Biology subjects

Milman, N.

Publications and source records attributed to Milman, N..

6 recordsLinked to original sources

bioRxiv2026

Immune Aging is an Independent Risk Factor for Cardiovascular Disease

Cardiovascular disease remains the leading cause of mortality, yet current clinical predictors miss substantial disease-risk. While the immune system contributes to this residual risk, its complexity has hindered broadly applicable, clinically scalable metrics of immune-state. Here, we establish the prognostic relevance of IMM-AGE, a system-level metric of immune-aging, to cardiovascular disease. We learn reference-free, low-dimensional representations of IMM-AGE across cell, protein, and mRNA measurements, enabling high-fidelity quantification across modalities, blood fractions, and platforms, including standard hospital flow cytometers. Among UK-Biobank participants, 56.9% of IMM-AGE variation remained unexplained by routine clinical measures, and across diverse cohorts totaling ~48,000 individuals, elevated IMM-AGE was independently associated with future cardiovascular risk, intervention outcomes, and mortality. Moreover, incorporation of IMM-AGE into the PREVENT 10-year risk equation significantly improved risk stratification. These findings establish immune-aging as an independent biological dimension of cardiovascular disease-risk and support IMM-AGE as a practical tool for precision risk assessment.

immunology↗

bioRxiv2025

Systems level analysis of B-cell development identifies BDNF as a driver for human B lymphopoiesis

B-cell aplasia is a major consequence of aging, chemotherapy, and B-cell-depleting immunotherapies, compromising immune protection against infections, cancer, and vaccines. Yet, unlike the myeloid and erythroid lineages, no strategy exists to accelerate human B-cell reconstitution. Here, we used an integrative systems biology approach to identify regulators of human B lymphopoiesis in the bone marrow (BM) microenvironment. By combining single-cell transcriptomic analysis of human BM with intercellular communication mapping, we generated an initial set of candidate factors predicted to act on developing B cells. To distinguish biologically meaningful putative regulators from a broad candidate space, we further intersected these findings with orthogonal human datasets capturing age-impaired B lymphopoiesis and protein dynamics associated with B-cell depletion and reconstitution. This convergent prioritization strategy highlighted a focused set of putative regulators, among which brain-derived neurotrophic factor (BDNF) emerged repeatedly as a top putative regulator. Functional interrogation in progenitor BM cells showed that several prioritized putative regulators induced transcriptional programs linked to early immune development, with BDNF consistently promoting pathways associated with B-cell differentiation. Importantly, in a human in vitro BM co-culture system, BDNF enhanced the differentiation of CD34+ hematopoietic progenitors into CD19+ progenitor B cells. Together, these findings identify BDNF as a previously unrecognized regulator of early human B lymphopoiesis and establish a general framework for uncovering functional hematopoietic regulators by integrating single-cell analysis with complementary biological and clinical signals. This approach may support future strategies to improve immune reconstitution in settings of prolonged B-cell depletion.

systems biology↗

bioRxiv2025

Centella asiatica improves sleep quality and quantity in aged mice

Age-related sleep disruption is common in older adults. Not only does the total amount of time spent in sleep decline, but the number of arousals during sleep increases with age. As sleep is important for both memory consolidation and to prevent neurodegenerative pathology, this decline in sleep and/or sleep consolidation may underlie age-related cognitive decline and dementias. Furthermore, treatment of sleep disruption can improve quality of life. However, few interventions have successfully reversed age-related sleep decline. Extracts from the plant Centella asiatica have demonstrated neuroprotective effects in human, rodent, and fly models of aging and neurodegenerative diseases, and is a promising intervention for dementias, yet little is known about how these extracts affect sleep patterns. Here, we administered Centella asiatica water extract (CAW) dosed or control chow to male and female C57BL6/J mice aged 18 months. Effects on sleep composition were determined using electrodes that recorded EEG and EMG signals. We found that CAW dosed chow (1000 mg/kg/day) increased REM sleep time in aged male mice and decreased the number of arousals during sleep observed in aged females, compared to age- and sex-matched controls. We conclude that CAW administered in food has a moderate, sex-dependent effect on sleep quantity and quality. Statement of SignificanceSleep declines with age and may underline age-related cognitive changes. However, few interventions have successfully reversed age-related sleep and cognitive decline. This study found that botanical extract from the plant Centella asiatica increased total REM sleep time in aged male mice, and decreased sleep fragmentation in aged female mice, compared to age- and sex-matched controls. Whether these moderate, sex-dependent effect sizes on sleep in aged mice are impactful enough to affect cognition, quality of life, and/or neurodegenerative pathology could be explored in future studies.

neuroscience↗

bioRxiv2022

Systematic mapping of neural signals in the periphery reveals a rich and specific alphabet for immune cell communication

Accumulating evidence indicate a strong link between neural signals and the immune system. Given neural signals constitute a large family that may be leveraged for communication, we systematically explored the neuro-immune regulation network in the periphery and uncovered a broad yet lineage selective expression of neuro-receptors on immune cells. We constructed a rich social immune network map showing the neural molecular pathways supporting the regulation of the immune system at steady state. Our results emphasize neuro-receptors role in the commitment and differentiation of B and T cells along their developmental process. We identified the immune cells functionality in the specific tissue is extensively shaped by the communication with the microenvironment and nervous systems via a rich alphabet of neural mediators. Collectively, our findings suggest neural genes are an integral part of the immune regulatory system and provide clear testable new avenues of experimental follow up for neuroimmunologists and immunologists alike. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=185 SRC="FIGDIR/small/522179v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@d4032eorg.highwire.dtl.DTLVardef@11ce763org.highwire.dtl.DTLVardef@9b279eorg.highwire.dtl.DTLVardef@45fc89_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LI160 neural genes potentially active in immune cells in the periphery with high specificity to lineage C_LIO_LINeuro-receptors co-expressed in immune lineages are enriched for biological functions C_LIO_LIChanges in neuro-receptors expression influence the HCS differentiation and commitment C_LIO_LIImmune-microenvironment neural signaling architecture reflects tissue biological role C_LI

immunology↗

bioRxiv2021

Multiple trajectory alignment reconstructs disease dynamics for discovery and clinical benefit

Diseases change over time, both phenotypically and in underlying driving molecular processes. Though understanding disease progression dynamics is critical for diagnostics and treatment, capturing these dynamics is difficult, due to their complexity and the high heterogeneity between individuals. We developed TimeAx, an algorithm which builds a comparative framework for capturing disease dynamics using high-dimensional short time-series data. We demonstrate TimeAx utility by studying disease progression dynamics for multiple diseases and data types. Notably, for urothelial bladder cancer tumorigenesis, we identified a stromal pro-invasion point on the disease progression axis, characterized by massive immune cell infiltration to the tumor microenvironment and increased mortality. Moreover, the continuous TimeAx model differentiated between early and late tumors within the same tumor subtype, uncovering novel molecular transitions and potential targetable pathways. Overall, we present a powerful approach for studying disease progression dynamics, providing improved molecular interpretability and clinical benefits for patient stratification and outcome prediction.

systems biology↗

bioRxiv2021

A personalized network framework reveals predictive axis of anti-TNF response across diseases

Personalized treatment of complex diseases has been mostly predicated on biomarker identification of one drug-disease combination at a time. Here, we used a novel computational approach termed Disruption Networks to generate a new data type, contextualized by cell-centered individual-level networks, that captures biology otherwise overlooked when performing standard statistics. The new data-type extends beyond the feature level space, to the relations space, by quantifying individual-level breaking or rewiring of cross-feature relations. Applying disruption network to dissect high-dimensional blood data, we discover and validate that the RAC1-PAK1 axis is predictive of anti-TNF response in inflammatory bowel disease. Intermediate monocytes, which correlate with the inflammatory state, play a key role in the RAC1-PAK1 responses, supporting their modulation as a therapeutic target. This axis also predicts response in rheumatoid arthritis, validated in three public cohorts. Our findings support blood-based drug response diagnostics across immune-mediated diseases, implicating common mechanisms of non-response.

systems biology↗