The characterization of the epigenetic changes within the obesity-related adipose tissue will provide new insights to understand this metabolic disorder, but adipose tissue is not easy to sample in ...population-based studies. We aimed to evaluate the capacity of circulating leukocytes to reflect the adipose tissue-specific DNA methylation status of obesity susceptibility. DNA samples isolated from subcutaneous adipose tissue and circulating leukocytes were hybridized in the Infinium HumanMethylation 450 BeadChip. Data were compared between samples from obese (n = 45) and non-obese (n = 8-10) patients by Wilcoxon-rank test, unadjusted for cell type distributions. A global hypomethylation of the differentially methylated CpG sites (DMCpGs) was observed in the obese subcutaneous adipose tissue and leukocytes. The overlap analysis yielded a number of genes mapped by the common DMCpGs that were identified to reflect the obesity state in the leukocytes. Specifically, the methylation levels of FGFRL1, NCAPH2, PNKD and SMAD3 exhibited excellent and statistically significant efficiencies in the discrimination of obesity from non-obesity status (AUC > 0.80; p < 0.05) and a great correlation between both tissues. Therefore, the current study provided new and valuable DNA methylation biomarkers of obesity-related adipose tissue pathogenesis through peripheral blood analysis, an easily accessible and minimally invasive biological material instead of adipose tissue.
Eradication of HIV-1 (HIV) is hindered by stable viral reservoirs. Viral latency is epigenetically regulated. While the effects of histone acetylation and methylation at the HIV long-terminal repeat ...(LTR) have been described, our knowledge of the proviral epigenetic landscape is incomplete. We report that a previously unrecognized epigenetic modification of the HIV LTR, histone crotonylation, is a regulator of HIV latency. Reactivation of latent HIV was achieved following the induction of histone crotonylation through increased expression of the crotonyl-CoA-producing enzyme acyl-CoA synthetase short-chain family member 2 (ACSS2). This reprogrammed the local chromatin at the HIV LTR through increased histone acetylation and reduced histone methylation. Pharmacologic inhibition or siRNA knockdown of ACSS2 diminished histone crotonylation-induced HIV replication and reactivation. ACSS2 induction was highly synergistic in combination with either a protein kinase C agonist (PEP005) or a histone deacetylase inhibitor (vorinostat) in reactivating latent HIV. In the SIV-infected nonhuman primate model of AIDS, the expression of ACSS2 was significantly induced in intestinal mucosa in vivo, which correlated with altered fatty acid metabolism. Our study links the HIV/SIV infection-induced fatty acid enzyme ACSS2 to HIV latency and identifies histone lysine crotonylation as a novel epigenetic regulator for HIV transcription that can be targeted for HIV eradication.
Las leguminosas forrajeras nativas presentan un gran potencial productivo y un ejemplo de ellas es Desmanthus virgatus de amplia distribución en el centro norte de Argentina. El objetivo del trabajo ...fue realizar una caracterización feno-genotípica y simbiótica de rizobios que forman nódulos en D. virgatus con vista hacia el uso sustentable integral de dicha leguminosa. Para ello, se estableció una colección de 17 aislamientos recuperados de suelos de Jujuy. La caracterización fenotípica permitió reconocer rizobios de crecimiento rápido que mostraron un desarrollo óptimo entre pH 5 y 8, temperaturas de 28 a 35°C, y en concentraciones de 1% (p/v) de NaCl. Se hallaron rizobios con capacidad de crecimiento en condiciones extremas de pH 9 y a 40°C. Los aislamientos se identificaron como pertenecientes a Ensifer spp. y los perfiles de amplificación de ADN genómico mostraron escasa diversidad genética. La inoculación de D. virgatus con la cepa 8L12.1 (Ensifer sp.) produjo incrementos de biomasa seca aérea de 73% en cámara de cultivo y 124% a campo respecto a las plantas sin inocular y sin fertilizar.
Surgery is the main modality of cure for solid cancers and was prioritised to continue during COVID-19 outbreaks. This study aimed to identify immediate areas for system strengthening by comparing ...the delivery of elective cancer surgery during the COVID-19 pandemic in periods of lockdown versus light restriction.
This international, prospective, cohort study enrolled 20 006 adult (≥18 years) patients from 466 hospitals in 61 countries with 15 cancer types, who had a decision for curative surgery during the COVID-19 pandemic and were followed up until the point of surgery or cessation of follow-up (Aug 31, 2020). Average national Oxford COVID-19 Stringency Index scores were calculated to define the government response to COVID-19 for each patient for the period they awaited surgery, and classified into light restrictions (index <20), moderate lockdowns (20–60), and full lockdowns (>60). The primary outcome was the non-operation rate (defined as the proportion of patients who did not undergo planned surgery). Cox proportional-hazards regression models were used to explore the associations between lockdowns and non-operation. Intervals from diagnosis to surgery were compared across COVID-19 government response index groups. This study was registered at ClinicalTrials.gov, NCT04384926.
Of eligible patients awaiting surgery, 2003 (10·0%) of 20 006 did not receive surgery after a median follow-up of 23 weeks (IQR 16–30), all of whom had a COVID-19-related reason given for non-operation. Light restrictions were associated with a 0·6% non-operation rate (26 of 4521), moderate lockdowns with a 5·5% rate (201 of 3646; adjusted hazard ratio HR 0·81, 95% CI 0·77–0·84; p<0·0001), and full lockdowns with a 15·0% rate (1775 of 11 827; HR 0·51, 0·50–0·53; p<0·0001). In sensitivity analyses, including adjustment for SARS-CoV-2 case notification rates, moderate lockdowns (HR 0·84, 95% CI 0·80–0·88; p<0·001), and full lockdowns (0·57, 0·54–0·60; p<0·001), remained independently associated with non-operation. Surgery beyond 12 weeks from diagnosis in patients without neoadjuvant therapy increased during lockdowns (374 9·1% of 4521 in light restrictions, 317 10·4% of 3646 in moderate lockdowns, 2001 23·8% of 11 827 in full lockdowns), although there were no differences in resectability rates observed with longer delays.
Cancer surgery systems worldwide were fragile to lockdowns, with one in seven patients who were in regions with full lockdowns not undergoing planned surgery and experiencing longer preoperative delays. Although short-term oncological outcomes were not compromised in those selected for surgery, delays and non-operations might lead to long-term reductions in survival. During current and future periods of societal restriction, the resilience of elective surgery systems requires strengthening, which might include protected elective surgical pathways and long-term investment in surge capacity for acute care during public health emergencies to protect elective staff and services.
National Institute for Health Research Global Health Research Unit, Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, Medtronic, Sarcoma UK, The Urology Foundation, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research.
The properties of quantum systems interacting with their environment, commonly called open quantum systems, can be affected strongly by this interaction. Although this can lead to unwanted ...consequences, such as causing decoherence in qubits used for quantum computation, it can also be exploited as a probe of the environment. For example, magnetic resonance imaging is based on the dependence of the spin relaxation times of protons in water molecules in a host's tissue. Here we show that the excitation energy of a single spin, which is determined by magnetocrystalline anisotropy and controls its stability and suitability for use in magnetic data-storage devices, can be modified by varying the exchange coupling of the spin to a nearby conductive electrode. Using scanning tunnelling microscopy and spectroscopy, we observe variations up to a factor of two of the spin excitation energies of individual atoms as the strength of the spin's coupling to the surrounding electronic bath changes. These observations, combined with calculations, show that exchange coupling can strongly modify the magnetic anisotropy. This system is thus one of the few open quantum systems in which the energy levels, and not just the excited-state lifetimes, can be renormalized controllably. Furthermore, we demonstrate that the magnetocrystalline anisotropy, a property normally determined by the local structure around a spin, can be tuned electronically. These effects may play a significant role in the development of spintronic devices in which an individual magnetic atom or molecule is coupled to conducting leads.
Abstract Background Adolescents with previous self-injurious thoughts and behaviors (SITB) have over 2-fold risk of dying by suicide, higher than older ages. This meta-analysis aims to disentangle ...the association of each SITB with subsequent suicidal behavior in adolescence/young adulthood, the contribution of each SITB, and the proportion of suicide deaths with no previous suicide attempt. Methods We searched 6 databases until June 2015. Inclusion criteria: 1. Assessment of any previous SITB a) suicidal thoughts and behaviors (ideation; threat/gesture; plan; attempt); b) non-suicidal thoughts and behaviors (thoughts; threat/gesture; self-injury); c) self-harm as a risk factor of suicide attempt or suicide death; 2. Case-control or cohort studies; 3. Subjects aged 12-26y. Random effect models, metaregression analyses including mental health and environmental variables, and population attributable risks (PAR)s were estimated. Results From 23,682 potentially eligible articles, 29 were included in the meta-analysis (1,122,054 individuals). While 68% of all youth suicide deaths had no previous suicide attempt, suicide death was very strongly associated with any previous SITB (OR= 22.53, 95%CI: 18.40–27.58). Suicide attempts were also associated with a history of previous SITB (OR= 3.48, 95%CI: 2.71–4.43). There were no moderating effects for mental health and environmental features. The PAR of previous SITB to suicide attempts is 26%. Limitations There is considerable heterogeneity between the available studies. Due to limitations in the original studies, an over-estimation of the proportion dying at their first attempt cannot be ruled out, since they might have missed unrecognized previous suicide attempts. Conclusions Although more than two thirds of suicide deaths in adolescence/young adulthood have occurred with no previous suicidal behavior, previous SITBs have a much higher risk of dying by suicide than previously reported in this age group.
The coronary arteriosclerotic disease is the most common cardiovascular disease. Atherosclerosis affects large- and medium-sized arteries leading to severe thrombosis or artery stenosis that could ...evolve to myocardial infarction, ischemic stroke, ischemic injury of kidneys and intestines, and several other life-threatening clinical manifestations. Nitric oxide has been shown to be a promising therapeutic agent against cardiovascular diseases. The eNOS gene assumes several important functions, including regulation of vascular tone and regional blood flow, the suppression of vascular smooth muscle cell proliferation, and modulation of leukocyte-endothelium interactions. The T786C polymorphism is an important point mutation, where thymine is changed to cytosine. T786C significantly reduces the activity of the eNOS promoter gene. Two hundred and ninety-seven peripheral blood samples were collected from patients with the previous diagnosis of atherosclerotic disease based on clinical examination and confirmed by imaging methods. Results were compared using the chi-square test and the G-test. In the present study, the TC genotype was more frequent in both case and control groups with no statistically significant difference. Comparing the relation TC/TT and CC genotypes in the case and control groups, there was no statistically significant difference. No significant difference was found when genotypes were analyzed regarding gender and smoking. Our results suggest a strong tendency of the T allele, in single or double dose, to be associated with atherosclerosis that was not confirmed by the scientific data.
During semen freezing, approximately 90% of the seminal plasma is discarded, resulting in higher sperm vulnerability to lipid peroxidation. Thus, the addition of antioxidants, such as resveratrol, to ...equine semen freezing extenders may increase the viability of cryopreserved sperm. Further, non- capacitated sperm usually bind to the isthmus region of the oviduct, which can be a way to identify the sperm able to fertilize the oocyte. The aim of the present study was to evaluate the binding capacity of cryopreserved equine sperm to bovine oviduct explants. To prepare the oviduct explants, the reproductive system of slaughtered cows was transported in saline solution at 35°C to the laboratory. After sectioning the uterus-tubal junction ipsilateral to the ovaries without a corpus luteum, the isthmus region was pressed towards the uterus and its contents were expelled in a Petri dish with culture medium. These oviduct content with the medium was deposited in 14 ml tube decanted and after five minutes it was disaggregated with a needle and syringe. After repeating this process three times, the contents were deposited in Petri dishes and cultured for 24 hours in an incubator in atmosphere with 5% CO2. The explants were distributed in six treatments according to the resveratrol concentration added to the INRA 96 freezing extender. Semen from sixstallions were frozen in the INRA96 (control, no resveratrol) and with 5, 10, 50, 100 and 150 μM resveratrol. The six treated semen samples were co-incubated with the explants for a min. Then, the explants were washed with a medium to withdraw the loosened sperm and placed on glass slide and covered with a coverslip. The number of sperm bound per nm of oviduct was observed with microscopy and analysed with the ImageJ software. For the statistical analysis, mean and standard error were calculated and when the data did not have a normal distribution, logarithmic transformation was performed, and the log means were evaluated with variance analysis and compared with Duncan's test. The probability of P<0.05 was considered significant. The addition of 5μM resveratrol to the equine semen freezing extender increased the number of sperm bound explants (64.6 ± 1.1 sperm/nm explant), while 50μM resveratrol reduced (21.4 ± 1.1 sperm/nm of explant) compared to the other treatments (control: 48.1 ± 1.0, 10 μM: 56.2 ± 1.0, 100 μM: 46.8 ± 1.0 and 150 μM resveratrol: 53.7 ± 1.1 sperm/nm of explant). In conclusion, the addition of 5 μM resveratrol in frozen equine semen extender was improved equine sperm binding ability to oviduct explants.
Increased portal pressure during variceal bleeding may have an influence on the treatment failure rate, as well as on short- and long-term survival. However, the usefulness of hepatic hemodynamic ...measurement during the acute episode has not been prospectively validated, and no information exists about the outcome of hemodynamically defined high-risk patients treated with early portal decompression. Hepatic venous pressure gradient (HVPG) measurement was made within the first 24 hours after admission of 116 consecutive patients with cirrhosis with acute variceal bleeding treated with a single session of sclerotherapy injection during urgent endoscopy. Sixty-four patients had an HVPG less than 20 mm Hg (low-risk LR group), and 52 patients had an HVPG greater than or equal to 20 mm Hg (high-risk HR group). HR patients were randomly allocated into those receiving transjugular intrahepatic portosystemic shunt (TIPS; HR-TIPS group, n = 26) within the first 24 hours after admission and those not receiving TIPS (HR-non-TIPS group). The HR-non-TIPS group had more treatment failures (50% vs. 12%, P =.0001), transfusional requirements (3.7 +/- 2.7 vs. 2.2 +/- 2.3, P =.002), need for intensive care (16% vs. 3%, P <.05), and worse actuarial probability of survival than the LR group. Early TIPS placement reduced treatment failure (12%, P =.003), in-hospital and 1-year mortality (11% and 31%, respectively; P <.05). In conclusion, increased portal pressure estimated by early HVPG measurement is a main determinant of treatment failure and survival in variceal bleeding, and early TIPS placement reduces treatment failure and mortality in high risk patients defined by hemodynamic criteria.
Indexation of regulatory T cells (Treg) to the number of activated T cells constitutes a homeostatic mechanism ensuring that T-cell expansion remains under control. However, immune hyperactivation ...observed in HIV-infected patients suggests a possible dysfunction of this mechanism. Here we show that the Treg/IL-2-producing cells' balance is deeply disturbed in viremic HIV-infected patients. We found a lower expression of IL-2 receptor alpha on Treg from viremic patients. We confirmed in vitro that HIV infection of Treg downregulates IL-2 receptor alpha and phosphorylated STAT5. Our results argue for an impaired capacity of Treg to sense the expansion of activated T cells in HIV-infected patients that could contribute to the immune deregulation.
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