Synaptic imbalance and increased inhibition impair motor function in SMA.

Movement is executed through the balanced action of excitatory and inhibitory neurotransmission in motor circuits of the spinal cord. Short-term perturbations in one of the two types of transmission are counteracted by homeostatic changes of the opposing type. Prolonged failure to balance excitatory and inhibitory drive results in dysfunction at the single neuron, as well as neuronal network levels. However, whether dysfunction in one or both types of neurotransmission leads to pathogenicity in neurodegenerative diseases characterized by select synaptic deficits is not known. Here, we used mouse genetics, functional assays, morphological methods, and viral-mediated approaches to uncover the pathogenic contribution of unbalanced excitation-inhibition neurotransmission in a mouse model of spinal muscular atrophy (SMA). We show that vulnerable motor circuits in the SMA spinal cord fail to respond homeostatically to the reduction of excitatory drive and instead increase inhibition. This imposes an excessive burden on motor neurons and further restricts their recruitment to activate muscle contraction. Importantly, genetic or pharmacological reduction of inhibitory synaptic drive improves neuronal function and provides behavioural benefit in SMA mice. Our findings identify the lack of excitation-inhibition homeostasis as a major maladaptive mechanism in SMA, by which the combined effects of reduced excitation and increased inhibition diminish the capacity of premotor commands to recruit motor neurons and elicit muscle contractions.

Genetic tracing of market wildlife and viruses at the epicenter of the COVID-19 pandemic.

Zoonotic spillovers of viruses have occurred through the animal trade worldwide. The start of the COVID-19 pandemic was traced epidemiologically to the Huanan Seafood Wholesale Market. Here, we analyze environmental qPCR and sequencing data collected in the Huanan market in early 2020. We demonstrate that market-linked severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genetic diversity is consistent with market emergence and find increased SARS-CoV-2 positivity near and within a wildlife stall. We identify wildlife DNA in all SARS-CoV-2-positive samples from this stall, including species such as civets, bamboo rats, and raccoon dogs, previously identified as possible intermediate hosts. We also detect animal viruses that infect raccoon dogs, civets, and bamboo rats. Combining metagenomic and phylogenetic approaches, we recover genotypes of market animals and compare them with those from farms and other markets. This analysis provides the genetic basis for a shortlist of potential intermediate hosts of SARS-CoV-2 to prioritize for serological and viral sampling.

The subthalamic nucleus contributes causally to perceptual decision-making in monkeys.

The subthalamic nucleus (STN) plays critical roles in the motor and cognitive function of the basal ganglia (BG), but the exact nature of these roles is not fully understood, especially in the context of decision-making based on uncertain evidence. Guided by theoretical predictions of specific STN contributions, we used single-unit recording and electrical microstimulation in the STN of healthy monkeys to assess its causal, computational roles in visual-saccadic decisions based on noisy evidence. The recordings identified subpopulations of STN neurons with distinct task-related activity patterns that related to different theoretically predicted functions. Microstimulation caused changes in behavioral choices and response times that reflected multiple contributions to an 'accumulate-to-bound'-like decision process, including modulation of decision bounds and evidence accumulation, and to non-perceptual processes. These results provide new insights into the multiple ways that the STN can support higher brain function.

Implications of frailty before and after intensive care unit admission.

PURPOSE OF REVIEW: In the decade since the first publications related to frailty in those with critical illness, the study of frailty has rapidly increased. The purpose of this review is to update the reader on recent advances across several important areas of frailty research: how best to identify frailty in those with critical illness, studies describing the relationship between frailty and delirium, and how frailty affects outcomes for those with coronavirus disease 2019 (COVID-19), which, despite rates and severity of acute infection declining, still tremendously impacts patients long after the acute infection, resulting in symptoms of long COVID-19. RECENT FINDINGS: A number of frailty assessment tools exist, to date, the Clinical Frailty Scale based on the deficit accumulation approach to defining frailty, is the most commonly used in ICU studies. Several novel frailty instruments for the ICU are being developed. Because tools assessing frailty by the phenotypic and deficit accumulation approaches identify different populations, careful choice of a frailty assessment tool is warranted.Frailty and delirium are hypothesized to represent different clinical expressions of a similar underlying vulnerability, thus identifying frailty may be a useful means by which to identify patients at high risk of becoming delirious. Recent studies show that frailty at ICU admission is a predictor of the development of delirium.Finally, frailty and its outcomes were studied in patients with COVID-19. As with other causes of critical illness, frailty was highly prevalent in those admitted to the ICU and is associated with greater mortality. Frailty was also associated with increased decisions to limit life support treatments, but these decisions were not different among those admitted with COVID-19 or for other reasons. SUMMARY: Frailty in those with critical illness is an emerging field of study. Future work to define the optimal means by which to identify this syndrome and how best to manage critically ill patients with frailty are needed.

Prevalence, risk factors, natural history, and prognostic significance of Modic changes in the cervical spine: a comprehensive systematic review and meta-analysis of 12,754 participants.

OBJECTIVE: Modic changes (MCs) in the cervical spine are common, but remain an under-researched phenomenon, particularly regarding their prevalence, natural history, risk factors, and implications for surgical outcomes. This systematic review and meta-analysis endeavors to elucidate the multifactorial dimensions and clinical significance of cervical MCs. METHODS: Following PRISMA guidelines, a comprehensive systematic search was performed using Medline (via PubMed), EMBASE, Scopus, and Web of Science databases from their dates of inceptions to September 4, 2023. All identified articles were meticulously screened based on their relevance to our investigative criteria. Bias was assessed using quality assessments tools, including Quality in Prognosis Studies (QUIPS) and Newcastle-Ottawa Scale (NOS). Diverse datasets encompassing MCs prevalence, demographic influences, risk factors, cervical sagittal parameters, and surgical outcomes were extracted. Meta-analysis using both random and common effects model was used to synthesis the metadata. RESULTS: From a total of 867 studies, 38 met inclusion criteria and underwent full-text assessment. The overall prevalence of cervical MCs was 26.0% (95% CI: 19.0%, 34.0%), with a predominance of type 2 MCs (15% ; 95% CI: 0.10%, 0.23%). There was no significant difference between MCs and non-MCs in terms of neck pain (OR:3.09; 95% CI: 0.81, 11.88) and radicular pain (OR: 1.44; 95% CI: 0.64, 3.25). The results indicated a significantly higher mean age in the MC group (MD: 1.69 years; 95% CI: 0.29 years, 3.08 years). Additionally, smokers had 1.21 times the odds (95% CI: 1.01, 1.45) of a higher risk of developing MCs compared to non-smokers. While most cervical sagittal parameters remained unaffected, the presence of MCs indicated no substantial variation in pain intensity. However, a significant finding was the lower Japanese Orthopaedic Association (JOA) scores observed in MC patients at the 3-month (MD: -0.34, 95% CI: -0.62, -0.07) and 6-month (MD: -0.40, 95% CI: -0.80, 0.00) postoperative periods, indicating a prolonged recovery phase. CONCLUSION: This study found a predominant of type 2 MCs in the cervical spine. However, there was no significant mean difference between MCs and non-MC groups regarding neck pain and radicular pain. The results underscore the necessity for expansive, longitudinal research to elucidate the complexity of cervical MCs, particularly in surgical and postoperative contexts.

Comparing reactive versus empiric cerebrospinal fluid drainage strategies for spinal perfusion pressure optimization in patients with acute traumatic spinal cord injuries.

BACKGROUND: Spinal cord hypoperfusion undermines clinical recovery in acute traumatic spinal cord injuries. New guidelines suggest cerebrospinal fluid (CSF) drainage is an important strategy for preventing spinal cord hypoperfusion in the acute post-injury phase. METHODS: This study included participants presenting to a single level 1 trauma center between 2018 and 2022 with cervical or thoracic traumatic spinal cord injury severity grade A-C, as evaluated by the American spinal injury association impairment scale (AIS). The primary objective of this study was to compare the efficacy of two CSF drainage protocols in preventing spinal cord hypoperfusion; 1) draining CSF only when spinal cord perfusion pressure (SCPP) drops below 65 mmHg (i.e. reactive) versus 2) empiric CSF drainage of 5-10 mL every hour. Intrathecal pressure, spinal cord perfusion pressure (SCPP), mean arterial pressure (MAP), and vasopressor utilization were compared using univariate T-test statistical analysis. RESULTS: While there was no difference in the incidence of sub-optimal SCPP (<65 mmHg; p = 0.1658), reactively drained participants were more likely to exhibit critical hypoperfusion (<50 mmHg; p = 0.0030) despite also having lower average intrathecal pressures (p < 0.001). There were no differences in average SCPP, mean arterial pressure (MAP), or vasopressor utilization between the two groups (p > 0.05). CONCLUSIONS: Empiric (vs reactive) CSF drainage resulted in fewer incidences of critical spinal cord hypoperfusion for patients with acute traumatic spinal cord injuries.

Clinicopathological risk factors associated with tumor relapse of upper tract urothelial carcinoma after radical nephroureterectomy: A single institution 20-year experience.

Upper tract urothelial carcinoma (UTUC) is a relatively rare yet aggressive malignancy. While radical nephroureterectomy (RNU) remains the cornerstone treatment, UTUC has high local and metastatic relapse rates, leading to a dismal prognosis. To identify the clinicopathological factors associated with an increased risk of local and metastatic relapse in UTUC, we conducted a retrospective analysis of 133 consecutive UTUC patients who underwent RNU from 1998 to 2018. Patients lost to follow-up or with a history of bladder cancer were excluded from the study. The remaining 87 patients were categorized into two subgroups: those with tumor recurrence/relapse (40 cases) and those without recurrence/relapse (47 cases). Clinical and pathological characteristics were compared across the two groups. Multiple factors are associated with UTUC recurrence/relapse including larger tumor size, histology divergent differentiations/subtypes, high tumor grade, advanced pathologic T stage, positive margin, lymphovascular invasion (LVI), positive lymph node status, and preoperative hydronephrosis. Multivariate Cox regression analysis revealed that squamous differentiation predicted recurrence/relapse (p = 0.012), independent of tumor stage. Moreover, compared to the conventional histology type, UTUC with squamous differentiation had a significantly higher relapse rate (p = 0.0001) and poorer survival (p = 0.0039). This observation was further validated in invasive high-grade UTUC cases. Our findings suggest that many pathological factors contribute to UTUC recurrence/relapse, particularly, squamous differentiation may serve as an independent risk predictor for relapse and a potent prognosticator for adverse cancer-specific survival in UTUC patients. Recognizing and thoroughly assessing the pathological factors is essential for better oncologic management of UTUC.

Dual network structure of the AV node.

Biological systems, particularly the brain, are frequently analyzed as networks, conveying mechanistic insights into their function and pathophysiology. This is the first study of a functional network of cardiac tissue. We use calcium imaging to obtain two functional networks in a subsidiary but essential pacemaker of the heart, the atrioventricular node (AVN). The AVN is a small cellular structure with dual functions: a) to delay the pacemaker signal passing from the sinoatrial node (SAN) to the ventricles, and b) to serve as a back-up pacemaker should the primary SAN pacemaker fail. Failure of the AVN can lead to syncope and death. We found that the shortest path lengths and clustering coefficients of the AVN are remarkably similar to those of the brain. The network is ``small-world," thus optimized for energy use vs transmission efficiency. We further study the network properties of AVN tissue with knock-out of the sodium-calcium exchange transporter. In this case, the average shortest path-lengths remained nearly unchanged showing network resilience, while the clustering coefficient was somewhat reduced, similar to schizophrenia in brain networks. When we removed the global action potential using principal component analysis (PCA) in wild-type model, the network lost its ``small-world" characteristics with less information-passing efficiency due to longer shortest path lengths but more robust signal propagation resulting from higher clustering. These two wild-type networks (with and without global action potential) may correspond to fast and slow conduction pathways. Laslty, a one-parameter non-linear preferential attachment model is a good fit to all three AVN networks.

The association of microvascular disease and endothelial dysfunction with vertebral trabecular bone mineral density : The MESA study.

Retinopathy and albuminuria are associated with hip fracture risk. We investigated whether these disorders and endothelial dysfunction (which underlies microvascular diseases) were associated with low trabecular bone density. No significant associations were found, suggesting that microvascular diseases are not related to fracture risk through low trabecular bone density. PURPOSE: Microvascular diseases of the eye, kidney, and brain are associated with endothelial dysfunction and increased hip fracture risk. To explore the basis for higher hip fracture risk, we comprehensively examined whether markers of microvascular disease and/or endothelial dysfunction are related to trabecular bone mineral density (BMD), a proximate risk factor for osteoporotic fractures. METHODS: Among 6814 participants in the Multi-Ethnic Study of Atherosclerosis study (MESA), we derived thoracic vertebral trabecular BMD from computed tomography of the chest and measured urine albumin to creatinine ratios (UACR), retinal arteriolar and venular widths, flow mediated dilation (FMD) of the brachial artery after 5 min of ischemia; and levels of five soluble endothelial adhesion markers (ICAM-1, VCAM-1, L-selectin, P-selectin, and E-selectin). Linear regression models were used to examine the association of trabecular BMD with markers of microvascular disease and with markers of endothelial dysfunction. RESULTS: We observed no significant associations of UACR, retinal arteriolar or venular widths, or FMD with BMD. We also observed no statistically significant association of spine trabecular BMD with levels of endothelial adhesion markers. Men and women had largely similar results. CONCLUSION: We conclude that there is little evidence to connect thoracic spine trabecular BMD to microvascular disorders or to endothelial dysfunction among multi-ethnic middle-aged and older adults. Other factors beyond trabecular BMD (e.g., bone quality or predisposition to falling) may be responsible for the associations of microvascular disease with osteoporotic fractures.

Human γδ T cells in diverse tissues exhibit site-specific maturation dynamics across the life span.

During ontogeny, γδ T cells emerge from the thymus and directly seed peripheral tissues for in situ immunity. However, their functional role in humans has largely been defined from blood. Here, we analyzed the phenotype, transcriptome, function, and repertoire of human γδ T cells in blood and mucosal and lymphoid tissues from 176 donors across the life span, revealing distinct profiles in children compared with adults. In early life, clonally diverse Vδ1 subsets predominate across blood and tissues, comprising naïve and differentiated effector and tissue repair functions, whereas cytolytic Vδ2 subsets populate blood, spleen, and lungs. With age, Vδ1 and Vδ2 subsets exhibit clonal expansions and elevated cytolytic signatures, which are disseminated across sites. In adults, Vδ2 cells predominate in blood, whereas Vδ1 cells are enriched across tissues and express residency profiles. Thus, antigenic exposures over childhood drive the functional evolution and tissue compartmentalization of γδ T cells, leading to age-dependent roles in immunity.

Association of serum levels of phenylalanine and tyrosine with hip fractures and frailty in older adults: The cardiovascular health study.

This study examined if the amino acids phenylalanine or tyrosine contribute to risk of hip fracture or frailty in older adults. We determined that neither phenylalanine nor tyrosine are important predictors of hip fracture or frailty. We suggest advice on protein intake for skeletal health consider specific amino acid composition. PURPOSE: Protein is essential for skeletal health, but the specific amino acid compositions of protein may have differential associations with fracture risk. The aim of this study was to determine the association of serum levels of the aromatic amino acids phenylalanine and tyrosine with risk for incident hip fractures over twelve years of follow-up and cross sectional associations with frailty. METHODS: We included 131 older men and women from the Cardiovascular Health Study (CHS) who sustained a hip fracture over twelve years of follow-up and 131 men and women without an incident hip fracture over this same period of time. 42% of this cohort were men and 95% were Caucasian. Weighted multivariable Cox hazards molecules were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of incident hip fracture associated with a one standard deviation (SD) higher serum level of phenylalanine or tyrosine. Relative risk regression was used to determine the cross-sectional association of these amino acids with Freid's frailty index. RESULTS: Neither serum levels of phenylalanine (HR 0.85 (95% CI 0.62-1.16) or tyrosine (HR 0.82 (95% CI 0.62-1.1) were significantly associated with incident hip fractures or cross sectionally with frailty (frail compared with prefrail/not frail) (HR 0.92 (95% CI 0.48-1.76) and HR (0.86 (95% CI 0.46-1.61) respectively. CONCLUSION: Phenylalanine and tyrosine are not significant contributors to hip fractures or frailty in older men and women.

Benign Natural Progression of Small Cavernous Carotid Aneurysms Suggests Limited Clinical Utility of Serial Longitudinal Follow-up.

BACKGROUND AND OBJECTIVES: Aneurysms in the cavernous segment of the internal carotid artery (ICA) often present in an indolent fashion with limited morbidity. However, their growth progression and possible rupture over time remains poorly defined, thereby limiting optimization of serial follow-up. Thus, we aim to describe the progression of cavernous ICA aneurysms over time, as well as the patient and aneurysm characteristics associated with possible growth and rupture status. METHODS: We identified a consecutive cohort of 157 patients from 2007 to 2021 with cavernous ICA aneurysms. Patient demographic data, possible risk factors, presenting symptoms, radiographic features of aneurysms, size progression, rupture status, and concomitant noncavernous aneurysm rupture data were manually extracted. RESULTS: One hundred and fifty-seven patients (mean age at diagnosis 57.2 ± 15.6 years; 85.4% females) with 174 cavernous carotid aneurysms (CCAs) were followed for an average of 7.1 ± 4.8 years. 76.4% of aneurysms were identified incidentally, with predominantly ocular palsies as the presenting symptoms in remaining primary cases. Most aneurysms were small, and of the 168 aneurysms that were followed, 98.2% did not demonstrate appreciable growth. Of the aneurysms that grew, it took an average of 6.0 years to grow 1.6 ± 0.2 mm. Demographic data, hypertension, and smoking status were not associated with aneurysm growth. Most radiographic features also were not associated with growth, except long-axis diameter, which had an odds ratio of 1.4 (CI: 1.2, 1.8) on multivariable analysis. Presenting clinical symptoms were not associated with growth. No CCAs ruptured during follow-up. CONCLUSION: Cavernous ICA aneurysms in our series demonstrate no rupture and limited growth over years of clinical follow-up. No radiographic or patient risk factors were associated with growth except initial aneurysm size. Hence, small CCAs may not require close follow-up over time.

Lung influenza virus-specific memory CD4 T cell location and optimal cytokine production are dependent on interactions with lung antigen-presenting cells.

Influenza A virus (IAV) infection leads to the formation of mucosal memory CD4 T cells that can protect the host. An in-depth understanding of the signals that shape memory cell development is required for more effective vaccine design. We have examined the formation of memory CD4 T cells in the lung following IAV infection of mice, characterizing changes to the lung landscape and immune cell composition. IAV-specific CD4 T cells were found throughout the lung at both primary and memory time points. These cells were found near lung airways and in close contact with a range of immune cells including macrophages, dendritic cells, and B cells. Interactions between lung IAV-specific CD4 T cells and major histocompatibility complex (MHC)II+ cells during the primary immune response were important in shaping the subsequent memory pool. Treatment with an anti-MHCII blocking antibody increased the proportion of memory CD4 T cells found in lung airways but reduced interferon-γ expression by IAV-specific immunodominant memory CD4 T cells. The immunodominant CD4 T cells expressed higher levels of programmed death ligand 1 (PD1) than other IAV-specific CD4 T cells and PD1+ memory CD4 T cells were located further away from MHCII+ cells than their PD1-low counterparts. This distinction in location was lost in mice treated with anti-MHCII antibodies. These data suggest that sustained antigen presentation in the lung impacts the formation of memory CD4 T cells by regulating their cytokine production and location.

Evaluating the Need for Durotomy and Duraplasty in Adults Undergoing Suboccipital Craniectomy for Chiari Decompression: A Case Series Analysis of Radiographic and Clinical Outcomes.

Background Suboccipital craniectomy (SOC) in conjunction with dura opening and duraplasty for posterior fossa decompression is an effective treatment for symptomatic Chiari 1 malformations (CM1), primarily carried out in the pediatric population. However, dural opening and reconstruction are associated with an increased risk of complications, and their necessity in the adult population has not yet been robustly demonstrated. Given differences in clinical presentation and disease severity between the pediatric and adult patients, we aimed to identify if SOC alone with intraoperative ultrasound confirmation of adequate restoration of pulsatile motion of cerebellar tonsil is sufficient to treat symptomatic CM1 while mitigating surgical risks. Methods We identified a retrospective, institutional cohort of adult patients who underwent SOC for Chiari decompression between 2014 and 2023. Demographic, clinical, and radiographic features were extracted for each patient. Clinical outcomes were assessed using the Chicago Chiari Outcome Scale (CCOS) and Motor-Sensory-Sphincter signs score (Clinical Sign Score (CSS)). Radiographic outcomes assessed cerebellar ectopia and associated syrinx characteristics. Results A total of 15 patients were identified, with an average follow-up period of three years. Eight patients underwent SOC with duraplasty, whereas seven patients underwent SOC only without duraplasty. Both groups of patients were of similar age at surgery and had similar nature and duration of symptoms prior to surgery. On pre-operative radiographic evaluation, both groups of patients had similar lengths of cerebellar ectopia (9.9±11.0 mm to 11.1±5.7 mm, p=0.591), and associated syrinxes (75% vs. 42.9%, p=0.205). Intraoperatively, both groups had similar estimated blood losses, though the length of surgery was significantly shorter when durotomy was spared (202±58.3 minutes to 116.3±47.8 minutes, p=0.011). The length of ICU stay was also significantly longer in the durotomy group (1.1±0.6 days to 0.0 days, p<0.001). Neither group reported any post-operative complications. On follow-up, both groups demonstrated similar reductions in cerebellar ectopia and syrinx characteristics. Clinically, the CCOS and CSS scores were similar between the two cohorts at follow-up, with no repeat surgery required in either group. Conclusion Our cohort suggests that for adult CM1 patients, SOC decompression alone without dural reconstruction might lead to comparable clinical and radiographic outcomes to SOC decompression with durotomy/duraplasty, especially if intraoperative ultrasound confirms good cerebrospinal fluid (CSF) flow after SOC. Notably, sparing durotomy and duraplasty is also associated with decreased operative time and decreased ICU stay.

Trajectory-Based Time-Resolved Mechanism for Benzene Reductive Elimination from Cyclopentadienyl Mo/W Phenyl Hydride Complexes.

Calculated potential energy structures and landscapes are very often used to define the sequence of reaction steps in an organometallic reaction mechanism and interpret kinetic isotope effect (KIE) measurements. Underlying most of this structure-to-mechanism translation is the use of statistical rate theories without consideration of atomic/molecular motion. Here we report direct dynamics simulations for an organometallic benzene reductive elimination reaction, where nonstatistical intermediates and dynamic-controlled pathways were identified. Specifically, we report single spin state as well as mixed spin state quasiclassical direct dynamics trajectories in the gas phase and explicit solvent for benzene reductive elimination from Mo and W bridged cyclopentadienyl phenyl hydride complexes ([Me2Si(C5Me4)2]M(H)(Ph), M = Mo and W). Different from the energy landscape mechanistic sequence, the dynamics trajectories revealed that after the benzene C-H bond forming transition state (often called reductive coupling), σ-coordination and π-coordination intermediates are either skipped or circumvented and that there is a direct pathway to forming a spin flipped solvent caged intermediate, which occurs in just a few hundred femtoseconds. Classical molecular dynamics simulations were then used to estimate the lifetime of the caged intermediate, which is between 200 and 400 picoseconds. This indicates that when the η2-π-coordination intermediate is formed, it occurs only after the first formation of the solvent-caged intermediate. This dynamic mechanism intriguingly suggests the possibility that the solvent-caged intermediate rather than a coordination intermediate is responsible (or partially responsible) for the inverse KIE value experimentally measured for W. Additionally, this dynamic mechanism prompted us to calculate the kH/kD KIE value for the C-H bonding forming transition states of Mo and W. Surprisingly, Mo gave a normal value, while W gave an inverse value, albeit small, due to a much later transition state position.

Normative evidence weighting and accumulation in correlated environments.

The brain forms certain deliberative decisions following normative principles related to how sensory observations are weighed and accumulated over time. Previously we showed that these principles can account for how people adapt their decisions to the temporal dynamics of the observations (Glaze et al., 2015). Here we show that this adaptability extends to accounting for correlations in the observations, which can have a dramatic impact on the weight of evidence provided by those observations. We tested online human participants on a novel visual-discrimination task with pairwise-correlated observations. With minimal training, the participants adapted to uncued, trial-by-trial changes in the correlations and produced decisions based on an approximately normative weighting and accumulation of evidence. The results highlight the robustness of our brain's ability to process sensory observations with respect to not just their physical features but also the weight of evidence they provide for a given decision.

The transcription factor sex-determining region Y-box 2 (SOX2) in bladder cancer.

Sex-determining region Y-box 2 (SOX2) is a transcription factor with a central role in embryologic development. SOX2 is also an oncogene in several cancer types. Prior work by our group has shown SOX2 activity associates with cell cycle dysregulation in early-stage bladder cancer. The present study was thus undertaken to broadly investigate SOX2 in bladder cancer, with emphasis on associations with tumor stage, clinical outcomes, and tumorigenicity. Gene expression was quantified by immunohistochemistry in an established tissue microarray (n=303 cystectomy specimens, all stages) and whole tissue sections of noninvasive papillary urothelial carcinoma (n=25). Gene expression by RNA sequencing was evaluated in non-muscle invasive and muscle-invasive cohorts from publicly available repositories. By immunohistochemistry, SOX2 was expressed in 40% of whole tissue sections of noninvasive papillary carcinoma, which correlated with SOX2 expression by RNA sequencing (r=0.6, P=0.001, Spearman correlation). Expression tended to be focal (median H-score =6). SOX2 was expressed in only 9% of TMA cases, consistent with focal expression. SOX2 expression was substantially higher in muscle-invasive compared with noninvasive papillary urothelial carcinoma by RNA sequencing (P<0.001, Wilcoxon rank sum test). SOX2 expression associated with stage progression in lamina-propria invasive cancers (hazard ratio =2, P=0.05, Cox model, binary, RNA sequencing) but not noninvasive papillary cancers (P=0.5, Cox model, binary, RNA sequencing). SOX2 expression did not associate with overall survival in muscle-invasive carcinoma. Activity of SOX2 in bladder cancer was tested in vivo using murine allografts created with MB49 cells that express human SOX2 (MB49-SOX). MB49-SOX allografts expressed this protein focally by immunohistochemistry, much like human tumors. Compared with controls, MB49 allografts demonstrated larger tumor size (P=0.03, Wilcoxon rank sum test) and higher tumor burden in mesenteric metastases (P=0.009, Wilcoxon rank sum test). Though SOX2 expression is focal within tumors, it may drive tumorigenesis, increase growth rate, and promote aggressive features of bladder cancer, particularly stage progression of early-stage disease.

Time of day does not impact spinal serotonin levels in humans.

Spinal serotonin enables neuro-motor recovery (i.e., plasticity) in patients with debilitating paralysis. While there exists time of day fluctuations in serotonin-dependent spinal plasticity, it is unknown, in humans, whether this is due to dynamic changes in spinal serotonin levels or downstream signaling processes. The primary objective of this study was to determine if time of day variations in spinal serotonin levels exists in humans. To assess this, intrathecal drains were placed in seven adults with cerebrospinal fluid (CSF) collected at diurnal (05:00 to 07:00) and nocturnal (17:00 to 19:00) intervals. High performance liquid chromatography with mass spectrometry was used to quantify CSF serotonin levels with comparisons being made using univariate analysis. From the 7 adult patients, 21 distinct CSF samples were collected: 9 during the diurnal interval and 12 during nocturnal. Diurnal CSF samples demonstrated an average serotonin level of 216.6 ± $ \pm $ 67.7 nM. Nocturnal CSF samples demonstrated an average serotonin level of 206.7 ± $ \pm $ 75.8 nM. There was no significant difference between diurnal and nocturnal CSF serotonin levels (p = .762). Within this small cohort of spine healthy adults, there were no differences in diurnal versus nocturnal spinal serotonin levels. These observations exclude spinal serotonin levels as the etiology for time of day fluctuations in serotonin-dependent spinal plasticity expression.

γδ T cells: The first line of defense for neonates.

A distinct CD83-expressing subset of γδ T cells are enriched in preterm infants with sepsis, providing insights into their functional maturation dynamics in settings of homeostasis and disease (León-Lara et al. https://doi.org/10.1084/jem.20231987).