Tousled-like kinases (TLKs) are nuclear serine-threonine kinases essential for genome maintenance and proper cell division in animals and plants. A major function of TLKs is to phosphorylate the ...histone chaperone proteins ASF1a and ASF1b to facilitate DNA replication-coupled nucleosome assembly, but how TLKs selectively target these critical substrates is unknown. Here, we show that TLK2 selectivity towards ASF1 substrates is achieved in two ways. First, the TLK2 catalytic domain recognizes consensus phosphorylation site motifs in the ASF1 C-terminal tail. Second, a short sequence at the TLK2 N-terminus docks onto the ASF1a globular N-terminal domain in a manner that mimics its histone H3 client. Disrupting either catalytic or non-catalytic interactions through mutagenesis hampers ASF1 phosphorylation by TLK2 and cell growth. Our results suggest that the stringent selectivity of TLKs for ASF1 is enforced by an unusual interaction mode involving mutual recognition of a short sequence motifs by both kinase and substrate.
Plastic photovoltaic devices offer a real potential for making solar energy economically viable. Unfortunately, bulk heterojunction (BHJ) solar cells fabricated from blends of the commonly used ...materials poly(3-hexylthiophene), P3HT, and phenyl-C61-butyric acid methyl ester, PCBM, sometimes exhibit low efficiencies even when the procedures followed often produce solar cells with efficiencies exceeding 5%. In this Letter, we show that this irreproducibility is caused by subtleties in the film processing conditions that ultimately lead to poor electron extraction from the devices. For low-performing devices, photogeneration and charge extraction with a linearly increasing voltage ramp (photo−CELIV) measurements show an order-of-magnitude difference in the effective mobilities of the electrons and holes. Atomic force microscopy (AFM) experiments reveal that the top surface of these low-performing devices is nearly pure P3HT. We argue that small variations in the solvent evaporation kinetics during spin-coating of the BHJ active layer, which are difficult to control, cause PCBM to segregate toward the bottom of the P3HT film to different extents, explaining why electron extraction from the PCBM component of the BHJ is so difficult in poorly performing devices. Finally, we show that electron extraction can be greatly improved by spin-coating a thin PCBM layer on top of the BHJ before deposition of the cathode, allowing the reproducible fabrication of high-efficiency polymer solar cells.
Graphene and its multilayers have attracted considerable interest because their fourfold spin and valley degeneracy enables a rich variety of broken-symmetry states arising from electron-electron ...interactions, and raises the prospect of controlled phase transitions among them. Here we report local electronic compressibility measurements of ultraclean suspended graphene that reveal a multitude of fractional quantum Hall states surrounding filling factors ν=-1/2 and -1/4. Several of these states exhibit phase transitions that indicate abrupt changes in the underlying order, and we observe many additional oscillations in compressibility as ν approaches -1/2, suggesting further changes in spin and/or valley polarization. We use a simple model based on crossing Landau levels of composite fermions with different internal degrees of freedom to explain many qualitative features of the experimental data. Our results add to the diverse array of many-body states observed in graphene and demonstrate substantial control over their order parameters.
Modern endovascular thrombectomy (MET), using stent retrievers or large-bore distal aspiration catheters in stroke patients with acute basilar artery occlusion (BAO), is routinely performed to date. ...However, more than 35% of BAO patients treated with MET die within 90 days despite high recanalization rates. The purpose of this study is to investigate the parameters associated with 90-day mortality in patients with BAO after MET.
We analyzed 117 consecutive BAO patients included in the Endovascular Treatment in Ischemic Stroke prospective clinical registry of consecutive acute ischemic stroke patients treated with MET (60 patients 51.3% treated with a stent retriever as first-line technique) between March 2010 and April 2017. Successful recanalization was defined as modified thrombolysis In cerebral infarction scores 2b-3 at the end of MET, and mortality was defined as modified Rankin Scale 6 at 90 days. Associations of baseline characteristics (patient and treatment characteristics) and intermediate outcomes (recanalization, complications) with 90-day mortality were investigated in univariate and multivariate analyses.
Overall successful recanalization rate was 79.5, and 41.9% (95% CI 32.8-51.0%) of patients died within 90 days after MET. Patients with successful recanalization had a lower mortality rate (32.9 vs. 74.4%; p < 0.001). Failure of successful recanalization was an independent predictor of mortality (OR 5.1; 95% CI 1.34-19.33). In multivariate analysis, age ≥60 years (OR 6.37; 95% CI 1.74-23.31), admission National Institute of Health Stroke Scale (NIHSS) ≥13 (OR 4.62; 95% CI 1.42-15.03), lower posterior circulation-Alberta Stroke Program Early CT Score (pc-ASPECTS; OR 1.71; 95% CI 1.19-2.44), use of antithrombotic medication prior to stroke onset (OR 3.38; 95% CI 1.03-11.08), absence of intravenous thrombolysis (OR 3.36; 95% CI 1.12-10.03), and angioplasty/stenting of the basilar artery (OR 4.71; 95% CI 1.34-16.54) were independent predictors for mortality after MET.
Failure of successful recanalization was a strong predictor for mortality. In the setting of recanalization, age, admission NIHSS, pc-ASPECTS, absence of intravenous thrombolysis, and angioplasty/stenting of the basilar artery were also independent predictors for mortality after MET of BAO patients.
SARS-CoV-2 has been responsible for considerable mortality worldwide, owing in particular to pulmonary failures such as ARDS, but also to other visceral failures and secondary infections. Recent ...progress in the characterization of the immunological mechanisms that result in severe organ injury led to the emergence of two successive hypotheses simultaneously tested here: hyperinflammation with cytokine storm syndrome or dysregulation of protective immunity resulting in immunosuppression and unrestrained viral dissemination.
In a prospective observational monocentric study of 134 patients, we analysed a panel of plasma inflammatory and anti-inflammatory cytokines and measured monocyte dysregulation via their membrane expression of HLA-DR. We first compared the results of patients with moderate forms hospitalized in an infectious disease unit with those of patients with severe forms hospitalized in an intensive care unit. In the latter group of patients, we then analysed the differences between the surviving and non-surviving groups and between the groups with or without secondary infections.
Higher blood IL-6 levels, lower quantitative expression of HLA-DR on blood monocytes and higher IL-6/mHLA-DR ratios were statistically associated with the risk of severe forms of the disease and among the latter with death and the early onset of secondary infections.
The unique immunological profile in patients with severe COVID-19 corresponds to a moderate cytokine inflammation associated with severe monocyte dysregulation. Individuals with major CSS were rare in our cohort of hospitalized patients, especially since the use of corticosteroids, but formed a very severe subgroup of the disease.
None.
Background
Coronavirus disease 2019 (COVID-19) is a respiratory disease associated with endotheliitis and microthrombosis.
Objectives
To correlate endothelial dysfunction to in-hospital mortality in ...a bi-centric cohort of COVID-19 adult patients.
Methods
Consecutive ambulatory and hospitalized patients with laboratory-confirmed COVID-19 were enrolled. A panel of endothelial biomarkers and von Willebrand factor (VWF) multimers were measured in each patient ≤ 48 h following admission.
Results
Study enrolled 208 COVID-19 patients of whom 23 were mild outpatients and 189 patients hospitalized after admission. Most of endothelial biomarkers tested were found increased in the 89 critical patients transferred to intensive care unit. However, only von Willebrand factor antigen (VWF:Ag) scaled according to clinical severity, with levels significantly higher in critical patients (median 507%, IQR 428–596) compared to non-critical patients (288%, 230–350,
p
< 0.0001) or COVID-19 outpatients (144%, 133–198,
p
= 0.007). Moreover, VWF high molecular weight multimers (HMWM) were significantly higher in critical patients (median ratio 1.18, IQR 0.86–1.09) compared to non-critical patients (0.96, 1.04–1.39,
p
< 0.001). Among all endothelial biomarkers measured, ROC curve analysis identified a VWF:Ag cut-off of 423% as the best predictor for in-hospital mortality. The accuracy of VWF:Ag was further confirmed in a Kaplan–Meier estimator analysis and a Cox proportional Hazard model adjusted on age, BMI, C-reactive protein and
d
-dimer levels.
Conclusion
VWF:Ag is a relevant predictive factor for in-hospital mortality in COVID-19 patients. More than a biomarker, we hypothesize that VWF, including excess of HMWM forms, drives microthrombosis in COVID-19.
Purpose
To evaluate the efficiency, safety and outcome of high flow nasal cannula oxygen (HFNC) in ICU patients with acute respiratory failure.
Methods
Pilot prospective monocentric study. ...Thirty-eight patients were included. Baseline demographic and clinical data, as well as respiratory variables at baseline and various times after HFNC initiation during 48 h, were recorded. Arterial blood gases were measured before and after the use of HFNC. Noise and discomfort were monitored along with outcome and need for invasive mechanical ventilation.
Results
HFNC significantly reduced the respiratory rate, heart rate, dyspnea score, supraclavicular retraction and thoracoabdominal asynchrony, and increased pulse oxymetry. These improvements were observed as early as 15 min after the beginning of HFNC for respiratory rate and pulse oxymetry. PaO
2
and PaO
2
/FiO
2
increased significantly after 1 h HFNC in comparison with baseline (141 ± 106 vs. 95 ± 40 mmHg,
p
= 0.009 and 169 ± 108 vs. 102 ± 23,
p
= 0.036; respectively). These improvements lasted throughout the study period. HFNC was used for a mean duration of 2.8 days and a maximum of 7 days. It was never interrupted for intolerance. No nosocomial pneumonia occurred during HFNC. Nine patients required secondary invasive mechanical ventilation. Absence of a significant decrease in the respiratory rate, lower oxygenation and persistence of thoracoabdominal asynchrony after HFNC initiation were early indicators of HFNC failure.
Conclusions
HFNC has a beneficial effect on clinical signs and oxygenation in ICU patients with acute respiratory failure. These favorable results constitute a prerequisite to launching a randomized controlled study to investigate whether HFNC reduces intubation in these patients.
Background:
Physicians should consider an increased posterior tibial slope (PTS) as a risk factor for graft failure when proposing anterior cruciate ligament (ACL) re-revision.
Purpose:
To describe ...the surgical technique of combined ACL revision and proximal tibial anterior closing wedge osteotomy and to evaluate its clinical outcome in cases of recurrent graft failure with associated increased tibial slope.
Study Design:
Case series; Level of evidence, 4.
Methods:
Between 2008 and 2010, 5 combined ACL re-revisions with proximal tibial anterior closing wedge osteotomy were retrospectively evaluated after a mean 31.6 months’ follow-up (range, 23-45 months). All patients reported subjective knee instability preoperatively and demonstrated increased laxity on physical examination. Intrinsic risk factors for graft failure (excessive tibial slope) were identified in all cases. Preoperative and postoperative functional assessments included the International Knee Documentation Committee (IKDC) score along with the Lysholm score and Tegner activity scale.
Results:
The mean Lysholm score was 46.2 preoperatively (range, 26-69) and 87.8 (range, 60-100) postoperatively. The mean IKDC subjective score was 39.5 (range, 21.8-64.4) before surgery and 79.1 (range, 48.3-98.9) at the last follow-up. The mean Tegner activity score was 7.4 (range, 5-9) before the latest ACL injury and 7.2 (range, 5-9) at the last follow-up. The mean PTS was 13.6° (range, 13°-14°) preoperatively and 9.2° (range, 8°-10°) postoperatively (P = .0005). The mean differential anterior laxity was 10.4 mm (range, 8-14 mm), and this significantly decreased to 2.8 mm (range, 2-4 mm) at the last follow-up. Using the Kellgren-Lawrence classification to evaluate the presence of arthritis, 1 patient was grade 1, 3 patients were grade 2, and 1 patient was grade 3.
Conclusion:
Combined ACL re-revision with proximal tibial anterior closing wedge osteotomy restores knee stability and function with satisfactory clinical outcomes in patients who experience recurrent ACL ruptures with an associated increased PTS.
The circadian clock and associated feeding rhythms have a profound impact on metabolism and the gut microbiome. To what extent microbiota reciprocally affect daily rhythms of physiology in the host ...remains elusive. Here, we analyzed transcriptome and metabolome profiles of male and female germ-free mice. While mRNA expression of circadian clock genes revealed subtle changes in liver, intestine, and white adipose tissue, germ-free mice showed considerably altered expression of genes associated with rhythmic physiology. Strikingly, the absence of the microbiome attenuated liver sexual dimorphism and sex-specific rhythmicity. The resulting feminization of male and masculinization of female germ-free animals is likely caused by altered sexual development and growth hormone secretion, associated with differential activation of xenobiotic receptors. This defines a novel mechanism by which the microbiome regulates host metabolism.
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•The microbiome is required for sexual dimorphism in gene expression and metabolism•Most already-described changes in GF mice are hallmarks of a feminized metabolism•Altered sexual maturation and GH secretion cause the damping of sexual dimorphism•Microbiota-derived metabolites and ghrelin likely drive these alterations
Physiology is dynamic over the day and different between sexes. Weger et al. show that the microbiome play a key role in sustaining these sex differences in gene expression and metabolism by ensuring proper sexual maturation and growth hormone secretion. Microbiota-derived metabolites and ghrelin likely drive these sexually dimorphic dynamics.
The aim of the study was to assess the efficacy and safety of rituximab (RTX) for treating systemic lupus erythematosus (SLE)‐associated immune cytopenias. This multicenter retrospective cohort study ...of adults from French referral centers and networks for adult immune cytopenias and SLE involved patients ≥18 years old with a definite diagnosis of SLE treated with RTX specifically for SLE‐associated immune cytopenia from 2005 to 2015. Response assessment was based on standard definitions. In total, 71 patients, 61 women (85.9%), with median age 36 years interquartile range 31‐48, were included. The median duration of SLE at the time of the first RTX administration was 6.1 years 2.6‐11.6 and the reason for using RTX was immune thrombocytopenia (ITP) for 44 patients (62.0%), autoimmune hemolytic anemia (AIHA) for 16 (22.5%), Evans syndrome for 10 (14.1%), and pure red cell aplasia for one patient. Before receiving RTX, patients had received a mean of 3.1 ± 1.3 treatments that included corticosteroids (100%), and hydroxychloroquine (88.5%). The overall initial response rate to RTX was 86% (91% with ITP, 87.5% with AIHA, and 60% with Evans syndrome), including 60.5% with complete response. Median follow‐up after the first injection of RTX was 26.4 months 14.3‐71.2. Among 61 initial responders, relapse occurred in 24 (39.3%); for 18, RTX retreatment was successful in 16 (88.8%). Severe infections occurred after RTX in three patients, with no fatal outcome. No cases of RTX‐induced neutropenia were observed. In conclusion, RTX seems effective and relatively safe for treating SLE‐associated immune cytopenias.
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