Mitochondrial complex III is essential for suppressive function of regulatory T cells.

Regulatory T cells (Treg cells), a distinct subset of CD4+ T cells, are necessary for the maintenance of immune self-tolerance and homeostasis1,2. Recent studies have demonstrated that Treg cells exhibit a unique metabolic profile, characterized by an increase in mitochondrial metabolism relative to other CD4+ effector subsets3,4. Furthermore, the Treg cell lineage-defining transcription factor, Foxp3, has been shown to promote respiration5,6; however, it remains unknown whether the mitochondrial respiratory chain is required for the T cell-suppression capacity, stability and survival of Treg cells. Here we report that Treg cell-specific ablation of mitochondrial respiratory chain complex III in mice results in the development of fatal inflammatory disease early in life, without affecting Treg cell number. Mice that lack mitochondrial complex III specifically in Treg cells displayed a loss of T cell-suppression capacity without altering Treg cell proliferation and survival. Treg cells deficient in complex III showed decreased expression of genes associated with Treg function, whereas Foxp3 expression remained stable. Loss of complex III in Treg cells increased DNA methylation as well as the metabolites 2-hydroxyglutarate (2-HG) and succinate that inhibit the ten-eleven translocation (TET) family of DNA demethylases7. Thus, Treg cells require mitochondrial complex III to maintain immune regulatory gene expression and suppressive function.

PROTACs in Ovarian Cancer: Current Advancements and Future Perspectives.

Ovarian cancer is the deadliest gynecologic malignancy. The majority of patients diagnosed with advanced ovarian cancer will relapse, at which point additional therapies can be administered but, for the most part, these are not curative. As such, a need exists for the development of novel therapeutic options for ovarian cancer patients. Research in the field of targeted protein degradation (TPD) through the use of proteolysis-targeting chimeras (PROTACs) has significantly increased in recent years. The ability of PROTACs to target proteins of interest (POI) for degradation, overcoming limitations such as the incomplete inhibition of POI function and the development of resistance seen with other inhibitors, is of particular interest in cancer research, including ovarian cancer research. This review provides a synopsis of PROTACs tested in ovarian cancer models and highlights PROTACs characterized in other types of cancers with potential high utility in ovarian cancer. Finally, we discuss methods that will help to enable the selective delivery of PROTACs to ovarian cancer and improve the pharmacodynamic properties of these agents.

Similarity but not equivalence: Ecological niche comparison between sandflies from the Pleistocene and future scenarios in Central and South America.

Sandfly species (Diptera: Psychodidae) are suspected or proven vectors of Leishmania spp. in the American region. Understanding niche conservatism (NC) in insect vectors allows an understanding of constraints on adaptive responses, and thus implications for disease ecology. Therefore, in this study, the authors evaluated NC in three vector species of leishmaniasis (Lutzomyia gomezi, Psathyromyia shannoni and Pintomyia ovallesi) in Central and South America. For this, the authors performed niche identity and similarity testing through paired comparisons in ENMTools and niche overlap in Niche Analyst. The authors found that species niches were more similar to each other than if the points had been randomly extracted, and they also found extensive similarity between Pa. shannoni and Lu. gomezi niches and in Pa. shannoni niches over different timescales. The authors suggest Pa. shannoni as a priority species due to fundamental niche similarity with phylogenetically related species and also its extensive evolutionary history and ecological plasticity that could affect the emergence and resurgence of leishmaniasis in areas endemic by this vector.

Comprehensive Evaluation of the Impact of Sociodemographic Inequalities on Adverse Outcomes and Excess Mortality During the Coronavirus Disease 2019 (COVID-19) Pandemic in Mexico City.

BACKGROUND: The impact of the coronavirus disease 2019 (COVID-19) pandemic in Mexico City has been sharp, as several social inequalities at all levels coexist. Here we conducted an in-depth evaluation of the impact of individual and municipal-level social inequalities on the COVID-19 pandemic in Mexico City. METHODS: We analyzed suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cases, from the Mexico City Epidemiological Surveillance System from 24 February 2020 to 31 March 2021. COVID-19 outcomes included rates of hospitalization, severe COVID-19, invasive mechanical ventilation, and mortality. We evaluated socioeconomic occupation as an individual risk, and social lag, which captures municipal-level social vulnerability, and urban population density as proxies of structural risk factors. Impact of reductions in vehicular mobility on COVID-19 rates and the influence of risk factors were also assessed. Finally, we assessed discrepancies in COVID-19 and non-COVID-19 excess mortality using death certificates from the general civil registry. RESULTS: We detected vulnerable groups who belonged to economically unfavored sectors and experienced increased risk of COVID-19 outcomes. Cases living in marginalized municipalities with high population density experienced greater risk for COVID-19 outcomes. Additionally, policies to reduce vehicular mobility had differential impacts modified by social lag and urban population density. Finally, we report an under-registry of COVID-19 deaths along with an excess mortality closely related to marginalized and densely populated communities in an ambulatory setting. This could be attributable to a negative impact of modified hospital admission criteria during the pandemic. CONCLUSIONS: Socioeconomic occupation and municipality-wide factors played a significant role in shaping the course of the COVID-19 pandemic in Mexico City.

Elevated serum uric acid is a facilitating mechanism for insulin resistance mediated accumulation of visceral adipose tissue.

OBJECTIVE: Serum uric acid (SUA) has been associated with cardiometabolic conditions such as insulin resistance (IR) and visceral adipose tissue (VAT) accumulation. Here, we aimed to clarify a unifying mechanism linking elevated SUA to IR and VAT. METHODS: We conducted analyses in 226 subjects from the UIEM cohort with both euglycemic hyperinsulinemic clamp (EHC) and dual X-ray absorptiometry (DXA) measurements for IR and VAT accumulation and explored the role of SUA and adiponectin by developing a network of causal mediation analyses to assess their impact on IR and VAT. These models were then translated to two population-based cohorts comprising 6337 subjects from NHANES 2003-2004 and 2011-2012 cycles in the US and ENSANUT Medio Camino 2016 in Mexico, using HOMA2IR and adipoIR as indicators of peripheral and adipose tissue IR, and METS-VF as a surrogate for VAT accumulation. RESULTS: SUA has a mediating role inside a bidirectional relationship between IR and visceral obesity, which was similar using either gold standard measurements or surrogate measures for IR and VAT. Furthermore, adiponectin acts as a linking mediator between elevated SUA and both peripheral IR and VAT accumulation. The proportion of the mechanism for IR-mediated (in either peripheral or adipose tissue) VAT accumulation was greater, compared to VAT-mediated IR accumulation (10.53% [9.23%-12.00%] to 5.44% [3.78%-7.00%]). Normal-range SUA levels can be used to rule-out underlying cardio-metabolic abnormalities in both men and women. CONCLUSIONS: Elevated SUA acts as a mediator inside the bidirectional relationship between IR and VAT accumulation and these observations could be applicable at a phenotype scale.

The Single-Component Flavin Reductase/Flavin-Dependent Halogenase AetF is a Versatile Catalyst for Selective Bromination and Iodination of Arenes and Olefins.

Flavin-dependent halogenases (FDHs) natively catalyze selective halogenation of electron rich aromatic and enolate groups. Nearly all FDHs reported to date require a separate flavin reductase to supply them with FADH2 , which complicates biocatalysis applications. In this study, we establish that the single component flavin reductase/flavin dependent halogenase AetF catalyzes halogenation of a diverse set of substrates using a commercially available glucose dehydrogenase to drive its halogenase activity. High site selectivity, activity on relatively unactivated substrates, and high enantioselectivity for atroposelective bromination and bromolactonization was demonstrated. Site-selective iodination and enantioselective cycloiodoetherification was also possible using AetF. The substrate and reaction scope of AetF suggest that it has the potential to greatly improve the utility of biocatalytic halogenation.

Profiling Cases With Nonrespiratory Symptoms and Asymptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Infections in Mexico City.

We profiled cases with nonrespiratory symptoms (NRS) and asymptomatic severe acute respiratory syndrome coronavirus 2 infections assessed within Mexico City's Epidemiological Surveillance System. Initially asymptomatic or NRS cases have decreased risk of adverse outcomes compared with cases with respiratory symptoms. Comorbidity and age influence symptom development in initially asymptomatic cases.

Assessing the Burden of Coronavirus Disease 2019 (COVID-19) Among Healthcare Workers in Mexico City: A Data-Driven Call to Action.

BACKGROUND: Healthcare workers (HCWs) could be at increased occupational risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections due to increased exposure. Information regarding the burden of coronavirus disease 2019 (COVID-19) epidemic in HCWs living in Mexico is scarce. Here, we aimed to explore the epidemiology, symptoms, and risk factors associated with adverse outcomes in HCWs in Mexico City. METHODS: We explored data collected by the National Epidemiological Surveillance System in Mexico City, in HCWs who underwent real-time reverse transcription polymerase chain reaction (RT-PCR) test. We explored COVID-19 outcomes in HCWs and the performance of symptoms to detect SARS-CoV-2 infection. RESULTS: As of 20 September 2020, 57 758 HCWs were tested for SARS-CoV-2 and 17 531 were confirmed (30.35%); 6610 were nurses (37.70%), 4910 physicians (28.0%), 267 dentists (1.52%), and 5744 laboratory personnel and other HCWs (32.76%). Overall, 2378 HCWs required hospitalization (4.12%), 2648 developed severe COVID-19 (4.58%), and 336 required mechanical-ventilatory support (.58%). Lethality was recorded in 472 (.82%) cases. We identified 635 asymptomatic SARS-CoV-2 infections (3.62%). Compared with general population, HCWs had higher incidence, testing, asymptomatic cases, and mortality rates. No individual symptom offers adequate performance to detect SARS-CoV2. Older HCWs with chronic noncommunicable diseases and severe respiratory symptoms were associated with higher risk for adverse outcome; physicians were at higher risk compared with nurses and other HCWs. CONCLUSIONS: We report a high prevalence of SARS-CoV-2 infection in HCWs in Mexico City. Symptoms as a screening method are not efficient to discern those HCWs with a positive PCR-RT test. Particular attention should focus on HCWs with risk factors to prevent adverse outcomes.

Are the interaction effects of warming and drought on nutritional status and biomass production in a tropical forage legume greater than their individual effects?

MAIN CONCLUSION: Drought alone and drought plus warming will change the nutrient requirements and biomass distributions of Stylosanthes capitata, while warming will be advantageous only under well-watered condition for the next decades. Climate change effects on natural and managed ecosystems are difficult to predict due to its multi-factor nature. However, most studies that investigate the impacts of climate change factors on plants, such as warming or drought, were conducted under one single stress and controlled environments. In this study, we evaluated the effects of elevated temperature (+ 2 °C) (T) under different conditions of soil water availability (W) to understand the interactive effects of both factors on leaf, stem, and inflorescence macro and micronutrients concentration and biomass allocation of a tropical forage species, Stylosanthes capitata Vogel under field conditions. Temperature control was performed by a temperature free-air controlled enhancement (T-FACE) system. We observed that warming changed nutrient concentrations and plant growth depending on soil moisture levels, but the responses were specific for each plant organ. In general, we found that warming under well-watered conditions greatly improved nutrient concentration and biomass production, whilst the opposite effect was observed under non-irrigated and non-warmed conditions. However, under warmed and non-irrigated conditions, leaf biomass and leaf nutrient concentration were greatly reduced when compared to non-warmed and irrigated plants. Our findings suggest that warming (2 °C above ambient temperature) and drought, as well as both combined stresses, will change the nutrient requirements and biomass distributions between plant aerial organs of S. capitata in tropical ecosystems, which may impact animal feeding in the future.

Increased visceral fat accumulation modifies the effect of insulin resistance on arterial stiffness and hypertension risk.

BACKGROUND AND AIMS: Both insulin resistance (IR) and visceral adipose tissue (VAT) are related cardiometabolic risk factors; nevertheless, their joint effect on endothelial functionality is controversial. This study aims to evaluate the joint effect of IR and VAT on endothelial functionality using the pulse-waveform analysis and explore the mediating role of VAT on the effect of IR on arterial pressure, arterial stiffness and incident arterial hypertension. METHODS AND RESULTS: We measured VAT (n = 586) using two methods (dual-energy X-ray absorptiometry and a clinical surrogate), arterial stiffness (with pulse-waveform velocity), and IR (using three methods: HOMA2-IR (n = 586), a frequently sampled intravenous glucose tolerance test (n = 131) and euglycemic hyperinsulinemic clamping (n = 97)) to confirm the mediator effect of IR on VAT. The incidence of arterial hypertension attributable to the mediating effect of IR related to VAT was evaluated using a prospective cohort (n = 6850). Adjusted linear regression models, causal mediation analysis, and Cox-proportional hazard risk regression models were performed to test our objective. IR and VAT led to increased arterial stiffness and increased blood pressure; the combination of both further worsened vascular parameters. Nearly, 57% (ΔE→MY 95% CI: 31.7-100.0) of the effect of IR on altered pulse-wave velocity (PWV) analysis was mediated through VAT. Moreover, VAT acts as a mediator of the effect of IR on increased mean arterial pressure (ΔE→MY 35.7%, 95% CI: 23.8-59) and increased hypertension risk (ΔE→MY 69.1%, 95% CI: 46.1-78.8). CONCLUSION: VAT acts as a mediator of IR in promoting arterial stiffness and arterial hypertension. Both phenomena should be targeted to ameliorate the cardiometabolic risk.

Metabolite and transcript profiling of Guinea grass (Panicum maximum Jacq) response to elevated [CO2] and temperature.

INTRODUCTION: By mid-century, global atmospheric carbon dioxide concentration ([CO2]) is predicted to reach 600 µmol mol-1 with global temperatures rising by 2 °C. Rising [CO2] and temperature will alter the growth and productivity of major food and forage crops across the globe. Although the impact is expected to be greatest in tropical regions, the impact of climate-change has been poorly studied in those regions. OBJECTIVES: This experiment aimed to understand the effects of elevated [CO2] (600 µmol mol-1) and warming (+ 2 °C), singly and in combination, on Panicum maximum Jacq. (Guinea grass) metabolite and transcript profiles. METHODS: We created a de novo assembly of the Panicum maximum transcriptome. Leaf samples were taken at two time points in the Guinea grass growing season to analyze transcriptional and metabolite profiles in plants grown at ambient and elevated [CO2] and temperature, and statistical analyses were used to integrate the data. RESULTS: Elevated temperature altered the content of amino acids and secondary metabolites. The transcriptome of Guinea grass shows a clear time point separations, with the changes in the elevated temperature and [CO2] combination plots. CONCLUSION: Field transcriptomics and metabolomics revealed that elevated temperature and [CO2] result in alterations in transcript and metabolite profiles associated with environmental response, secondary metabolism and stomatal function. These metabolic responses are consistent with greater growth and leaf area production under elevated temperature and [CO2]. These results show that tropical C4 grasslands may have unpredicted responses to global climate change, and that warming during a cool growing season enhances growth and alleviates stress.

Impacts of warming and water deficit on antioxidant responses in Panicum maximum Jacq.

Agricultural activities are affected by many biotic and abiotic stresses associated with global climate change. Predicting the response of plants to abiotic stress under future climate scenarios requires an understanding of plant biochemical performance in simulated stress conditions. In this study, the antioxidant response of Panicum maximum Jacq. cv. Mombaça exposed to warming (+2°C above ambient temperature) (eT), water deficit (wS) and the combination eT + wS was analysed under field conditions using a temperature free-air-controlled enhancement facility. Warming was applied during the entire growth period. Data were collected at 13, 19 and 37 days after the start of the water deficit treatment (DAT) and at two sampling times (6:00 and 12:00 h). A significant decrease in chlorophyll was observed under the wS treatment, but an increment in total chlorophyll was observed in eT + wS, particularly at 19 DAT. Significant increase in H2 O2 content, malondialdehyde and protein oxidation was observed in the wS treatment at noon of the third sampling. In the combined wS + eT stress treatment, the activity of the enzymatic antioxidant system increased, particularly of superoxide dismutase (SOD; EC 1.15.1.1) and ascorbate peroxidase (APX; EC 1.11.1.11). The chlorophyll fluorescence images showed that the photochemical performance was not significantly affected by the treatments. In conclusion, under simulated future warming and water stress conditions, the photosystem II (PSII) activity of P. maximum acclimated to moderate warming and a water-stressed environment associated with a relatively favourable antioxidant response, particularly in the activity of APX and SOD.

A structure-activity relationship study of Forkhead Domain Inhibitors (FDI): The importance of halogen binding interactions.

The Forkhead boX M1 (FOXM1) protein is an essential transcription factor required for the normal activation of human cell cycle. However, increasing evidence supports a correlation between FOXM1 overexpression and the onset of several types of cancer. Based on a previously reported molecular modeling and molecular dynamics simulations (MD) study, we hypothesized the role of an essential halogen-bonding interaction between the 4-fluorophenyl group in the forkhead domain inhibitor-6 (FDI-6) and an Arg297 residue inside the FOXM1-DNA binding domain (DBD). To prove the importance of this binding interaction, we synthesized and screened ten FDI-6 derivatives possessing different groups at the 4-fluorophenyl position of the lead molecule. Briefly, we found that derivatives possessing a 4-chlorophenyl, 4-bromophenyl, or a 4-iodophenyl group, were equipotent to the original 4-fluorophenyl moiety present in FDI-6, whereas derivatives without this 4-halogen moiety were inactive. We also observed that positional isomers in which the halogen was relocated to positions 2- or 3- on the phenyl group were significantly less active. These results provide evidence to support the essential role of a 4-halophenyl bonding interaction, with the Arg297 residue in the FOXM1-DBD, to exert inhibition of transcriptional activity.

Identification and Characterization of Novel Receptor-Interacting Serine/Threonine-Protein Kinase 2 Inhibitors Using Structural Similarity Analysis.

Receptor-interacting protein kinase 2 (RIP2 or RICK, herein referred to as RIPK2) is linked to the pathogen pathway that activates nuclear factor κ-light-chain-enhancer of activated B cells (NFκB) and autophagic activation. Using molecular modeling (docking) and chemoinformatics analyses, we used the RIPK2/ponatinib crystal structure and searched in chemical databases for small molecules exerting binding interactions similar to those exerted by ponatinib. The identified RIPK2 inhibitors potently inhibited the proliferation of cancer cells by > 70% and also inhibited NFκB activity. More importantly, in vivo inhibition of intestinal and lung inflammation rodent models suggests effectiveness to resolve inflammation with low toxicity to the animals. Thus, our identified RIPK2 inhibitor may offer possible therapeutic control of inflammation in diseases such as inflammatory bowel disease, asthma, cystic fibrosis, primary sclerosing cholangitis, and pancreatitis.

Anti-inflammatory and antioxidant properties of a novel resveratrol-salicylate hybrid analog.

Resveratrol is a natural compound with a plethora of activities as well as limitations. We recently reported a series of resveratrol-salicylate analogs with potential chemopreventive activity. Herein, we report the anti-inflammatory and antioxidant properties of these resveratrol derivatives. Using an in vitro COX inhibition assay, and two in vivo protocols (carrageenan-induced peritonitis and paw edema), we identified a novel compound (C10) as a potent anti-inflammatory agent. The enhanced potency of C10 was associated with the ability of C10 to decrease the activity of myeloperoxidase (MPO) enzyme at 10mg/kg, whereas resveratrol and it's natural analog (TMS) did not exert the same effect. Additionally, C10 significantly reduced the concentration of intracellular reactive oxygen species. Because of the proven association between cancer, inflammation, and oxidative stress, we believe that C10 is a promising chemopreventive molecule.

NSAIDs do not require the presence of a carboxylic acid to exert their anti-inflammatory effect - why do we keep using it?

The carboxylic acid group (-COOH) present in classical NSAIDs is partly responsible for the gastric toxicity associated with the administration of these drugs. This concept has been extensively proven using NSAID prodrugs. However, the screening of NSAIDs with no carboxylic acid at all has been neglected. The goal of this work was to determine if new NSAID derivatives devoid of acidic moieties would retain the anti-inflammatory activity of the parent compound, without causing gastric toxicity. To test this concept, we replaced the carboxylic acid group in ibuprofen, flurbiprofen, and naproxen with three ammonium moieties. We tested the resulting water-soluble NSAID derivatives for anti-inflammatory and ulcerogenic activity in vitro and in vivo. In this regard, we observed that all non-acidic NSAIDs exerted a potent anti-inflammatory activity, suggesting that the acid group in commercial 2-phenylpropionic acid NSAIDs not be an essential requirement for anti-inflammatory activity. These data provide complementary evidence supporting the discontinuation of ulcerogenic acidic NSAIDs.

Resveratrol-salicylate derivatives as selective DNMT3 inhibitors and anticancer agents.

Resveratrol is a natural polyphenol with plethora of biological activities. Resveratrol has previously shown to decrease DNA-methyltransferase (DNMT) enzymes expression and to reactivate silenced tumor suppressor genes. Currently, it seems that no resveratrol analogs have been developed as DNMT inhibitors. Recently, we reported the synthesis of resveratrol-salicylate derivatives and by examining the chemical structure of these analogs, we proposed that these compounds could exhibit DNMT inhibition especially that they resembled NSC 14778, a compound we previously identified as a DNMT inhibitor by virtual screening. Indeed, using in vitro DNMT inhibition assay, some of the resveratrol-salicylate analogs we screened in this work that showed selective inhibition against DNMT3 enzymes which were greater than resveratrol. A molecular docking study revealed key binding interactions with DNMT3A and DNMT3B enzymes. In addition, the most active analog, 10 showed considerable cytotoxicity against three human cancer cells; HT-29, HepG2 and SK-BR-3, which was greater than resveratrol. Further studies are needed to understand the anticancer mechanisms of these derivatives.

Deep Inferior Epigastric Artery Perforator Flap Breast Reconstruction in Patients With Previous Bariatric Surgery: Is It Safe and Feasible?

BACKGROUND: Obesity is widely recognized as a major health concern and a leading cause of preventable death. The correlation between obesity and breast cancer has been thoroughly described by several authors. Bariatric surgery is often associated with redundant abdominal tissue, often leading patients to consider body-contouring procedures. Autologous tissue breast reconstruction using the deep inferior epigastric artery perforator (DIEP) flap has advantages because it is tissue that is normally discarded during postbariatric body contouring. METHODS: We conducted a retrospective chart review of 18 DIEP flaps performed by the senior author in 9 patients for breast reconstruction between February 2008 and May 2013. All patients underwent mastectomies. All patients underwent bariatric surgery preceding breast reconstruction. Breast reconstruction was performed immediately in 13 cases and delayed in 5 cases. RESULTS: Mean age of the study population was 44.6 years (range, 41-57 years). The mean maximum body mass index of the patients was 44 (range, 37.6-52.1), and the mean current body mass index at the time of the reconstruction was 30.7 (range, 24.3-38.1). No intraoperative complications were reported. No fascia or muscle was taken during flap dissection. Mean operative time was 632 minutes (range, from 480 to 750 minutes). Average hospital stay was 4 days. No partial or total flap loss was reported. There were no postoperative hernias or bulges at the abdominal donor site. CONCLUSIONS: This series represents the largest group of patients undergoing DIEP flap breast reconstruction after bariatric surgery. In the hands of experienced microsurgeons, breast reconstruction with the DIEP flap in postbariatric patients represents a low-risk option with high satisfaction.

3,4',5-trans-Trimethoxystilbene; a natural analogue of resveratrol with enhanced anticancer potency.

Resveratrol is a phytoalexin produced by many plant species as a defence mechanism. Over the last decade, this polyphenol has been reported to be active against multiple targets associated with chronic disorders. However, its poor pharmacokinetic profile, as well as multiple discrepancies related to its in vitro and in vivo profile, has resulted not only on the study of suitable delivery systems, but the use of resveratrol derivatives. In this regard, the 3,4',5-trans-trimethoxystilbene (TMS), a natural analogue of resveratrol, has emerged as a strong candidate. TMS has an enhanced anticancer profile compared to resveratrol, exhibiting higher potency than resveratrol, as shown by multiple reports describing an improved cancer cell proliferation inhibition, induction of cell cycle arrest, decreased metastasis, reduced angiogenesis, and increased apoptosis. In this review, we provide a concise summary of results reported in the literature, related to the similarities and differences between resveratrol and TMS, and we submit to the scientific community that TMS is a promising and (still) understudied natural agent candidate, with potential applications in cancer research. Nevertheless, based on the available evidence, we also submit to the scientific community that TMS may also find a niche in any other research area in which resveratrol has been used.