Sex-Specific Vulnerabilities to Subclinical Vascular Brain Injury in Early Late-Life: The Framingham Heart Study.

Objective: Subclinical vascular brain injury is an increasingly recognized risk factor for stroke and dementia. Despite well-established sex differences in vascular risk and disease prevalence, the impact of sex on drivers of subclinical vascular brain injury remains unclear, presenting a barrier to developing sex-specific prevention guidelines. We aimed to establish the extent to which sex moderates associations between vascular risk factors and magnetic resonance imaging (MRI) measures of subclinical brain injury in stroke-free older adults.

Comparison of Medial Hamstring Length Between Harvesting Methods Using Anterior and Posterior Approaches.

Background: Medial hamstring tendons harvesting can be performed through either an anterior or a posterior approach. It has been suggested that using a posterior approach may result in a longer length of harvestable tendon compared with an anterior approach.

Hypothesis: There would be no difference in the length of the harvestable tendon between the anterior and posterior approaches.

Conformations of a low-complexity protein in homogeneous and phase-separated frozen solutions.

Solutions of the intrinsically disordered, low-complexity domain of the FUS protein (FUS-LC) undergo liquid-liquid phase separation (LLPS) below a temperature T. To investigate whether local conformational distributions are detectably different in the homogeneous (i.e.

Cryo-electron tomography reveals coupled flavivirus replication, budding and maturation.

Flaviviruses replicate their genomes in replication organelles (ROs) formed as bud-like invaginations on the endoplasmic reticulum (ER) membrane, which also functions as the site for virion assembly. While this localization is well established, it is not known to what extent viral membrane remodeling, genome replication, virion assembly, and maturation are coordinated. Here, we imaged tick-borne flavivirus replication in human cells using cryo-electron tomography.

Conformations of a Low-Complexity Protein in Homogeneous and Phase-Separated Frozen Solutions.

Unlabelled: Solutions of the intrinsically disordered, low-complexity domain of the FUS protein (FUS-LC) undergo liquid-liquid phase separation (LLPS) below temperatures T in the 20-40° C range. To investigate whether local conformational distributions are detectably different in the homogeneous and phase-separated states of FUS-LC, we performed solid state nuclear magnetic resonance (ssNMR) measurements on solutions that were frozen on sub-millisecond time scales after equilibration at temperatures well above (50° C) or well below (4° C) T. Measurements were performed at 25 K with signal enhancements from dynamic nuclear polarization.

Greater White Matter Hyperintensity Volume Is Associated with the Number of Microhemorrhages in Preclinical Alzheimer's Disease.

Background: Increased white matter hyperintensity (WMH) volume visible on MRI is a common finding in Alzheimer's disease (AD). We hypothesized that WMH in preclinical AD is associated with the presence of advanced vessel amyloidosis manifested as microhemorrhages (MCH).

Objectives: 1) To assess the relationship between baseline WMH volume and baseline MCH.

PPP2R5D heterozygous pathogenic variant causes early-onset parkinsonism and treatment implications: A case report.

Neurodevelopmental disorders with early-onset parkinsonism have diverse genetic aetiologies and can mimic Parkinson's disease. We report the clinical evaluation and neuroimaging studies of a woman with intellectual disability and levodopa-responsive akinetic rigid parkinsonism. Whole-genome sequencing of family trio identified a de novo missense variant in PPP2R5D in the proband.

POLR3A-related disorders: From spastic ataxia to generalised dystonia and long-term efficacy of deep brain stimulation.

While biallelic POLR3A loss-of-function variants are traditionally linked to hypomyelinating leukodystrophy, patients with a specific splice variant c.1909+22G>A manifest as adolescent-onset spastic ataxia without overt leukodystrophy. In this study, we reported eight new cases, POLR3A-related disorder with c.

VPg-based bidirectional synthetic mRNA circuits enable orthogonal protein regulation for high-resolution cell separation.

Synthetic mRNA circuits commonly sense input to produce binary output signals for cell separation. Based on virus-origin cap-independent translation initiation machinery and RBP-aptamer interaction, we designed smart synthetic mRNA-based circuits that sense single input molecules to bidirectionally tune output signals in an orthogonal manner, enabling high-resolution separation of cell populations.

Assembly of SARS-CoV-2 nucleocapsid protein with nucleic acid.

The viral genome of SARS-CoV-2 is packaged by the nucleocapsid (N-)protein into ribonucleoprotein particles (RNPs), 38 ± 10 of which are contained in each virion. Their architecture has remained unclear due to the pleomorphism of RNPs, the high flexibility of N-protein intrinsically disordered regions, and highly multivalent interactions between viral RNA and N-protein binding sites in both N-terminal (NTD) and C-terminal domain (CTD). Here we explore critical interaction motifs of RNPs by applying a combination of biophysical techniques to ancestral and mutant proteins binding different nucleic acids in an in vitro assay for RNP formation, and by examining nucleocapsid protein variants in a viral assembly assay.

Vascular contributions to cognitive decline: Beyond amyloid and tau in the Harvard Aging Brain Study.

In addition to amyloid and tau pathology, elevated systemic vascular risk, white matter injury, and reduced cerebral blood flow contribute to late-life cognitive decline. Given the strong collinearity among these parameters, we proposed a framework to extract the independent latent features underlying cognitive decline using the Harvard Aging Brain Study (N = 166 cognitively unimpaired older adults at baseline). We used the following measures from the baseline visit: cortical amyloid, inferior temporal cortex tau, relative cerebral blood flow, white matter hyperintensities, peak width of skeletonized mean diffusivity, and Framingham Heart Study cardiovascular disease risk.

Differences in Clinical Outcomes Between Patients With Retear After Supraspinatus Tendon Repair and Those With Intact Repair at 5-Year Follow-up.

Background: It is well known that rotator cuff repair is associated with an overall retear rate of 21% to 26%. However, a cuff retear may not necessarily be associated with poor clinical outcomes.

Hypothesis: There would be no difference in clinical outcomes between patients with a cuff retear and those with an intact repair at a midterm follow-up of 5 years.

Smokers Achieved Minimal Clinically Important Difference for Visual Analog Scale and American Shoulder and Elbow Surgeons Scores at a Lower Rate Than Nonsmokers Even When Repaired Supraspinatus Tendons Were Intact on Postoperative Magnetic Resonance Imaging.

Purpose: To investigate the impact of smoking on clinical outcomes after repair of supraspinatus tendon in patients who had an intact repair found on postoperative magnetic resonance imaging.

Methods: Patients who received primary complete repair of supraspinatus tendon tear between 2014 and 2020 were retrospectively identified. Patients were excluded if a postoperative magnetic resonance imaging scan was not available or if the follow-up was less than 2 years.

Structure of Amyloid Peptide Ribbons Characterized by Electron Microscopy, Atomic Force Microscopy, and Solid-State Nuclear Magnetic Resonance.

Polypeptides often self-assemble to form amyloid fibrils, which contain cross-β structural motifs and are typically 5-15 nm in width and micrometers in length. In many cases, short segments of longer amyloid-forming protein or peptide sequences also form cross-β assemblies but with distinctive ribbon-like morphologies that are characterized by a well-defined thickness (on the order of 5 nm) in one lateral dimension and a variable width (typically 10-100 nm) in the other. Here, we use a novel combination of data from solid-state nuclear magnetic resonance (ssNMR), dark-field transmission electron microscopy (TEM), atomic force microscopy (AFM), and cryogenic electron microscopy (cryoEM) to investigate the structures within amyloid ribbons formed by residues 14-23 and residues 11-25 of the Alzheimer's disease-associated amyloid-β peptide (Aβ and Aβ).

From Milliseconds to Minutes: Melittin Self-Assembly from Concerted Non-Equilibrium Pressure-Jump and Equilibrium Relaxation Nuclear Magnetic Resonance.

Non-equilibrium kinetics techniques like pressure-jump nuclear magnetic resonance (NMR) are powerful in tracking changes in oligomeric populations and are not limited by relaxation rates for the time scales of exchange that can be probed. However, these techniques are less sensitive to minor, transient populations than are Carr-Purcell-Meiboom-Gill (CPMG) relaxation dispersion experiments. We integrated non-equilibrium pressure-jump and equilibrium CPMG relaxation dispersion data to fully map the kinetic landscape of melittin tetramerization.

Experimental Evidence for Millisecond-Timescale Structural Evolution Following the Microsecond-Timescale Folding of a Small Protein.

Prior work has shown that small proteins can fold (i.e., convert from unstructured to structured states) within 10  μs.

Plasma VEGFA and PGF impact longitudinal tau and cognition in preclinical Alzheimer's disease.

Vascular dysfunction is increasingly recognized as an important contributor to the pathogenesis of Alzheimer's disease. Alterations in vascular endothelial growth factor (VEGF) pathways have been implicated as potential mechanisms. However, the specific impact of VEGF proteins in preclinical Alzheimer's disease and their relationships with other Alzheimer's disease and vascular pathologies during this critical early period remain to be elucidated.

Modification of Outside-In Technique In Preparing Femoral Tunnel During Anterior Cruciate Ligament Reconstruction-"PL-Portal Outside-In Technique".

We propose modifying the outside-in technique by adopting a posterolateral (PL) portal as the working portal to introduce the anterior cruciate ligament reconstruction (ACLR) aiming guide while keeping the anteromedial portal as the viewing portal, the "PL-portal outside-in technique." This modification facilitates the preparation of an anatomical femoral tunnel, even when preserving a "big" ACL remnant or in small joint scenarios, such as pediatric ACLR. There is a minimal learning curve in adopting this technique because a standard 30° arthroscope is used, and the viewing portal is anterior.

Evaluation of Graft Maturation by MRI in Anterior Cruciate Ligament Reconstruction With and Without Concomitant Anterolateral Ligament Reconstruction.

Background: Single-bundle anterior cruciate ligament reconstruction (SB-ACLR) with concomitant anterolateral ligament reconstruction (ALLR) has been associated with better clinical results when compared with isolated SB-ACLR. However, it is not known whether the improved outcomes are the result of the influence of concomitant ALLR on ACL graft healing.

Purpose/hypothesis: The purpose of this study was to determine whether concomitant ALLR is associated with improved graft ligamentization after SB-ACLR.