In contrast to studies on class I histone deacetylase (HDAC) inhibitors, the elucidation of the molecular mechanisms and therapeutic potential of class IIa HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) is ...impaired by the lack of potent and selective chemical probes. Here we report the discovery of inhibitors that fill this void with an unprecedented metal-binding group, trifluoromethyloxadiazole (TFMO), which circumvents the selectivity and pharmacologic liabilities of hydroxamates. We confirm direct metal binding of the TFMO through crystallographic approaches and use chemoproteomics to demonstrate the superior selectivity of the TFMO series relative to a hydroxamate-substituted analog. We further apply these tool compounds to reveal gene regulation dependent on the catalytic active site of class IIa HDACs. The discovery of these inhibitors challenges the design process for targeting metalloenzymes through a chelating metal-binding group and suggests therapeutic potential for class IIa HDAC enzyme blockers distinct in mechanism and application compared to current HDAC inhibitors.
The human gut microbiota produces dozens of metabolites that accumulate in the bloodstream, where they can have systemic effects on the host. Although these small molecules commonly reach ...concentrations similar to those achieved by pharmaceutical agents, remarkably little is known about the microbial metabolic pathways that produce them. Here we use a combination of genetics and metabolic profiling to characterize a pathway from the gut symbiont Clostridium sporogenes that generates aromatic amino acid metabolites. Our results reveal that this pathway produces twelve compounds, nine of which are known to accumulate in host serum. All three aromatic amino acids (tryptophan, phenylalanine and tyrosine) serve as substrates for the pathway, and it involves branching and alternative reductases for specific intermediates. By genetically manipulating C. sporogenes, we modulate serum levels of these metabolites in gnotobiotic mice, and show that in turn this affects intestinal permeability and systemic immunity. This work has the potential to provide the basis of a systematic effort to engineer the molecular output of the gut bacterial community.
Abstract Perioperative patient optimization can minimize the need for blood transfusions in patients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA). The purpose of this ...study was to determine predictors and complications of transfusions. This retrospective review analyzed 1795 patients who underwent primary THA and TKA at our institution between January 2011 and December 2012. Of the 1573 patients ultimately included the rates of transfusion were 9.27% in TKA and 26.6% in THA. Significant predictors for transfusion include: preoperative hemoglobin, age, female gender, body mass index, creatinine, TKA, operating room time, operative blood loss, and intra-operative fluids. The DVT rate was comparable, but deep surgical site infection rate among transfused patients was 2.4% compared to 0.5% in non-transfused patients (P = 0.0065).
Rapid eye movement (REM) sleep is an important component of the natural sleep/wake cycle, yet the mechanisms that regulate REM sleep remain incompletely understood. Cholinergic neurons in the ...mesopontine tegmentum have been implicated in REM sleep regulation, but lesions of this area have had varying effects on REM sleep. Therefore, this study aimed to clarify the role of cholinergic neurons in the pedunculopontine tegmentum (PPT) and laterodorsal tegmentum (LDT) in REM sleep generation. Selective optogenetic activation of cholinergic neurons in the PPT or LDT during non-REM (NREM) sleep increased the number of REM sleep episodes and did not change REM sleep episode duration. Activation of cholinergic neurons in the PPT or LDT during NREM sleep was sufficient to induce REM sleep.
To generate haploid gametes, germ cells undergo two consecutive meiotic divisions requiring key changes to the cell division machinery. Here, we demonstrate that the protease separase rewires key ...cell division processes at the meiosis I/II transition by cleaving the meiosis-specific protein Meikin. Separase proteolysis does not inactivate Meikin but instead alters its function to create a distinct activity state. Full-length Meikin and the C-terminal Meikin separase cleavage product both localize to kinetochores, bind to Plk1 kinase, and promote Rec8 cleavage, but our results reveal distinct roles for these proteins in controlling meiosis. Mutations that prevent Meikin cleavage or that conditionally inactivate Meikin at anaphase I result in defective meiosis II chromosome alignment in mouse oocytes. Finally, as oocytes exit meiosis, C-Meikin is eliminated by APC/C-mediated degradation prior to the first mitotic division. Thus, multiple regulatory events irreversibly modulate Meikin activity during successive meiotic divisions to rewire the cell division machinery at two distinct transitions.
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•The meiosis-specific kinetochore protein Meikin is cleaved by the protease separase•Preventing Meikin cleavage causes meiosis II chromosome alignment defects in oocytes•The C-terminal Meikin fragment retains key activities and is required for meiosis II•Meikin is eliminated by APC/C-mediated degradation at meiotic exit
Meiosis requires the dramatic rewiring of the chromosome segregation machinery at each division. Maier et al. find that the critical meiosis-specific kinetochore protein, Meikin, is regulated at key meiotic transitions through separase-mediated proteolytic cleavage and ubiquitin-mediated degradation, to enable distinct activities during the two meiotic divisions.
Although the main focus of immuno-oncology has been manipulating the adaptive immune system, harnessing both the innate and adaptive arms of the immune system might produce superior tumour reduction ...and elimination. Tumour-associated macrophages often have net pro-tumour effects, but their embedded location and their untapped potential provide impetus to discover strategies to turn them against tumours. Strategies that deplete (anti-CSF-1 antibodies and CSF-1R inhibition) or stimulate (agonistic anti-CD40 or inhibitory anti-CD47 antibodies) tumour-associated macrophages have had some success. We hypothesized that pharmacologic modulation of macrophage phenotype could produce an anti-tumour effect. We previously reported that a first-in-class selective class IIa histone deacetylase (HDAC) inhibitor, TMP195, influenced human monocyte responses to the colony-stimulating factors CSF-1 and CSF-2 in vitro. Here, we utilize a macrophage-dependent autochthonous mouse model of breast cancer to demonstrate that in vivo TMP195 treatment alters the tumour microenvironment and reduces tumour burden and pulmonary metastases by modulating macrophage phenotypes. TMP195 induces the recruitment and differentiation of highly phagocytic and stimulatory macrophages within tumours. Furthermore, combining TMP195 with chemotherapy regimens or T-cell checkpoint blockade in this model significantly enhances the durability of tumour reduction. These data introduce class IIa HDAC inhibition as a means to harness the anti-tumour potential of macrophages to enhance cancer therapy.
This 2020 International Consensus on Cardiopulmonary Resuscitation (CPR) and Emergency Cardiovascular Care Science With Treatment Recommendations on basic life support summarizes evidence evaluations ...performed for 22 topics that were prioritized by the Basic Life Support Task Force of the International Liaison Committee on Resuscitation. The evidence reviews include 16 systematic reviews, 5 scoping reviews, and 1 evidence update. Per agreement within the International Liaison Committee on Resuscitation, new or revised treatment recommendations were only made after a systematic review.Systematic reviews were performed for the following topicsdispatch diagnosis of cardiac arrest, use of a firm surface for CPR, sequence for starting CPR (compressions-airway-breaths versus airway-breaths-compressions), CPR before calling for help, duration of CPR cycles, hand position during compressions, rhythm check timing, feedback for CPR quality, alternative techniques, public access automated external defibrillator programs, analysis of rhythm during chest compressions, CPR before defibrillation, removal of foreign-body airway obstruction, resuscitation care for suspected opioid-associated emergencies, drowning, and harm from CPR to victims not in cardiac arrest.The topics that resulted in the most extensive task force discussions included CPR during transport, CPR before calling for help, resuscitation care for suspected opioid-associated emergencies, feedback for CPR quality, and analysis of rhythm during chest compressions. After discussion of the scoping reviews and the evidence update, the task force prioritized several topics for new systematic reviews.
Abstract Aims and methods To systematically review the accuracy of early (≤7 days) predictors of poor outcome, defined as death or vegetative state (Cerebral Performance Categories CPC 4–5) or death, ...vegetative state or severe disability (CPC 3–5), in comatose adult survivors from cardiac arrest (CA) treated using therapeutic hypothermia (TH). Electronic databases were searched for eligible studies. Sensitivity, specificity, and false positive rates (FPR) for each predictor were calculated. Quality of evidence (QOE) was evaluated according to the GRADE guidelines. Results 37 studies (2403 patients) were included. A bilaterally absent N20 SSEP wave during TH (4 studies; QOE: Moderate) or after rewarming (5 studies; QOE: Low), a nonreactive EEG background (3 studies; QOE: Low) after rewarming, a combination of absent pupillary light and corneal reflexes plus a motor response no better than extension ( M ≤ 2) (1 study; QOE: Very low) after rewarming predicted CPC 3–5 with 0% FPR and narrow (<10%) 95% confidence intervals. No consistent threshold for 0% FPR could be identified for blood levels of biomarkers. In 6/8 studies on SSEP, in 1/3 studies on EEG reactivity and in the single study on clinical examination the investigated predictor was used for decisions to withdraw treatment, causing the risk of a self-fulfilling prophecy. Conclusions in the first 7 days after CA, a bilaterally absent N20 SSEP wave anytime, a nonreactive EEG after rewarming or a combination of absent ocular reflexes and M ≤ 2 after rewarming predicted CPC 3–5 with 0% FPR and narrow 95% CIs, but with a high risk of bias.
Objective/Hypothesis
In this study, optical coherence tomography (OCT) is used to noninvasively and quantitatively determine tympanic membrane (TM) thickness and the presence and thickness of any ...middle‐ear biofilm located behind the TM. These new metrics offer the potential to differentiate normal, acute, and chronic otitis media (OM) infections in pediatric subjects.
Study Design
Case series with comparison group.
Methods
The TM thickness of 34 pediatric subjects was acquired using a custom‐built, handheld OCT system following a traditional otoscopic ear exam.
Results
Overall thickness (TM and any associated biofilm) was shown to be statistically different for normal, acute, and chronic infection groups (normal‐acute and normal‐chronic: P value < 0.001; acute‐chronic: P value = 0.0016). Almost all observed scans from the chronic group had an accompanying biofilm structure. When the thickness of the TM and biofilm were considered separately in chronic OM, the chronic TM thickness correlated with the normal group (P value = 0.68) yet was still distinct from the acute OM group (P value < 0.001), indicating that the TM in chronic OM returns to relatively normal thickness levels.
Conclusion
Identifying these physical changes in vivo provides new metrics for noninvasively and quantitatively differentiating normal, acute, and chronic OM. This new diagnostic information has the potential to assist physicians to more effectively and efficiently screen, manage, and refer patients based on quantitative data.
Level of Evidence
4. Laryngoscope, 125:E276–E282, 2015
Income Status and Life Satisfaction FitzRoy, Felix R.; Nolan, Michael A.
Journal of happiness studies,
01/2022, Letnik:
23, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The importance of both income rank and relative income, as indicators of status, has long been recognised in the literature on life satisfaction and happiness. Recently, several authors have made ...explicit comparisons of the relative importance of these two measures of income status, and concluded that rank dominates to the extent that reference income becomes insignificant in regressions including both these explanatory variables, and that even absolute or household income, otherwise always positively related to happiness, may lose statistical significance. Here we test this hypothesis with a large UK panel (British Household Panel Survey and Understanding Society) for 1996–2017, split by age and retirement status, and find, contrary to previous results, that rank, household income and reference income are all usually important explanatory variables, but with significant differences between subgroups. This finding holds when rank is in its often-used relative form, and also with absolute rank.
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