Biology subjects

Weiner, A.

Publications and source records attributed to Weiner, A..

8 recordsLinked to original sources

bioRxiv2026

Caenorhabditis elegans avoids Todstoff, a novel nociceptive necrotaxis cue

To survive in hazardous environments, organisms must navigate and avoid myriad threats. Many species across phyla detect warning cues in the remains of dead or injured conspecifics, allowing them to enact defensive strategies and avoid a similar fate. Here, we demonstrate that Caenorhabditis elegans senses a novel aversive cue (which we term Todstoff, or death substance) present in the remains of dead worms that induces living conspecifics to perform negative necrotaxis behaviors. Todstoff is distinct from previously-identified social signals in C. elegans, including ascaroside and alarm pheromones, and our biochemical analysis has revealed that Todstoff may be a protein-associated amino acid derivative less than 1.35 kDa in size. We determined that Todstoff is sensed by the ASH polymodal nociceptive neurons, and further, that the necrotaxis signal is transduced via the activity of G-protein coupled receptor (GPCR) signaling, the Gi/o-like protein ODR-3, TRPV channels OSM-9 and OCR-2, and glutamatergic synaptic transmission to downstream AIB interneurons. Taken together, our work illuminates a post-mortem inter-animal chemical signaling pathway that promotes death avoidance, and thus, survival.

genetics↗

bioRxiv2025

Candida albicans epithelial invasion induces host membrane rupture at distinct subcellular niches following priming by the fungal toxin candidalysin

Candida albicans is an opportunistic fungal pathogen normally found as a commensal in human mucosa. In susceptible patients, its hyphal filamentous form can invade and damage host epithelium leading to local or systemic infection. The secreted fungal toxin candidalysin is required for epithelial damage, although both hyphal extension and candidalysin are required for inducing maximal infection damage, for reasons that are not well understood. Here we study the interplay between hyphal extension and epithelial damage in vitro using live cell imaging combined with damage-sensitive reporters and volume electron microscopy. We first quantify candidalysin-induced host membrane rupture and host cell death at the single cell level and determine the three-dimensional architecture of invasion in our experimental system. We then show that the spatial organization of host membrane rupture is regulated by candidalysin and is predictive of host cell death. Finally, we demonstrate that membrane rupture occurs at two distinct host subcellular niches: the juxtanuclear region and the cell-cell boundary, with the latter the main driver of subsequent host cell death. Based on these results, we propose that C. albicans invasion damages epithelial membranes in a sequential process in which candidalysin secretion first acts to weaken host membranes enveloping invading hyphae, followed by membrane rupture occurring as hyphae traverse two distinct host subcellular niches.

microbiology↗

bioRxiv2024

CINner: modeling and simulation of chromosomal instability in cancer at single-cell resolution

Cancer development is characterized by chromosomal instability, manifesting in frequent occurrences of different genomic alteration mechanisms ranging in extent and impact. Mathematical modeling can help evaluate the role of each mutational process during tumor progression, however existing frameworks can only capture certain aspects of chromosomal instability (CIN). We present CINner, a mathematical framework for modeling genomic diversity and selection during tumor evolution. The main advantage of CINner is its flexibility to incorporate many genomic events that directly impact cellular fitness, from driver gene mutations to copy number alterations (CNAs), including focal amplifications and deletions, missegregations and whole-genome duplication (WGD). We apply CINner to find chromosome-arm selection parameters that drive tumorigenesis in the absence of WGD in chromosomally stable cancer types. We found that the selection parameters predict WGD prevalence among different chromosomally unstable tumors, hinting that the selective advantage of WGD cells hinges on their tolerance for aneuploidy and escape from nullisomy. Direct application of CINner to model the WGD proportion and fraction of genome altered (FGA) further uncovers the increase in CNA probabilities associated with WGD in each cancer type. CINner can also be utilized to study chromosomally stable cancer types, by applying a selection model based on driver gene mutations and focal amplifications or deletions. Finally, we used CINner to analyze the impact of CNA probabilities, chromosome selection parameters, tumor growth dynamics and population size on cancer fitness and heterogeneity. We expect that CINner will provide a powerful modeling tool for the oncology community to quantify the impact of newly uncovered genomic alteration mechanisms on shaping tumor progression and adaptation.

genomics↗

bioRxiv2022

The AMA1-RON complex drives Plasmodium sporozoite invasion in the mosquito and mammalian hosts

Plasmodium sporozoites that are transmitted by blood-feeding female Anopheles mosquitoes invade hepatocytes for an initial round of intracellular replication, leading to the release of merozoites that invade and multiply within red blood cells. Sporozoites and merozoites share a number of proteins that are expressed by both stages, including the Apical Membrane Antigen 1 (AMA1) and the Rhoptry Neck Proteins (RONs). Although AMA1 and RONs are essential for merozoite invasion of erythrocytes during asexual blood stage replication of the parasite, their function in sporozoites is still unclear. Here we show that AMA1 interacts with RONs in mature sporozoites. By using DiCre-mediated conditional gene deletion in P. berghei, we demonstrate that loss of AMA1, RON2 or RON4 in sporozoites impairs colonization of the mosquito salivary glands and invasion of mammalian hepatocytes, without affecting transcellular parasite migration. Our data establish that AMA1 and RONs facilitate host cell invasion across Plasmodium invasive stages, and suggest that sporozoites use the AMA1-RON complex to safely enter the mosquito salivary glands without causing cell damage, to ensure successful parasite transmission. These results open up the possibility of targeting the AMA1-RON complex for transmission-blocking antimalarial strategies.

microbiology↗

bioRxiv2021

Trans-cellular tunnels induced by the fungal pathogen Candida albicans facilitate invasion through successive epithelial cells without host damage

The opportunistic fungal pathogen Candida albicans is normally commensal, residing in the mucosa of most healthy individuals. In susceptible hosts, its filamentous hyphal form can invade epithelial layers leading to superficial or severe systemic infection. Invasion is mainly intracellular, though it causes no apparent damage to host cells. We investigated the invasive lifestyle of C. albicans in vitro using live-cell imaging and the damage-sensitive reporter galectin-3. Quantitative single cell analysis showed that invasion can result in host membrane breaching at different stages of invasion and cell death, or in traversal of host cells without membrane breaching. Membrane labelling and three-dimensional "volume" electron microscopy revealed that hyphae can traverse several host cells within trans-cellular tunnels that are progressively remodelled and may undergo inflations linked to host glycogen stores, possibly during nutrient uptake. Thus, C. albicans invade epithelial tissues by either inflicting or avoiding host damage, the latter facilitated by trans-cellular tunnelling.

microbiology↗

bioRxiv2021

Microstructured hydrogels to guide self-assembly and function of lung alveolospheres

Epithelial cell organoids have increased opportunities to probe questions on tissue development and disease in vitro and for therapeutic cell transplantation. Despite their potential, current protocols to grow these organoids almost exclusively depend on culture within three-dimensional (3D) Matrigel, which limits defined culture conditions, introduces animal components, and results in heterogenous organoids (i.e., shape, size, composition). Here, we describe a method that relies on polymeric hydrogel substrates for the generation and expansion of lung alveolar organoids (alveolospheres). Using synthetic hydrogels with defined chemical and physical properties, human induced pluripotent stem cell (iPSC)-derived alveolar type 2 cells (iAT2s) self-assemble into alveolospheres and propagate in Matrigel-free conditions. By engineering pre-defined microcavities within these hydrogels, the heterogeneity of alveolosphere size and structure was reduced when compared to 3D culture while maintaining alveolar type 2 cell fate of human iAT2 and primary mouse tissue-derived progenitor cells. This hydrogel system is a facile and accessible culture system for the culture of primary and iPSC-derived lung progenitors and the method could be expanded to the culture of other epithelial progenitor and stem cell aggregates.

bioengineering↗

bioRxiv2021

Red Blood Cells Function as DNA Sensors

Erythrocytes have long been mistaken as exclusively inert oxygen carriers lacking immune function. Here we show that red blood cells (RBCs) serve as immune sensors through surface expression of the nucleic acid-sensing toll-like receptor 9 (TLR9), a classically endosomal receptor that initiates immune responses following the detection of unmethylated CpG motifs present in pathogen and mitochondrial DNA. Mammalian RBCs express TLR9 on their surface and bind CpG-containing bacterial, malarial, and mitochondrial DNA. Erythrocyte-bound CpG DNA increases during infection, and CpG-carrying RBCs trigger accelerated erythrophagocytosis and innate immune activation characterized by RBC-TLR9 dependent local and systemic cytokine production. Thus, RBC nucleic acid detection and capture regulates red cell clearance and immune responses and provides evidence for RBCs as innate immune sentinels during pathologic states. One Sentence SummaryThe ability of RBCs to detect and bind cell-free nucleic acids contributes to immunity during acute inflammatory states.

immunology↗

bioRxiv2018

IgG is differentially and selectively transferred across the placenta in HIV-infected women

SUMMARY\n\nThe transplacental transfer of maternal IgG to the developing fetus is critical for infant protection against infectious pathogens in the first year of life. However, factors that modulate the transplacental transfer efficiency of maternal IgG that could be harnessed for maternal vaccine design remain largely undefined. HIV-infected women have impaired placental IgG transfer, yet the mechanism underlying this impaired transfer is unknown, presenting an opportunity to explore factors that contribute to the efficiency of placental IgG transfer. We measured the transplacental transfer efficiency of maternal HIV and other pathogen-specific IgG in historical U.S. (n=120) and Malawian (n=47) cohorts of HIV-infected mothers and their HIV- exposed uninfected and HIV-infected infants. We then examined the role of maternal HIV disease progression, infant factors, placental Fc receptor expression, and IgG Fc region subclass and glycan signatures and their association with transplacental transfer efficiency of maternal antigen-specific IgG. We established 3 distinct phenotypes of placental IgG transfer efficiency in HIV-infected women, including: 1) efficient transfer of the majority of antigen-specific IgG populations; 2) generally poor IgG transfer phenotype that was strongly associated with maternal CD4+ T cell counts, hypergammaglobulinemia, and frequently yielded non-protective levels of vaccine-specific IgG; and 3) variable transfer of IgG across distinct antigen specificities. Interestingly, maternal IgG characteristics, such as binding to placentally expressed Fc receptors Fc{gamma}RIIa and Fc{gamma}RIIIa, IgG subclass frequency, and Fc region glycan profiles were associated with placental IgG transfer efficiency. These maternal IgG transplacental transfer determinants were distinct among different antigen-specific IgG populations. Our findings suggest that in HIV-infected women, both maternal disease progression and Fc region characteristics modulate the selective placental transfer of distinct IgG subpopulations, with implications for both the health of HIV-exposed uninfected infants and maternal vaccine design.\n\nHighlightsO_LILow peripheral blood CD4 + T cell count and hypergammaglobulinemia are associated with inefficient transplacental IgG transfer in HIV-infected women\nC_LIO_LIAntigen-specific IgG binding strength to placentally-expressed Fc receptors, but not placental Fc receptor expression levels, mediates selective placental IgG transfer\nC_LIO_LIAntigen-specific IgG Fc region glycan profiles also contribute to the selective placental IgG transfer of maternal IgG populations in HIV-infected women\nC_LI

microbiology↗