Microcephaly is a neurodevelopmental disorder causing significantly reduced cerebral cortex size. Many known microcephaly gene products localize to centrosomes, regulating cell fate and ...proliferation. Here, we identify and characterize a nuclear zinc finger protein, ZNF335/NIF-1, as a causative gene for severe microcephaly, small somatic size, and neonatal death. Znf335 null mice are embryonically lethal, and conditional knockout leads to severely reduced cortical size. RNA-interference and postmortem human studies show that ZNF335 is essential for neural progenitor self-renewal, neurogenesis, and neuronal differentiation. ZNF335 is a component of a vertebrate-specific, trithorax H3K4-methylation complex, directly regulating REST/NRSF, a master regulator of neural gene expression and cell fate, as well as other essential neural-specific genes. Our results reveal ZNF335 as an essential link between H3K4 complexes and REST/NRSF and provide the first direct genetic evidence that this pathway regulates human neurogenesis and neuronal differentiation.
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► Mutation in ZNF335, an essential brain development gene, leads to severe microcephaly ► ZNF335 is essential for progenitor maintenance and prevents premature differentiation ► ZNF335 interacts with a H3K4 methyltransferase complex to regulate gene expression ► ZNF335 is upstream of REST/NRSF, a master regulator controlling key neuronal genes
A zinc finger protein disrupted is found to be disrupted in human cases of microcephaly, providing insight into the transcriptional pathways underlying the syndrome and revealing a connection between the histone-modifying complex Trithorax and the transcriptional regulator REST.
DNA is thought to behave as a stiff elastic rod with respect to the ubiquitous mechanical deformations inherent to its biology. To test this model at short DNA lengths, we measured the mean and ...variance of end-to-end length for a series of DNA double helices in solution, using small-angle x-ray scattering interference between gold nanocrystal labels. In the absence of applied tension, DNA is at least one order of magnitude softer than measured by single-molecule stretching experiments. Further, the data rule out the conventional elastic rod model. The variance in end-to-end length follows a quadratic dependence on the number of base pairs rather than the expected linear dependence, indicating that DNA stretching is cooperative over more than two turns of the DNA double helix. Our observations support the idea of long-range allosteric communication through DNA structure.
Innate-like natural killer T (NKT) cells critically enhance cell and humoral immunity against infections through recognition of conserved microbial lipid antigens presented by CD1d-expressing ...antigen-presenting cells, and provision of CD40L and cytokine signals. Whereas NKT cells efficiently licensed dendritic cells to prime potent effector and memory T cells, studies based on model antigens such as alphagalactosylceramide-nitrophenyl conjugates concluded that help to B cells was associated with NKT follicular helper differentiation, but limited to short-term responses without induction of memory. We revisited this surprising conclusion in the context of the extracellular encapsulated pathogen Streptococcus pneumoniae , where recognition of lipid and capsular polysaccharide antigens by NKT cells and B cells, respectively, provide critical host protection. Using liposomal nanoparticles displaying synthetic lipid and polysaccharide antigens to elicit pure and direct NKT–B-cell interactions in vivo, we observed intense and prolonged antibody responses with isotype switch, affinity maturation, and long-lasting B-cell memory, despite modest or absent NKT follicular helper differentiation. Furthermore, conditional ablation of Cd1d demonstrated a requirement for a two-step process involving first cognate interactions with dendritic cells, for NKT cell activation, and then with B cells, for induction of isotype switch and memory. Thus, NKT help to B cells represents both a major arm of antimicrobial defense and a promising target for B-cell vaccines.
The transcription factor PLZF promyelocytic leukemia zinc finger, encoded by zinc finger BTB domain containing 16 (Zbtb16) is induced during the development of innate and innate-like lymphocytes to ...direct their acquisition of a T-helper effector program, but the molecular mechanisms involved are poorly understood. Using biotinylation-based ChIP-seq and microarray analysis of both natural killer T (NKT) cells and PLZF-transgenic thymocytes, we identified several layers of regulation of the innate-like NKT effector program. First, PLZF bound and regulated genes encoding cytokine receptors as well as homing and adhesion receptors; second, PLZF bound and activated T-helper–specific transcription factor genes that in turn control T-helper–specific programs; finally, PLZF bound and suppressed the transcription of Bach2, a potent general repressor of effector differentiation in naive T cells. These findings reveal the multilayered architecture of the transcriptional program recruited by PLZF and elucidate how a single transcription factor can drive the developmental acquisition of a broad effector program.
Interactions driven by the T cell antigen receptor (TCR) determine the lineage fate of CD4(+)CD8(+) thymocytes, but the molecular mechanisms that induce the lineage-determining transcription factors ...are unknown. Here we found that TCR-induced transcription factors Egr2 and Egr1 had higher and more-prolonged expression in precursors of the natural killer T (NKT) than in cells of conventional lineages. Chromatin immunoprecipitation followed by deep sequencing showed that Egr2 directly bound and activated the promoter of Zbtb16, which encodes the NKT lineage-specific transcription factor PLZF. Egr2 also bound the promoter of Il2rb, which encodes the interleukin 2 (IL-2) receptor β-chain, and controlled the responsiveness to IL-15, which signals the terminal differentiation of the NKT lineage. Thus, we propose that persistent higher expression of Egr2 specifies the early and late stages of NKT lineage differentiation, providing a discriminating mechanism that enables TCR signaling to 'instruct' a thymic lineage.
Post-cardiac arrest, outcomes for most patients are poor, regardless of setting. Many patients who do achieve spontaneous return of circulation require vasopressor therapy to maintain organ ...perfusion. There is some evidence to support the use of corticosteroids in cardiac arrest.
Assess the efficacy and safety of corticosteroids in patients following in- and out-of-hospital cardiac arrest.
We searched databases CINAHL, EMBASE, LILACS, MEDLINE, Web of Science, CENTRAL, ClinicalTrails.gov, and ICTRP. We included randomized controlled trials (RCTs) that examined the efficacy and safety of corticosteroids, as compared to placebo or usual care in patients post-cardiac arrest. We pooled estimates of effect size using random effects meta-analysis and report relative risk (RR) with 95% confidence intervals (CIs). We assessed risk of bias (ROB) for the included trials using the modified Cochrane ROB tool and rated the certainty of evidence using Grading of Recommendations Assessment, Development and Evaluation methodology.
We included 8 RCTs (n = 2213 patients). Corticosteroids administered post-cardiac arrest had an uncertain effect on mortality measured at the longest point of follow-up (RR 0.96, 95% CI 0.90-1.02, very low certainty, required information size not met using trial sequential analysis). Corticosteroids probably increase return of spontaneous circulation (ROSC) (RR 1.32, 95% CI 1.18-1.47, moderate certainty) and may increase the likelihood of survival with good functional outcome (RR 1.49, 95% CI 0.87-2.54, low certainty). Corticosteroids may decrease the risk of ventilator associated pneumonia (RR 0.76, 95% CI 0.46-1.09, low certainty), may increase renal failure (RR 1.29, 95% CI 0.84-1.99, low certainty), and have an uncertain effect on bleeding (RR 2.04, 95% CI 0.53-7.84, very low certainty) and peritonitis (RR 10.54, 95% CI 2.99-37.19, very low certainty).
In patients during or after cardiac arrest, corticosteroids have an uncertain effect on mortality but probably increase ROSC and may increase the likelihood of survival with good functional outcome at hospital discharge. Corticosteroids may decrease ventilator associated pneumonia, may increase renal failure, and have an uncertain effect on bleeding and peritonitis. However, the pooled evidence examining these outcomes was sparse and imprecision contributed to low or very low certainty of evidence.
Accurate determination of molecular distances is fundamental to understanding the structure, dynamics, and conformational ensembles of biological macromolecules. Here we present a method to determine ...the full distance distribution between small (∼7 Å radius) gold labels attached to macromolecules with very high-precision (≤1 Å) and on an absolute distance scale. Our method uses anomalous small-angle X-ray scattering close to a gold absorption edge to separate the gold–gold interference pattern from other scattering contributions. Results for 10–30 bp DNA constructs achieve excellent signal-to-noise and are in good agreement with previous results obtained by single-energy SAXS measurements without requiring the preparation and measurement of single labeled and unlabeled samples. The use of small gold labels in combination with ASAXS read out provides an attractive approach to determining molecular distance distributions that will be applicable to a broad range of macromolecular systems.
New-onset atrial fibrillation (NOAF) is commonly encountered in critically ill adults. Evidence evaluating the association between NOAF and patient-important outcomes in this population is ...conflicting. Furthermore, little is known regarding the association between NOAF and resource use or hospital costs.
Retrospective analysis (2011-2016) of a prospectively collected registry from two Canadian hospitals of consecutive ICU patients aged ≥ 18 years. We excluded patients with a known history of AF prior to hospital admission. Any occurrence of atrial fibrillation (AF) was prospectively recorded by bedside nurses. The primary outcome was hospital mortality, and we used multivariable logistic regression to adjust for confounders. We used a generalized linear model to evaluate contributors to total cost.
We included 15,014 patients, and 1541 (10.3%) had NOAF during their ICU admission. While NOAF was not associated with increased odds of hospital death among the entire cohort (adjusted odds ratio aOR 1.02 95% confidence interval CI 0.97-1.08), an interaction was noted between NOAF and sepsis, and the presence of both was associated with higher odds of hospital mortality (aOR 1.28 95% CI 1.09-1.36) than either alone. Patients with NOAF had higher total costs (cost ratio CR 1.09 95% CI 1.02-1.20). Among patients with NOAF, treatment with a rhythm-control strategy was associated with higher costs (CR 1.24 95% CI 1.07-1.40).
While NOAF was not associated with death or requiring discharge to long-term care among critically ill patients, it was associated with increased length of stay in ICU and increased total costs.
Cho et al. (Reports, 2 October 2015, p. 82) report that gene repression after contextual fear conditioning regulates hippocampal memory formation. We observe low levels of expression for many of the ...top candidate genes in the hippocampus and robust expression in the choroid plexus, as well as repression at 4 hours after contextual fear conditioning, suggesting the inclusion of choroid plexus messenger RNAs in Cho et al. hippocampal samples.
Background
An oro‐antral communication is an unnatural opening between the oral cavity and maxillary sinus. When it fails to close spontaneously, it remains patent and is epithelialized to develop ...into an oro‐antral fistula. Various surgical and non‐surgical techniques have been used for treating the condition. Surgical procedures include flaps, grafts and other techniques like re‐implantation of third molars. Non‐surgical techniques include allogenic materials and xenografts. This is an update of a review first published in May 2016.
Objectives
To assess the effectiveness and safety of various interventions for the treatment of oro‐antral communications and fistulae due to dental procedures.
Search methods
Cochrane Oral Health’s Information Specialist searched the following databases: Cochrane Oral Health’s Trials Register (to 23 May 2018), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2018, Issue 4), MEDLINE Ovid (1946 to 23 May 2018), and Embase Ovid (1980 to 23 May 2018). The US National Institutes of Health Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. We also searched the reference lists of included and excluded trials for any randomised controlled trials (RCTs).
Selection criteria
We included RCTs evaluating any intervention for treating oro‐antral communications or oro‐antral fistulae due to dental procedures. We excluded quasi‐RCTs and cross‐over trials. We excluded studies on participants who had oro‐antral communications, fistulae or both related to Caldwell‐Luc procedure or surgical excision of tumours.
Data collection and analysis
Two review authors independently selected trials. Two review authors assessed trial risk of bias and extracted data independently. We estimated risk ratios (RR) for dichotomous data, with 95% confidence intervals (CI). We assessed the overall quality of the evidence using the GRADE approach.
Main results
We included only one study in this review, which compared two surgical interventions: pedicled buccal fat pad flap and buccal flap for the treatment of oro‐antral communications. The study involved 20 participants. The risk of bias was unclear. The relevant outcome reported in this trial was successful (complete) closure of oro‐antral communication.
The quality of the evidence for the primary outcome was very low. The study did not find evidence of a difference between interventions for the successful (complete) closure of an oro‐antral communication (RR 1.00, 95% Cl 0.83 to 1.20) one month after the surgery. All oro‐antral communications in both groups were successfully closed so there were no adverse effects due to treatment failure.
We did not find trials evaluating any other intervention for treating oro‐antral communications or fistulae due to dental procedures.
Authors' conclusions
We found very low quality evidence from a single small study that compared pedicled buccal fat pad and buccal flap. The evidence was insufficient to judge whether there is a difference in the effectiveness of these interventions as all oro‐antral communications in the study were successfully closed by one month after surgery. Large, well‐conducted RCTs investigating different interventions for the treatment of oro‐antral communications and fistulae caused by dental procedures are needed to inform clinical practice.
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