Inactivation in the potassium channel KcsA.

Inactivation, the slow cessation of transmission after activation, is a general feature of potassium channels. It is essential for their function, and malfunctions in inactivation leads to numerous pathologies. The detailed mechanism for the C-type inactivation, distinct from the N-type inactivation, remains an active area of investigation.

Prospective Assessment of Systemic MicroRNAs as Markers of Response to Neoadjuvant Chemotherapy in Breast Cancer.

Neoadjuvant chemotherapy (NACT) is used in locally advanced breast cancer to reduce tumour burden prior to surgical resection. However, only a subset of NACT treated patients will respond to treatment or achieve a pathologic complete response (pCR). This multicenter, prospective study (CTRIAL-IE (ICORG) 10-11 study) evaluated circulating microRNA as novel non-invasive prognostic biomarkers of NACT response in breast cancer.

Convergent Evolution in Breadth of Two V6-1-Encoded Influenza Antibody Clonotypes from a Single Donor.

Understanding how broadly neutralizing antibodies (bnAbs) to influenza hemagglutinin (HA) naturally develop in humans is critical to the design of universal influenza vaccines. Several classes of bnAbs directed to the conserved HA stem were found in multiple individuals, including one encoded by heavy-chain variable domain V6-1. We describe two genetically similar V6-1 bnAb clonotypes from the same individual that exhibit different developmental paths toward broad neutralization activity.

Refining the resolution of craniofacial dysmorphology in bipolar disorder as an index of brain dysmorphogenesis.

As understanding of the genetics of bipolar disorder increases, controversy endures regarding whether the origins of this illness include early maldevelopment. Clarification would be facilitated by a 'hard' biological index of fetal developmental abnormality, among which craniofacial dysmorphology bears the closest embryological relationship to brain dysmorphogenesis. Therefore, 3D laser surface imaging was used to capture the facial surface of 21 patients with bipolar disorder and 45 control subjects; 21 patients with schizophrenia were also studied.

A Global lmmunological Observatory to meet a time of pandemics.

SARS-CoV-2 presents an unprecedented international challenge, but it will not be the last such threat. Here, we argue that the world needs to be much better prepared to rapidly detect, define and defeat future pandemics. We propose that a Global Immunological Observatory and associated developments in systems immunology, therapeutics and vaccine design should be at the heart of this enterprise.

The Transcription Factor T-bet Resolves Memory B Cell Subsets with Distinct Tissue Distributions and Antibody Specificities in Mice and Humans.

B cell subsets expressing the transcription factor T-bet are associated with humoral immune responses and autoimmunity. Here, we examined the anatomic distribution, clonal relationships, and functional properties of T-bet and T-bet memory B cells (MBCs) in the context of the influenza-specific immune response. In mice, both T-bet and T-bet hemagglutinin (HA)-specific B cells arose in germinal centers, acquired memory B cell markers, and persisted indefinitely.

Higher PIK3C2B gene expression of H1N1+ specific B-cells is associated with lower H1N1 immunogenicity after trivalent influenza vaccination in HIV infected children.

Perinatally HIV-infected children (PHIV), despite successful antiretroviral therapy, present suboptimal responses to vaccinations compared to healthy-controls (HC). Here we investigated phenotypic and transcriptional signatures of H1N1-specific B-cells (H1N1-Sp) in PHIV, differentially responding to trivalent-influenza-vaccine (TIV), and HC. Patients were categorized in responders (R) and non-responders (NR) according to hemagglutination-inhibition-assay at baseline and 21 days after TIV.

Development of a 3Mut-Apex-Stabilized Envelope Trimer That Expands HIV-1 Neutralization Breadth When Used To Boost Fusion Peptide-Directed Vaccine-Elicited Responses.

HIV-1 envelope (Env) trimers, stabilized in a prefusion-closed conformation, can elicit humoral responses capable of neutralizing HIV-1 strains closely matched in sequence to the immunizing strain. One strategy to increase elicited neutralization breadth involves vaccine priming of immune responses against a target site of vulnerability, followed by vaccine boosting of these responses with prefusion-closed Env trimers. This strategy has succeeded at the fusion peptide (FP) site of vulnerability in eliciting cross-clade neutralizing responses in standard vaccine-test animals.

Probing allosteric coupling in a constitutively open mutant of the ion channel KcsA using solid-state NMR.

Transmembrane allosteric coupling is a feature of many critical biological signaling events. Here we test whether transmembrane allosteric coupling controls the potassium binding affinity of the prototypical potassium channel KcsA in the context of C-type inactivation. Activation of KcsA is initiated by proton binding to the pH gate upon an intracellular drop in pH.

Presentation, Treatment, and Outcome of Survivors of In-Hospital Versus Out-of-Hospital Sudden Cardiac Arrest.

We examined the baseline characteristics, rates of implantable cardioverter defibrillator implantation, and long-term all-cause mortality for survivors of in-hospital (IHSCA) versus out-of-hospital (OHSCA) sudden cardiac arrest (SCA). A total of 1,433 SCA survivors (807 IHSCA and 626 OHSCA) from 2002 to 2012 were followed through February 2017. Baseline characteristics and potential triggers of SCA, including significant electrolyte and metabolic abnormalities and acute myocardial infarction and ischemia, were collected.

Glycan repositioning of influenza hemagglutinin stem facilitates the elicitation of protective cross-group antibody responses.

The conserved hemagglutinin (HA) stem has been a focus of universal influenza vaccine efforts. Influenza A group 1 HA stem-nanoparticles have been demonstrated to confer heterosubtypic protection in animals; however, the protection does not extend to group 2 viruses, due in part to differences in glycosylation between group 1 and 2 stems. Here, we show that introducing the group 2 glycan at Asn38 to a group 1 stem-nanoparticle (gN38 variant) based on A/New Caledonia/20/99 (H1N1) broadens antibody responses to cross-react with group 2 HAs.

Potent Zika and dengue cross-neutralizing antibodies induced by Zika vaccination in a dengue-experienced donor.

Zika virus (ZIKV) has caused significant disease, with widespread cases of neurological pathology and congenital neurologic defects. Rapid vaccine development has led to a number of candidates capable of eliciting potent ZIKV-neutralizing antibodies (reviewed in refs. ).

Measuring Tie Chains and Trapped Entanglements in Semicrystalline Polymers.

A label-free method for quantifying stress-transmitter (or elastically effective molecule) content (p) in semicrystalline polymers, including both tie molecules and bridging entanglements, is developed and demonstrated based on swelling with deuterated vapor and characterization with small angle neutron scattering. The p results are compared with the predictions of recent semi empirical, statistical values for tie molecule content and structural characterization parameters, including strain hardening modulus and an infrared spectroscopy derived parameter ( ) that describes the degree of difficulty for the amorphous content to align and reshape over a distance with applied load. A strong correspondence is observed, suggesting that the initial network of elastically active molecules, dictated by the molecular architecture and crystallization conditions, can be directly correlated to the post yield tensile values irrespective of the subsequent morphological changes that result during the tensile deformation.

'Everything was just getting worse and worse': deteriorating job quality as a driver of doctor emigration from Ireland.

Background: Medicine is a high-status, high-skill occupation which has traditionally provided access to good quality jobs and relatively high salaries. In Ireland, historic underfunding combined with austerity-related cutbacks has negatively impacted job quality to the extent that hospital medical jobs have begun to resemble extreme jobs. Extreme jobs combine components of a good quality job-high pay, high job control, challenging demands, with those of a low-quality job-long working hours, heavy workloads.

Overexpression of T-bet in HIV infection is associated with accumulation of B cells outside germinal centers and poor affinity maturation.

Nearly all chronic human infections are associated with alterations in the memory B cell (MBC) compartment, including a large expansion of CD19T-bet MBC in the peripheral blood of HIV-infected individuals with chronic viremia. Despite their prevalence, it is unclear how these B cells arise and whether they contribute to the inefficiency of antibody-mediated immunity in chronic infectious diseases. We addressed these questions by characterizing T-bet-expressing B cells in lymph nodes (LN) and identifying a strong T-bet signature among HIV-specific MBC associated with poor immunologic outcome.

Hemagglutinin head-specific responses dominate over stem-specific responses following prime boost with mismatched vaccines.

Broadly neutralizing Abs targeting the HA stem can provide broad protection against different influenza subtypes, raising the question of how best to elicit such Abs. We have previously demonstrated that vaccination with pandemic live-attenuated influenza vaccine (pLAIV) establishes immune memory for HA head-specific Abs. Here, we determine the extent to which matched versus mismatched LAIV-inactivated subunit vaccine (IIV) prime-boost vaccination elicits stem-specific memory B cells and Abs.