Biology subjects

Hermann, B. P.

Publications and source records attributed to Hermann, B. P..

13 recordsLinked to original sources

bioRxiv2026

Sperm development requires TMC5-dependent mechanoresponsive calcium entry

Spermiogenesis, the transformation of round spermatids into streamlined, fertilization-competent sperm, represents cellular morphogenesis at its most extreme. Despite decades of effort, spermiogenesis remains difficult to recapitulate outside the testis, highlighting the importance of cues within the native tissue environment. The nature of these cues, however, remains poorly understood. Here, we discover that mechanical stimulation elicits Ca2+ entry in spermatids and identify transmembrane channel-like protein 5 (TMC5) as a principal mediator of this response. In both mouse and human testes, TMC5 is selectively expressed in spermatids and localized to the plasma membrane. TMC5 associates with TMC7 and calcium- and integrin-binding (CIB) proteins, mirroring TMC-CIB mechanotransduction complexes in sensory organs. Mechanistically, loss of Tmc5 blocks mechanically evoked Ca2+ entry, leading to disruptions in cytoskeletal remodeling and failure of CREM [&tau] dependent transcriptional programs required for spermiogenesis. Thus, TMC5 is required to couple mechanical cues to sperm development, with direct implications for male infertility.

cell biology↗

bioRxiv2026

Thermodynamic rigidity of harmonic brain states relates to general mental ability in juvenile myoclonic epilepsy

Cognitive difficulties are increasingly recognized in juvenile myoclonic epilepsy (JME), but scalable biomarkers linking resting-state brain dynamics to general mental ability remain limited. Here, we combined topological data analysis, graph signal processing, machine learning, inverse Langevin modeling, and biophysical simulations to test whether EEG-derived network dynamics capture individual differences in general mental ability in JME. We studied 54 patients with JME and 45 healthy controls using resting-state high-density EEG and the raw estimated full-scale score derived from the Wechsler Abbreviated Scale of Intelligence (WASI), used here as an index of general mental ability. Subject-specific low-alpha activity was reconstructed with generalized eigendecomposition, and graph-derived features were extracted from the projection of topological and alpha-power signals onto the functional connectome, providing a graph-harmonic description of large-scale brain-state dynamics. In controls, dynamic EEG-derived features significantly predicted general mental ability, whereas the same framework failed in JME. Because prediction in controls was driven mainly by dynamic measures of smoothness (Dirichlet energy), we next examined the temporal organization of alpha-power smoothness using an inverse Langevin framework. Within the patient group, greater thermodynamic rigidity--that is, stronger confinement of fluctuations around preferred network states--was associated with lower general mental ability. Relative to controls, patients also showed lower thermodynamic noise, indicating a reduced tendency to explore alternative network regimes. Biophysical simulations suggested that reduced dendritic arborization can generate rigidity directly, whereas pharmacological stabilization of hyperexcitable circuits can shift the system toward a more rigid, lower-noise regime. Together, these findings suggest that cognition in JME is linked not only to altered resting-state network dynamics but also to stronger confinement of network-state fluctuations, with both intrinsic circuit abnormalities and treatment-related stabilization representing plausible routes to this rigid phenotype.

neuroscience↗

bioRxiv2024

Role of Dual Specificity Phosphatase 1 (DUSP1) in influencing inflammatory pathways in macrophages modulated by Borrelia burgdorferi lipoproteins

Borrelia burgdorferi (Bb), the spirochetal agent of Lyme disease, has a large array of lipoproteins that play a significant role in mediating host-pathogen interactions within ticks and vertebrates. Although there is substantial information on the effects of B. burgdorferi lipoproteins (BbLP) on immune modulatory pathways, the application of multi-omics methodologies to decode the transcriptional and proteomic patterns associated with host cell responses induced by lipoproteins in murine bone marrow-derived macrophages (BMDMs) has identified additional effectors and pathways. Single-cell RNA-Seq (scRNA-Seq) performed on BMDMs treated with various concentrations of borrelial lipoproteins revealed macrophage subsets within the BMDMs. Differential expression analysis showed that genes encoding various receptors, type I IFN-stimulated genes, signaling chemokines, and mitochondrial genes are altered in BMDMs in response to lipoproteins. Unbiased proteomics analysis of lysates of BMDMs treated with lipoproteins corroborated several of these findings. Notably, dual specificity phosphatase 1 (Dusp1) gene was upregulated during the early stages of BMDM exposure to BbLP. Pre-treatment with benzylidene-3-cyclohexylamino-1-indanone hydrochloride (BCI), an inhibitor of both DUSP1 and 6 prior to exposure to BbLP, demonstrated that DUSP1 negatively regulates NLRP3-mediated pro-inflammatory signaling and positively regulates the expression of interferon-stimulated genes and those encoding Ccl5, Il1b, and Cd274. Moreover, DUSP1, IkB kinase complex and MyD88 also modulate mitochondrial changes in BMDMs treated with borrelial lipoproteins. These findings advance the potential for exploiting DUSP1 as a therapeutic target to regulate host responses in reservoir hosts to limit survival of B. burgdorferi during its infectious cycle between ticks and mammalian hosts. ImportanceBorrelia burgdorferi, the agent of Lyme disease, encodes numerous lipoproteins that play a crucial role as a pathogen associated molecular pattern affecting interactions with tick- and vertebrate-host cells. Single cell transcriptomics validated using unbiased proteomics and conventional molecular biology approaches have demonstrated significant differences in gene expression patterns in a dose- and time-dependent manner following treatment of murine bone marrow derived macrophages with borrelial lipoproteins. Distinct populations of macrophages, alterations in immune signaling pathways, cellular energy production and mitochondrial responses were identified and validated using primary murine macrophages and human reporter cell lines. Notably, the role of Dual Specificity Phosphatase 1 (DUSP1) in influencing several inflammatory, metabolic and mitochondrial responses of macrophages were observed in these studies using known pharmacological inhibitors. Significant outcomes include novel strategies to interfere with immunomodulatory and survival capabilities of B. burgdorferi in reservoir hosts affecting its natural infectious life cycle between ticks and vertebrate hosts.

immunology↗

bioRxiv2024

Normative and individual, non-normative intrinsic networks and the transition to impaired cognition

Despite their temporal lobe pathology, a significant subgroup of temporal lobe epilepsy (TLE) patients are able to maintain normative cognitive functioning. Here, we identify TLE patients with intact versus impaired cognitive profiles, and interrogate for the presence of both normative and highly individual intrinsic connectivity networks(ICN) - all towards understanding the transition from impaired to intact neurocognitive status. We retrospectively investigated data from 88 TLE patients and matched 91 healthy controls with resting-state functional MRI. Functional MRI data were decomposed using independent component analysis to obtain individualized ICNs. Here, we calculated the degree of match between individualized ICNs and canonical ICNs (e.g., Yeo et.al 17 resting-state network) and divided each participants ICNs into normative or non-normative status based on the degree of match. We found that the individualized networks matched the canonical networks less well in the cognitively impaired compared to the cognitively intact TLE patients. The cognitively impaired patients showed significant abnormalities in the profiles of both normative and non-normative networks, whereas the intact patients showed abnormalities only in non-normative networks. At the same time, we found normative networks held a strong, positive association with the neuropsychological measures, with this association negative in non-normative networks. We were able to provide the initial data demonstrating that significant cognitive deficits are associated with the status of highly-individual ICNs, making clear that the transition from intact to impaired cognitive status is not simply the result of disruption to normative brain networks.

neuroscience↗

bioRxiv2022

Efficient generation of marmoset primordial germ cell-like cells using induced pluripotent stem cells

Reconstitution of germ cell fate from pluripotent stem cells provides an opportunity to understand the molecular underpinnings of germ cell development. Here, we established robust methods for pluripotent stem cells (iPSCs) culture in the common marmoset (Callithrix jacchus, cj), which stably propagate in an undifferentiated state. Notably, iPSCs cultured on a feeder layer in the presence of a WNT signaling inhibitor upregulated genes related to ubiquitin-dependent protein catabolic processes and enter a permissive state that enables differentiation into primordial germ cell-like cells (PGCLCs) bearing immunophenotypic and transcriptomic similarities to pre-migratory cjPGCs in vivo. Induction of cjPGCLCs is accompanied by transient upregulation of mesodermal genes culminating in the establishment of a primate specific germline transcriptional network. Moreover, cjPGCLCs can be expanded in monolayer while retaining the germline state. Upon co-culture with mouse testicular somatic cells, these cells acquire an early prospermatogonia-like phenotype. Our findings provide a framework for understanding and reconstituting marmoset germ cell development in vitro, thus providing a comparative tool and foundation for a preclinical modeling of human in vitro gametogenesis.

developmental biology↗

bioRxiv2020

Reconstitution of prospermatogonial specification in vitro from human induced pluripotent stem cells

Establishment of spermatogonia throughout the fetal and postnatal period is essential for production of spermatozoa and male fertility. Here, we established a protocol for in vitro reconstitution of human prospermatogonial specification whereby human primordial germ cell (PGC)-like cells (hPGCLCs) differentiated from human induced pluripotent stem cells were further induced into M-prospermatogonia-like cells (MLCs) and T1 prospermatogonia-like cells (T1LCs) using long-term cultured xenogeneic reconstituted testes. Single cell RNA-sequencing was used to delineate the lineage trajectory leading to T1LCs, which closely resemble human T1-prospermatogonia in vivo and exhibited gene expression related to spermatogenesis and diminished proliferation, a hallmark of quiescent T1 prospermatogonia. Notably, this system enabled us to visualize the dynamic and stage-specific regulation of transposable elements during human prospermatogonial specification. Together, our findings pave the way for understanding and reconstructing human male germline development in vitro.

developmental biology↗

bioRxiv2020

Proper names from story recall are associated with beta-amyloid in cognitively unimpaired adults at risk for Alzheimer's disease

Due to advances in the early detection of Alzheimers disease (AD) biomarkers including beta-amyloid (A{beta}), neuropsychological measures that are sensitive to concurrent, subtle changes in cognition are critically needed. Story recall tasks have shown sensitivity to early memory declines in persons with Mild Cognitive Impairment and early stage dementia, as well as in persons with autosomal dominantly inherited AD up to 10 years prior to a dementia diagnosis. However, the evidence is inconclusive regarding relationships between evidence of A{beta} and story recall measures. Because story recall tasks require the encoding and delayed retrieval of several lexical-semantic categories, such as proper names, verbs, and numerical expressions, and because lexical categories have been shown to be differentially impaired in persons with MCI, we focused on item-level analyses of lexical-semantic retrieval from a quintessential story recall task, Logical Memory from the Wechsler Memory Scale. Our objective was to investigate whether delayed recall of lexical categories (proper names, verbs and/or numerical expressions), as well as the traditional total score measure, was associated with "preclinical AD," or cognitively unimpaired adults with positive A{beta} deposition on positron emission tomography (PET) neuroimaging using Pittsburgh Compound B. We developed an item-level scoring system, in which we parsed items into lexical categories and examined the immediate and delayed recall of these lexical categories from 217 cognitively unimpaired participants from the Wisconsin Registry for Alzheimers Prevention. We performed binary logistic regression models with story recall score as predictor and A{beta} status (positive/negative) as the outcome. Using baseline Logical Memory data, proper names from delayed story recall were significantly associated with A{beta} status, such that participants who recalled more proper names were less likely to be classified as PiB(+) (odds ratio = .58, p=.01). None of the other story recall variables, including total score, were associated with PiB status. Secondary analyses determined that immediate recall of proper names was not significantly associated with A{beta}, suggesting a retrieval deficit rather than that of encoding. The present findings suggest that lexical semantic retrieval measures from existing story recall tasks may be sensitive to A{beta} deposition, and may provide added utility to a widely-used, long-standing neuropsychological test for early detection of cognitive decline on the AD continuum.

neuroscience↗

bioRxiv2019

Amyloid duration is associated with preclinical cognitive decline and tau PET

INTRODUCTIONThis study applies a novel algorithm to longitudinal amyloid positron emission tomography (PET) imaging to identify age-heterogeneous amyloid trajectory groups, estimate the age and duration (chronicity) of amyloid positivity, and investigate chronicity in relation to cognitive decline and tau burden.\n\nMETHODSCognitively unimpaired participants (n=257) underwent 1-4 amyloid PET scans. Group-based trajectory modeling was applied to participants with longitudinal scans (n=171) to identify and model amyloid trajectory groups, which were combined with Bayes theorem to estimate age and chronicity of amyloid positivity. Relationships between chronicity, cognition, clinical progression and tau PET (MK-6240) were investigated using regression models.\n\nRESULTSChronicity explained more heterogeneity in amyloid binding than age and binary amyloid status. Chronicity was associated with faster cognitive decline, increased risk of abnormal cognition, and higher entorhinal tau.\n\nDISCUSSIONAmyloid chronicity provides unique information about cognitive decline and neurofibrillary tangle development and may be useful to investigate preclinical AD.

neuroscience↗

bioRxiv2019

Self-reported health behaviors and longitudinal cognitive performance: Results from the Wisconsin Registry for Alzheimer’s Prevention

BackgroundStudies have suggested associations between self-reported engagement in health behaviors and reduced risk of cognitive decline. Most studies explore these relationships using one health behavior, often cross-sectionally or with dementia as the outcome. In this study, we explored whether several individual self-reported health behaviors were associated with cognitive decline when considered simultaneously, using data from the Wisconsin Registry for Alzheimers Prevention (WRAP), an Alzheimers disease risk-enriched cohort who were non-demented and in late midlife at baseline.\n\nMethodWe analyzed longitudinal cognitive data from 828 participants in WRAP, with a mean age at baseline cognitive assessment of 57 (range = 36-78, sd = 6.8) and an average of 6.3 years (standard deviation = 1.9, range = 2-10) of follow-up. The primary outcome was a multi-domain cognitive composite, and secondary outcomes were immediate/delayed memory and executive function composites. Predictors of interest were self-reported measures of physical activity, cognitive activity, adherence to a Mediterranean-style diet (MIND), and interactions with each other and age. We conducted linear mixed effects analyses within an Information-theoretic (IT) model averaging (MA) approach on a set of models including covariates and combinations of these 2- and 3-way interactions. The IT approach was selected due to the large number of interactions of interest and to avoid pitfalls of traditional model selection approaches.\n\nResultsModel-averaged results identified no significant modifiable behavior*age interactions in relationship to the primary composite outcome. In secondary outcomes, higher MIND diet scores associated with slower decline in executive function. Men showed faster decline than women on delayed memory, independent of health behaviors. There were no other significant interactions among any other health behaviors and cognitive trajectories.\n\nConclusionsWhen multiple covariates and health behaviors were considered simultaneously, there were limited weak associations with cognitive decline in this age range. These results may be explained alone or in combination by three alternative explanations: 1) the range of cognitive decline is in middle age is too small to observe relationships with health behaviors, 2) the putative associations of these health behaviors on cognition may not be robust in this age range, or 3) the self-reported measures of the health behaviors may not be optimal for predicting cognitive decline. More study may be needed that incorporates sensitive measures of health behaviors, AD biomarker profiles, and/or other disease comorbidities.

neuroscience↗

bioRxiv2019

Unique Epigenetic Programming Distinguishes Regenerative Spermatogonial Stem Cells in the Developing Mouse Testis

Spermatogonial stem cells (SSCs) both self-renew and give rise to progenitor spermatogonia that enter steady-state spermatogenesis in the mammalian testis. However, questions remain regarding the extent to which SSCs and progenitors represent stably distinct spermatogonial subtypes. Here we provide the first multiparametric integrative analysis of mammalian germ cell epigenomes comparable to that done by the ENCODE Project for >100 somatic cell types. Differentially expressed genes distinguishing SSCs and progenitors showed distinct histone modification patterns as well as differences in distal intergenic low-methylated regions. Motif-enrichment analysis predicted transcription factors that regulate this spermatogonial subtype-specific epigenetic programming, and gene-specific chromatin immunoprecipitation analyses confirmed subtype-specific differences in binding of a subset of these factors to target genes. Collectively, these results suggest that SSCs and progenitors are stably distinct spermatogonial subtypes differentially programmed to either self-renew and maintain regenerative capacity as SSCs, or lose regenerative capacity and initiate lineage commitment as progenitors.

developmental biology↗

bioRxiv2017

Characterizing the effects of sex, APOE 4, and literacy on mid-life cognitive trajectories: Application of Information-Theoretic model-averaging and multi-model inference techniques to the Wisconsin Registry for Alzheimer’s Prevention Study

In this paper we apply Information-Theoretic (IT) model averaging to characterize a set of complex interactions in a longitudinal study on cognitive decline. Prior research has identified numerous genetic (including sex), education, health and lifestyle factors that predict abnormal cognitive decline.Traditional model selection approaches (e.g., backward or stepwise selection), attempt to find models that best fit the observed data; these techniques risk interpretations that only the selected predictors are important. In reality, several models may fit similarly well but result in different conclusions (e.g., about size and significance of parameter estimates), and inference from a single model chosen after a selection procedure can lead to overly simplistic conclusions. Here we utilize longitudinal cognitive data from the Wisconsin Registry for Alzheimers Prevention to examine the effects of sex and the Apolipoprotein E (APOE) 4 allele (non-modifiable factors), and reading literacy achievement (modifiable) on cognitive decline. For each outcome, we applied IT model averaging to a model set with combinations of interactions among sex, APOE, literacy, and age. For a list-learning test, model-averaged results showed better performance for women vs men, with faster decline among men; increased literacy was associated with better performance, particularly among men. APOE had less effect in this age range (~40-70). These results illustrate the utility of the IT approach and point to verbal ability as a potential modifier of decline. Whether the protective effect of literacy is due to educational attainment or intrinsic verbal intellectual ability is the topic of ongoing work.

neuroscience↗

bioRxiv2017

Longitudinal standards for mid-life cognitive performance: Identifying abnormal within-person changes in the Wisconsin Registry for Alzheimer’s Prevention

A major challenge in the field of cognitive aging is differentiating disease-related cognitive change that has not yet become overt impairment from the more gradual decline in performance expected with normal aging. Published normative reference values are nearly always for single time point performances rather than longitudinal change in performance. To gain insight into how we might tackle the problem of identifying worrisome trajectories, we borrow a method from anthropometry: the development of standards that are conditional on an individuals past measurements. We use quantile regression to create growth-curve-like models of performance on several common neuropsychological tests of memory and executive function while accounting for age, sex, education, estimated verbal ability, and past performance on the test, and then use these to estimate individuals percentile ranks. Choosing the 7th percentile as a threshold (corresponding to approximately 1.5 standard deviations below the expected mean), we then explore relationships between subthreshold performance, clinical outcomes, and subjective impairment. Participants whose performance fell below the 7th percentile were more likely to be given an abnormal research diagnosis at the current visit, but not at later visits. Performance below this threshold was also linked to subjective and informant reports of worsening memory function. We discuss potential uses of this method in theoretical and applied research and clinical settings.

neuroscience↗

bioRxiv2017

The Wisconsin Registry for Alzheimer’s Prevention: A Review of findings and current directions

The Wisconsin Registry for Alzheimers Prevention (WRAP) is a longitudinal observational cohort study enriched with persons with a parental history (PH) of probable Alzheimers Disease (AD) dementia. Since late 2001, WRAP has enrolled 1,561 people at a mean baseline age of 54. Participants return for a second visit four years after baseline and subsequent visits occur every two years. Eighty-one percent (1270) of participants remain active in the study at a current mean age of 64 and 9 years of follow-up. Serially assessed cognition, self-reported medical and lifestyle histories (e.g. diet, physical and cognitive activity, sleep, and mood), laboratory tests, genetics, and linked studies comprising molecular imaging, structural imaging and cerebrospinal fluid data, have yielded many important findings. In this cohort, PH of probable AD is associated with 46% APOE {varepsilon}4 positivity, more than twice the rate of 22% among persons without PH. Subclinical or worse cognitive decline relative to internal normative data has been observed in 17.6% of the cohort. Twenty-eight percent exhibit amyloid and/or tau positivity. Biomarker elevations, but not APOE or PH status, are associated with cognitive decline. Salutary health and lifestyle factors are associated with better cognition and brain structure, and lower AD pathophysiologic burden. Of paramount importance is establishing the amyloid and tau AD endophenotypes to which cognitive outcomes can be linked. Such data will provide new knowledge on the early temporal course of AD pathophysiology and inform the design of secondary prevention clinical trials.

neuroscience↗