The circadian clock is a cell-autonomous transcription-translation feedback mechanism that anticipates and adapts physiology and behavior to different phases of the day. A variety of factors ...including hormones, temperature, food-intake, and exercise can act on tissue-specific peripheral clocks to alter the expression of genes that influence metabolism, all in a time-of-day dependent manner. The aim of this study was to elucidate the effects of exercise timing on adipose tissue metabolism. We performed RNA sequencing on inguinal adipose tissue of mice immediately following maximal exercise or sham treatment at the early rest or early active phase. Only during the early active phase did exercise elicit an immediate increase in serum nonesterified fatty acids. Furthermore, early active phase exercise increased expression of markers of thermogenesis and mitochondrial proliferation in inguinal adipose tissue. In vitro, synchronized 3T3-L1 adipocytes showed a timing-dependent difference in
expression, as well as a greater lipolytic activity. Thus, the response of adipose tissue to exercise is time-of-day sensitive and may be partly driven by the circadian clock. To determine the influence of feeding state on the time-of-day response to exercise, we replicated the experiment in 10-h-fasted early rest phase mice to mimic the early active phase metabolic status. A 10-h fast led to a similar lipolytic response as observed after active phase exercise but did not replicate the transcriptomic response, suggesting that the observed changes in gene expression are not driven by feeding status. In conclusion, acute exercise elicits timing-specific effects on adipose tissue to maintain metabolic homeostasis.
To contribute to the WHO initiative, VISION 2020: The Right to Sight, an assessment of global vision impairment in 2020 and temporal change is needed. We aimed to extensively update estimates of ...global vision loss burden, presenting estimates for 2020, temporal change over three decades between 1990–2020, and forecasts for 2050.
We did a systematic review and meta-analysis of population-based surveys of eye disease from January, 1980, to October, 2018. Only studies with samples representative of the population and with clearly defined visual acuity testing protocols were included. We fitted hierarchical models to estimate 2020 prevalence (with 95% uncertainty intervals UIs) of mild vision impairment (presenting visual acuity ≥6/18 and <6/12), moderate and severe vision impairment (<6/18 to 3/60), and blindness (<3/60 or less than 10° visual field around central fixation); and vision impairment from uncorrected presbyopia (presenting near vision <N6 or <N8 at 40 cm where best-corrected distance visual acuity is ≥6/12). We forecast estimates of vision loss up to 2050.
In 2020, an estimated 43·3 million (95% UI 37·6–48·4) people were blind, of whom 23·9 million (55%; 20·8–26·8) were estimated to be female. We estimated 295 million (267–325) people to have moderate and severe vision impairment, of whom 163 million (55%; 147–179) were female; 258 million (233–285) to have mild vision impairment, of whom 142 million (55%; 128–157) were female; and 510 million (371–667) to have visual impairment from uncorrected presbyopia, of whom 280 million (55%; 205–365) were female. Globally, between 1990 and 2020, among adults aged 50 years or older, age-standardised prevalence of blindness decreased by 28·5% (–29·4 to −27·7) and prevalence of mild vision impairment decreased slightly (–0·3%, −0·8 to −0·2), whereas prevalence of moderate and severe vision impairment increased slightly (2·5%, 1·9 to 3·2; insufficient data were available to calculate this statistic for vision impairment from uncorrected presbyopia). In this period, the number of people who were blind increased by 50·6% (47·8 to 53·4) and the number with moderate and severe vision impairment increased by 91·7% (87·6 to 95·8). By 2050, we predict 61·0 million (52·9 to 69·3) people will be blind, 474 million (428 to 518) will have moderate and severe vision impairment, 360 million (322 to 400) will have mild vision impairment, and 866 million (629 to 1150) will have uncorrected presbyopia.
Age-adjusted prevalence of blindness has reduced over the past three decades, yet due to population growth, progress is not keeping pace with needs. We face enormous challenges in avoiding vision impairment as the global population grows and ages.
Brien Holden Vision Institute, Fondation Thea, Fred Hollows Foundation, Bill & Melinda Gates Foundation, Lions Clubs International Foundation, Sightsavers International, and University of Heidelberg.
NKG2D is an activating receptor on CD8(+) T cells and NK cells that has been implicated in immunity against tumors and microbial pathogens. Here we show that RAE-1 is present in prediabetic pancreas ...islets of NOD mice and that autoreactive CD8(+) T cells infiltrating the pancreas express NKG2D. Treatment with a nondepleting anti-NKG2D monoclonal antibody (mAb) during the prediabetic stage completely prevented disease by impairing the expansion and function of autoreactive CD8(+) T cells. These findings demonstrate that NKG2D is essential for disease progression and suggest a new therapeutic target for autoimmune type I diabetes.
Bifidobacterium longum subsp. infantis (B. infantis) is a commensal bacterium that colonizes the gastrointestinal tract of breast-fed infants. B. infantis can efficiently utilize the abundant supply ...of oligosaccharides found in human milk (HMO) to help establish residence. We hypothesized that metabolites from B. infantis grown on HMO produce a beneficial effect on the host.
In a previous study, we demonstrated that B. infantis routinely dominated the fecal microbiota of a breast fed Bangladeshi infant cohort (1). Characterization of the fecal metabolome of binned samples representing high and low B. infantis populations from this cohort revealed higher amounts of the tryptophan metabolite indole-3-lactic acid (ILA) in feces with high levels of B. infantis. Further in vitro analysis confirmed that B. infantis produced significantly greater quantities of the ILA when grown on HMO versus lactose, suggesting a growth substrate relationship to ILA production. The direct effects of ILA were assessed in a macrophage cell line and intestinal epithelial cell lines. ILA (1-10 mM) significantly attenuated lipopolysaccharide (LPS)-induced activation of NF-kB in macrophages. ILA significantly attenuated TNF-α- and LPS-induced increase in the pro-inflammatory cytokine IL-8 in intestinal epithelial cells. ILA increased mRNA expression of the aryl hydrogen receptor (AhR)-target gene CYP1A1 and nuclear factor erythroid 2-related factor 2 (Nrf2)-targeted genes glutathione reductase 2 (GPX2), superoxide dismutase 2 (SOD2), and NAD(P) H dehydrogenase (NQO1). Pretreatment with either the AhR antagonist or Nrf-2 antagonist inhibited the response of ILA on downstream effectors.
These findings suggest that ILA, a predominant metabolite from B. infantis grown on HMO and elevated in infant stool high in B. infantis, and protects gut epithelial cells in culture via activation of the AhR and Nrf2 pathway.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Prodrugs engineered for preferential activation in diseased versus normal tissues offer immense potential to improve the therapeutic indexes (TIs) of preclinical and clinical-stage active ...pharmaceutical ingredients that either cannot be developed otherwise or whose efficacy or tolerability it is highly desirable to improve. Such approaches, however, often suffer from trial-and-error design, precluding predictive synthesis and optimization. Here, using bromodomain and extra-terminal (BET) protein inhibitors (BETi)–a class of epigenetic regulators with proven anticancer potential but clinical development hindered in large part by narrow TIs–we introduce a macromolecular prodrug platform that overcomes these challenges. Through tuning of traceless linkers appended to a “bottlebrush prodrug” scaffold, we demonstrate correlation of in vitro prodrug activation kinetics with in vivo tumor pharmacokinetics, enabling the predictive design of novel BETi prodrugs with enhanced antitumor efficacies and devoid of dose-limiting toxicities in a syngeneic triple-negative breast cancer murine model. This work may have immediate clinical implications, introducing a platform for predictive prodrug design and potentially overcoming hurdles in drug development.
The recently discovered chitin-based scaffolds derived from poriferans have the necessary prosperities for potential use in tissue engineering. Among the various demosponges of the Verongida order, ...Aplysina aerophoba is an attractive target for more in-depth investigations, as it is a renewable source of unique 3D microporous chitinous scaffolds. We found these chitinous scaffolds were cytocompatible and supported attachment, growth and proliferation of human mesenchymal stromal cells (hMSCs) in vitro. Cultivation of hMSCs on the scaffolds for 7days resulted in a two-fold increase in their metabolic activity, indicating increased cell numbers. Cells cultured onto chitin scaffolds in differentiation media were able to differentiate into the chondrogenic, adipogenic and osteogenic lineages, respectively. These results indicate A. aerophoba is a novel source of chitin scaffolds to futher hMSCs-based tissue engineering strategies.
Pulmonary vein (PV) cardiomyocytes play an important role in atrial fibrillation; however, little is known about their specific
cellular electrophysiological properties. We applied standard ...microelectrode recording and whole-cell patch-clamp to evaluate
action potentials and ionic currents in canine PVs and left atrium (LA) free wall. Resting membrane potential (RMP) averaged
â66 ± 1 mV in PVs and â74 ± 1 mV in LA ( P < 0.0001) and action potential amplitude averaged 76 ± 2 mV in PVs vs. 95 ± 2 mV in LA ( P < 0.0001). PVs had smaller maximum phase 0 upstroke velocity ( V max : 98 ± 9 vs. 259 ± 16 V s â1 , P < 0.0001) and action potential duration (APD): e.g. at 2 Hz, APD to 90 % repolarization in PVs was 84 % of LA ( P < 0.05). Na + current density under voltage-clamp conditions was similar in PV and LA, suggesting that smaller V max in PVs was due to reduced RMP. Inward rectifier current density in the PV cardiomyocytes was â¼58 % that in the LA, potentially
accounting for the less negative RMP in PVs. Slow and rapid delayed rectifier currents were greater in the PV (by â¼60 and
â¼50 %, respectively), whereas transient outward K + current and L-type Ca 2+ current were significantly smaller (by â¼25 and â¼30 %, respectively). Na + -Ca 2+ -exchange (NCX) current and T-type Ca 2+ current were not significantly different. In conclusion, PV cardiomyocytes have a discrete distribution of transmembrane
ion currents associated with specific action potential properties, with potential implications for understanding PV electrical
activity in cardiac arrhythmias.
There is a paucity of data on pesticide-related morbidity and mortality in South Africa. A review of notifications to the western Cape office of the Department of National Health and Population ...Development from 1987 to 1991 was undertaken to describe the epidemiological profile of pesticide poisoning in the region. Two hundred and twenty-five cases of pesticide poisoning were identified, of which the majority were from rural areas. Farmers, farm workers and their families were most frequently involved in poisoning events, which included accidents arising outside of workplace production (44%), self-inflicted injury (35%) and direct occupational contamination (11%). Farm pesticide stores were the most frequent source of pesticide and a seasonal variation in the trend of poisoning events could be discerned; this corresponded to agricultural spraying practices in the region. The mortality rate was significantly higher among those with self-inflicted injury, particularly farm workers. A concurrent review of hospital admissions for 1991 found that 78% of cases had not been notified. In view of the key role of surveillance in reducing pesticide-related morbidity and mortality, a call is made to improve notification of pesticide poisoning so as to facilitate control of an important potential public health problem.
Polygenic inheritance plays a central role in Parkinson disease (PD). A priority in elucidating PD etiology lies in defining the biological basis of genetic risk. Unraveling how risk leads to ...disruption will yield disease-modifying therapeutic targets that may be effective. Here, we utilized a high-throughput and hypothesis-free approach to determine biological processes underlying PD using the largest currently available cohorts of genetic and gene expression data from International Parkinson’s Disease Genetics Consortium (IPDGC) and the Accelerating Medicines Partnership-Parkinson’s disease initiative (AMP-PD), among other sources. We applied large-scale gene-set specific polygenic risk score (PRS) analyses to assess the role of common variation on PD risk focusing on publicly annotated gene sets representative of curated pathways. We nominated specific molecular sub-processes underlying protein misfolding and aggregation, post-translational protein modification, immune response, membrane and intracellular trafficking, lipid and vitamin metabolism, synaptic transmission, endosomal–lysosomal dysfunction, chromatin remodeling and apoptosis mediated by caspases among the main contributors to PD etiology. We assessed the impact of rare variation on PD risk in an independent cohort of whole-genome sequencing data and found evidence for a burden of rare damaging alleles in a range of processes, including neuronal transmission-related pathways and immune response. We explored enrichment linked to expression cell specificity patterns using single-cell gene expression data and demonstrated a significant risk pattern for dopaminergic neurons, serotonergic neurons, hypothalamic GABAergic neurons, and neural progenitors. Subsequently, we created a novel way of building de novo pathways by constructing a network expression community map using transcriptomic data derived from the blood of PD patients, which revealed functional enrichment in inflammatory signaling pathways, cell death machinery related processes, and dysregulation of mitochondrial homeostasis. Our analyses highlight several specific promising pathways and genes for functional prioritization and provide a cellular context in which such work should be done.
Update
This article was updated on September 4, 2020, because of a previous error. On page 1211, in the author affiliation section, “W.L. Walter, MBBS, PhD
3
” now reads “W.L. Walter, MBBS, PhD
3,4
...,” the affiliation for Dr. Van Onsem that had read “
3
Specialist Orthopedic Group, The Mater Clinic, North Sydney, New South Wales, Australia” now reads “
3
Royal North Shore Hospital, St. Leonards, New South Wales, Australia,” and the affiliation for Dr. Walter that had read “
3
Specialist Orthopedic Group, The Mater Clinic, North Sydney, New South Wales, Australia” now reads “
3
Royal North Shore Hospital, St. Leonards, New South Wales, Australia” and “
4
University of Sydney, Sydney, New South Wales, Australia.”
An erratum has been published: J Bone Joint Surg Am. 2020 Oct 7;102(19):e113
» As we resume elective surgical procedures, it is important to understand what practices and protocols should be altered or implemented in order to minimize the risk of pathogen transfer during the severe acute respiratory syndrome (SARS)-CoV-2 pandemic.
» Each hospital and health system should consider their unique situation in terms of SARS-CoV-2 prevalence, staffing capabilities, personal protection equipment supply, and so on when determining how and when to implement these recommendations.
» All patients should be screened for SARS-CoV-2 by means of a thorough history and physical examination, as well as reverse transcription-polymerase chain reaction (RT-PCR) testing whenever possible, prior to undergoing elective surgery.
» Patients who are currently infected with coronavirus disease 2019 (COVID-19) should not undergo elective surgery.
» These guidelines are based on the available scientific evidence, albeit scant. The recommendations have been reviewed and voted on by the expert delegates who produced this document.
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