Chromatin-to-nucleoprotamine transition is controlled by the histone H2B variant TH2B

The conversion of male germ cell chromatin to a nucleoprotamine structure is fundamental to the life cycle, yet the underlying molecular details remain obscure. Here we show that an essential step is the genome-wide incorporation of TH2B, a histone H2B variant of hitherto unknown function. Using mouse models in which TH2B is depleted or C-terminally modified, we show that TH2B directs the final transformation of dissociating nucleosomes into protamine-packed structures. Depletion of TH2B induces compensatory mechanisms that permit histone removal by up-regulating H2B and programming nucleosome instability through targeted histone modifications, including lysine crotonylation and arginine methylation. Furthermore, after fertilization, TH2B reassembles onto the male genome during protamine-to-histone exchange. Thus, TH2B is a unique histone variant that plays a key role in the histone-to-protamine packing of the male genome and guides genome-wide chromatin transitions that both precede and follow transmission of the male genome to the egg.     

Postmortem coronary artery calcium score in cases of myocardial infarction

International Journal of Legal Medicine - Sudden cardiac death (SCD) related to atherosclerotic coronary artery disease (ACAD) resulting in myocardial infarction is the most prevalent cause of...     

Household illness is the strongest predictor of upper respiratory tract symptom risk in elite rugby union players

ObjectivesTo identify periods of increased risk for upper respiratory tract symptom (URTS) episodes, and examine whether biomarkers and/or self-reported lifestyle and wellness data can predict URTS risk in elite rugby union players.DesignProspective, longitudinal and repeated-measures study.MethodsSalivary secretory immunoglobulin A (SIgA), salivary cortisol, URTS, internal training load and self-reported lifestyle and wellness data including household illness, stress, mood, fatigue, muscle soreness and sleep quality were repeatedly measured in elite Southern hemisphere rugby union players (n = 28) throughout a season. Univariate frailty model analysis, which included 495 observations, was used to determine predictors of URTS risk.ResultsSurprisingly, the highest incidence of URTS occurred after rest weeks, namely the Christmas break and bye weeks (i.e., no scheduled trainings or matches); whereas URTS risk was reduced during weeks involving international travel (Hazard ratio (HR): 0.43, p < 0.001)). Household illness was the strongest predictor of URTS risk; players were almost three-fold more at risk for an URTS episode when illness in the household was present (HR: 2.90, p = 0.002). A non-significant, but potentially important trend for an inverse association between SIgA concentration and URTS incidence was also observed (HR: 0.99, p = 0.070).ConclusionsRest weeks were identified as periods of increased risk for URTS; while international travel did not appear to increase players risk for URTS. Incidence of household illness and SIgA concentration independently predicted URTS risk, with household illness being the strongest predictor. These findings can assist practitioners monitoring and management of athletes to potentially reduce URTS risk.     

Effect of build orientation on the manufacturing process and the properties of stereolithographic dental ceramics for crown frameworks

Statement of problemStereolithography (SLA) ceramic crown frameworks are suitable for clinical use, but the impact of SLA build orientation has not been identified.PurposeThe purpose of this in vitro study was to investigate the effect of 3 build orientations on the physical and mechanical properties and the microstructure of SLA alumina dental ceramics.Material and methodsThe physical and mechanical properties and microstructures of 3 different oriented SLA alumina ceramics (ZX, ZY, and XY) were evaluated by visual observation, hydrostatic weighing (n=10/group), Weibull analyses (n=30/group), scanning electron microscopy, 3-point flexural strength (n=30/group), fracture toughness (indentation, single-edge-V-notched-beam) (n=4/group), and Vickers hardness (n=15/group) testing. The hydrostatic weighing, 3-point flexural strength, fracture toughness, and Vickers hardness testing data were statistically analyzed (α=.05).ResultsThe minimum resting period of slurries between the polymerization of 2 layers was shorter for the ZY- and ZX-oriented specimens and increased with the layer surface. The density and Vickers hardness of the SLA-manufactured specimens were similar for all groups (P>.05). The 95% confidence intervals of the Weibull moduli of the ZX- and ZY-oriented specimens were higher than that of the XY-oriented specimens, with no overlap fraction. The ZY-oriented specimens displayed significantly higher 3-point flexural strength (P<.05) and fracture toughness as evaluated by the single-edge-V-notched-beam method than the ZX-oriented specimens (P<.05). They also displayed significantly higher 3-point flexural strength than the XY-oriented specimens (P<.05). The microstructural analysis showed that the texturing was heterogeneous and that the major axis of the large grains of alumina ran parallel to the orientation of the layers.ConclusionsThe ZY orientation produced a reliable dental ceramic by SLA, with the shortest general manufacturing time and the highest mechanical strength when the layers were perpendicular to the test load surface.     

How to Avoid Nontherapeutic Laparotomy in Patients With Multiple Organ Failure of Unknown Origin. The Role of CT Scan Revisited

Diagnosis of intra-abdominal diseases in critically ill patients remains a clinical challenge. Physical examination is unreliable whereas exploratory laparotomy may aggravate patient''s condition and delay further evaluation. Only a few studies have investigated the place of computed tomography (CT) on this hazardous situation. We aimed to evaluate the ability of CT to prevent unnecessary laparotomy during the management of critically ill patients. Charts of all consecutive patients who had undergone an emergency nontherapeutic laparotomy from 1996 to 2013 were retrospectively studied and patient''s demographic, clinical characteristics, and surgical findings were collected. During this period 59 patients had an unnecessary laparotomy. Fifty-one patients had at least one preoperative imaging and 36 had a CT scan. CT scans were interpreted to be normal (n = 12), with minor anomalies (n = 10), or major anomalies (pneumoperitoneum, portal venous gas/pneumatosis intestinalis, thickened gallbladder wall, and small bowel obstruction signs). Surgical exploration was performed through laparotomy (n = 55) or laparoscopy. Overall mortality was 37% with a median survival after surgery of 7 days. In univariate analysis, hospitalization in ICU before surgical exploration was the only factor related to death. In our series CT scans, objectively interpreted, helped avoid unnecessary surgical exploration in 61% of our patients.Key words: Laparotomy, Critical care, Abnormalities, Digestive system, CT scansEarly diagnosis of acute nontraumatic life-threatening intra-abdominal diseases remains a clinical challenge. In critically ill patients, pathologies such as mesenteric ischemia, intestinal perforation, pancreatitis and biliary diseases carry a high mortality rate ranging from 50% to 100%.^1,2 For these patients, physical examination can be unreliable due to deep sedation and absence of acute abdomen symptoms, and use of imaging studies may therefore be necessary to identify intra-abdominal pathologies and prevent delay in diagnosis. Also, imaging studies may help avoiding unnecessary laparotomy which can be associated with a morbidity rate up to 22%.³ Ultrasonography (US) can be performed at the bedside and is a good alternative for the diagnosis of biliary tract disease; however, it is highly operator dependent, made difficult by abdominal distension,⁴ and not effective for bowel perforation or ischemia.⁵ Computed tomography (CT) scans are increasingly used for emergency patients with acute nontraumatic abdominal pain and tenderness, however, misinterpretation or overinterpretation of CT findings are not rare.^6,7 Despite the large use of imaging procedures in the evaluation of intra-abdominal pathologies, few studies have attempted to assess their impact on the management of critically ill patients.^8,9 The aim of this observational work was to evaluate the results of preoperative imaging procedures, especially CT, in a consecutive series of nontraumatic critically ill patients who underwent nontherapeutic surgical abdominal exploration in a French university tertiary care hospital.     

Evaluating the landscape of gene cooperativity with receptor tyrosine kinases in liver tumorigenesis using transposon-mediated mutagenesis

1. Download high-res image (166KB)
2. Download full-size image

     

Calculation of crystalline lens power using a modification of the Bennett method

We present a method for measuring lens power from extended depth OCT biometry, corneal topography, and refraction using an improvement on the Bennett method. A reduced eye model was used to derive a formula for lens power in terms of ocular distances, corneal power, and objective spherical equivalent refraction. An error analysis shows that the formula predicts relaxed lens power with a theoretical accuracy of ± 0.5 D for refractive error ranging from −10 D to + 10 D. The formula was used to calculate lens power in 16 eyes of 8 human subjects. Mean lens power was 24.3 D ± 1.7 D.OCIS codes: (170.4500) Optical coherence tomography, (170.4580) Optical diagnostics for medicine, (330.7325) Visual optics, metrology, (330.7326) Visual optics, modeling     

Hydrolysis of Clavulanate by Mycobacterium tuberculosis β-Lactamase BlaC Harboring a Canonical SDN Motif

Combinations of β-lactams with clavulanate are currently being investigated for tuberculosis treatment. Since Mycobacterium tuberculosis produces a broad spectrum β-lactamase, BlaC, the success of this approach could be compromised by the emergence of clavulanate-resistant variants, as observed for inhibitor-resistant TEM variants in enterobacteria. Previous analyses based on site-directed mutagenesis of BlaC have led to the conclusion that this risk was limited. Here, we used a different approach based on determination of the crystal structure of β-lactamase Bla_MAb of Mycobacterium abscessus, which efficiently hydrolyzes clavulanate. Comparison of Bla_MAb and BlaC allowed for structure-assisted site-directed mutagenesis of BlaC and identification of the G¹³²N substitution that was sufficient to switch the interaction of BlaC with clavulanate from irreversible inactivation to efficient hydrolysis. The substitution, which restored the canonical SDN motif (SDG→SDN), allowed for efficient hydrolysis of clavulanate, with a more than 10⁴-fold increase in k_cat (0.41 s⁻¹), without affecting the hydrolysis of other β-lactams. Mass spectrometry revealed that acylation of BlaC and of its G¹³²N variant by clavulanate follows similar paths, involving sequential formation of two acylenzymes. Decarboxylation of the first acylenzyme results in a stable secondary acylenzyme in BlaC, whereas hydrolysis occurs in the G¹³²N variant. The SDN/SDG polymorphism defines two mycobacterial lineages comprising rapidly and slowly growing species, respectively. Together, these results suggest that the efficacy of β-lactam–clavulanate combinations may be limited by the emergence of resistance. β-Lactams active without clavulanate, such as faropenem, should be prioritized for the development of new therapies.