Rational design of a highly immunogenic prefusion-stabilized F glycoprotein antigen for a respiratory syncytial virus vaccine.

Respiratory syncytial virus (RSV) is the leading, global cause of serious respiratory disease in infants and is an important cause of respiratory illness in older adults. No RSV vaccine is currently available. The RSV fusion (F) glycoprotein is a key antigen for vaccine development, and its prefusion conformation is the target of the most potent neutralizing antibodies.

Structural basis of the acyl-transfer mechanism of human GPAT1.

Glycerol-3-phosphate acyltransferase (GPAT)1 is a mitochondrial outer membrane protein that catalyzes the first step of de novo glycerolipid biosynthesis. Hepatic expression of GPAT1 is linked to liver fat accumulation and the severity of nonalcoholic fatty liver diseases. Here we present the cryo-EM structures of human GPAT1 in substrate analog-bound and product-bound states.

Phosphorylation of SAMHD1 Thr592 increases C-terminal domain dynamics, tetramer dissociation and ssDNA binding kinetics.

SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) is driven into its activated tetramer form by binding of GTP activator and dNTP activators/substrates. In addition, the inactive monomeric and dimeric forms of the enzyme bind to single-stranded (ss) nucleic acids. During DNA replication SAMHD1 can be phosphorylated by CDK1 and CDK2 at its C-terminal threonine 592 (pSAMHD1), localizing the enzyme to stalled replication forks (RFs) to promote their restart.

Accelerated hypofractionated radiation for elderly or frail patients with a newly diagnosed glioblastoma: A pooled analysis of patient-level data from 4 prospective trials.

Background: The standard of care for elderly or frail patients with glioblastoma (GBM) is 40 Gy in 15 fractions of radiotherapy. However, this regimen has a lower biological effective dose (BED) compared with the Stupp regimen of 60 Gy in 30 fractions. It is hypothesized that accelerated hypofractionated radiation of 52.

Dose-escalated accelerated hypofractionation for elderly or frail patients with a newly diagnosed glioblastoma.

Background: The standard of care for elderly glioblastoma patients is 40 Gy in 15 fraction radiotherapy with temozolomide (TMZ). However, this regimen has a lower biologic equivalent dose (BED) compared to the Stupp regimen of 60 Gy in 30 fractions. We hypothesize that accelerated hypofractionated radiation of 52.

Structural basis for chemokine receptor CCR6 activation by the endogenous protein ligand CCL20.

Chemokines are important protein-signaling molecules that regulate various immune responses by activating chemokine receptors which belong to the G protein-coupled receptor (GPCR) superfamily. Despite the substantial progression of our structural understanding of GPCR activation by small molecule and peptide agonists, the molecular mechanism of GPCR activation by protein agonists remains unclear. Here, we present a 3.

The Effects of Patient Positioning on the Outcome During Posterior Cranial Fossa and Pineal Region Surgery.

Surgery on posterior cranial fossa (PCF) and pineal region (PR) carries the risks of intraoperative trauma to the brainstem structures, blood loss, venous air embolism (VAE), cardiovascular instability, and other complications. Success in surgery, among other factors, depends on selecting the optimal patient position. Our objective was to find associations between patient positioning, incidence of intraoperative complications, neurological recovery, and the extent of surgery.

Synthetic antibodies against BRIL as universal fiducial marks for single-particle cryoEM structure determination of membrane proteins.

We propose the concept of universal fiducials based on a set of pre-made semi-synthetic antibodies (sABs) generated by customized phage display selections against the fusion protein BRIL, an engineered variant of apocytochrome b562a. These sABs can bind to BRIL fused either into the loops or termini of different GPCRs, ion channels, receptors and transporters without disrupting their structure. A crystal structure of BRIL in complex with an affinity-matured sAB (BAG2) that bound to all systems tested delineates the footprint of interaction.

Surgical management of craniopharyngiomas in adult patients: a systematic review and consensus statement on behalf of the EANS skull base section.

Background And Objective: Craniopharyngiomas are locally aggressive neuroepithelial tumors infiltrating nearby critical neurovascular structures. The majority of published surgical series deal with childhood-onset craniopharyngiomas, while the optimal surgical management for adult-onset tumors remains unclear. The aim of this paper is to summarize the main principles defining the surgical strategy for the management of craniopharyngiomas in adult patients through an extensive systematic literature review in order to formulate a series of recommendations.

The Role of Decompressive Craniectomy in the Context of Severe Traumatic Brain Injury: Summary of Results and Analysis of the Confidence Level of Conclusions From Systematic Reviews and Meta-Analyses.

Traumatic brain injury (TBI) is a global epidemic. The incidence of TBI in low and middle-income countries (LMICs) is three times greater than in high-income countries (HICs). Decompressive craniectomy (DC) is a surgical procedure to reduce intracranial pressure (ICP) and prevent secondary injury.

Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on the Role of Surgery in the Management of Adults With Metastatic Brain Tumors.

Unlabelled: Please see the full-text version of this guideline https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter_2) for the target population of each recommendation listed below.

Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on Treatment Options for Adults With Multiple Metastatic Brain Tumors.

Target Population: These recommendations apply to adult patients newly diagnosed with multiple (more than 1) brain metastases.

Question 1: In what circumstances should whole brain radiation therapy be recommended to improve tumor control and survival in patients with multiple brain metastases?

Recommendation: Level 2: It is recommended that whole brain radiation therapy can be added to stereotactic radiosurgery to improve local and distant control keeping in mind the potential for worsened neurocognitive outcomes and that there is unlikely to be a significant impact on overall survival.

Question 2: In what circumstances should stereotactic radiosurgery be recommended to improve tumor control and survival in patients with multiple brain metastases?

Recommendations: Level 1: In patients with 2 to 3 brain metastases not amenable to surgery, the addition of stereotactic radiosurgery to whole brain radiation therapy is not recommended to improve survival beyond that obtained with whole brain radiation therapy alone.

Fabrication and characterization of implantable flushable electrodes for electric field-mediated drug delivery in a brain tissue-mimic agarose gel.

Every forty minutes, one person dies in the USA due to glioblastoma multiforme; a deadly form of brain cancer with an average five-year survival rate less than 3%. The current standard of care for treatment involves surgical resection of the accessible tumor followed by radiation therapy and concomitant chemotherapy. Despite their potency, delivering chemotherapeutic agents to the brain is limited by the highly selective blood-brain barrier, which prevents molecules >500 Da from reaching the brain.

2-Aminopyridine-Based Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4) Inhibitors: Assessment of Mechanism-Based Safety.

Studies have linked the serine-threonine kinase MAP4K4 to the regulation of a number of biological processes and/or diseases, including diabetes, cancer, inflammation, and angiogenesis. With a majority of the members of our lead series (e.g.

Quantitative evaluation of different far lateral approaches to the cranio-vertebral junction using the microscope and the endoscope: a cadaveric study using a tumor model.

Background: Several far lateral approaches have been proposed to deal with cranio-vertebral junction (CVJ) tumors including the basic, transcondylar, and supracondylar far lateral approaches (B-FLA, T-FLA, and S-FLA). However, the indications on when to use one versus the other are not well systematized yet. Our purpose is to evaluate in an experimental cadaveric setting which approach is best suited to remove tumors of different sizes.

NCCN Guidelines Insights: Central Nervous System Cancers, Version 1.2017.

For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options.

The Changing Health Care Landscape and Implications of Organizational Ethics on Modern Medical Practice.

Introduction: Medicine is rapidly changing, both in the level of collective medical knowledge and in how it is being delivered. The increased presence of administrators in hospitals helps to facilitate these changes and ease administrative workloads on physicians; however, tensions sometimes form between physicians and administrators.

Analysis: This situation is based on perceptions from both sides that physicians obstruct cost-saving measures and administrators put profits before patients.

Efficient Liver Targeting by Polyvalent Display of a Compact Ligand for the Asialoglycoprotein Receptor.

A compact and stable bicyclic bridged ketal was developed as a ligand for the asialoglycoprotein receptor (ASGPR). This compound showed excellent ligand efficiency, and the molecular details of binding were revealed by the first X-ray crystal structures of ligand-bound ASGPR. This analogue was used to make potent di- and trivalent binders of ASGPR.

Ethical clinical translation of stem cell interventions for neurologic disease.

The application of stem cell transplants in clinical practice has increased in frequency in recent years. Many of the stem cell transplants in neurologic diseases, including stroke, Parkinson disease, spinal cord injury, and demyelinating diseases, are unproven-they have not been tested in prospective, controlled clinical trials and have not become accepted therapies. Stem cell transplant procedures currently being carried out have therapeutic aims, but are frequently experimental and unregulated, and could potentially put patients at risk.