Common host variation drives malaria parasite fitness in healthy human red cells
The replication ofPlasmodium falciparum parasites within red blood cells (RBCs) causes severe disease in humans, especially in Africa. Deleterious alleles like hemoglobin S are well-known to confer strong resistance to malaria, but the effects of common RBC variation are largely undetermined. Here we collected fresh blood samples from 121 healthy donors, most with African ancestry, and performed exome sequencing, detailed RBC phenotyping, and parasite fitness assays. Over one third of healthy donors unknowingly carried alleles for G6PD deficiency or hemoglobinopathies, which were associated with characteristic RBC phenotyp...
Source: eLife - September 23, 2021 Category: Biomedical Science Tags: Evolutionary Biology Microbiology and Infectious Disease Source Type: research

Integrin α5β1 nano-presentation regulates collective keratinocyte migration independent of substrate rigidity
Nanometer-scale properties of the extracellular matrix influence many biological processes, including cell motility. While much information is available for single-cell migration, to date, no knowledge exists on how the nanoscale presentation of extracellular matrix receptors influences collective cell migration. In wound healing, basal keratinocytes collectively migrate on a fibronectin-rich provisional basement membrane to re-epithelialize the injured skin. Among other receptors, the fibronectin receptor integrin α5β1 plays a pivotal role in this process. Using a highly specific integrin α5β1 peptidomimetic combined ...
Source: eLife - September 23, 2021 Category: Biomedical Science Tags: Cell Biology Physics of Living Systems Source Type: research

Task-specific roles of local interneurons for inter- and intraglomerular signaling in the insect antennal lobe
Local interneurons (LNs) mediate complex interactions within the antennal lobe, the primary olfactory system of insects, and the functional analog of the vertebrate olfactory bulb. In the cockroachPeriplaneta americana, as in other insects, several types of LNs with distinctive physiological and morphological properties can be defined. Here, we combined whole-cell patch-clamp recordings and Ca2+ imaging of individual LNs to analyze the role of spiking and nonspiking LNs in inter- and intraglomerular signaling during olfactory information processing. Spiking GABAergic LNs reacted to odorant stimulation with a uniform rise i...
Source: eLife - September 23, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

Mapping the future for coral reefs
The ability of corals to adapt to global warming may involve trade-offs among the traits that influence their success as the foundational species of coral reefs. (Source: eLife)
Source: eLife - September 22, 2021 Category: Biomedical Science Tags: Ecology Source Type: research

Circadian regulation of vertebrate cone photoreceptor function
Eukaryotes generally display a circadian rhythm as an adaption to the reoccurring day/night cycle. This is particularly true for visual physiology that is directly affected by changing light conditions. Here we investigate the influence of the circadian rhythm on the expression and function of visual transduction cascade regulators in diurnal zebrafish and nocturnal mice. We focused on regulators of shut-off kinetics such asrecoverins, arrestins, opsin kinases,and GTPase-accelerating protein that have direct effects on temporal vision. Transcript as well as protein levels of most analyzed genes show a robust circadian rhyt...
Source: eLife - September 22, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

A zebrafish screen reveals Renin-angiotensin system inhibitors as neuroprotective via mitochondrial restoration in dopamine neurons
Parkinson ’s disease (PD) is a common neurodegenerative disorder without effective disease-modifying therapeutics. Here, we establish a chemogenetic dopamine (DA) neuron ablation model in larval zebrafish with mitochondrial dysfunction and robustness suitable for high-content screening. We use this system t o conduct an in vivo DA neuron imaging-based chemical screen and identify the Renin-Angiotensin-Aldosterone System (RAAS) inhibitors as significantly neuroprotective. Knockdown of the angiotensin receptor 1 (agtr1) in DA neurons reveals a cell-autonomous mechanism of neuroprotection. DA neuron-specific RNA-seq identif...
Source: eLife - September 22, 2021 Category: Biomedical Science Tags: Genetics and Genomics Neuroscience Source Type: research

Infection-exposure in infancy is associated with reduced allergy-related disease in later childhood in a Ugandan cohort
(Source: eLife)
Source: eLife - September 22, 2021 Category: Biomedical Science Tags: Epidemiology and Global Health Source Type: research

Evolution of pathogen tolerance and emerging infections: A missing experimental paradigm
Researchers worldwide are repeatedly warning us against future zoonotic diseases resulting from humankind ’s insurgence into natural ecosystems. The same zoonotic pathogens that cause severe infections in a human host frequently fail to produce any disease outcome in their natural hosts. What precise features of the immune system enable natural reservoirs to carry these pathogens so efficiently? To un derstand these effects, we highlight the importance of tracing the evolutionary basis of pathogen tolerance in reservoir hosts, while drawing implications from their diverse physiological and life-history traits, and ecolog...
Source: eLife - September 21, 2021 Category: Biomedical Science Tags: Evolutionary Biology Immunology and Inflammation Source Type: research

Metformin alleviates stress-induced cellular senescence of aging human adipose stromal cells and the ensuing adipocyte dysfunction
Aging is associated with central fat redistribution and insulin resistance. To identify age-related adipose features, we evaluated the senescence and adipogenic potential of adipose-derived-stromal cells (ASCs) from abdominal subcutaneous fat obtained from healthy normal-weight young (<25y) or older women (>60y). Increased cell passages of young-donor ASCs (in vitro aging), resulted in senescence but not oxidative stress. ASC-derived adipocytes presented impaired adipogenesis but no early mitochondrial dysfunction. Conversely, aged-donor ASCs at early passages displayed oxidative stress and mild senescence. ASC-deriv...
Source: eLife - September 21, 2021 Category: Biomedical Science Tags: Cell Biology Source Type: research

Stretching of the retinal pigment epithelium contributes to zebrafish optic cup morphogenesis
The vertebrate eye-primordium consists of a pseudostratified neuroepithelium, the optic vesicle (OV), in which cells acquire neural retina or retinal pigment epithelium (RPE) fates. As these fates arise, the OV assumes a cup-shape, influenced by mechanical forces generated within the neural retina. Whether the RPE passively adapts to retinal changes or actively contributes to OV morphogenesis remains unexplored. We generated a zebrafish Tg(E1-bhlhe40:GFP) line to track RPE morphogenesis and interrogate its participation in OV folding. We show that, in virtual absence of proliferation, RPE cells stretch and flatten, thereby...
Source: eLife - September 21, 2021 Category: Biomedical Science Tags: Developmental Biology Neuroscience Source Type: research

Fine-tuned repression of Drp1 driven mitochondrial fission primes a 'stem/progenitor-like state' to support neoplastic transformation
Gene knockout of the master regulator of mitochondrial fission, Drp1, prevents neoplastic transformation. Also, mitochondrial fission and its opposing process of mitochondrial fusion are emerging as crucial regulators of stemness. Intriguingly, stem/progenitor cells maintaining repressed mitochondrial fission are primed for self-renewal and proliferation. Using our newly derived carcinogen transformed human cell model we demonstrate that fine-tuned Drp1 repression primes a slow cycling 'stem/progenitor-like state', which is characterized by small networks of fused mitochondria and a gene-expression profile with elevated fu...
Source: eLife - September 21, 2021 Category: Biomedical Science Tags: Cancer Biology Cell Biology Source Type: research

Activity-dependent Golgi satellite formation in dendrites reshapes the neuronal surface glycoproteome
Activity-driven changes in the neuronal surface glycoproteome are known to occur with synapse formation, plasticity and related diseases, but their mechanistic basis and significance are unclear. Here, we observed thatN-glycans on surface glycoproteins of dendrites shift from immature to mature forms containing sialic acid in response to increased neuronal activation. In exploring the basis of theseN-glycosylation alterations, we discovered they result from the growth and proliferation of Golgi satellites scattered throughout the dendrite. Golgi satellites that formed during neuronal excitation were in close association wi...
Source: eLife - September 21, 2021 Category: Biomedical Science Tags: Cell Biology Neuroscience Source Type: research

Impaired mRNA splicing and proteostasis in preadipocytes in obesity-related metabolic disease
We report that down-regulation of a key member of the major spliceosome,PRFP8/PRP8, as observed in IR/T2D preadipocytes from subcutaneous (SC) fat, prevented adipogenesis by altering both the expression and splicing patterns of adipogenic transcription factors and lipid droplet-related proteins, while adipocyte differentiation was restored upon recovery ofPRFP8/PRP8 normal levels. Adipocyte differentiation was also compromised under conditions of endoplasmic reticulum (ER)-associated protein degradation (ERAD) hyperactivation, as occurs in SC and omental (OM) preadipocytes in IR/T2D obesity. Thus, targeting mRNA splicing a...
Source: eLife - September 21, 2021 Category: Biomedical Science Tags: Cell Biology Source Type: research

A prion accelerates proliferation at the expense of lifespan
In fluctuating environments, switching between different growth strategies, such as those affecting cell size and proliferation, can be advantageous to an organism. Trade-offs arise, however. Mechanisms that aberrantly increase cell size or proliferation —such as mutations or chemicals that interfere with growth regulatory pathways—can also shorten lifespan. Here we report a natural example of how the interplay between growth and lifespan can be epigenetically controlled. We find that a highly conserved RNA-modifying enzyme, the pseudouridine sy nthase Pus4/TruB, can act as a prion, endowing yeast with greater prolifer...
Source: eLife - September 21, 2021 Category: Biomedical Science Tags: Chromosomes and Gene Expression Genetics and Genomics Source Type: research

The cell adhesion molecule Sdk1 shapes assembly of a retinal circuit that detects localized edges
Nearly 50 different mouse retinal ganglion cell (RGC) types sample the visual scene for distinct features. RGC feature selectivity arises from their synapses with a specific subset of amacrine (AC) and bipolar cell (BC) types, but how RGC dendrites arborize and collect input from these specific subsets remains poorly understood. Here we examine the hypothesis that RGCs employ molecular recognition systems to meet this challenge. By combining calcium imaging and type-specific histological stains we define a family of circuits that express the recognition molecule Sidekick 1 (Sdk1) which include a novel RGC type (S1-RGC) tha...
Source: eLife - September 21, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research