Endocardial cells form the coronary arteries by angiogenesis through myocardial-endocardial VEGF signaling.

The origins and developmental mechanisms of coronary arteries are incompletely understood. We show here by fate mapping, clonal analysis, and immunohistochemistry that endocardial cells generate the endothelium of coronary arteries. Dye tracking, live imaging, and tissue transplantation also revealed that ventricular endocardial cells are not terminally differentiated; instead, they are angiogenic and form coronary endothelial networks. Myocardial Vegf-a or endocardial Vegfr-2 deletion inhibited coronary angiogenesis and arterial formation by ventricular endocardial cells. In contrast, lineage and knockout studies showed that endocardial cells make a small contribution to the coronary veins, the formation of which is independent of myocardial-to-endocardial Vegf signaling. Thus, contrary to the current view of a common source for the coronary vessels, our findings indicate that the coronary arteries and veins have distinct origins and are formed by different mechanisms. This information may help develop better cell therapies for coronary artery disease.

The clustered gamma protocadherin PcdhγC4 isoform regulates cortical interneuron programmed cell death in the mouse cortex.

Cortical inhibitory interneurons (cINs) are born in the ventral forebrain and migrate into the cortex where they make connections with locally produced excitatory glutamatergic neurons. Cortical function critically depends on the number of cINs, which is also key to establishing the appropriate inhibitory/excitatory balance. The final number of cINs is determined during a postnatal period of programmed cell death (PCD) when ~40% of the young cINs are eliminated. Previous work shows that the loss of clustered gamma protocadherins (Pcdhgs), but not of genes in the Pcdha or Pcdhb clusters, dramatically increased BAX-dependent cIN PCD. Here, we show that PcdhγC4 is highly expressed in cINs of the mouse cortex and that this expression increases during PCD. The sole deletion of the PcdhγC4 isoform, but not of the other 21 isoforms in the Pcdhg gene cluster, increased cIN PCD. Viral expression of the PcdhγC4, in cIN lacking the function of the entire Pcdhg cluster, rescued most of these cells from cell death. We conclude that PcdhγC4 plays a critical role in regulating the survival of cINs during their normal period of PCD. This highlights how a single isoform of the Pcdhg cluster, which has been linked to human neurodevelopmental disorders, is essential to adjust cIN cell numbers during cortical development.

A bout of aerobic exercise in the heat increases carbohydrate use but does not enhance the disposal of an oral glucose load, in healthy active individuals.

We investigated if a bout of exercise in a hot environment (HEAT) would reduce the postprandial hyperglycemia induced by glucose ingestion. The hypothesis was that HEAT stimulating carbohydrate oxidation and glycogen use would increase the disposal of an ingested glucose load [i.e., oral glucose tolerance test (OGTT); 75 g of glucose]. Separated by at least 1 wk, nine young healthy individuals underwent three trials after an overnight fast in a randomized order. Two trials included 50 min of pedaling at 58 ± 5% V̇o2max either in a thermoneutral (21 ± 1°C; NEUTRAL) or in a hot environment (33 ± 1°C; HEAT) eliciting similar energy expenditure (503 ± 101 kcal). These two trials were compared with a no-exercise trial (NO EXER). Twenty minutes after exercise (or rest), subjects underwent an OGTT, while carbohydrate oxidation (CHOxid, using indirect calorimetry) plasma blood glucose, insulin concentrations (i.e., [glucose], [insulin]), and double tracer glucose kinetics ([U-13C] glucose ingestion and [6,6-2H2] glucose infusion) were monitored for 120 min. At rest, [glucose], [insulin], and rates of appearance/disappearance of glucose in plasma (glucose Ra/Rd) were similar among trials. During exercise, heart rate, tympanic temperature, [glucose], glycogen oxidation, and total CHOxid were higher during HEAT than NEUTRAL (i.e., 149 ± 35 vs. 124 ± 31 µmol·kg-1·min-1, P = 0.010). However, during the following OGTT, glucose Rd was similar in HEAT and NEUTRAL trials (i.e., 25.1 ± 3.6 vs. 25.2 ± 5.3 µmol·kg-1·min-1, P = 0.981). Insulin sensitivity (i.e., ISIndexMATSUDA) only improved in NEUTRAL compared with NO EXER (10.1 ± 4.6 vs. 8.8 ± 3.7 au; P = 0.044). In summary, stimulating carbohydrate use with exercise in a hot environment does not improve postprandial plasma glucose disposal or insulin sensitivity in a subsequent OGTT.NEW & NOTEWORTHY Exercise in the heat increases estimated muscle glycogen use. Reduced muscle glycogen after exercise in the heat could increase insulin-mediated glucose uptake during a subsequent oral glucose tolerance test (OGTT). However, plasma glucose kinetics are not improved during the OGTT in response to a bout of exercise in the heat, and insulin sensitivity worsens. Heat stress activates glucose counterregulatory hormones whose actions may linger during the OGTT, preventing increased glucose uptake.

Dynamic Configuration on a Chiral-at-Rhodium Catalyst Featuring a Flexible Tetradentate Ligand.

The unique dynamic configuration of an enantioselective chiral-at-metal catalyst based on Rh(III) and a non-chiral tetradentate ligand is described and resolved. At room temperature, the catalyst undergoes a dynamic configuration process leading to the formation of two interconvertible metal-stereoisomers, remarkably without racemization. Density functional theory (DFT) calculations indicate that this metal-isomerization proceeds via a concerted transition state, which features a trigonal bipyramidal geometry stabilized by the tetradentate ligand. Furthermore, the resolved enantiopure complex shows high catalytic enantioinduction in the Friedel-Crafts reaction, achieving enantiomeric ratios as high as 99 : 1.

Glucose volume of distribution affects insulin sensitivity measured by intravenous glucose tolerance test.

AIM: To determine whether glucose volume of distribution (VdGLUCOSE ) affects the diagnosis of impaired insulin sensitivity (IS) when using an intravenous glucose tolerance test (IVGTT). METHODS: Individuals with distinct levels of IS underwent IVGTT after an overnight fast. The prediabetic group (Prediab; n = 33) differed from the healthy group (Healthy; n = 14) in their larger glycosylated hemoglobin (HbA1c of 5.9 ± 0.3 vs. 5.4 ± 0.1%; 41 ± 4 vs. 36 ± 1 mmol/mol; p < 0.001), percent body fat (37 ± 6 vs. 24 ± 3%; p < 0.001) and cardiovascular fitness level (VO2MAX 22 ± 5 vs. 44 ± 5 mL of O2 ·kg-1 ·min-1 ; p < 0.001). Ten minutes after intravenous infusion of the glucose bolus (i.e., 35 g in a 30% solution), VdGLUCOSE was assessed from the increases in plasma glucose concentration. IS was calculated during the next 50 min using the slope of glucose disappearance and the insulin time-response curve. RESULTS: VdGLUCOSE was higher in Healthy than in Prediab (230 ± 49 vs. 185 ± 21 mL·kg-1 ; p < 0.001). VdGLUCOSE was a strong predictor of IS (ß standardized coefficient 0.362; p = 0.004). VO2MAX was associated with VdGLUCOSE and IS (Pearson r = 0.582 and 0.704, respectively; p < 0.001). However, body fat was inversely associated with VdGLUCOSE and IS (r = -0.548 and -0.555, respectively; p < 0.001). CONCLUSIONS: Since fat mass is inversely related to VdGLUCOSE and in turn, VdGLUCOSE affects the calculations of IS, the IV glucose bolus dose should be calculated based on fat-free mass rather than body weight for a more accurate diagnosis of impaired IS.

Comparison of DNA damage in granulosa cells of women undergoing controlled ovarian stimulation in in vitro fertilization protocols with the recombinant human follicle-stimulating hormones Corneumon®, Gonal-F®, Pergoveris® and Puregon®: a randomized trial.

PURPOSE: To compare the DNA damage in granulosa cells (GCs) of women undergoing ovarian-stimulated cycles with four widely used recombinant human follicle-stimulating hormones (rhFSH) in in vitro fertilization (IVF) protocols (Corneumon®, Gonal-F®, Pergoveris® and Puregon®). METHODS: A randomized trial was carried out at a Mexican hospital. GCs were isolated from 18 women with infertility undergoing assisted reproductive techniques (ART). Four controlled ovarian stimulation (COS) protocols including Corneumon®, Gonal-F®, Pergoveris® or Puregon® were used. GCs DNA damage was assessed by the Comet assay. Two parameters were measured: comet tail length (CTL), and Olive tail moment (OTM, the percentage of DNA in the tail multiplied by the distance between the center of the tail and head). RESULTS: Use of the different hrFSH in COS caused variable and statistically significant levels of DNA damage in GCs of infertile women. CTL was similar in the Corneumon® and Pergoveris® groups (mean values of 48.73 and 55.18, respectively) and Corneumon® CTL was significantly lower compared to the Gonal-F® and Puregon® groups (mean values of 61.98 and 91.17, respectively). Mean OTM values were significantly lower in Corneumon® and Pergoveris® groups, compared to Gonal-F® and Puregon® groups (25.59, 27.35, 34.76, and 47.27, respectively). CONCLUSION: Use of Corneumon® and Pergoveris® in COS caused statistically significantly lower levels of DNA damage in GCs of infertile women undergoing ART, which could potentially correlate with better reproductive outcomes.

Efficacy of morning versus afternoon aerobic exercise training on reducing metabolic syndrome components: A randomized controlled trial.

A supervised intense aerobic exercise program improves the health of individuals with metabolic syndrome (MetS). However, it is unclear whether the timing of training within the 24 h day would influence those health benefits. The present study aimed to determine the influence of morning vs. afternoon exercise on body composition, cardiometabolic health and components of MetS. One hundred thirty-nine individuals with MetS were block randomized into morning (AMEX; n = 42) or afternoon (PMEX; n = 59) exercise training groups, or a non-training control group (Control; n = 38). Exercise training was comprised of 48 supervised high-intensity interval sessions distributed over 16 weeks. Body composition, cardiorespiratory fitness (assessed by V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ ), maximal fat oxidation (FOmax ), blood pressure and blood metabolites were assessed before and after the intervention. Compared with the non-training Control, both exercise groups improved similarly body composition (-0.7% fat loss; P = 0.002), waist circumference (-2.1 cm; P < 0.001), diastolic blood pressure (-3.8 mmHg; P = 0.004) and V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ (3.5 mL kg-1   min-1 ; P < 0.001) with no differences between training groups. AMEX, in comparison with PMEX, reduced systolic blood pressure (-4% vs. -1%; P = 0.019), plasma fasting insulin concentration (-12% vs. -5%; P = 0.001) and insulin resistance (-14% vs. -4%; P = 0.006). Furthermore, MetS Z score was further reduced in the AMEX compared to PMEX (-52% vs. -19%; P = 0.021) after training. In summary, high-intensity aerobic exercise training in the morning in comparison to training in the afternoon is somewhat more efficient at reducing cardiometabolic risk factors (i.e. systolic blood pressure and insulin sensitivity). KEY POINTS: The effect of exercise time of day on health promotion is an area that has gained interest in recent years; however, large-scale, randomized-control studies are scarce. People with metabolic syndrome (MetS) are at risk of developing cardiometabolic diseases and reductions in this risk with exercise training can be precisely gauged using a compound score sensitive to subtle evolution in each MetS component (i.e. Z score). Supervised aerobic exercise for 16 weeks (morning and afternoon), without dietary restriction, improved cardiorespiratory and metabolic fitness, body composition and mean arterial pressure compared to a non-exercise control group. However, training in the morning, without changes in exercise dose or intensity, reduced systolic blood pressure and insulin resistance further compared to when training in the afternoon. Thus, high-intensity aerobic exercise training in the morning is somewhat more efficient in improving the health of individuals with metabolic syndrome.

Metformin and exercise effects on postprandial insulin sensitivity and glucose kinetics in pre-diabetic and diabetic adults.

The potential interaction between metformin and exercise on glucose-lowering effects remains controversial. We studied the separated and combined effects of metformin and/or exercise on fasting and postprandial insulin sensitivity in individuals with pre-diabetes and type 2 diabetes (T2D). Eight T2D adults (60 ± 4 yr) with overweight/obesity (32 ± 4 kg·m-2) under chronic metformin treatment (9 ± 6 yr; 1281 ± 524 mg·day-1) underwent four trials; 1) taking their habitual metformin treatment (MET), 2) substituting during 96 h their metformin medication by placebo (PLAC), 3) placebo combined with 50 min bout of high-intensity interval exercise (PLAC + EX), and 4) metformin combined with exercise (MET + EX). Plasma glucose kinetics using stable isotopes (6,6-2H2 and [U-13C] glucose), and glucose oxidation by indirect calorimetry, were assessed at rest, during exercise, and in a subsequent oral glucose tolerance test (OGTT). Postprandial glucose and insulin concentrations were analyzed as mean and incremental area under the curve (iAUC), and insulin sensitivity was calculated (i.e., MATSUDAindex and OGISindex). During OGTT, metformin reduced glucose iAUC (i.e., MET and MET + EX lower than PLAC and PLAC + EX, respectively; P = 0.023). MET + EX increased MATSUDAindex above PLAC (4.8 ± 1.4 vs. 3.3 ± 1.0, respectively; P = 0.018) and OGISindex above PLAC (358 ± 52 vs. 306 ± 46 mL·min-1·m-2, respectively; P = 0.006). Metformin decreased the plasma appearance of the ingested glucose (Ra OGTT; MET vs. PLAC, -3.5; 95% CI -0.1 to -6.8 µmol·kg-1·min-1; P = 0.043). Metformin combined with exercise potentiates insulin sensitivity during an OGTT in individuals with pre-diabetes and type 2 diabetes. Metformin's blood glucose-lowering effect seems mediated by decreased oral glucose entering the circulation (gut-liver effect) an effect partially blunted after exercise.NEW & NOTEWORTHY Metformin is the most prescribed oral antidiabetic medicine in the world but its mechanism of action and its interactions with exercise are not fully understood. Our stable isotope tracer data suggested that metformin reduces the rates of oral glucose entering the circulation (gut-liver effect). Exercise, in turn, tended to reduce postprandial insulin blood levels potentiating metformin improvements in insulin sensitivity. Thus, exercise potentiates metformin improvements in glycemic control and should be advised to metformin users.

Follistatin-controlled activin-HNF4α-coagulation factor axis in liver progenitor cells determines outcome of acute liver failure.

BACKGROUND AND AIMS: In patients with acute liver failure (ALF) who suffer from massive hepatocyte loss, liver progenitor cells (LPCs) take over key hepatocyte functions, which ultimately determines survival. This study investigated how the expression of hepatocyte nuclear factor 4α (HNF4α), its regulators, and targets in LPCs determines clinical outcome of patients with ALF. APPROACH AND RESULTS: Clinicopathological associations were scrutinized in 19 patients with ALF (9 recovered and 10 receiving liver transplantation). Regulatory mechanisms between follistatin, activin, HNF4α, and coagulation factor expression in LPC were investigated in vitro and in metronidazole-treated zebrafish. A prospective clinical study followed up 186 patients with cirrhosis for 80 months to observe the relevance of follistatin levels in prevalence and mortality of acute-on-chronic liver failure. Recovered patients with ALF robustly express HNF4α in either LPCs or remaining hepatocytes. As in hepatocytes, HNF4α controls the expression of coagulation factors by binding to their promoters in LPC. HNF4α expression in LPCs requires the forkhead box protein H1-Sma and Mad homolog 2/3/4 transcription factor complex, which is promoted by the TGF-ß superfamily member activin. Activin signaling in LPCs is negatively regulated by follistatin, a hepatocyte-derived hormone controlled by insulin and glucagon. In contrast to patients requiring liver transplantation, recovered patients demonstrate a normal activin/follistatin ratio, robust abundance of the activin effectors phosphorylated Sma and Mad homolog 2 and HNF4α in LPCs, leading to significantly improved coagulation function. A follow-up study indicated that serum follistatin levels could predict the incidence and mortality of acute-on-chronic liver failure. CONCLUSIONS: These results highlight a crucial role of the follistatin-controlled activin-HNF4α-coagulation axis in determining the clinical outcome of massive hepatocyte loss-induced ALF. The effects of insulin and glucagon on follistatin suggest a key role of the systemic metabolic state in ALF.

Pulmonary ventilation and gas exchange during prolonged exercise in humans: Influence of dehydration, hyperthermia and sympathoadrenal activity.

NEW FINDINGS: What is the central question of the study? Ventilation increases during prolonged intense exercise, but the impact of dehydration and hyperthermia, with associated blunting of pulmonary circulation, and independent influences of dehydration, hyperthermia and sympathoadrenal discharge on ventilatory and pulmonary gas exchange responses remain unclear. What is the main finding and its importance? Dehydration and hyperthermia led to hyperventilation and compensatory adjustments in pulmonary CO2 and O2 exchange, such that CO2 output increased and O2 uptake remained unchanged despite the blunted circulation. Isolated hyperthermia and adrenaline infusion, but not isolated dehydration, increased ventilation to levels similar to combined dehydration and hyperthermia. Hyperthermia is the main stimulus increasing ventilation during prolonged intense exercise, partly via sympathoadrenal activation. ABSTRACT: The mechanisms driving hyperthermic hyperventilation during exercise are unclear. In a series of retrospective analyses, we evaluated the impact of combined versus isolated dehydration and hyperthermia and the effects of sympathoadrenal discharge on ventilation and pulmonary gas exchange during prolonged intense exercise. In the first study, endurance-trained males performed two submaximal cycling exercise trials in the heat. On day 1, participants cycled until volitional exhaustion (135 ± 11 min) while experiencing progressive dehydration and hyperthermia. On day 2, participants maintained euhydration and core temperature (Tc ) during a time-matched exercise (control). At rest and during the first 20 min of exercise, pulmonary ventilation ( V ̇ E ${\skew2\dot V_{\rm{E}}}$ ), arterial blood gases, CO2 output and O2 uptake were similar in both trials. At 135 ± 11 min, however, V ̇ E ${\skew2\dot V_{\rm{E}}}$ was elevated with dehydration and hyperthermia, and this was accompanied by lower arterial partial pressure of CO2 , higher breathing frequency, arterial partial pressure of O2 , arteriovenous CO2 and O2 differences, and elevated CO2 output and unchanged O2 uptake despite a reduced pulmonary circulation. The increased V ̇ E ${\skew2\dot V_{\rm{E}}}$ was closely related to the rise in Tc and circulating catecholamines (R2  ≥ 0.818, P ≤ 0.034). In three additional studies in different participants, hyperthermia independently increased V ̇ E ${\skew2\dot V_{\rm{E}}}$ to an extent similar to combined dehydration and hyperthermia, whereas prevention of hyperthermia in dehydrated individuals restored V ̇ E ${\skew2\dot V_{\rm{E}}}$ to control levels. Furthermore, adrenaline infusion during exercise elevated both Tc and V ̇ E ${\skew2\dot V_{\rm{E}}}$ . These findings indicate that: (1) adjustments in pulmonary gas exchange limit homeostatic disturbances in the face of a blunted pulmonary circulation; (2) hyperthermia is the main stimulus increasing ventilation during prolonged intense exercise; and (3) sympathoadrenal activation might partly mediate the hyperthermic hyperventilation.

The interaction between liver cirrhosis, infection by Streptococcus bovis, and colon cancer.

Whether cirrhotic patients with Streptococcus bovis bacteremia have an increased risk of colorectal neoplasm is uncertain. A multicentric retrospective cohort study was conducted investigating associations between S. bovis biotype and species, cirrhosis, and colorectal neoplasm. Out of 779 patients with S. bovis bacteremia, 69 (8.7%) had cirrhosis. No differences were found in the prevalence of colorectal neoplasm between cirrhotic and non-cirrhotic patients undergoing colonoscopy. Among cirrhotic patients, prevalence of colorectal neoplasms was higher in S. bovis biotype I (S. gallolyticus) bacteremia (80%) than in S. bovis biotype II (33.3%; p < 0.007). In conclusion, risk of colorectal neoplasm is high among cirrhotic patients with S. gallolyticus bacteremia.

Determinants of COVID-19 vaccine hesitancy among pregnant persons.

BACKGROUND: Vaccines reduce the risk of contracting and developing complications from coronavirus disease 2019 (COVID-19). Pregnant people are at increased risk of disease-related complications but have a higher prevalence of vaccine hesitancy (VH) than their nonpregnant counterparts. OBJECTIVE: This study aimed to describe risk factors and COVID-19- and vaccine-related perspectives that lead to VH among pregnant people in Mexico to target strategies to increase vaccine acceptance in this population. METHODS: A cross-sectional survey-based study to evaluate risk factors and COVID-19- and vaccine-related perspectives associated with VH among pregnant people was conducted. Respondents were pregnant people of all ages attending a regular follow-up visit or admitted to labor and delivery in a third-level maternity hospital in Mexico. VH was defined as not having received a COVID-19 vaccine and either declining or being undecided to accept a vaccine during their pregnancy. We used bivariate and multivariable logistic regression models to estimate assess the relationship among demographic factors, COVID-19- and vaccine-related perspectives, and VH. RESULTS: A total of 1475 respondents completed the questionnaire; 216 (18%) were under the age of 18 years, and 860 (58%) had received at least one dose of a COVID-19 vaccine. In this sample, 264 (18%) were classified as vaccine hesitant. Key factors associated with VH were adolescence, having family as a primary source of information, first pregnancy, and history of vaccines in previous pregnancies. COVID-19 perspectives were also strongly associated with VH. CONCLUSIONS: Among pregnant people in Mexico, VH is associated with demographic factors, vaccination history, sources of information, and perceived risks to the fetus. This information is relevant to policy makers and health care professionals to identify those more likely to be hesitant and to inform strategies to increase vaccine uptake among pregnant people.

Chronic Statin Treatment Does Not Impair Exercise Lipolysis or Fat Oxidation in Exercise-Trained Individuals With Obesity and Dyslipidemia.

OBJECTIVE: To determine whether statin medication in individuals with obesity, dyslipidemia, and metabolic syndrome affects their capacity to mobilize and oxidize fat during exercise. METHODS: Twelve individuals with metabolic syndrome pedaled during 75 min at 54 ± 13% V˙O2max (5.7 ± 0.5 metabolic equivalents) while taking statins (STATs) or after 96-hr statin withdrawal (PLAC) in a randomized double-blind fashion. RESULTS: At rest, PLAC increased low-density lipoprotein cholesterol (i.e., STAT 2.55 ± 0.96 vs. PLAC 3.16 ± 0.76 mmol/L; p = .004) and total cholesterol blood levels (i.e., STAT 4.39 ± 1.16 vs. PLAC 4.98 ± 0.97 mmol/L; p = .008). At rest, fat oxidation (0.99 ± 0.34 vs. 0.76 ± 0.37 µmol·kg-1·min-1 for STAT vs. PLAC; p = .068) and the rates of plasma appearance of glucose and glycerol (i.e., Ra glucose-glycerol) were not affected by PLAC. After 70 min of exercise, fat oxidation was similar between trials (2.94 ± 1.56 vs. 3.06 ± 1.94 µmol·kg-1·min-1, STA vs. PLAC; p = .875). PLAC did not alter the rates of disappearance of glucose in plasma during exercise (i.e., 23.9 ± 6.9 vs. 24.5 ± 8.2 µmol·kg-1·min-1 for STAT vs. PLAC; p = .611) or the rate of plasma appearance of glycerol (i.e., 8.5 ± 1.9 vs. 7.9 ± 1.8 µmol·kg-1·min-1 for STAT vs. PLAC; p = .262). CONCLUSIONS: In patients with obesity, dyslipidemia, and metabolic syndrome, statins do not compromise their ability to mobilize and oxidize fat at rest or during prolonged, moderately intense exercise (i.e., equivalent to brisk walking). In these patients, the combination of statins and exercise could help to better manage their dyslipidemia.

The Synthesis, Characterization, and Fluxional Behavior of a Hydridorhodatetraborane.

The octahydridotriborate anion plays a crucial role in the field of polyhedral boron chemistry, facilitating the synthesis of higher boranes and the preparation of diverse transition metal complexes. Among the stable forms of this anion, CsB3H8 (or (n-C4H9)4N)[B3H8] have been identified. These salts serve as valuable precursors for the synthesis of metallaboranes, wherein the triborate anion acts as a ligand coordinating to the metal center. In this study, we have successfully synthesized a novel rhodatetraborane dihydride, [Rh(η2-B3H8)(H)2(PPh3)2] (1), which represents a Rh(III) complex featuring a bidentate chelate ligand fasormed by B3H8-. Extensive characterization of this rhodatetraborane complex has been performed using NMR spectroscopy in solution and X-ray diffraction analysis in the solid state. Notably, the complex exhibits intriguing fluxional behavior, which has been investigated using NMR techniques. Moreover, we have explored the reactivity of complex 1 towards pyridine (py) and dimethylphenylphosphine (PMe2Ph). Our findings highlight the labile nature of this four-vertex rhodatetraborane as it undergoes disassembly upon attack from the corresponding Lewis base, resulting in the formation of borane adducts, LBH3, where L = py, PMe2Ph. Furthermore, in these reactions, we report the characterization of new cationic hydride complexes, such as [Rh(H)2(PPh3)2 (py)]+ (2) and [Rh(H)2(PMe2Ph)4]+. Notably, the latter complex has been characterized as the octahydridotriborate salt [Rh(H)2(PMe2Ph)4][B3H8] (3), which extends the scope of rhodatetraborane derivatives.

Novel therapeutic avenues for the study of chronic liver disease and regeneration: The foundation of the Iberoamerican Consortium for the study of liver Cirrhosis.

Unfortunately, there is a gap of understanding in the pathophysiology of chronic liver disease due to the lack of experimental models that exactly mimic the human disease. Additionally, the diagnosis of patients is very poor due to the lack of biomarkers than can detect the disease in early stages. Thus, it is of utmost interest the generation of a multidisciplinary consortium from different countries with a direct translation. The present reports the meeting of the 2021 Iberoamerican Consortium for the study of liver Cirrhosis, held online, in October 2021. The meeting, was focused on the recent advancements in the field of chronic liver disease and cirrhosis with a specific focus on cell pathobiology and liver regeneration, molecular and cellular targets involved in non-alcoholic hepatic steatohepatitis, alcoholic liver disease (ALD), both ALD and western diet, and end-stage liver cirrhosis and hepatocellular carcinoma. In addition, the meeting highlighted recent advances in targeted novel technology (-omics) and opening therapeutic avenues in this field of research.

Activation of H-H, HO-H, C(sp2)-H, C(sp3)-H, and RO-H Bonds by Transition-Metal Frustrated Lewis Pairs Based on M/N (M = Rh, Ir) Couples.

Reaction of the dimers [(Cp*MCl)2(µ-Cl)2] (Cp* = η5-C5Me5) with Ph2PCH2CH2NC(NH(p-Tolyl))2 (H2L) in the presence of NaSbF6 affords the chlorido complexes [Cp*MCl(κ2N,P-H2L)][SbF6] (M = Rh, 1; Ir, 2). Upon treatment with aqueous NaOH, solutions of 1 and 2 yield the corresponding complexes [Cp*M(κ3N,N',P-HL)][SbF6] (M = Rh, 3; Ir, 4) in which the ligand HL presents a fac κ3N,N',P coordination mode. Treatment of THF solutions of complexes 3 and 4 with hydrogen gas, at room temperature, results in the formation of the metal hydrido-complexes [Cp*MH(κ2N,P-H2L)][SbF6] (M = Rh, 5; Ir, 6) in which the N(p-Tolyl) group has been protonated. Complexes 3 and 4 react with deuterated water in a reversible fashion resulting in the gradual deuteration of the Cp* group. Heating at 383 K THF/H2O solutions of the complexes 3 and 4 affords the orthometalated complexes [Cp*M(κ3C,N,P-H2L-H)][SbF6] [M = Rh, 7; Ir, 8, H2L-H = Ph2PCH2CH2NC(NH(p-Tolyl))(NH(4-C6H3Me))], respectively. At 333 K, complexes 3 and 4 react in THF with methanol, primary alcohols, or 2-propanol giving the metal-hydrido complexes 5 and 6, respectively. The reaction involves the acceptorless dehydrogenation of the alcohols at a relatively low temperature, without the assistance of an external base. The new complexes have been characterized by the usual analytical and spectroscopic methods including the X-ray diffraction determination of the crystal structures of complexes 1-5, 7, and 8. Notably, the chlorido complexes 1 and 2 crystallize both as enantiopure conglomerates and as racemates. Reaction mechanisms are proposed based on stoichiometric reactions, nuclear magnetic resonance studies, and X-ray crystallography as well as density functional theory calculations.

Synovial membrane mesenchymal stem cells for cartilaginous tissues repair.

BACKGROUND: The present review is focused on general aspects of the synovial membrane as well as specialized aspects of its cellular constituents, particularly the composition and location of synovial membrane mesenchymal stem cells (S-MSCs). S-MSC multipotency properties are currently at the center of translational medicine for the repair of multiple joint tissues, such as articular cartilage and meniscus lesions. METHODS AND RESULTS: We reviewed the results of in vitro and in vivo research on the current clinical applications of S-MSCs, surface markers, cell culture techniques, regenerative properties, and immunomodulatory mechanisms of S-MSCs as well as the practical limitations of the last twenty-five years (1996 to 2021). CONCLUSIONS: Despite the poor interest in the development of new clinical trials for the application of S-MSCs in joint tissue repair, we found evidence to support the clinical use of S-MSCs for cartilage repair. S-MSCs can be considered a valuable therapy for the treatment of repairing joint lesions.

Statins effect on insulin resistance after a meal and exercise in hypercholesterolemic pre-diabetic individuals.

AIM: To study if statins, a widely prescribed, inexpensive medication to prevent coronary artery diseases may cause insulin resistance (IR). METHODS: Fasted (HOMA-IR) and post-meal insulin resistance were assessed in 21 pre-diabetic hypercholesterolemic individuals treated with statins (STA trial). Measurements were compared to another trial conducted 96 h after statin withdrawal using placebo pills (PLAC trial). Trials were duplicated 16-18 h after a bout of moderate-intensity exercise (500 kcal of energy expenditure) to reduce IR and better appreciate statin effects (EXER+STA and EXER+PLAC trials). RESULTS: Statin withdrawal did not affect fasting (HOMA-IR; 2.35 ± 1.05 vs. 2.18 ± 0.87 for STA vs. PLAC trials; p = 0.150) or post-meal insulin resistance (i.e., Matsuda-index, STA 6.23 ± 2.83 vs. PLAC 6.49 ± 3.74; p = 0.536). A bout of aerobic exercise lowered post-meal IR (p = 0.043), but statin withdrawal did not add to the exercise actions (p = 0.564). Statin withdrawal increased post-meal plasma free glycerol concentrations (0.136 ± 0.073 vs. 0.185 ± 0.090 mmol·L-1 for STA vs. PLAC trials; p < 0.001) but not plasma free fatty acids or fat oxidation (p = 0.981, and p = 0.621, respectively). Post-meal fat oxidation was higher in the exercise trials (p = 0.002). CONCLUSIONS: Withdrawal of statin medication does not affect fasting or post-meal insulin resistance in pre-diabetic hypercholesterolemic individuals. Furthermore, statin use does not interfere with the beneficial effects of exercise on lowering IR.

Endurance Exercise Training reduces Blood Pressure according to the Wilder's Principle.

The effect of antihypertensive medicine (AHM) is larger the higher the pre-treatment blood pressure level. It is unknown whether this Wilder's principle, also applies for the exercise-training blood pressure (BP) lowering effect. One hundred seventy-eight (n=178) middle-aged individuals (55±8 y) with metabolic syndrome (MetS), underwent high intensity interval training (3 days·week-1) for 16 weeks. Participants were divided into medicated (Med; n=103) or not medicated (No Med; n=75) with AHM. Office BP was evaluated before and after the exercise-training. Correlations and stepwise regression analysis were used to determine which variable better predicted the reductions in systolic BP (SBP) with training. After training, participants with hypertension lowered SBP by a similar magnitude regardless of if they were in the Med (-15 mmHg, 95% CI-12,-19; P<0.001) or No Med group (-13 mmHg, 95% CI-9,-16; P<0.001). However, SBP did not decrease among normotensive groups (P=0.847 for Med and P=0.937 for No Med). Pre-treatment SBP levels was the best predictor of exercise-training lowering effect (r=-0.650; ß=-0.642; P<0.001). For each 10 mmHg higher pre-training SBP there were a 5 mmHg deeper SBP reduction (Wilder principle). Furthermore, AHM does not interfere with exercise-training BP-lowering effect.

Osteogenic Potential of Monosodium Urate Crystals in Synovial Mesenchymal Stem Cells.

Background and Objectives: Deposits of monosodium urate (MSU) crystals due to increased levels of uric acid (UA) have been associated with bone formation and erosion, mainly in patients with chronic gout. The synovial membrane (SM) comprises several types of cells, including mesenchymal stem cells (SM-MSCs); however, it is unknown whether UA and MSU induce osteogenesis through SM-MSCs. Materials and Methods: Cultures of SM were immunotyped with CD44, CD69, CD90, CD166, CD105, CD34, and CD45 to identify MSCs. CD90+ cells were isolated by immunomagnetic separation (MACS), colony-forming units (CFU) were identified, and the cells were exposed to UA (3, 6.8, and 9 mg/dL) and MSU crystals (1, 5, and 10 µg/mL) for 3 weeks, and cellular morphological changes were evaluated. IL-1ß and IL-6 were determined by ELISA, mineralization was assessed by alizarin red, and the expression of Runx2 was assessed by Western blot. Results: Cells derived from SM and after immunomagnetic separation were positive for CD90 (53 ± 8%) and CD105 (52 ± 18%) antigens, with 53 ± 5 CFU identified. Long-term exposure to SM-MSCs by UA and MSU crystals did not cause morphological damage or affect cell viability, nor were indicators of inflammation detected. Mineralization was observed at doses of 6.8 mg/dL UA and 5 µg/mL MSU crystals; however, the differences were not significant with respect to the control. The highest dose of MSU crystals (10 µg/mL) induced significant Runx2 expression with respect to the control (1.4 times greater) and SM-MSCs cultured in the osteogenic medium. Conclusions: MSU crystals may modulate osteogenic differentiation of SM-MSCs through an increase in Runx2.