Intermittent fasting （IF）, a periodic energy restriction, has been shown to provide health benefits equivalent to prolonged fasting or caloric restriction. However, our understanding of the ...underlying mechanisms of IF-mediated metabolic benefits is limited. Here we show that isocaloric IF improves metabolic homeostasis against diet-induced obesity and metabolic dysfunction primarily through adipose thermogenesis in mice. IF-induced metabolic benefits require fasting-mediated increases of vascular endothelial growth factor （VEGF） expression in white adipose tissue （WAT）. Furthermore, periodic adipose-VEGF overexpression could recapitulate the metabolic improvement of IF in non-fasted animals. Importantly, fasting and adipose-VEGF induce alternative activation of adipose macrophage, which is critical for thermogenesis. Human adipose gene analysis further revealed a positive correlation of adipose VEGF-M2 macrophage-WAT browning axis. The present study uncovers the molecular mechanism of IF-mediated metabolic benefit and suggests that isocaloric IF can be a preventive and therapeutic approach against obesity and metabolic disorders.
Epigenetic dysregulation is a defining feature of tumorigenesis that is implicated in immune escape
. Here, to identify factors that modulate the immune sensitivity of cancer cells, we performed in ...vivo CRISPR-Cas9 screens targeting 936 chromatin regulators in mouse tumour models treated with immune checkpoint blockade. We identified the H3K9 methyltransferase SETDB1 and other members of the HUSH and KAP1 complexes as mediators of immune escape
. We also found that amplification of SETDB1 (1q21.3) in human tumours is associated with immune exclusion and resistance to immune checkpoint blockade. SETDB1 represses broad domains, primarily within the open genome compartment. These domains are enriched for transposable elements (TEs) and immune clusters associated with segmental duplication events, a central mechanism of genome evolution
. SETDB1 loss derepresses latent TE-derived regulatory elements, immunostimulatory genes, and TE-encoded retroviral antigens in these regions, and triggers TE-specific cytotoxic T cell responses in vivo. Our study establishes SETDB1 as an epigenetic checkpoint that suppresses tumour-intrinsic immunogenicity, and thus represents a candidate target for immunotherapy.
One of the main components of the extracellular matrix (ECM) in natural tissues is collagen. Therefore, there has been a strong focus on processing of collagen for biomaterials application in tissue ...engineering such as in anisotropic tissues like muscles and tendons. To achieve native‐like mechanical properties of the in vitro processed collagen, various crosslinking methods have been tested, but the used crosslinkers often do not yield sufficient mechanical properties or induce considerable inflammatory reactions. Here, good mechanical stability of collagen fibers is achieved by self‐assembly during wet‐spinning without the need of additional crosslinkers. The produced endless collagen fibers show fibril alignment within the fiber with a typical D‐band pattern and a periodicity of approximately 67 nm, which is unique for fibril‐forming collagens. Furthermore, the collagen fibers are processed into hierarchical assemblies using textile‐engineering techniques. The woven assemblies are shown to be excellent substrates for the formation of muscle microtissue with long, aligned, and contractile myofibers. Such constructs are highly important at the muscle‐tendon‐junction (MTJ) and therefore myoblasts and fibroblasts are co‐cultured to develop an MTJ‐model.
Continuous production of non‐crosslinked collagen microfibers with good mechanical properties combined with textile‐engineering techniques allowed the processing of complex scaffold morphologies. Differentiated skeletal muscle cells on collagen fibers are contractile and showed organized sarcomere structure. Successful co‐culture of muscle cells and fibroblasts confirmed the feasibility of the collagen‐based assemblies to mimic the anisotropic structure of the muscle‐tendon junction (MTJ).
Primary care is a key element of health care systems and addresses the main health problems of the population. Due to the demographic change, primary care even gains in importance. The knowledge of ...the patients' preferences can help policy makers as well as physicians to set priorities in their effort to make health care delivery more responsive to patients' needs. Our objective was to describe which aspects of primary care were included in preference studies and which of them were the most preferred aspects.
In order to elicit the preferences for primary care, a systematic literature search was conducted. Two researchers searched three electronic databases (PubMed, Scopus, and PsycINFO) and conducted a narrative synthesis. Inclusion criteria were: focus on primary health care delivery, discrete choice experiment as elicitation method, and studies published between 2006 and 2015 in English language.
We identified 18 studies that elicited either the patients' or the population's preferences for primary care based on a discrete choice experiment. Altogether the studies used 16 structure attributes, ten process attributes and four outcome attributes. The most commonly applied structure attribute was "Waiting time till appointment", the most frequently used process attribute was "Shared decision making / professional's attention paid to your views". "Receiving the 'best' treatment" was the most commonly applied outcome attribute. Process attributes were most often the ones of highest importance for patients or the population. The attributes and attribute levels used in the discrete choice experiments were identified by literature research, qualitative research, expert interviews, or the analysis of policy documents.
The results of the DCE studies show different preferences for primary health care. The diversity of the results may have several reasons, such as the method of analysis, the selection procedure of the attributes and their levels or the specific research question of the study. As the results of discrete choice experiments depend on many different factors, it is important for a better comprehensibility of the studies to transparently report the steps undertaken in a study as well as the interim results regarding the identification of attributes and levels.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
We conducted a multisite, randomized, double‐blinded, controlled trial to examine the effectiveness of a digital health intervention targeting the intrinsic regulation of goal‐directed ...alertness in patients with chronic hemispatial neglect.
Methods
Forty‐nine participants with hemispatial neglect, who demonstrated significant spatially biased attention after acquired brain injury, were randomly assigned to the experimental attention remediation treatment or the active control group. The participants engaged with the remotely administered interventions for 12 weeks. The primary outcome was spatial bias on the Posner cueing task (response time difference: left minus right target trials). Secondary outcomes included functional abilities (measured via the Catherine Bergego scale and Barthel index), spatial cognition, executive function, quality of life, and sleep. Assessments were conducted before and immediately after participation in the experimental intervention or control condition, and again after a 3‐month no‐contact period.
Results
Compared with the active control group, the intervention group exhibited a significant improvement in the primary outcome, a reduction in spatially biased attention on the Posner cueing task (p = 0.010, Cohen's d = 0.96), in addition to significant improvements in functional abilities as measured on the Catherine Bergego and Barthel indices (p = 0.027, Cohen's d = 0.24).
Interpretation
Our results demonstrate that our attention training program was effective in improving the debilitating attention deficits common to hemispatial neglect. This benefit generalized to improvements in real‐world functional abilities. This safe, highly scalable, and self‐administered treatment for hemispatial neglect might serve as a useful addition to the existing standard of care. ANN NEUROL 2020;88:747–758
Selective macro-autophagy is an intracellular process by which large cytoplasmic materials are selectively sequestered and degraded in the lysosomes. Substrate selection is mediated by ubiquitylation ...and recruitment of ubiquitin-binding autophagic receptors such as p62, NBR1, NDP52 and Optineurin. Although it has been shown that these receptors act cooperatively to target some types of substrates to nascent autophagosomes, their precise roles are not well understood. We examined selective autophagic degradation of peroxisomes (pexophagy), and found that NBR1 is necessary and sufficient for pexophagy. Mutagenesis studies of NBR1 showed that the amphipathic α-helical J domain, the ubiquitin-associated (UBA) domain, the LC3-interacting region and the coiled-coil domain are necessary to mediate pexophagy. Strikingly, substrate selectivity is partly achieved by NBR1 itself by coincident binding of the J and UBA domains to peroxisomes. Although p62 is not required when NBR1 is in excess, its binding to NBR1 increases the efficiency of NBR1-mediated pexophagy. Together, these results suggest that NBR1 is the specific autophagy receptor for pexophagy.
pH-triggered membrane-permeabilizing peptides could be exploited in a variety of applications, such as to enable cargo release from endosomes for cellular delivery, or as cancer therapeutics that ...selectively permeabilize the plasma membranes of malignant cells. Such peptides would be especially useful if they could enable the movement of macromolecules across membranes, a rare property in membrane-permeabilizing peptides. Here we approach this goal by using an orthogonal high-throughput screen of an iterative peptide library to identify peptide sequences that have the following two properties: (i) little synthetic lipid membrane permeabilization at physiological pH 7 at high peptide concentration and (ii) efficient formation of macromolecule-sized defects in synthetic lipid membranes at acidic pH 5 and low peptide concentration. The peptides we selected are remarkably potent macromolecular sized pore-formers at pH 5, while having little or no activity at pH 7, as intended. The action of these peptides likely relies on tight coupling between membrane partitioning, α-helix formation, and electrostatic repulsions between acidic side chains, which collectively drive a sharp pH-triggered transition between inactive and active configurations with apparent pK a values of 5.5–5.8. This work opens new doors to developing applications that utilize peptides with membrane-permeabilizing activities that are triggered by physiologically relevant decreases in pH.
AIM: To evaluate whether Helicobacter pylori(H. pylori) eradication therapy benefits patients with functional dyspepsia(FD).METHODS: Randomized controlled trials(RCTs) investigating the efficacy and ...safety of H. pylori eradication therapy for patients with functional dyspepsia published in English(up to May 2015) were identified by searching Pub Med, EMBASE, and The Cochrane Library. Pooled estimates were measured using the fixed or random effect model. Overall effect was expressed as a pooled risk ratio(RR) or a standard mean difference(SMD). All data were analyzed with Review Manager 5.3 and Stata 12.0.RESULTS: This systematic review included 25 RCTs with a total of 5555 patients with FD. Twenty-three of these studies were used to evaluate the benefits of H. pylori eradication therapy for symptom improvement; the pooled RR was 1.23(95%CI: 1.12-1.36, P < 0.0001). H. pylori eradication therapy demonstrated symptom improvement during long-term follow-up at ≥ 1 year(RR = 1.24; 95%CI: 1.12-1.37, P < 0.0001) but not during short-term follow-up at < 1 year(RR = 1.26; 95%CI: 0.83-1.92, P = 0.27). Seven studies showed no benefit of H. pylori eradication therapy on quality of life with an SMD of-0.01(95%CI:-0.11 to 0.08, P = 0.80). Six studies demonstrated that H. pylori eradication therapy reduced the development of peptic ulcer disease compared to no eradication therapy(RR = 0.35; 95%CI: 0.18-0.68, P = 0.002). Eight studies showed that H. pylori eradication therapy increased the likelihood of treatment-related side effects compared to no eradication therapy(RR = 2.02; 95%CI: 1.12-3.65, P = 0.02). Ten studies demonstrated that patients who received H. pylori eradication therapy were more likely to obtain histologic resolution of chronic gastritis compared to those who did not receive eradication therapy(RR = 7.13; 95%CI: 3.68-13.81, P < 0.00001).CONCLUSION: The decision to eradicate H. pylori in patients with functional dyspepsia requires individual assessment.
During viral infection, tight regulation of CD8+ T-cell functions determines the outcome of the disease. Recently, others and we determined that the natural killer (NK) cells kill hyperproliferative ...CD8+ T cells in the context of viral infection, but molecules that are involved in shaping the regulatory capability of NK cells remain virtually unknown. Here we used mice lacking the Fc-receptor common gamma chain (FcRγ, FcεRIγ, Fcer1g-/- mice) to determine the role of Fc-receptor and NK-receptor signaling in the process of CD8+ T-cell regulation. We found that the lack of FcRγ on NK cells limits their ability to restrain virus-specific CD8+ T cells and that the lack of FcRγ in Fcer1g-/- mice leads to enhanced CD8+ T-cell responses and rapid control of the chronic docile strain of the lymphocytic choriomeningitis virus (LCMV). Mechanistically, FcRγ stabilized the expression of NKp46 but not that of other killer cell-activating receptors on NK cells. Although FcRγ did not influence the development or activation of NK cell during LCMV infection, it specifically limited their ability to modulate CD8+ T-cell functions. In conclusion, we determined that FcRγ plays an important role in regulating CD8+ T-cell functions during chronic LCMV infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Since the early 1980's, with the clinical advent of in vitro fertilization resulting in so-called "test tube babies," a wide array of ethical considerations and concerns regarding artificial womb ...technology (AWT) have been described. Recent breakthroughs in the development of extracorporeal neonatal life support by means of AWT have reinitiated ethical interest about this topic with a sense of urgency. Most of the recent ethical literature on the topic, however, pertains not to the more imminent scenario of a physiologically improved method of neonatal care through AWT, but instead to the remote scenario of "complete ectogenesis" that imagines human gestation occurring entirely outside of the womb. This scoping review of the ethical literature on AWT spans from more abstract concerns about complete ectogenesis to more immediate concerns about the soon-to-be-expected clinical life support of what we term the fetal neonate or fetonate. Within an organizing framework of different stages of human gestational development, from conception to the viable premature infant, we discuss both already identified and newly emerging ethical considerations and concerns regarding AWT and the care of the fetonate.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK, VSZLJ
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