bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of direct Purkinje cell outputs to the brainstem
Authors: Chen Christopher H. , Yao Zhiyi , Wu Shuting , Regehr Wade G. 
Published: August 2024

AbstractPurkinje cells (PCs) primarily project to cerebellar nuclei but also directly innervate the brainstem. Some PC-brainstem projections have been described previously, but most have not been thoroughly characterized. Here we use a PC-specific cre line to anatomically and electrophysiologically characterize PC projections to the brainstem. PC synapses are surprisingly widespread, with the highest densities found in the vestibular and parabrachial nuclei. However, there are pronounced regional differences in synaptic densities within both the vestibular and parabrachial nuclei. Large optogenetically-evoked PC-IPSCs are preferentially observed in subregions with the highest densities of PC synapses, suggesting that PCs selectively influence these areas and the behaviors they regulate. Unexpectedly, the pontine central gray and nearby subnuclei also contained a low density of PC synapses, and large PC-IPSCs are observed in a small fraction of cells. We combined electrophysiological recordings with immunohistochemistry to assess the molecular identities of two putative PC targets: PC synapses onto mesencephalic trigeminal neurons were not observed even though these cells are in close proximity to PC boutons. PC synapses onto locus coeruleus neurons are exceedingly rare or absent, even though previous studies concluded that PCs are a major input to these neurons. The availability of a highly selective cre line for PCs allowed us to study functional synapses, while avoiding complications that can accompany the use of viral approaches. We conclude that PCs directly innervate numerous brainstem nuclei, but only inhibit a small fraction of cells in many nuclei. This suggests that PCs target cell types with specific behavioral roles in brainstem regions.
C-C chemokine receptor 4 deficiency exacerbates early atherosclerosis in mice
Authors: Tanaka Toru , Sasaki Naoto , Krisnanda Aga , Amin Hilman Zulkifli , Ito Ken , Horibe Sayo , Matsuo Kazuhiko , Hirata Ken-ichi , Nakayama Takashi , Rikitake Yoshiyuki 
Published: August 2024

AbstractChronic inflammation via dysregulation of T cell immune responses is critically involved in the pathogenesis of atherosclerotic cardiovascular disease. Improving the balance between proinflammatory T cells and anti-inflammatory regulatory T cells (Tregs) may be an attractive approach for treating atherosclerosis. Although C-C chemokine receptor 4 (CCR4) has been shown to mediate the recruitment of T cells to inflamed tissues, its role in atherosclerosis is unclear. Here, we show that genetic deletion of CCR4 in hypercholesterolemic mice accelerates the development of early atherosclerotic lesions characterized by an inflammatory plaque phenotype. This was associated with the augmentation of proinflammatory T helper type 1 (Th1) cell responses in peripheral lymphoid tissues, para-aortic lymph nodes, and atherosclerotic aorta. Mechanistically, CCR4 deficiency in Tregs impaired their suppressive function and tended to inhibit their migration to the atherosclerotic aorta, and subsequently augmented Th1 cell-mediated immune responses through defective regulation of dendritic cell function, which accelerated aortic inflammation and atherosclerotic lesion development. Thus, we revealed a previously unrecognized role for CCR4 in controlling the early stage of atherosclerosis via Treg-dependent regulation of proinflammatory T cell responses. Our data suggest that CCR4 is an important negative regulator of atherosclerosis.
Acute systemic macrophage depletion in osteoarthritic mice alleviates pain-related behaviors and does not affect joint damage
Authors: Geraghty Terese , Ishihara Shingo , Obeidat Alia M. , Adamczyk Natalie S. , Hunter Rahel S. , Li Jun , Wang Lai , Lee Hoomin , Ko Frank C. , Malfait Anne-Marie , Miller Rachel E. 
Published: August 2024

AbstractBackgroundOsteoarthritis (OA) is a painful degenerative joint disease and a leading source of years lived with disability globally due to inadequate treatment options. Neuroimmune interactions reportedly contribute to OA pain pathogenesis. Notably, in rodents, macrophages in the DRG are associated with onset of persistent OA pain. Our objective was to determine the effects of acute systemic macrophage depletion on pain-related behaviors and joint damage using surgical mouse models in both sexes.MethodsWe depleted CSF1R+ macrophages by treating male macrophage Fas-induced apoptosis (MaFIA) transgenic mice 8-or 16-weekspostdestabilization of the medial meniscus (DMM) with AP20187 or vehicle control (10 mg/kgi.p., 1x/day for 5 days), or treating female MaFIA mice 12 weekspostpartial meniscectomy (PMX) with AP20187 or vehicle control. We measured pain-related behaviors 1-3 days before and after depletion, and, 3-4 days after the last injection we examined joint histopathology and performed flow cytometry of the dorsal root ganglia (DRGs). In a separate cohort of male 8-week DMM mice or age-matched naïve vehicle controls, we conducted DRG bulk RNA-sequencing analyses after the 5-day vehicle or AP20187 treatment.ResultsEight-and 16-weekspostDMM in male mice, AP20187-induced macrophage depletion resulted in attenuated mechanical allodynia and knee hyperalgesia. Female mice showed alleviation of mechanical allodynia, knee hyperalgesia, and weight bearing deficits after macrophage depletion at 12 weekspostPMX. Macrophage depletion did not affect the degree of cartilage degeneration, osteophyte width, or synovitis in either sex. Flow cytometry of the DRG revealed that macrophages and neutrophils were reduced after AP20187 treatment. In addition, in the DRG, only MHCII+ M1-like macrophages were significantly decreased, while CD163+MHCII-M2-like macrophages were not affected in both sexes. DRG bulk RNA-seq revealed thatCxcl10andIl1bwere upregulated with DMM surgery compared to naïve mice, and downregulated in DMM after acute macrophage depletion.ConclusionsAcute systemic macrophage depletion reduced the levels of pro-inflammatory macrophages in the DRG and alleviated pain-related behaviors in established surgically induced OA in mice of both sexes, without affecting joint damage. Overall, these studies provide insight into immune cell regulation in the DRG during OA.
Mispitools: An R package for comprehensive statistical methods in Kinship Inference
Authors: Marsico Franco L. 
Published: August 2024

AbstractThe search for missing persons is a complex process that involves the comparison of data from two entities: unidentified persons (UP), who may be alive or deceased, and missing persons (MP), whose whereabouts are unknown. Although existing tools support DNA-based kinship analyses for the search, they typically do not integrate or statistically evaluate diverse lines of evidence collected throughout the investigative process. Examples of alternative lines of evidence are pigmentation traits, biological sex, and age, among others. The packageMispitoolsfills this gap by providing comprehensive statistical methods adapted to a holistic investigation workflow.Mispitoolssystematically assesses the data from each investigative stage, computing the statistical weight of various types of evidence through a likelihood ratio (LR) approach. It also provides models for combining obtained LRs. Furthermore,Mispitoolsoffers customized visualizations and a user-friendly interface, broadening its applicability among forensic practitioners and genealogical researchers.
Crosslink Strength Governs Yielding Behavior in Dynamically Crosslinked Hydrogels
Authors: Eckman Noah , Grosskopf Abigail K. , Jiang Grace , Kamani Krutarth , Huang Michelle S. , Schmittlein Brigitte , Heilshorn Sarah C. , Rogers Simon , Appel Eric A. 
Published: August 2024

SummaryYielding of dynamically crosslinked hydrogels, or transition between a solid-like and liquid-like state, allows facile injection and utility in translational biomedical applications including delivery of therapeutic cells. Unfortunately, characterizing the time-varying nature of the transition has not been attempted, nor are there design rules for understanding the effects of yielding on encapsulated cells. Here, we unveil underlying molecular mechanisms governing the yielding transition of dynamically crosslinked gels currently being researched for use in cell therapy. We demonstrate through nonlinear rheological characterization that the network dynamics of the dynamic hydrogels dictate the speed and character of their yielding transition. Rheological testing of these materials reveals unexpected elastic strain stiffening during yielding, as well as characterizing the rapidity of the yielding transition. A slower yielding speed explains enhanced protection of directly injected cells from shear forces, highlighting the importance of mechanical characterization of all phases of yield-stress biomaterials.Significance StatementMany direct-injection cell therapies suffer from poor viability of injected cells due to membrane disruption by shear stresses during injection. Injectable hydrogels with dynamic crosslinks can increase viability during injection, utilizing the ability of these materials to undergo a reversible solid-to-liquid shear-rate dependent yielding transition. Much effort has been applied to understanding the yielding transition of these materials, yet design rules for connecting the character of yielding to viability of injected cells has not been established. Here, we apply rheological testing to show that faster network dynamics result in a more gradual yielding transition, affording greater protection to cells during injection. This work introduces a new rheological protocol for the development of injectable hydrogels for cell therapy.
Stabilizing microtubules aids neurite structure and disrupts syncytia formation in human cytomegalovirus-infected human forebrain neurons
Authors: Adelman Jacob W , Sukowaty Andrew T , Partridge Kaitlyn J , Gawrys Jessica E. , Terhune Scott S. , Ebert Allison D. 
Published: August 2024

ABSTRACTHuman cytomegalovirus (HCMV) is a prolific human herpesvirus that infects most individuals by adulthood. While typically asymptomatic in adults, congenital infection can induce serious neurological symptoms including hearing loss, visual deficits, cognitive impairment, and microcephaly in 10-15% of cases. HCMV has been shown to infect most neural cells with our group recently demonstrating this capacity in stem cell-derived forebrain neurons. Infection of neurons induces deleterious effects on calcium dynamics and electrophysiological function paired with gross restructuring of neuronal morphology. Here, we utilize an iPSC-derived model of the human forebrain to demonstrate how HCMV infection induces syncytia, drives neurite retraction, and remodels microtubule networks to promote viral production and release. We establish that HCMV downregulates microtubule associated proteins at 14 days postinfection while simultaneously sparing other cytoskeletal elements, and this includes HCMV-driven alterations to microtubule stability. Further, we pharmacologically modulate microtubule dynamics using paclitaxel (stabilize) and colchicine (destabilize) to examine the effects on neurite structure, syncytial morphology, assembly compartment formation, and viral release. With paclitaxel, we found improvement of neurite outgrowth with a corresponding disruption to HCMV-induced syncytia formation and Golgi network disruptions but with limited impact on viral titers. Together, these data suggest that HCMV infection-induced disruption of microtubules in human cortical neurons can be partially mitigated with microtubule stabilization, suggesting a potential avenue for future neuroprotective therapeutic exploration.IMPORTANCEInfection by human cytomegalovirus (HCMV) continues to cause significant damage to human health. In the absence of a vaccine, vertical transmission from mother to fetus can result in profound neurological damage impacting quality of life. These studies focus on understanding the impact of HCMV infection on forebrain cortical neurons derived from iPSCs. We show that infection results in loss of neurite extension accompanied by cell-to-cell fusion. These pathogenic changes involve HCMV infection-mediated disruption to the microtubule network. Upon addition of the microtubule stabilization agent paclitaxel, the structural damage was limited, but infection still progressed to produce infectious particles. This work is part of our continued efforts to define putative strategies to limit HCMV-induced neurological damage.
The CoREST complex is a therapeutic vulnerability in malignant peripheral nerve sheath tumors
Authors: Soukar Imad , Fisher Robert , Bhagavatula Sanjana , Collard Marianne , Cole Philip A. , Alani Rhoda M. 
Published: August 2024

AbstractMalignant peripheral nerve sheath tumor (MPNST) is a highly aggressive sarcoma that may be seen in patients with neurofibromatosis type 1 (NF1) or occur sporadically. While surgery is the primary treatment for localized MPNST with a 61.9% overall survival rate, metastatic disease is often fatal due to resistance to systemic therapies which underscores the urgent need for effective treatments. MPNSTs frequently harbor inactivating driver mutations in the PRC2 epigenetic repressor complex suggesting epigenetic therapies may represent a specific vulnerability in these tumors. Here, we investigate the role of the LSD1-HDAC1-CoREST (LHC) repressor complex in mediating MPNST tumor growth and progression. Our findings demonstrate that the LHC small molecule inhibitor, corin, induces apoptosis and significantly inhibits proliferation in MPNST cells. Transcriptomic analysis of corin-treated MPNST cells demonstrates specific increases in genes associated with axonogenesis and neuronal differentiation as well as altered extracellular matrix; additionally, corin treatment is shown to inhibit MPNST invasion in vitro. These results underscore the critical role of the LHC complex in facilitating MPNST growth and progression and suggest that targeting the LHC complex represents a promising therapeutic approach for this aggressive malignancy.
ROLE OF WORKING MEMORY IN INTERLIMB GENERALIZATION OF NEWLY LEARNED SKILLS
Authors: Yadav Goldy , Pal Rahul , Matkar Shraddha , Kumar Neeraj 
Published: August 2024

ABSTRACTNewly acquired skill memory can generalize/transfer to the untrained arm. Such interlimb generalization of a learned skill has been shown to be symmetric in nature and is thought to be mediated by cognitive processes that emerge during skill learning. However, it is unknown whether engaging in other cognitively demanding tasks following skill acquisition can influence skill generalization. Our research goal was to uncover how a secondary task, involving working memory, interacts with a newly formed skill memory and influences subsequent interlimb generalization. To test this idea, we conducted a set of three experiments by recruiting right-handed young healthy individuals (N=92) who learned a novel motor skill (long or short training on a skilled reaching task) followed by performing a working memory or control task with the right arm. Finally, all individuals were tested for immediate or delayed (after 24 hours) interlimb skill generalization to the untrained left arm. We found significant immediate as well as delayed generalization in individuals who received long training on the motor skill task, irrespective of whether they performed working memory or control task. On the other hand, performing the working memory but not control task following short skill training impaired generalization when the untrained arm was tested 24 hours later. These findings indicate that short training reflecting early stages of skill learning and the subsequent skill memory stabilization are dependent on working memory such that the underlying neural interactions mediating these processes can have implications for skill generalization.NEW AND NOTEWORTHYSkill learning is deemed successful if it can generalize to untrained conditions. Despite the potential clinical relevance of interlimb skill generalization for motor rehabilitation, such as in case of unilateral stroke, the underlying mechanisms that can influence such generalization are not fully understood. Specifically, whether interlimb skill memory generalization can be impacted by another memory system is unknown. Here, we show that engaging in a working memory task following short skill training is detrimental for interlimb skill generalization, and such interference caused by working memory is not evident when the skill training is longer. These behavioral findings bridge the link between traditionally distinct memory systems, i.e., procedural skill memory and working memory.
Macrophage WDFY3, a protector against autoimmunity
Authors: Wu Xun , Wang Ziyi , Croce Katherine R. , Li Fang , Cui Jian , D’Agati Vivette D. , Soni Rajesh K. , Khalid Shareef , Saleheen Danish , Tabas Ira , Yamamoto Ai , Zhang Hanrui 
Published: August 2024

AbstractEfficient efferocytosis is essential for maintaining homeostasis. Excessive apoptotic cell (AC) death and impaired macrophage efferocytosis lead to autoantigen release and autoantibody production, immune activation, and organ damage. It remains unclear whether these immunogenic autoantigens are the sole cause of increased autoimmunity or if efferocytosis of ACs directly influences macrophage function, impacting their ability to activate T cells and potentially amplifying autoimmune responses. Additionally, it has not been established if enhancing macrophage efferocytosis or modulating macrophage responses to AC engulfment can be protective in autoimmune-like disorders. Our previous work showed WDFY3 is crucial for efficient macrophage efferocytosis. This study reveals that myeloid knockout ofWdfy3exacerbates autoimmunity in young mice with increased AC burden by systemic injections of ACs and in middle-aged mice developing spontaneous autoimmunity, whereas ectopic overexpression of WDFY3 suppresses autoimmunity in these models. Macrophages, as efferocytes, can activate T cells and the inflammasome upon engulfing ACs, which are suppressed by overexpressing WDFY3. This work uncovered the role of WDFY3 as a protector against autoimmunity by promoting macrophage efferocytosis thus limiting autoantigen production, as well as mitigating T cell activation and inflammasome activation.
Utilization of CoRDS Registry to Monitor Quality of Life in Patients with VCP Multisystem Proteinopathy
Authors: Abdoalsadig Eiman , Hamid Merwa , Peck Allison , Johar Leepakshi , Kimonis Virginia 
Published: August 2024

AbstractBackgroundVCP disease, also known as multisystem proteinopathy (MSP1), is a rare, autosomal dominant, adult-onset, neuromuscular disease that is caused by variants in the valosin-containing protein (VCP) gene. VCP disease may exhibit one or more of the following primary features: Inclusion Body Myopathy (IBM), Paget’s disease of bone (PDB), Frontotemporal Dementia (IBMPFD), and Amyotrophic Lateral Sclerosis (ALS). Due to its progressive nature, death normally occurs in their sixties due to respiratory and cardiac failure. The purpose of this study is to utilize the Cure VCP Disease patient registry hosted by the Coordination of Rare Diseases at Sanford (CoRDS) to conduct a prospective natural history study.MethodsSeventy-nine participants enrolled in the patient registry and answered demographic,VCPvariant type, Patient-Reported Outcome Measures (PROMs), and Quality of Life (QOL) questionnaires over the course of three years. We additionally investigated if any sex differences existed and if genotype-phenotype correlations affected the rate of progression of the varying clinical manifestations.ResultsOverall, participants’ mobility declined significantly as the disease progressed. Participants reported a 0.6% decline in upper extremity function, 1.2% decline in lower extremity function, and 0.3% decline in cognitive function per year of age. Furthermore, participants reported a 1.6% decline in upper and lower extremity function and a 0.1% decline in cognitive function per year of disease duration. The highest PROMs correlations between overall health and lower extremity function, upper extremity function, fatigue, and the ability to perform vigorous activities. Genotype-phenotype correlations revealed no significant differences except for the absense of PDB in thep.Arg159Cysgroup.ConclusionThe VCP CoRDS Registry was found to be a valuable tool for monitoring the QOL in patients with VCP disease and capturing patient perspectives for future clinical trials.
Learning to use landmarks for navigation amplifies their representation in retrosplenial cortex
Authors: Fischer Lukas F. , Xu Liane , Murray Keith T. , Harnett Mark T. 
Published: August 2024

AbstractVisual landmarks provide powerful reference signals for efficient navigation by altering the activity of spatially tuned neurons, such as place cells, head direction cells, and grid cells. To understand the neural mechanism by which landmarks exert such strong influence, it is necessary to identify how these visual features gain spatial meaning. In this study, we characterized visual landmark representations in mouse retrosplenial cortex (RSC) using chronic two-photon imaging of the same neuronal ensembles over the course of spatial learning. We found a pronounced increase in landmark-referenced activity in RSC neurons that, once established, remained stable across days. Changing behavioral context by uncoupling treadmill motion from visual feedback systematically altered neuronal responses associated with the coherence between visual scene flow speed and self-motion. To explore potential underlying mechanisms, we modeled how burst firing, mediated by supralinear somatodendritic interactions, could efficiently mediate context- and coherence-dependent integration of landmark information. Our results show that visual encoding shifts to landmark-referenced and context-dependent codes as these cues take on spatial meaning during learning.