Sleep is a complex and plastic behavior regulated by multiple brain regions and influenced by numerous internal and external stimuli. Thus, to fully uncover the function(s) of sleep, cellular ...resolution of sleep-regulating neurons needs to be achieved. Doing so will help to unequivocally assign a role or function to a given neuron or group of neurons in sleep behavior. In the Drosophila brain, neurons projecting to the dorsal fan-shaped body (dFB) have emerged as a key sleep-regulating area. To dissect the contribution of individual dFB neurons to sleep, we undertook an intersectional Split-GAL4 genetic screen focusing on cells contained within the 23E10-GAL4 driver, the most widely used tool to manipulate dFB neurons. In this study, we demonstrate that 23E10-GAL4 expresses in neurons outside the dFB and in the fly equivalent of the spinal cord, the ventral nerve cord (VNC). Furthermore, we show that 2 VNC cholinergic neurons strongly contribute to the sleep-promoting capacity of the 23E10-GAL4 driver under baseline conditions. However, in contrast to other 23E10-GAL4 neurons, silencing these VNC cells does not block sleep homeostasis. Thus, our data demonstrate that the 23E10-GAL4 driver contains at least 2 different types of sleep-regulating neurons controlling distinct aspects of sleep behavior.
In couples dealing with health problems, we-disease appraisals can influence dyadic coping strategies to alleviate distress. This study describes the development and validation of a self-report scale ...to assess we-disease appraisals of health problems. The newly developed We-Disease Questionnaire (WDQ) was administered in three samples: parents of children with type 1 diabetes (
= 240) or cancer (
= 125) and individuals with visual impairment and their partners (
= 216). Reliability was measured by coefficient omega. To assess construct validity, correlations with other measures of individual and dyadic adjustment were examined. Descriptive statistics across all samples were compared. A 4-item version of the WDQ demonstrated good reliability and validity and showed meaningful associations with established scales. We-disease appraisals were highest among parents of children with cancer and lowest among couples with visual impairment. The WDQ is a reliable and valid measure that can be used across different health problems.
Prognosis of patients with advanced extrahepatic cholangiocarcinoma (eCCA) is poor. The current standard first-line treatment is systemic chemotherapy (CT) with gemcitabine and a platinum derivate. ...Additionally, endobiliary radiofrequency ablation (eRFA) can be applied to treat biliary obstructions. This study aimed to evaluate the additional benefit of scheduled regular eRFA in a real-life patient cohort with advanced extrahepatic cholangiocarcinoma under standard systemic CT. All patients with irresectable eCCA treated at University Hospital Bonn between 2010 and 2020 were eligible for inclusion. Patients were stratified according to treatment: standard CT (n = 26) vs. combination of eRFA with standard CT (n = 40). Overall survival (OS), progression free survival (PFS), feasibility and toxicity were retrospectively analyzed using univariate and multivariate approaches. Combined eRFA and CT resulted in significantly longer median OS (17.3 vs. 8.6 months, p = 0.004) and PFS (12.9 vs. 5.7 months, p = 0.045) compared to the CT only group. While groups did not differ regarding age, sex, tumor stage and chemotherapy treatment regimen, mean MELD was even higher (10.1 vs. 6.7, p = 0.015) in the eRFA + CT group. The survival benefit of concomitant eRFA was more evident in the subgroup with locally advanced tumors. Severe hematological toxicities (CTCAE grades 3 - 5) did not differ significantly between the groups. However, therapy-related cholangitis occurred more often in the combined treatment group (p = 0.031). Combination of eRFA and systemic CT was feasible, well-tolerated and could significantly prolong survival compared to standard CT alone. Thus, eRFA should be considered during therapeutic decision making in advanced eCCA.
Effective and modular synthetic approaches toward phosphine–phosphite ligands and phosphine–phosphonite ligands featuring a diphenyl ether backbone have been developed. The phosphine–phosphite ...ligands are obtained by a two‐step protocol from 2‐bromo‐2′‐methoxydiphenyl ether. The phosphine–phosphonite ligands are prepared in a four‐step synthetic protocol that involves a novel, unsymmetrical diphenyl ether derived phosphine–phosphorusdiamide as key building block. Structural studies on PtII complexes with either phosphine–phosphite or phosphine–phosphonite ligands indicate strict cis coordination for these ligand systems. High‐pressure NMR spectroscopy studies of Rh complexes under syngas indicate the presence of two ea isomers for Rh(H)(CO)2(PP). The existence of this mixture is further supported by high‐pressure IR spectroscopy studies. In order to benchmark the activity and selectivity of these novel, wide‐bite‐angle, mixed‐donor ligands, they were screened in Pd‐catalyzed asymmetric allylic alkylation as well as Rh‐catalyzed hydrogenation and hydroformylation reactions. The ligands give 100 % conversion and low‐to‐moderate enantioselectivity in the allylic alkylation of 1,3‐diphenyl‐2‐propenyl acetate and cyclohexyl‐2‐enyl acetate with dimethyl malonate. In the hydroformylation of styrene, good conversion and regioselectivities are achieved but only moderate enantioselectivity. The ligands give good conversions in asymmetric hydrogenation of typical substrates, with good‐to‐excellent enantioselectivities of up to 97 % depending on the substrate.
The design of two subclasses of chiral, mixed‐donor diphosphorus ligands with a diphenylether backbone is described. Both phosphine–phosphonite and phosphine–phosphite derivatives are accessible. Coordination to PtII and RhI is described, and high‐pressure spectroscopy under syngas provides information on coordination geometry. The chiral ligand systems are benchmarked in Pd‐catalyzed allylic alkylation and Rh‐catalyzed hydrogenation and hydroformylation.
Mafb and c-Maf transcription factor (TF) expression is enriched in medial ganglionic eminence (MGE) lineages, beginning in late-secondary progenitors and continuing into mature parvalbumin (PV+) and ...somatostatin (SST+) interneurons. However, the functions of Maf TFs in MGE development remain to be elucidated. Herein, Mafb and c-Maf were conditionally deleted, alone and together, in the MGE and its lineages. Analyses of Maf mutant mice revealed redundant functions of Mafb and c-Maf in secondary MGE progenitors, where they repress the generation of SST+ cortical and hippocampal interneurons. By contrast, Mafb and c-Maf have distinct roles in postnatal cortical interneuron (CIN) morphological maturation, synaptogenesis, and cortical circuit integration. Thus, Mafb and c-Maf have redundant and opposing functions at different steps in CIN development.
Display omitted
•Mafb and c-Maf are expressed in MGE-derived CINs but not projection neurons•Mafb and c-Maf control the numbers of MGE-lineage CINs•Loss of Mafb and c-Maf leads to increased SST+ CIN perinatally•Mafb and c-Maf control CIN synaptic maturation antagonistically
Using mouse genetics and ex vivo physiology studies, Pai et al. show that Mafb and c-Maf together are necessary to generate the proper numbers of parvalbumin and somatostatin GABAergic interneurons. However, in maturing interneurons, Mafb and c-Maf function divergently to control their firing properties and communication with other neurons.
Background
Perioperative myocardial infarction/injury (PMI) diagnosed by high-sensitivity troponin (hs-cTn) T is frequent and a prognostically important complication of non-cardiac surgery. We ...aimed to evaluate the incidence and outcome of PMI diagnosed using hs-cTnI, and compare it to PMI diagnosed using hs-cTnT.
Methods
We prospectively included 2455 patients at high cardiovascular risk undergoing 3111 non-cardiac surgeries, for whom hs-cTnI and hs-cTnT concentrations were measured before surgery and on postoperative days 1 and 2. PMI was defined as a composite of perioperative myocardial infarction (PMI
Infarct
) and perioperative myocardial injury (PMI
Injury
), according to the Fourth Universal Definition of Myocardial Infarction. All-cause mortality was the primary endpoint.
Results
Using hs-cTnI, the incidence of overall PMI was 9% (95% confidence interval CI 8–10%), including PMI
Infarct
2.6% (95% CI 2.0–3.2) and PMI
Injury
6.1% (95% CI 5.3–6.9%), which was lower versus using hs-cTnT: overall PMI 15% (95% CI 14–16%), PMI
Infarct
3.7% (95% CI 3.0–4.4) and PMI
Injury
11.3% (95% CI 10.2–12.4%). All-cause mortality occurred in 52 (2%) patients within 30 days and 217 (9%) within 1 year. Using hs-cTnI, both PMI
Infarct
and PMI
Injury
were independent predictors of 30-day all-cause mortality (adjusted hazard ratio aHR 2.5 95% CI 1.1–6.0, and aHR 2.8 95% CI 1.4–5.5, respectively) and, 1-year all-cause mortality (aHR 2.0 95% CI 1.2–3.3, and aHR 1.8 95% CI 1.2–2.7, respectively). Overall, the prognostic impact of PMI diagnosed by hs-cTnI was comparable to the prognostic impact of PMI using hs-cTnT.
Conclusions
Using hs-cTnI, PMI is less common versus using hs-cTnT. Using hs-cTnI, both PMI
Infarct
and PMI
Injury
remain independent predictors of 30-day and 1-year mortality.
Graphic abstract
The Knockout Mouse Project Austin, Christopher P; Battey, James F; Bradley, Allan ...
Nature genetics,
09/2004, Letnik:
36, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Mouse knockout technology provides a powerful means of elucidating gene function in vivo, and a publicly available genome-wide collection of mouse knockouts would be significantly enabling for ...biomedical discovery. To date, published knockouts exist for only about 10% of mouse genes. Furthermore, many of these are limited in utility because they have not been made or phenotyped in standardized ways, and many are not freely available to researchers. It is time to harness new technologies and efficiencies of production to mount a high-throughput international effort to produce and phenotype knockouts for all mouse genes, and place these resources into the public domain.
Laparoscopic splenectomy is a second-line therapy for immune thrombocytopenia with a sustained success rate of 66%. In a climate of new available medical therapies for immune thrombocytopenia, the ...comparative safety and efficacy of laparoscopic splenectomy are worthy of attention. The purpose of this study is to identify factors predictive of laparoscopic splenectomy success that will enable preoperative prognostication.
A retrospective cohort study was conducted of patients undergoing laparoscopic splenectomy for immune thrombocytopenia. The data collected evaluated response to medical and surgical therapy, which was defined on a platelet level of 50 × 109/L with no bleeding events. Univariate and multivariate analyses were conducted to evaluate factors predictive of laparoscopic splenectomy success, with an additional subanalysis planned to assess for laparoscopic splenectomy safety in individuals ≥65 years.
One hundred forty-one patients were reviewed. Operative outcomes showed a 3.6% conversion rate and 8.5% complication rate. Disease remission was achieved in 78.7% of patients. Response to initial corticosteroid therapy was associated with a laparoscopic splenectomy success rate of 90% and increased odds of surgical success by 5.58 over individuals with no response to corticosteroids. Age did not confer an increased risk of failure or complications.
Laparoscopic splenectomy is a safe and effective intervention for immune thrombocytopenia regardless of age. Initial response to corticosteroids is associated with laparoscopic splenectomy success rate of 90% and improved odds of surgical success. Laparoscopic splenectomy should be the standard second-line therapy for immune thrombocytopenia, especially in patients responding to corticosteroids.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces B and T cell responses, contributing to virus neutralization. In a cohort of 2,911 young adults, we identified 65 individuals ...who had an asymptomatic or mildly symptomatic SARS-CoV-2 infection and characterized their humoral and T cell responses to the Spike (S), Nucleocapsid (N) and Membrane (M) proteins. We found that previous infection induced CD4 T cells that vigorously responded to pools of peptides derived from the S and N proteins. By using statistical and machine learning models, we observed that the T cell response highly correlated with a compound titer of antibodies against the Receptor Binding Domain (RBD), S and N. However, while serum antibodies decayed over time, the cellular phenotype of these individuals remained stable over four months. Our computational analysis demonstrates that in young adults, asymptomatic and paucisymptomatic SARS-CoV-2 infections can induce robust and long-lasting CD4 T cell responses that exhibit slower decays than antibody titers. These observations imply that next-generation COVID-19 vaccines should be designed to induce stronger cellular responses to sustain the generation of potent neutralizing antibodies.
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