Biology subjects

Friedman, N. R.

Publications and source records attributed to Friedman, N. R..

9 recordsLinked to original sources

bioRxiv2026

Progressive deterioration of adaptive immune repertoires in Down syndrome linked to interferon hyperactivity and lymphoid tissue disorganization

Persons with Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), display strong dysregulation of adaptive immunity, which underlies high risk of complications from infections, widespread autoimmunity, and poor vaccine responses. However, the mechanisms by which T21 dysregulates adaptive immunity across the lifespan remain poorly understood. We report here a multimodal analysis of adaptive immunity across development and aging in DS, including deep B cell profiling by mass cytometry matched to transcriptome and proteome data, B and T cell receptor sequencing (BCR, TCR), and spatial transcriptomics of tonsil tissue. T21 causes progressive shifts in B cell subsets together with accelerated age-dependent B cell loss linked to hyperactive interferon and JAK/STAT signaling. The peripheral immunoglobulin repertoire shows dysregulated class switching, progressive loss of diversity, differential VDJ usage, and imbalanced rates of somatic hypermutation across immunoglobulin isotypes mirrored by contraction and skewing of the TCR repertoire. In children with DS, tonsil tissues are highly disorganized with smaller germinal centers, fibrotic intrusions, lower rates of cell proliferation, strong inflammatory signaling, and transcriptional programs indicative of dysregulated lymphocyte homing and residence. Together, these results point to hyperactive interferon signaling as a driver of dysregulated adaptive immunity in DS amenable to early therapeutic intervention.

immunology↗

bioRxiv2026

Altered Tonsillar Microbiome in Children with Down Syndrome and Obstructive Sleep Apnea

Background and ObjectivesChildren with Down syndrome (DS) have a high prevalence of obstructive sleep apnea (OSA) due to anatomic, neuromuscular, immunological and metabolic factors, yet the contribution of the tonsillar microbiome to airway obstruction in this population remains unexplored. We hypothesized that DS-associated OSA would be associated with a distinct tonsillar microbiome compared to non-DS OSA. MethodsTonsillar tissue from 22 DS and 18 NDS participants were analyzed by 16S rRNA sequencing. Alpha and beta diversity were assessed using Faiths phylogenetic diversity and UniFrac distances, respectively, and significantly different taxa were identified with ANCOM-BC and Mann-Whitney testing. ResultsAlthough overall microbial richness and community structure were similar between groups, overweight DS participants demonstrated increased phylogenetic diversity compared to normal-weight DS peers. Taxonomic profiling of the entire patient cohort revealed that in DS tonsils there were selective alterations in key genera with selective depletion of Haemophilus and enrichment of Staphylococcus, Rothia, and Lactobacillales. Haemophilus abundance correlated positively with tonsil weight in both cohorts. ConclusionsThese findings suggest that while global diversity is preserved, specific microbial shifts distinguish the DS tonsillar niche, potentially reflecting altered immune and metabolic environments associated with trisomy 21. Understanding these microbial differences may reveal mechanisms underlying the higher incidence and persistence of OSA in DS and inform targeted therapeutic strategies.

microbiology↗

bioRxiv2025

Modulation statistics of natural soundscapes

Modulation statistics of "natural soundscapes" were estimated by calculating the modulation power spectrum (MPS) of a database of acoustic samples recorded in nine pristine terrestrial habitats for four moments of the day and two contrasting periods differing in precipitation level. Following Singh and Theunissen (2003), a set of statistics estimating low-pass quality, starriness, separability, asymmetry, modulation depth and [Formula] temporal-modulation power-law relationships were calculated from the MPS of the samples and related to geographical, meteorological factors and diel variations. MPS were found to be generally low-pass in shape in the modulation domain, with most of their modulation power restricted to low temporal (<10-20 Hz) and spectral modulations (<0.5-1 cycles/kHz). Modulation statistics distinguished between habitats irrespective of moment of the day and precipitation period, with a greater role of Modulation depth and Starriness. Separability and Starriness were found to be related to the global biodiversity decrease from tropical to polar regions, suggesting that the lack of joint high spectral and fast temporal modulations, and MPS complexity are important features characterising "biophony", the collective sound produced by animals in a given habitat. These findings may help guide research on monitoring auditory behaviors and underlying mechanisms expected to exploit regularities of natural scenes.

neuroscience↗

bioRxiv2024

Post-transcriptional regulation by the CCR4-NOT deadenylase complex maintains redox homeostasis in insulin biosynthesis in mouse pancreatic β cells

Pancreatic {beta} cells synthesize insulin to maintain glucose homeostasis. In diabetes, elevated blood glucose and insulin resistance compel {beta} cells to produce insulin, and hence {beta} cells are vulnerable to oxidative stress by glucotoxicity. In insulin biosynthesis, the conversion of proinsulin to insulin is initiated by forming disulfide bonds in proinsulin for oxidative protein folding. Insulin content and insulin secretion in {beta} cells are decreased by deletion of CNOT7, a catalytic subunit of the CCR4-NOT complex, and accompanied by increased proinsulin, implying the impaired conversion of proinsulin to insulin. We found that PRDX4 essential for disulfide bond formation in proinsulin, is reduced in Cnot7-KO {beta} cells. Moreover, protein expression of CNOT8, a paralog of CNOT7, is increased in Cnot7-KO {beta} cells and binds to Prdx4 mRNA via MSI2. Here, we demonstrate the post-transcriptional regulation of Prdx4 mRNA by the CCR4-NOT complex to maintain oxidative-reductive homeostasis in insulin biosynthesis. HIGHLIGHTSO_LIInsulin content and secretion are decreased in Cnot7-KO pancreatic {beta} cells. C_LIO_LIPRDX4, needed for proinsulin folding, is decreased in Cnot7-KO pancreatic islets. C_LIO_LIThe conversion of proinsulin to insulin is impaired in Cnot7-KO {beta} cells. C_LIO_LICNOT8, but not CNOT7, interacts with MSI2 that binds to Prdx4 mRNA C_LI

physiology↗

bioRxiv2023

Habitat degradation homogenizes ecological responses to typhoons across a subtropical island

Climate change is increasing the frequency, intensity, and duration of extreme weather events across the globe. Understanding the capacity for ecological communities to withstand and recover from such events is critical. Typhoons are extreme weather events that are expected to broadly homogenise ecological dynamics through structural damage to vegetation and longer-term effects of salinization. Given their unpredictable nature, monitoring ecological responses to typhoons is challenging, particularly for mobile animals such as birds. Here, we report spatially variable ecological responses to typhoons across terrestrial landscapes. Using a high temporal resolution passive acoustic monitoring network across 24 sites on the subtropical island of Okinawa, Japan, we found that typhoons elicit divergent ecological responses among Okinawas diverse terrestrial habitats, as indicated by increased spatial variability of biological sound production (biophony) and individual species detections. This suggests that soniferous communities are capable of a diversity of different responses to typhoons. That is, spatial insurance effects among local ecological communities provide resilience to typhoons at the landscape scale. Even though site-level typhoon impacts on soundscapes and bird detections were not particularly strong, monitoring at scale with high temporal resolution across a broad spatial extent nevertheless enabled detection of spatial heterogeneity in typhoon responses. Further, species-level responses mirrored those of acoustic indices, underscoring the utility of such indices for revealing insight into fundamental questions concerning disturbance and stability. Our findings demonstrate the significant potential of landscape-scale acoustic sensor networks to capture the understudied ecological impacts of unpredictable extreme weather events.

ecology↗

bioRxiv2022

Plumage color evolves as distinct dorsal and ventral modules in Australasian honeyeaters

Many animals exhibit contrast between their dorsal and ventral coloration. If selection acts differently on dorsal versus ventral coloration, these body parts should evolve as independent modules of trait evolution, irrespective of ancestral covariance. Here, we compare the evolution of feather color across 11 body regions for a clade of Australasian songbirds (Meliphagoidea). We find evidence for three modules of covarying color regions: dorsal, ventral, and flight feathers. Among these modules, ventral feathers had color that was highly labile, evolving at 3 times the rate for dorsal plumage and 20 times the rate for flight feathers. While both dorsal and ventral plumage tend to be correlated with precipitation or the degree of vegetation, we find that dorsal plumage is twice as similar to colors of background substrates in satellite photos. This finding, which a direct effect of climate in Glogers rule does not predict, adds support for background matching as an explanation for geographic gradients in animal color. Furthermore, it suggests that selection for background matching has had a greater effect on dorsal plumage than ventral plumage color. Overall, differential selection on ventral and dorsal colors likely maintains these as distinct modules over evolutionary time scales - a novel explanation for dorsoventral contrast in pigmentation.

evolutionary biology↗

bioRxiv2021

Idea paper: An envelope model of ecological disturbance

Disturbance is common in natural ecosystems, but increasingly defines them. While there are many descriptions for the dynamics of an ecosystems response to disturbance, there are few descriptions for the dynamics of the disturbance itself. I describe a novel application of a model based on the production of amplitude envelopes in acoustics and electronic music synthesis, with varying parameters Attack, Decay, Sustain, and Release (ADSR). I show that varying the parameters of the ADSR model is sufficient to produce and vary the qualitative disturbance regimes described by previous authors, and is capable of producing dynamics not previously considered. I tested the utility of the ADSR model by applying it to a logistic growth model. I found that manipulating the attack and release parameters of the ADSR model changes the population dynamics estimated by these models. This implies that responses to disturbance are determined not only by the resilience and resistance of the ecological system, but also the dynamics of the disturbance itself. My hope is that the ADSR model will prove useful to researchers in either describing disturbances in long-term ecological data, or in producing disturbances for simulations or experiments.

ecology↗

bioRxiv2019

High throughput Characterization of KCNB1 variants Associated with Developmental and Epileptic Encephalopathy

Pathogenic variants in KCNB1, encoding the voltage-gated potassium channel Kv2.1, are associated with developmental and epileptic encephalopathies (DEE). Previous functional studies on a limited number of KCNB1 variants indicated a range of molecular mechanisms by which variants affect channel function, including loss of voltage sensitivity, loss of ion selectivity, and reduced cell-surface expression. We evaluated a series of 17 KCNB1 variants associated with DEE or neurodevelopmental disorder (NDD) to rapidly ascertain channel dysfunction using high-throughput functional assays. Specifically, we investigated the biophysical properties and cell-surface expression of variant Kv2.1 channels expressed in heterologous cells using high-throughput automated electrophysiology and immunocytochemistry-flow cytometry. Pathogenic variants exhibited diverse functional defects, including altered current density and shifts in the voltage-dependence of activation and/or inactivation, as homotetramers or when co-expressed with wild-type Kv2.1. Quantification of protein expression also identified variants with reduced total Kv2.1 expression or deficient cell-surface expression.\n\nOur study establishes a platform for rapid screening of functional defects of KCNB1 variants associated with DEE and other NDDs, which will aid in establishing KCNB1 variant pathogenicity and may enable discovery of targeted strategies for therapeutic intervention based on molecular phenotype.

genetics↗

bioRxiv2019

Macroevolutionary integration of phenotypes within and across ant worker castes

Phenotypic traits are often integrated into evolutionary modules: sets of organismal parts that evolve together. In social insect colonies the concepts of integration and modularity apply to sets of traits both within and among functionally and phenotypically differentiated castes. On macroevolutionary timescales, patterns of integration and modularity within and across castes can be clues to the selective and ecological factors shaping their evolution and diversification. We develop a set of hypotheses describing contrasting patterns of worker integration and apply this framework in a broad (246 species) comparative analysis of major and minor worker evolution in the hyperdiverse ant genus Pheidole. Using geometric morphometrics in a phylogenetic framework, we inferred fast and tightly integrated evolution of mesosoma shape between major and minor workers, but slower and more independent evolution of head shape between the two worker castes. Thus, Pheidole workers are evolving as a mixture of intra- and inter-caste integration and rate heterogeneity. The decoupling of homologous traits across worker castes may represent an important process facilitating the rise of social complexity.

evolutionary biology↗