogen activator (rtPA) was infused via a tail vein catheter. The results of this study demonstrate that flow focusing microfluidic devices can be miniaturized to dimensions compatible with human catheterization and that large-diameter microbubbles comprised of high solubility gases can be safely administered intraarterially to deliver a sonothrombolytic therapy. Further, sonothrombolysis using intraarterial delivery of large microbubbles reduced cerebral infarct volumes by approximately 50% vs. no therapy, significantly improved functional neurological outcomes at 24 h, and permitted rtPA dose reduction of 3.3 (95% CI 1.8–3.8) fold when compared to therapy with intravenous rtPA alone.

Sensory hypersensitivity is one manifestation of the central sensitization that may underlie conditions such as fibromyalgia and chronic fatigue syndrome. We conducted five studies designed to develop and validate the Sensory Hypersensitive Scale (SHS); a 25-item self-report measure of sensory hypersensitivity. The SHS assesses both general sensitivity and modality-specific sensitivity (e.g. touch, taste, and hearing). 1202 participants (157 individuals with chronic pain) completed the SHS, which demonstrated an adequate overall internal reliability (Cronbach’s alpha) of 0.81, suggesting the tool can be used as a cross-modality assessment of sensitivity. SHS scores demonstrated only modest correlations (Pearson’s r ) with depressive symptoms (0.19) and anxiety (0.28), suggesting a low level of overlap with psychiatric complaints. Overall SHS scores showed significant but relatively modest correlations (Pearson’s r ) with three measures of sensory testing: cold pain tolerance (−0.34); heat pain tolerance (−0.285); heat pain threshold (−0.271). Women reported significantly higher scores on the SHS than did men, although gender-based differences were small. In a chronic pain sample, individuals with fibromyalgia syndrome demonstrated significantly higher SHS scores than did individuals with osteoarthritis or back pain. The SHS appears suitable as a screening measure for sensory hypersensitivity, though additional research is warranted to determine its suitability as a proxy for central sensitization.

Therapeutic approaches that enhance thrombolysis by combining recombinant tissue plasminogen activator (rtPA), ultrasound, and/or microbubbles (MBs) are known as sonothrombolysis techniques. To date, sonothrombolysis approaches have primarily utilized commercially available MB formulations (or derivatives thereof) with diameters in the range 1–4  µ m and circulation lifetimes between 5 and 15 min. The present study evaluated the in vitro sonothrombolysis efficacy of large diameter MBs ( d MB  ≥ 10  µ m) with much shorter lifetimes that were produced on demand and in close proximity to the blood clot using a flow-focusing microfluidic device. MBs with a N 2 gas core and a non-crosslinked bovine serum albumin shell were produced with diameters between 10 and 20  µ m at rates between 50 and 950 × 10 3 per second. Use of these large MBs resulted in approximately 4.0–8.8 fold increases in thrombolysis rates compared to a clinical rtPA dose and approximately 2.1–4.2 fold increases in thrombolysis rates compared to sonothrombolysis techniques using conventional MBs. The results of this study indicate that the large diameter microbubbles with transient stability are capable of significantly enhanced in vitro sonothrombolysis rates when delivered directly to the clot immediately following production by a flow focusing microfluidic device placed essentially in situ adjacent to the clot.

Within-patient HIV evolution reflects the strong selection pressure driving viral escape from cytotoxic T-lymphocyte (CTL) recognition. Whether this intrapatient accumulation of escape mutations translates into HIV evolution at the population level has not been evaluated. We studied over 300 patients drawn from the B- and C-clade epidemics, focusing on human leukocyte antigen (HLA) alleles HLA-B57 and HLA-B5801, which are associated with long-term HIV control and are therefore likely to exert strong selection pressure on the virus. The CTL response dominating acute infection in HLA-B57/5801-positive subjects drove positive selection of an escape mutation that reverted to wild-type after transmission to HLA-B57/5801-negative individuals. A second escape mutation within the epitope, by contrast, was maintained after transmission. These data show that the process of accumulation of escape mutations within HIV is not inevitable. Complex epitope- and residue-specific selection forces, including CTL-mediated positive selection pressure and virus-mediated purifying selection, operate in tandem to shape HIV evolution at the population level.

Introduction Addressing the intersection between mental health and HIV is critical for the wellbeing of persons living with HIV (PLWH). This systematic review synthesized the literature on mental health interventions for PLWH in low‐ and middle‐income countries (LMICs) to determine intervention components and explore their relationship with intervention effectiveness. Methods We included only controlled clinical trials of interventions aiming to improve the mental health of PLWH. We conducted a search in the following databases: PubMed, CINAHL, PsycINFO and EMBASE for eligible studies describing the evaluation of interventions for mental health problems among PLWH in LMICs published through August 2020. Two reviewers independently screened references in two successive stages of title/ screening and then full‐text screening for references meeting title/ criteria. Results We identified a total of 30 eligible articles representing 6477 PLWH who were assigned to either the intervention arm (n = 3182) or control arm (n = 3346). The mental health interventions evaluated were psychological (n = 17, 56.67%), pharmacological (n = 6, 20.00%), combined psychological and pharmacological (n = 1, 3.33%) and complementary/alternative treatments (n = 6, 20.00%). The mental health problems targeted were depression (n = 22, 73.33 %), multiple psychological symptoms (n = 1, 3.33%), alcohol and substance use problems (n = 4, 13.33%), post‐traumatic stress disorder (n = 1, 3.33%) and HIV‐related neuro‐cognitive impairment (n = 2, 6.67%). Studies of interventions with significant effects had significantly a higher number of active ingredients than those without significant effects [3.41 (2.24) vs. 1.84 (1.46) Mean (SD)] [Mean difference = −1.56, 95% CI = −3.03 to −0.09, p = 0.037]. Conclusions There continue to be advances in mental health interventions for PLWH with mental illness in LMICs. However, more research is needed to elucidate how intervention components lead to intervention effectiveness. We recommend scale up of culturally appropriate interventions that have been successfully evaluated in low‐ and middle‐income countries.

The marine trace gas dimethylsulfide (DMS) is the single most important biogenic source of atmospheric sulfur, accounting for up to 80% of global biogenic sulfur emissions. Approximately 300 million tons of DMS are produced annually, but the majority is degraded by microbes in seawater. The DMS precursor dimethylsulfoniopropionate (DMSP) and oxidation product dimethylsulphoxide (DMSO) are also important organic sulfur reservoirs. However, the marine sinks of dissolved DMSO remain unknown. We used a novel combination of stable and radiotracers to determine seasonal changes in multiple dissolved organic sulfur transformation rates to ascertain whether microbial uptake of dissolved DMSO was a significant loss pathway. Surface concentrations of DMS ranged from 0.5 to 17.0 nM with biological consumption rates between 2.4 and 40.8 nM·d . DMS produced from the reduction of DMSO was not a significant process. Surface concentrations of total DMSO ranged from 2.3 to 102 nM with biological consumption of dissolved DMSO between 2.9 and 111 nM·d . Comparisons between C -DMSO assimilation and dissimilation rates suggest that the majority of dissolved DMSO was respired (>94%). Radiotracer microbial consumption rates suggest that dissimilation of dissolved DMSO to CO can be a significant loss pathway in coastal waters, illustrating the significance of bacteria in controlling organic sulfur seawater concentrations.