The LRRK2 G2019S mutation alters astrocyte-to-neuron communication via extracellular vesicles and induces neuron atrophy in a human iPSC-derived model of Parkinson's disease
This study focuses on the effects of the PD-related mutation LRRK2 G2019S in astrocytes generated from patient-derived induced pluripotent stem cells. We report the alteration of extracellular vesicle (EV) biogenesis in astrocytes, and we identify the abnormal accumulation of key PD-related proteins within multi vesicular bodies (MVBs). We found that dopaminergic neurons internalize astrocyte-secreted EVs and that LRRK2 G2019S EVs are abnormally enriched in neurites and fail to provide full neurotrophic support to dopaminergic neurons. Thus, dysfunctional astrocyte-to-neuron communication via altered EV biological properti...
Source: eLife - September 30, 2021 Category: Biomedical Science Tags: Cell Biology Neuroscience Source Type: research

Competitive binding of MatP and topoisomerase IV to the MukB hinge domain
Structural Maintenance of Chromosomes (SMC) complexes have ubiquitous roles in compacting DNA linearly, thereby promoting chromosome organization-segregation. Interaction between theEscherichia coli SMC complex, MukBEF, andmatS-bound MatP in the chromosome replication termination region,ter, results in depletion of MukBEF fromter, a process essential for efficient daughter chromosome individualisation and for preferential association of MukBEF with the replication origin region. Chromosome-associated MukBEF complexes also interact with topoisomerase IV (ParC2E2), so that their chromosome distribution mirrors that of MukBEF...
Source: eLife - September 29, 2021 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Chromosomes and Gene Expression Source Type: research

Lying in a 3T MRI scanner induces neglect-like spatial attention bias
The static magnetic field of MRI scanners can induce a magneto-hydrodynamic stimulation of the vestibular organ (MVS). In common fMRI settings, this MVS effect leads to a vestibular ocular reflex (VOR). We asked whether – beyond inducing a VOR – putting a healthy subject in a 3T MRI scanner would also alter goal-directed spatial behavior, as is known from other types of vestibular stimulation. We investigated 17 healthy volunteers, all of which exhibited a rightward VOR inside the MRI-scanner as compared to out side-MRI conditions. More importantly, when probing the distribution of overt spatial attention inside the MR...
Source: eLife - September 29, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

Autonomous clocks that regulate organelle biogenesis, cytoskeletal organization, and intracellular dynamics
How do cells perceive time? Do cells use temporal information to regulate the production/degradation of their enzymes, membranes, and organelles? Does controlling biological time influence cytoskeletal organization and cellular architecture in ways that confer evolutionary and physiological advantages? Potential answers to these fundamental questions of cell biology have historically revolved around the discussion of ‘master’ temporal programs, such as the principal cyclin-dependent kinase/cyclin cell division oscillator and the circadian clock. In this review, we provide an overview of the recent evidence supporting a...
Source: eLife - September 29, 2021 Category: Biomedical Science Tags: Cell Biology Physics of Living Systems Source Type: research

Exposure to landscape fire smoke reduced birthweight in low- and middle-income countries: findings from a siblings-matched case-control study
Landscape fire smoke (LFS) has been associated with reduced birthweight, but evidence from low- and middle-income countries (LMICs) is rare. Here, we present a sibling-matched case-control study of 227,948 newborns to identify an association between fire-sourced fine particulate matter (PM2.5) and birthweight in 54 LMICs from 2000 to 2014. We selected mothers from the geocoded Demographic and Health Survey with at least two children and valid birthweight records. Newborns affiliated with the same mother were defined as a family group. Gestational exposure to LFS was assessed in each newborn using the concentration of fire-...
Source: eLife - September 29, 2021 Category: Biomedical Science Tags: Epidemiology and Global Health Source Type: research

Predicting cancer risk based on family history
A new software package provides more accurate cancer risk prediction profiles and has the ability to integrate more genes and cancer types in the future. (Source: eLife)
Source: eLife - September 29, 2021 Category: Biomedical Science Tags: Cancer Biology Genetics and Genomics Source Type: research

3'HS1 CTCF binding site in human β-globin locus regulates fetal hemoglobin expression
Mutations in the adult β-globin gene can lead to a variety of hemoglobinopathies, including sickle cell disease and β-thalassemia. An increase in fetal hemoglobin expression throughout adulthood, a condition named Hereditary Persistence of Fetal Hemoglobin (HPFH), has been found to ameliorate hemoglobinopathies. Deletio nal HPFH occurs through the excision of a significant portion of the 3' end of the β-globin locus, including a CTCF binding site termed 3'HS1. Here, we show that the deletion of this CTCF site alone induces fetal hemoglobin expression in both adult CD34+ hematopoietic stem and progenitor cells and HUDEP-...
Source: eLife - September 29, 2021 Category: Biomedical Science Tags: Chromosomes and Gene Expression Genetics and Genomics Source Type: research

Differentiation of mouse fetal lung alveolar progenitors in serum-free organotypic cultures
Lung epithelial progenitors differentiate into alveolar type 1 (AT1) and type 2 (AT2) cells. These cells form the air-blood interface and secrete surfactant, respectively, and are essential for lung maturation and function. Current protocols to derive and culture alveolar cells do not faithfully recapitulate the architecture of the distal lung, which influences cell fate patterns in vivo. Here, we report serum-free conditions that allow for growth and differentiation of mouse distal lung epithelial progenitors. We find that Collagen I promotes the differentiation of flattened, polarized AT1 cells. Using these organoids, we...
Source: eLife - September 29, 2021 Category: Biomedical Science Tags: Developmental Biology Source Type: research

mRNA vaccination in people over 80 years of age induces strong humoral immune responses against SARS-CoV-2 with cross neutralisation of P.1 Brazilian variant
Age is the major risk factor for mortality after SARS-CoV-2 infection and older people have received priority consideration for COVID-19 vaccination. However vaccine responses are often suboptimal in this age group and few people over the age of 80 years were included in vaccine registration trials. We determined the serological and cellular response to spike protein in 100 people aged 80-96 years at 2 weeks after second vaccination with the Pfizer BNT162b2 mRNA vaccine. Antibody responses were seen in every donor with high titres in 98%. Spike-specific cellular immune responses were detectable in only 63% and correlated w...
Source: eLife - September 29, 2021 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

Neural basis for regulation of vasopressin secretion by anticipated disturbances in osmolality
Water balance, tracked by extracellular osmolality, is regulated by feedback and feedforward mechanisms. Feedback regulation is reactive, occurring as deviations in osmolality aredetected. Feedforward or presystemic regulation is proactive, occurring when disturbances in osmolality areanticipated. Vasopressin (AVP) is a key hormone regulating water balance and is released during hyperosmolality to limit renal water excretion. AVP neurons are under feedback and feedforward regulation. Not only do they respond to disturbances in blood osmolality, but they are also rapidly suppressed and stimulated, respectively, by drinking ...
Source: eLife - September 29, 2021 Category: Biomedical Science Tags: Medicine Neuroscience Source Type: research

Phosphorylation of luminal region of the SUN-domain protein Mps3 promotes nuclear envelope localization during meiosis
During meiosis, protein ensembles in the nuclear envelope (NE) containing SUN- and KASH-domain proteins, called linker nucleocytoskeleton and cytoskeleton (LINC) complex, promote the chromosome motion. Yeast SUN-domain protein, Mps3, forms multiple meiosis-specific ensembles on NE, which show dynamic localisation for chromosome motion; however, the mechanism by which these Mps3 ensembles are formed during meiosis remains largely unknown. Here, we showed that the cyclin-dependent protein kinase (CDK) and Dbf4-dependent Cdc7 protein kinase (DDK) regulate meiosis-specific dynamics of Mps3 on NE, particularly by mediating the ...
Source: eLife - September 29, 2021 Category: Biomedical Science Tags: Chromosomes and Gene Expression Source Type: research

Profiling sensory neuron microenvironment after peripheral and central axon injury reveals key pathways for neural repair
This study provides a map of the distinct DRG mic roenvironment responses to peripheral and central injuries at the single-cell level and highlights that manipulating non-neuronal cells could lead to avenues to promote functional recovery after CNS injuries or disease. (Source: eLife)
Source: eLife - September 29, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

< i > APOE4 < /i > is associated with elevated blood lipids and lower levels of innate immune biomarkers in a tropical Amerindian subsistence population
In post-industrial settings, apolipoproteinE4 (APOE4) is associated with increased cardiovascular and neurological disease risk. However, the majority of human evolutionary history occurred in environments with higher pathogenic diversity and low cardiovascular risk. We hypothesize that in high-pathogen and energy-limited contexts, theAPOE4 allele confers benefits by reducing innate inflammation when uninfected, while maintaining higher lipid levels that buffer costs of immune activation during infection. Among Tsimane forager-farmers of Bolivia (N = 1266, 50% female),APOE4 is associated with 30% lower C-reactive protein, ...
Source: eLife - September 29, 2021 Category: Biomedical Science Tags: Evolutionary Biology Medicine Source Type: research

Total parasite biomass but not peripheral parasitaemia is associated with endothelial and haematological perturbations in < i > Plasmodium vivax < /i > patients
In this study we investigate associations between both peripheral and total parasite biomass and host response in vivax malaria. We analysed parasite and host signatures in a cohort of uncomplicated vivax malaria patients from Manaus, Brazil, combining clinical and parasite parameters, multiplexed analysis of host responses andex vivo assays. Patterns of clinical features, parasite burden and host signatures measured in plasma across the patient cohort were highly heterogenous. Further data deconvolution revealed two patient clusters, here termed Vivaxlow and Vivaxhigh. These patient subgroups were defined based on differe...
Source: eLife - September 29, 2021 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

A morphological transformation in respiratory syncytial virus leads to enhanced complement deposition
The complement system is a critical host defense against infection, playing a protective role that can also enhance disease if dysregulated. Although many consequences of complement activation during viral infection are well established, mechanisms that determine the extent to which viruses activate complement remain elusive. Here, we investigate complement activation by human respiratory syncytial virus (RSV), a filamentous respiratory pathogen that causes significant morbidity and mortality. By engineering a strain of RSV harboring tags on the surface glycoproteins F and G, we are able to monitor opsonization of single R...
Source: eLife - September 29, 2021 Category: Biomedical Science Tags: Microbiology and Infectious Disease Physics of Living Systems Source Type: research