Biology subjects

Strauss, T.

Publications and source records attributed to Strauss, T..

3 recordsLinked to original sources

bioRxiv2026

A unified framework links infant vulnerability with aging-related mortality dynamics

A central question in Geroscience is whether early-life mortality, which declines from birth to sexual maturity, and late-life mortality, which grows exponentially in time, can be understood within a shared conceptual framework. We show that stochastic threshold models can explain both phases by incorporating heterogeneity in neonatal vulnerability. Using U.S. National Center for Health Statistics data, we find that infant mortality risk is strongly associated with neonatal clinical markers such as Apgar scores, gestational age, and birth weight, suggesting that initial physiological differences persist across early life. We show that the [~]1/t mortality decline generically arises in stochastic threshold models via depletion of the most vulnerable, across a wide range of model specifications. Incorporating this mechanism into the Saturating-Removal model captures both the early decline and the later Gompertz acceleration, reproducing the full J-shaped mortality curve. Together, our findings link neonatal vulnerability to late-life mortality dynamics within a shared stochastic framework, supporting a life-course perspective on aging and longevity.

systems biology↗

bioRxiv2025

Truncating RELA variants drive autoinflammation and autoimmunity by impairing the negative feedback control of NF-kB

The NF-{kappa}B signaling pathway coordinates inflammation, cell survival, and proliferation, while restraining excessive cell death to maintain immune homeostasis. Truncating mutations in RELA, encoding the NF-{kappa}B subunit p65, have been linked to autoinflammation and autoimmunity, but the underlying mechanisms remain incompletely defined. We investigated six patients from five unrelated families carrying novel heterozygous truncating RELA variants. Despite reduced p65 expression, patients exhibited a broad spectrum of inflammatory manifestations alongside elevated baseline and stimulus-induced pro-inflammatory cytokines. Functional analyses in patient-derived cells and mutant RELA knock-in models showed that upstream NF-{kappa}B signaling was intact, but induction of inhibitory regulators such as I{kappa}B and A20 was impaired. This defective feedback control shifted immune homeostasis toward amplified inflammatory responses that depended on the residual activity of the remaining functional RELA allele. Single-cell transcriptomics revealed distinct cell type-specific consequences: monocytes displayed constitutive type I interferon and NF-{kappa}B activation, B cells retained partial compensatory signaling, whereas T and NK cells exhibited transcriptional signatures of cell death pathways. Patient fibroblasts and mutant RELA knock-in cells further confirmed enhanced TNF-induced inflammatory gene expression and hypersensitivity to apoptosis and necroptosis. These findings establish RELA haploinsufficiency as a cause of systemic immune dysregulation, and link defective NF-{kappa}B feedback control to unchecked inflammation and inflammatory cell death. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/687461v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@1f0bfe6org.highwire.dtl.DTLVardef@c6cb60org.highwire.dtl.DTLVardef@1522accorg.highwire.dtl.DTLVardef@177c724_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

Rescue of the increased susceptibility to Mild Chronic Oxidative Stress of iNeurons carrying the MAPT Chromosome 17q21.3 H1/H1 risk allele by FDA-approved compounds

The microtubule associated protein tau (MAPT) chromosome 17q21.31 locus lies within a region of high linkage disequilibrium (LD) conferring two extended haplotypes commonly referred to as H1 and H2. The major haplotype, H1 has been genetically associated with an increased risk for multiple neurodegenerative disorders, including Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), APOE {varepsilon}4-negative Alzheimers disease (AD) and Parkinsons disease (PD). The mechanism causing this increased risk is largely unknown. Here, we investigated the role of Mild Chronic Oxidative Stress (MCOS) in neurogenin 2 (NGN2) induced neurons (iNeurons) derived from iPS (induced pluripotent stem cells) from carriers of both haplotypes. We identified that iNeurons of the H1 homozygous haplotype showed an increased susceptibility to MCOS compared to homozygous H2 carriers, leading to cell death through ferroptosis. We performed a cellular screen in H1 iNeurons using a FDA-approved Drug Library and identified candidate molecules that rescued the increased susceptibility to MCOS and prevented ferroptosis in H1 iNeurons. HighlightsO_LIMild Chronic Oxidative Stress induces neurotoxicity via ferroptosis on iNGN2 neurons C_LIO_LIAxonal degeneration, disordered microtubules, blebs precede neurotoxicity C_LIO_LIMAPT-17q21.3 locus H1/H1, risk allele for NDD is more vulnerable to MCOS C_LIO_LIFDA-approved drugs reverse MCOS induced ferroptosis on H1/H1 risk allele C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=158 SRC="FIGDIR/small/515284v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@eddb2eorg.highwire.dtl.DTLVardef@1d0c00dorg.highwire.dtl.DTLVardef@1f0b00eorg.highwire.dtl.DTLVardef@b68f1b_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗