Biology subjects

Newell, K.

Publications and source records attributed to Newell, K..

6 recordsLinked to original sources

bioRxiv2026

Historic and contemporary museum specimens implicate Northern Red-backed Vole (Clethrionomys rutilus) as borealpox host as early as 1990s

Borealpox virus (BRPV; formerly Alaskapox) is an orthopoxvirus that has caused seven reported human infections in Alaska since 2015, including a fatal case in 2023. The natural reservoir of BRPV is unknown, although previous investigations have raised the possibility of wild small mammals transmitting the virus to humans, either through direct contact or via domestic cats and dogs. To understand which species may be involved in the maintenance and/or spillover of BRPV in Alaska, we trapped and sampled wild small mammals (including voles, shrews, and squirrels) in 2021 and 2024 near reported human case locations in Fairbanks and the Kenai Peninsula, respectively. We found evidence of previous exposure to orthopoxviruses in five species (including the House Mouse, Mus musculus) and detected BRPV DNA as well as viable virus in Northern Red-backed Voles (Clethrionomys rutilus). Further, screening of tissues from historical museum specimens revealed BRPV DNA in C. rutilus specimens collected in Denali National Park and Preserve in 1998 and 1999, 17 years before the first reported human case of BRPV. Phylogenomic analysis of all human and animal BRPV isolates strongly supports the hypothesis of local human infections through multiple spillover events. These findings suggest C. rutilus as a possible reservoir species for BRPV and indicate that BRPV has been present in Alaskan wild small-mammal populations for at least 25 years. Our study highlights the potential of museum collections to elucidate the temporal, spatial, and host ranges of emerging pathogens. Further museum- and field-based sampling will clarify the true geographic range of BRPV, which is closely related to Old World orthopoxviruses and may be circulating beyond North America.

ecology↗

bioRxiv2026

Cbfb2 gene dosage programs the differential lymphoid lineage developmental potential of fetal and adult hematopoietic progenitors

Innate-like lymphocyte subsets are generated predominantly during early-life windows, yet the mechanisms that restrict their development in adulthood remain unclear. Here we identify Cbfb2 gene dosage as a quantitative regulator of stage-specific lymphoid potential. We show that reduction of CBF{beta}2 levels unlocks fetal-like competence in adult hematopoietic progenitors, enabling robust generation of IL-17-producing {gamma}{delta} T (T{gamma}{delta}17) cells. Although Cbfb2 haploinsufficiency minimally alters steady-state transcription, chromatin profiling of H3K4me3 revealed promoter-level changes in adult lymphoid-primed multipotent progenitors consistent with altered developmental priming. In adult bone marrow chimeras, Cbfb+/2m progenitors efficiently generated functional V{gamma}2+ T{gamma}{delta}17 cells in lymph nodes and skin, and restoring Cbfb2 expression suppressed this capacity, establishing a dosage-dependent mechanism. Using an optimized in utero transplantation system, we further demonstrate that fetal niches amplify this latent competence and selectively favor IL-17-committed {gamma}{delta} T cell differentiation over conventional {beta} T cell output. Notch1 haploinsufficiency enhanced T{gamma}{delta}17 generation and phenocopied the effect of CBF{beta}2 dosage reduction, linking quantitative NOTCH1 signaling to innate-like lymphocyte developmental programming. Together, these findings reveal that fetal versus adult lymphopoiesis is governed by quantitative tuning of RUNX:CBF{beta} activity and uncover unexpected plasticity in adult hematopoiesis controlled by transcription factor dosage.

immunology↗

bioRxiv2026

Pathological TDP-43 filaments accumulate at synapses and cause synaptic dysfunction

The assembly of TAR DNA-binding protein 43 (TDP-43) into amyloid filaments within neurons is a hallmark of multiple neurodegenerative diseases, including motor neuron diseases (MND), frontotemporal dementias (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). These diseases result from the deterioration and loss of neurons, with synaptic dysfunction and neuronal hyperexcitability being prominent early events. Pathogenic mutations in the TDP-43 gene, TARDBP, that promote filament formation have established a causal role for TDP-43 assembly in neurodegenerative diseases. However, the molecular mechanisms underlying filament accumulation and their contribution to neurodegeneration are poorly understood. TDP-43 filaments can propagate between neurons in a prion-like manner, which may underlie the progressive spread and accumulation of TDP-43 pathology in disease. Here, we studied early stages of TDP-43 filament accumulation following internalisation of patient-derived TDP-43 filaments by mouse and human cortical neurons. Using proximity labelling, we identified molecular environments and putative interactions of TDP-43 filaments. We found that TDP-43 filaments accumulated at synapses, particularly in proximity to the presynaptic active zone, which we confirmed in FTD patient brain sections. Electron cryo-tomography (cryo-ET) directly visualised abundant TDP-43 filaments spanning the presynaptic cytoplasm in situ, which contacted synaptic vesicles and the plasma membrane. Functional measurements revealed that the accumulation of TDP-43 filaments led to presynaptic dysfunction and subsequent neuronal hyperexcitability. These findings suggest that synapses are a major early site of TDP-43 filament accumulation, relevant to their propagation, and directly link TDP-43 filament gain of function to synaptic dysfunction.

neuroscience↗

bioRxiv2026

Distinct TAF15 amyloid filament folds define multiple subtypes of FTLD-TAF15

Neurodegenerative diseases are characterised by the assembly of a limited number of disease-specific proteins into amyloid filaments, which form intracellular inclusions or extracellular deposits in the central nervous system (CNS)1,2. We previously found that amyloid filaments of TATA-binding protein-associated factor 15 (TAF15) characterise a subtype of frontotemporal lobar degeneration with FET protein-immunoreactive inclusions (FTLD-FET)3, termed atypical FTLD with ubiquitin-positive inclusions (aFTLD-U)4, which causes early-onset, rapidly progressive behavioural variant frontotemporal dementia (FTD). However, it was not clear if TAF15 proteinopathy was more widespread in neurodegenerative diseases. Two additional FTLD-FET subtypes have been proposed, neuronal intermediate filament inclusion body disease (NIFID) and basophilic inclusion body disease (BIBD)5,6, which have more heterogenous clinical presentations including FTD, motor neuron diseases (MND) and movement disorders. Here, we used electron cryo-microscopy (cryo-EM) to determine a total of 32 amyloid filament structures from the brains of 17 individuals encompassing all three proposed subtypes of FTLD-FET and their diverse clinical presentations. All cases were characterised by TAF15 filaments, in the absence of filaments of the other FET proteins, fused in sarcoma (FUS) and Ewings sarcoma (EWS). All three aFTLD-U cases had the previously-reported TAF15 fold3. Unexpectedly, we found four distinct TAF15 folds among 11 NIFID cases. Eight of these cases shared a common fold, while the remaining three were each distinct. Furthermore, we found distinct TAF15 folds for each of the three BIBD cases. Neuropathological reassessment of the neocortical TAF15 inclusion pathology of these cases distinguished the NIFID cases with the common fold from the others. Thus, TAF15 filament structures form the basis of a new, expanded classification of FTLD-FET subtypes. Moreover, we discovered a TAF15 Y38C variant in the filament fold of one of the individuals with BIBD. The structure is unable to incorporate wild-type TAF15, despite the individual being heterozygous, suggesting that this variant drives TAF15 filament assembly. This study provides structural and genetic evidence that TAF15 amyloid filaments underlie the diverse group of neurodegenerative diseases currently termed FTLD-FET, which we therefore rename FTLD-TAF15.

molecular biology↗

bioRxiv2024

The disappointment centre of the brain gets exciting: A systematic review of habenula dysfunction in depression

BackgroundThe habenula is an epithalamic brain structure that acts as a neuroanatomical hub connecting the limbic forebrain to the major monoamine centres. Abnormal habenula activity is increasingly implicated in depression, with a surge in publications on this topic in the last 5 years. Direct stimulation of the habenula is sufficient to induce a depressive phenotype in rodents, suggesting a causative role in depression. However, the molecular basis of habenula dysfunction in depression remains elusive and it is unclear how the preclinical advancements translate to the clinical field. MethodsA systematic literature search was conducted following the PRISMA guidelines. The two search terms depress* and habenula* were applied across the databases Scopus, Web of Science and PubMed. Studies eligible for inclusion must have examined changes in the habenula in clinical cases of depression or preclinical models of depression. ResultsPreclinical studies (n=57) measured markers of habenula activity (n=16) and neuronal firing (n=21), largely implicating habenula hyperactivity in depression. Neurotransmission was briefly explored (n=13), suggesting imbalances within excitatory and inhibitory habenula signalling. Additional preclinical studies reported neuroconnectivity (n=1), inflammatory (n=2), genomic (n=2) and circadian rhythm (n=2) abnormalities. Seven preclinical studies (12.2%) included both males and females. From these, 5 studies (71%) reported a significant difference between the sexes in at least one habenula measure taken. Clinical studies (n=18) reported abnormalities in habenula connectivity (n=11), volume (n=5) and molecular markers (n=2). Clinical studies generally included male and female subjects (n=15), however, few of these studies examined sex as a biological variable (n=5) ConclusionsBoth preclinical and clinical evidence suggest the habenula is disrupted in depression. However, there are opportunities for sex-specific analyses across both areas. Preclinical evidence consistently suggests habenula hyperactivity as a primary driver for the development of depressive symptoms. Clinical studies support gross habenula abnormalities such as altered activation, connectivity, and volume, with emerging evidence of blood brain barrier dysfunction, however, progress is limited by a lack of detailed molecular analyses.

neuroscience↗

bioRxiv2021

Functional characterization of ovine dorsal root ganglion neurons reveals peripheral sensitization after osteochondral defect

ObjectiveKnee joint trauma can cause an osteochondral defect (OD), a risk factor for osteoarthritis and cause of debilitating pain in patients. Modelling OD in rodents is difficult due to their smaller joint size. This study proposes sheep as a translationally relevant model to understand the neuronal basis of OD pain. MethodsUnilateral 6 mm deep OD was induced in adult sheep, 2-6 weeks after which dorsal root ganglion neurons (DRG neurons) were cultured from the control and OD side. Functional assessment of neuronal excitability and activity of the pain-related ion channels, TRPV1 and P2X3, was carried out using electrophysiology and Ca2+-imaging. Immunohistochemistry was utilized to verify expression of pain-related proteins. ResultsAn increased proportion of OD DRG neurons (sheep, n = 3, Ctrl neurons, n =15, OD neurons, n = 16) showed spontaneous electrical excitability (p = 0.009, unpaired t-test) and hyperexcitability upon TRPV1 agonist (capsaicin) application (p = 0.04, chi-sq test). Capsaicin also produced Ca2+ influx in an increased proportion of OD DRG neurons isolated (p = 0.001, chi-sq test). By contrast, neither protein expression, nor functionality of the P2X3 ion channel were altered in OD neurons. ConclusionsWe provide evidence of increased excitability of DRG neurons (which is an important neural correlate of pain) and TRPV1 function in an OD sheep model. Our data show that functional assessment of sheep DRG neurons can provide important insights into the neural basis of OD pain and thus potentially prevent its progression into arthritic pain.

neuroscience↗