The big chill: Growth of structural biology with cryo-electron tomography.

structural biology with cryo-electron tomography (cryo-ET) and subtomogram averaging (StA) is evolving as a major method to understand the structure, function, and interactions of biological molecules in cells in a single experiment. Since its inception, the method has matured with some stellar highlights and with further opportunities to broaden its applications. In this short review, I want to provide a personal perspective on the developments in cryo-ET as I have seen it for the last ~20 years and outline the major steps that led to its success.

A quantitative multi-parameter mapping protocol standardized for clinical research in multiple sclerosis.

Quantitative magnetic resonance imaging (qMRI) involves mapping microstructure in standardized units sensitive to histological properties and supplements conventional MRI, which relies on contrast weighted images where intensities have no biophysical meaning. While measuring tissue properties such as myelin, iron or water content is desired in a disease context, qMRI changes may typically reflect mixed influences from aging or pre-clinical degeneration. We used a fast multi-parameter mapping (MPM) protocol for clinical routine at 3T to reconstruct whole-brain quantitative maps of magnetization transfer saturation (MT), proton density (PD), longitudinal (R1), and transverse relaxation rate (R2*) with 1.

PDGFRA is a conserved HAND2 effector during early cardiac development.

The basic helix-loop-helix transcription factor HAND2 has multiple roles during vertebrate organogenesis, including cardiogenesis. However, much remains to be uncovered about its mechanism of action. Here, we show the generation of several hand2 mutant alleles in zebrafish and demonstrate that dimerization-deficient mutants display the null phenotype but DNA-binding-deficient mutants do not.

Tripartite interactions of PKA catalytic subunit and C-terminal domains of cardiac Ca channel may modulate its β-adrenergic regulation.

Background: The β-adrenergic augmentation of cardiac contraction, by increasing the conductivity of L-type voltage-gated Ca1.2 channels, is of great physiological and pathophysiological importance. Stimulation of β-adrenergic receptors (βAR) activates protein kinase A (PKA) through separation of regulatory (PKAR) from catalytic (PKAC) subunits.

Molecular architecture of synaptic vesicles.

Synaptic vesicles (SVs) store and transport neurotransmitters to the presynaptic active zone for release by exocytosis. After release, SV proteins and excess membrane are recycled via endocytosis, and new SVs can be formed in a clathrin-dependent manner. This process maintains complex molecular composition of SVs through multiple recycling rounds.

Arginine methylation of the p30 C/EBPα oncoprotein regulates progenitor proliferation and myeloid differentiation.

The transcription factor CCAAT enhancer binding protein alpha (C/EBPα) is a master regulator of myelopoiesis. encodes a long (p42) and a truncated (p30) protein isoform from a single mRNA. Mutations that abnormally enhance expression of p30 are associated with acute myelogenous leukemia (AML).

Generation of two isogenic human iPSC lines (ZIPi013-B-1, ZIPi013-B-2) carrying a CRISPR/Cas9-mediated deletion of TRPM4.

Two isogenic hiPSC lines, ZIPi013-B-1 and ZIPi013-B-2, were generated by CRISPR/Cas9-mediated indels in the TRPM4 gene of the previously published ZIPi013-B. TRPM4 belongs to the evolutionarily conserved family of transient receptor potential (TRP) channels. It is expressed ubiquitously and its activity is regulated by intracellular calcium binding, changes in membrane potential, phosphoinositide lipids in the plasma membrane and the local concentration of cytoplasmic ATP and ADP.

Transgenic rat with ubiquitous expression of angiotensin-(1-7)-producing fusion protein: a new tool to study the role of protective arm of the renin-angiotensin system in the pathophysiology of cardio-renal diseases.

The aim of the present study was to assess systemic circulatory and tissue activities of both the classical arm and of the alternative arm of the renin-angiotensin system (RAS) in a new transgenic rat line (TG7371) that expresses angiotensin-(1-7) (ANG 1-7)-producing fusion protein; the results were compared with the activities measured in control transgene-negative Hannover Sprague-Dawley (HanSD) rats. Plasma and tissue concentrations of angiotensin II (ANG II) and ANG 1-7, and kidney mRNA expressions of receptors responsible for biological actions of ANG II and ANG 1-7 [i.e.

Interpreting deep neural networks for the prediction of translation rates.

Background: The 5' untranslated region of mRNA strongly impacts the rate of translation initiation. A recent convolutional neural network (CNN) model accurately quantifies the relationship between massively parallel synthetic 5' untranslated regions (5'UTRs) and translation levels. However, the underlying biological features, which drive model predictions, remain elusive.

Expansion and Precise CRISPR-Cas9 Gene Repair of Autologous T-Memory Stem Cells from Patients with T-Cell Immunodeficiencies.

The adoptive transfer of autologous, long-lived, gene-repaired T cells is a promising way to treat inherited T-cell immunodeficiencies. However, adoptive T-cell therapies require a large number of T cells to be manipulated and infused back into the patient. This poses a challenge in primary immunodeficiencies that manifest early in childhood and where only small volumes of blood samples may be available.

Sex- and site-specific associations of circulating lipocalin 2 and incident colorectal cancer: Results from the EPIC cohort.

Experimental research has uncovered lipocalin 2 (LCN2) as a novel biomarker implicated in the modulation of intestinal inflammation, metabolic homeostasis, and colon carcinogenesis. However, evidence from human research has been scant. We, therefore, explored the association of pre-diagnostic circulating LCN2 concentrations with incident colorectal cancer (CRC) in a nested case-control study within the in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

Author Correction: Disrupting TSLP-TSLP receptor interactions via putative small molecule inhibitors yields a novel and efficient treatment option for atopic diseases.

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An integrated view of the structure and function of the human 4D nucleome.

The dynamic three-dimensional (3D) organization of the human genome (the "4D Nucleome") is closely linked to genome function. Here, we integrate a wide variety of genomic data generated by the 4D Nucleome Project to provide a detailed view of human 3D genome organization in widely used embryonic stem cells (H1-hESCs) and immortalized fibroblasts (HFFc6). We provide extensive benchmarking of 3D genome mapping assays and integrate these diverse datasets to annotate spatial genomic features across scales.

At home e-based physical exercise programs in patients with multiple sclerosis: a scoping review.

Introduction: Physical exercise (PE) improves symptoms and quality of life in people with multiple sclerosis (pwMS). However, incorporating PE into daily lives of pwMS pose difficulties. As an alternative to in-person PE, e-based PE has been proposed because of its advantages in terms of accessibility and convenience.

SPINEPS-automatic whole spine segmentation of T2-weighted MR images using a two-phase approach to multi-class semantic and instance segmentation.

Objectives: Introducing SPINEPS, a deep learning method for semantic and instance segmentation of 14 spinal structures (ten vertebra substructures, intervertebral discs, spinal cord, spinal canal, and sacrum) in whole-body sagittal T2-weighted turbo spin echo images.

Material And Methods: This local ethics committee-approved study utilized a public dataset (train/test 179/39 subjects, 137 female), a German National Cohort (NAKO) subset (train/test 1412/65 subjects, mean age 53, 694 female), and an in-house dataset (test 10 subjects, mean age 70, 5 female). SPINEPS is a semantic segmentation model, followed by a sliding window approach utilizing a second model to create instance masks from the semantic ones.

The IBEX Knowledge-Base: Achieving more together with open science.

Iterative Bleaching Extends multipleXity (IBEX) is a versatile method for highly multiplexed imaging of diverse tissues. Based on open science principles, we created the IBEX Knowledge-Base, a resource for reagents, protocols and more, to empower innovation.