Fibrocartilaginous Mesenchymoma of the Spine: A Case Report.

CASE: A healthy, 19-year-old woman was incidentally found to have a large, destructive tumor of T11 without neurologic symptoms. Biopsy demonstrated fibrocartilaginous mesenchymoma (FCM). The patient was treated with resection including subtotal corpectomy and T8-L1 fusion with use of cage and allograft strut construct. The patient remained without recurrence over 3 years of follow-up. CONCLUSION: FCM arising from the spine is a rare tumor, of which this is the sixth report. FCM affects primarily young adults and is benign but locally aggressive, requiring complete excision to prevent recurrence.

Influenza A virus during pregnancy disrupts maternal intestinal immunity and fetal cortical development in a dose- and time-dependent manner.

Epidemiological studies link exposure to viral infection during pregnancy, including influenza A virus (IAV) infection, with increased incidence of neurodevelopmental disorders (NDDs) in offspring. Models of maternal immune activation (MIA) using viral mimetics demonstrate that activation of maternal intestinal T helper 17 (TH17) cells, which produce effector cytokine interleukin (IL)-17, leads to aberrant fetal brain development, such as neocortical malformations. Fetal microglia and border-associated macrophages (BAMs) also serve as potential cellular mediators of MIA-induced cortical abnormalities. However, neither the inflammation-induced TH17 cell pathway nor fetal brain-resident macrophages have been thoroughly examined in models of live viral infection during pregnancy. Here, we inoculated pregnant mice with two infectious doses of IAV and evaluated peak innate and adaptive immune responses in the dam and fetus. While respiratory IAV infection led to dose-dependent maternal colonic shortening and microbial dysregulation, there was no elevation in intestinal TH17 cells nor IL-17. Systemically, IAV resulted in consistent dose- and time-dependent increases in IL-6 and IFN-γ. Fetal cortical abnormalities and global changes in fetal brain transcripts were observable in the high-but not the moderate-dose IAV group. Profiling of fetal microglia and BAMs revealed dose- and time-dependent differences in the numbers of meningeal but not choroid plexus BAMs, while microglial numbers and proliferative capacity of Iba1+ cells remained constant. Fetal brain-resident macrophages increased phagocytic CD68 expression, also in a dose- and time-dependent fashion. Taken together, our findings indicate that certain features of MIA are conserved between mimetic and live virus models, while others are not. Overall, we provide consistent evidence of an infection severity threshold for downstream maternal inflammation and fetal cortical abnormalities, which recapitulates a key feature of the epidemiological data and further underscores the importance of using live pathogens in NDD modeling to better evaluate the complete immune response and to improve translation to the clinic.

Force Field X: A computational microscope to study genetic variation and organic crystals using theory and experiment.

Force Field X (FFX) is an open-source software package for atomic resolution modeling of genetic variants and organic crystals that leverages advanced potential energy functions and experimental data. FFX currently consists of nine modular packages with novel algorithms that include global optimization via a many-body expansion, acid-base chemistry using polarizable constant-pH molecular dynamics, estimation of free energy differences, generalized Kirkwood implicit solvent models, and many more. Applications of FFX focus on the use and development of a crystal structure prediction pipeline, biomolecular structure refinement against experimental datasets, and estimation of the thermodynamic effects of genetic variants on both proteins and nucleic acids. The use of Parallel Java and OpenMM combines to offer shared memory, message passing, and graphics processing unit parallelization for high performance simulations. Overall, the FFX platform serves as a computational microscope to study systems ranging from organic crystals to solvated biomolecular systems.

Legal and Ethics Considerations in Capacity Evaluation for Medical Aid in Dying.

Evaluating decisional capacity for patients seeking medical aid in dying (MAID) raises challenging legal, logistical, and ethics questions. The existing literature on the subject has been shaped largely by early disagreements over whether effective capacity assessment for such patients is ever possible, which in turn stemmed from debates over the ethics of MAID itself. In attempting to establish meaningful criteria for assessments, many jurisdictions have sought either to apply or to adapt models of capacity evaluation designed for other forms of medical decision-making, such as the widely used "four skills" model, failing to account for the fundamental differences in kind between these other decisions and MAID. This article seeks to reexamine these questions with a focus on two logistical matters (the appropriate credentialing for the evaluator and the potential liability of the evaluator) and three clinical matters (level of understanding, clinical scrutiny and certainty, and impairment) in an effort to raise legal and ethics concerns that remain unresolved, even as MAID is permitted in an increasing number of jurisdictions.

Developmental prospects of carrageenan-based wound dressing films: Unveiling techno-functional properties and freeze-drying technology for the development of absorbent films - A review.

This review explores the intricate wound healing process, emphasizing the critical role of dressing material selection, particularly for chronic wounds with high exudate levels. The aim is to tailor biodegradable dressings for comprehensive healing, focusing on maximizing moisture retention, a vital element for adequate recovery. Researchers are designing advanced wound dressings that enhance techno-functional and bioactive properties, minimizing healing time and ensuring cost-effective care. The study delves into wound dressing materials, highlighting carrageenan biocomposites superior attributes and potential in advancing wound care. Carrageenan's versatility in various biomedical applications demonstrates its potential for tissue repair, bone regeneration, and drug delivery. Ongoing research explores synergistic effects by combining carrageenan with other novel materials, aiming for complete biocompatibility. As innovative solutions emerge, carrageenan-based wound-healing medical devices are poised for global accessibility, addressing challenges associated with the complex wound-healing process. The exceptional physico-mechanical properties of carrageenan make it well-suited for highly exudating wounds, offering a promising avenue to revolutionize wound care through freeze-drying techniques. This thorough approach to evaluating the wound healing effectiveness of carrageenan-based films, particularly emphasizing the development potential of lyophilized films, has the potential to significantly improve the quality of life for patients receiving wound healing treatments.

The impact of hematology electronic consultations on the management of iron deficiency.

OBJECTIVES: Delays in the evaluation and treatment of iron deficiency can lead to increased disease-related morbidity and mortality. Electronic consultation (e-consult) is a referral modality that allows providers quicker access to recommendations from a specialist based on electronic chart review. While the use of e-consult is expanding in classical hematology, gaps exist in the understanding of patient outcomes related to its use for iron deficiency. METHODS: We randomly selected 200 e-consults and 200 traditional referrals from 3,336 hematology referrals for iron deficiency at a single center. The primary outcomes of the retrospective analysis were: time to completion of the referral, and time to treatment with intravenous iron. Secondary outcomes included recurrence of iron deficiency, need for repeat e-consult, conversion to in-person evaluation, and assessment of whether the etiology of iron deficiency was addressed. RESULTS: E-consults significantly reduced the time from referral to intravenous iron repletion (e-consult, 33 days; traditional referral, 68 days; p < .05). Assessment of the underlying etiology occurred in 70.7% of the e-consult encounters compared to 92.5% of traditional referrals (p < .05). CONCLUSIONS: These findings highlight advantages of e-consults in improving care delivery in iron deficiency, and identifying gaps that can be improved through practice standardization to ensure equitable, high-value care.

Information theory reveals physiological manifestations of COVID-19 that correlate with symptom density of illness.

Algorithms for the detection of COVID-19 illness from wearable sensor devices tend to implicitly treat the disease as causing a stereotyped (and therefore recognizable) deviation from healthy physiology. In contrast, a substantial diversity of bodily responses to SARS-CoV-2 infection have been reported in the clinical milieu. This raises the question of how to characterize the diversity of illness manifestations, and whether such characterization could reveal meaningful relationships across different illness manifestations. Here, we present a framework motivated by information theory to generate quantified maps of illness presentation, which we term "manifestations," as resolved by continuous physiological data from a wearable device (Oura Ring). We test this framework on five physiological data streams (heart rate, heart rate variability, respiratory rate, metabolic activity, and sleep temperature) assessed at the time of reported illness onset in a previously reported COVID-19-positive cohort (N = 73). We find that the number of distinct manifestations are few in this cohort, compared to the space of all possible manifestations. In addition, manifestation frequency correlates with the rough number of symptoms reported by a given individual, over a several-day period prior to their imputed onset of illness. These findings suggest that information-theoretic approaches can be used to sort COVID-19 illness manifestations into types with real-world value. This proof of concept supports the use of information-theoretic approaches to map illness manifestations from continuous physiological data. Such approaches could likely inform algorithm design and real-time treatment decisions if developed on large, diverse samples.

Neocortical long-range inhibition promotes cortical synchrony and sleep.

Behavioral states such as sleep and wake are highly correlated with specific patterns of rhythmic activity in the cortex. During low arousal states such as slow wave sleep, the cortex is synchronized and dominated by low frequency rhythms coordinated across multiple regions. Although recent evidence suggests that GABAergic inhibitory neurons are key players in cortical state modulation, the in vivo circuit mechanisms coordinating synchronized activity among local and distant neocortical networks are not well understood. Here, we show that somatostatin and chondrolectin co-expressing cells (Sst-Chodl cells), a sparse and unique class of neocortical inhibitory neurons, are selectively active during low arousal states and are largely silent during periods of high arousal. In contrast to other neocortical inhibitory neurons, we show these neurons have long-range axons that project across neocortical areas. Activation of Sst-Chodl cells is sufficient to promote synchronized cortical states characteristic of low arousal, with increased spike co-firing and low frequency brain rhythms, and to alter behavioral states by promoting sleep. Contrary to the prevailing belief that sleep is exclusively driven by subcortical mechanisms, our findings reveal that these long-range inhibitory neurons not only track changes in behavioral state but are sufficient to induce both sleep-like cortical states and sleep behavior, establishing a crucial circuit component in regulating behavioral states.

Multimodal prehabilitation and postoperative outcomes in upper abdominal surgery: systematic review and meta-analysis.

The impact of multimodal prehabilitation on postoperative complications in upper abdominal surgeries is understudied. This review analyzes randomized trials on multimodal prehabilitation with patient and hospital outcomes. MEDLINE, Embase, CINAHL, and Cochrane CENTRAL were searched for trials on prehabilitation before elective (non-emergency) abdominal surgery. Two reviewers independently screened studies, extracted data, and assessed study quality. Primary outcomes of interest were postoperative pulmonary complications (PPCs) and all-cause complications; secondary outcomes included hospital and intensive care length of stay. A meta-analysis with random-effect models was performed, and heterogeneity was evaluated with I-square and Cochran's Q test. Dichotomous variables were reported in log-odds ratio and continuous variables were presented as mean difference. Ten studies (total 1503 patients) were included. Odds of developing complications after prehabilitation were significantly lower compared to various control groups (- 0.38 [- 0.75- - 0.004], P = 0.048). Five studies described PPCs, and participants with prehabilitation had decreased odds of PPC (- 0.96 [- 1.38- - 0.54], P < 0.001). Prehabilitation did not significantly reduce length of stay, unless exercise was implemented; with exercise, hospital stay decreased significantly (- 0.91 [- 1.67- - 0.14], P = 0.02). Multimodal prehabilitation may decrease complications in upper abdominal surgery, but not necessarily length of stay; research should address heterogeneity in the literature.

IGF-1 Peptide Mimetic-functionalized Hydrogels Enhance MSC Survival and Immunomodulatory Activity.

Human mesenchymal stem cells (MSCs) have demonstrated promise when delivered to damaged tissue or tissue defects for their cytokine secretion and inflammation modulation behaviors that can promote repair. Insulin-like growth factor 1 (IGF-1) has been shown to augment MSCs' viability and survival and promote their secretion of cytokines that signal to endogenous cells, in the treatment of myocardial infarction, wound healing, and age-related diseases. Biomaterial cell carriers can be functionalized with growth factor-mimetic peptides to enhance MSC function while promoting cell retention and minimizing off-target effects seen with direct administration of soluble growth factors. Here, we functionalized alginate hydrogels with three distinct IGF-1 peptide mimetics and the integrin-binding peptide, cyclic RGD. One IGF-1 peptide mimetic (IGM-3) was found to activate Akt signaling and support survival of serum-deprived MSCs. MSCs encapsulated in alginate hydrogels that presented both IGM-3 and cRGD showed a significant reduction in pro-inflammatory cytokine secretion when challenged with interleukin-1ß. Finally, MSCs cultured within the cRGD/IGM-3 hydrogels were able to blunt pro-inflammatory gene expression of human primary cells from degenerated intervertebral discs. These studies indicate the potential to leverage cell adhesive and IGF-1 growth factor peptide mimetics together to control therapeutic secretory behavior of MSCs. Significance Statement: Insulin-like growth factor 1 (IGF-1) plays a multifaceted role in stem cell biology and may promote proliferation, survival, migration, and immunomodulation for MSCs. In this study, we functionalized alginate hydrogels with integrin-binding and IGF-1 peptide mimetics to investigate their impact on MSC function. Embedding MSCs in these hydrogels enhanced their ability to reduce inflammatory cytokine production and promote anti-inflammatory gene expression in cells from degenerative human intervertebral discs exposed to proteins secreted by the MSC. This approach suggests a new way to retain and augment MSC functionality using IGF-1 peptide mimetics, offering an alternative to co-delivery of cells and high dose soluble growth factors for tissue repair and immune- system modulation.

Genetic Constitution and Variability in Synthetic Populations of Intermediate Wheatgrass, an Out-crossing Perennial Grain Crop.

Intermediate wheatgrass (IWG) is a perennial grass that produces nutritious grain while offering substantial ecosystem services. Commercial varieties of this crop are mostly synthetic panmictic populations that are developed by intermating a few selected individuals. As development and generation advancement of these synthetic populations is a multi-year process, earlier synthetic generations are tested by the breeders and subsequent generations are released to the growers. A comparison of generations within IWG synthetic cultivars is currently lacking. In this study, we used simulation models and genomic prediction to analyze population differences and trends of genetic variance in four synthetic generations of MN-Clearwater, a commercial cultivar released by the University of Minnesota. Little to no differences were observed among the four generations for population genetic, genetic kinship, and genome-wide marker relationships measured via linkage disequilibrium. A reduction in genetic variance was observed when 7 parents were used to generate synthetic populations while using 20 led to the best possible outcome in determining population variance. Genomic prediction of plant height, free threshing ability, seed mass, and grain yield among the four synthetic generations showed a few significant differences among the generations yet the difference in values were negligible. Based on these observations, we make two major conclusions: 1) The earlier and latter synthetic generations of IWG are mostly similar to each other with minimal differences; and 2) Using 20 genotypes to create synthetic populations is recommended to sustain ample genetic variance and trait expression among all synthetic generations.

Incision Closure for Direct Anterior Total Hip Arthroplasty: Is There a Difference in the Rate of Superficial Wound Complications With Suture Versus Staples?

Background Direct anterior total hip arthroplasty (DA-THA) has increased in popularity over recent decades. However, DA-THA has been reported to have a higher incidence of superficial wound complications, including infection and incisional dehiscence, compared to other surgical approaches to hip arthroplasty. While this indicates a need for optimal wound closure, little research exists on the preferred method of skin closure following DA-THA. This study aimed to determine if there was any difference in rates of superficial infection, wound dehiscence, or overall wound complications with skin closure using a running subcuticular 3-0 Monocryl® suture compared to surgical staples following DA-THA.  Methods Records of patients who underwent DA-THA at our institution between July 2017 to July 2022 were retrospectively reviewed. Data were abstracted on patient demographics, comorbidities, skin closure method, and wound complications from the electronic medical record. Superficial infection and wound dehiscence were classified based on explicit diagnosis in post-operative records and incision photographs taken during follow-up visits. Overall wound complications were classified in patients who experienced either superficial infection, incisional dehiscence, or both complications following surgery. Descriptive statistics and chi-squared measures were obtained from post-operative patient data, and significance was set at p [Formula: see text] 0.05. Results A total of 365 DA-THAs were completed in 349 patients. A running subcuticular 3-0 Monocryl® suture closed 207 surgeries (56.7%), while surgical staples closed 158 surgeries (43.3%). There was no significant difference in independent rates of superficial infection (p = 0.076) or wound dehiscence (p = 0.118) between suture and staple cohorts; however, suture closure (10, 2.7%) was associated with a significantly higher rate of overall wound complications compared to staple closure (1, 0.3%) (p = 0.020). Conclusion DA-THA carries the risk of overall wound complications, including superficial infection and wound dehiscence. Our findings suggest superficial skin closure with staples may be preferred over sutures due to lower rates of overall wound complications. Further studies are needed to determine the optimal method of skin closure following DA-THA.

Marine bacteria Alteromonas spp. require UDP-glucose-4-epimerase for aggregation and production of sticky exopolymer.

The physiology and ecology of particle-associated marine bacteria are of growing interest, but our knowledge of their aggregation behavior and mechanisms controlling their association with particles remains limited. We have found that a particle-associated isolate, Alteromonas sp. ALT199 strain 4B03, and the related type-strain A. macleodii 27126 both form large (>500 µm) aggregates while growing in rich medium. A non-clumping variant (NCV) of 4B03 spontaneously arose in the lab, and whole-genome sequencing revealed a partial deletion in the gene encoding UDP-glucose-4-epimerase (galEΔ308-324). In 27126, a knock-out of galE (ΔgalE::kmr) resulted in a loss of aggregation, mimicking the NCV. Microscopic analysis shows that both 4B03 and 27126 rapidly form large aggregates, whereas their respective galE mutants remain primarily as single planktonic cells or clusters of a few cells. Strains 4B03 and 27126 also form aggregates with chitin particles, but their galE mutants do not. Alcian Blue staining shows that 4B03 and 27126 produce large transparent exopolymer particles (TEP), but their galE mutants are deficient in this regard. This study demonstrates the capabilities of cell-cell aggregation, aggregation of chitin particles, and production of TEP in strains of Alteromonas, a widespread particle-associated genus of heterotrophic marine bacteria. A genetic requirement for galE is evident for each of the above capabilities, expanding the known breadth of requirement for this gene in biofilm-related processes. IMPORTANCE: Heterotrophic marine bacteria have a central role in the global carbon cycle. Well-known for releasing CO2 by decomposition and respiration, they may also contribute to particulate organic matter (POM) aggregation, which can promote CO2 sequestration via the formation of marine snow. We find that two members of the prevalent particle-associated genus Alteromonas can form aggregates comprising cells alone or cells and chitin particles, indicating their ability to drive POM aggregation. In line with their multivalent aggregation capability, both strains produce TEP, an excreted polysaccharide central to POM aggregation in the ocean. We demonstrate a genetic requirement for galE in aggregation and large TEP formation, building our mechanistic understanding of these aggregative capabilities. These findings point toward a role for heterotrophic bacteria in POM aggregation in the ocean and support broader efforts to understand bacterial controls on the global carbon cycle based on microbial activities, community structure, and meta-omic profiling.

Association of Specific Leg Muscle Strength and Motor Features in Parkinson's Disease.

Background: Postural instability and gait difficulties (PIGD) are a significant cause of falls, mobility loss, and lower quality of life in Parkinson's disease (PD). The connection between PD progression and diminished strength in the lower limbs has been acknowledged. However, the identification of specific muscle groups linked to PIGD and non-PIGD motor features is still unknown. Objective: To explore the relationship between the strength of specific lower limb muscle groups, along with muscle mass, and their associations with PIGD, PIGD subtypes, and non-PIGD motor features in PD. Methods: 95 PD participants underwent detailed motor and non-motor test batteries, including lower limb isometric strength testing and whole-body lean mass assessments. Correlation analysis and univariate and multivariate linear/logistic forward stepwise regression were performed to test associations between PIGD and non-PIGD motor features with normalized value (z-score) of lower limb muscle strength and measures of lean mass. Results: Multivariate regression analysis, adjusted for age, gender, and levodopa equivalent dose, revealed that hip abductor strength was significantly associated with overall PIGD motor severity ratings (p < 0.001), impaired balance (p < 0.001), and non-PIGD Parkinsonian motor features (p < 0.001). Conversely, hip extensor strength was significantly associated with falls, slow walking, and FoG motor features (p=0.016; p=0.003; p=0.020, respectively). Conclusion: We found that lower hip abductor strength was associated with PIGD and non-PIGD motor features. The association between non-PIGD motor features may suggest specific vulnerability of the hip abductors as part of a proposed brain-muscle loop hypothesis in PD. Moreover, lower hip extensor strength correlated with falls, slow walking, and FoG.

A Preoperative Risk Assessment Tool for Predicting Adverse Outcomes among Total Shoulder Arthroplasty Patients.

BACKGROUND: With the increased utilization of Total Shoulder Arthroplasty (TSA) in the outpatient setting, understanding the risk factors associated with complications and hospital readmissions becomes a more significant consideration. Prior developed assessment metrics in the literature either consisted of hard-to-implement tools or relied on postoperative data to guide decision-making. This study aimed to develop a preoperative risk assessment tool to help predict the risk of hospital readmission and other postoperative adverse outcomes. METHODS: We retrospectively evaluated the 2019-2022(Q2) Medicare fee-for-service inpatient and outpatient claims data to identify primary anatomic or reserve TSAs and to predict postoperative adverse outcomes within 90 days post-discharge, including all-cause hospital readmissions, postoperative complications, emergency room visits, and mortality. We screened 108 candidate predictors, including demographics, social determinants of health, TSA indications, prior 12-month hospital and skilled nursing home admissions, comorbidities measured by hierarchical conditional categories, and prior orthopedic device-related complications. We used two approaches to reduce the number of predictors based on 80% of the data: 1) the Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression and 2) the machine-learning-based cross-validation approach, with the resulting predictor sets being assessed in the remaining 20% of the data. A scoring system was created based on the final regression models' coefficients, and score cutoff points were determined for low, medium, and high-risk patients. RESULTS: A total of 208,634 TSA cases were included. There was a 6.8% hospital readmission rate with 11.2% of cases having at least one postoperative adverse outcome. Fifteen covariates were identified for predicting hospital readmission with the area under the curve (AUC) of 0.70, and 16 were selected to predict any adverse postoperative outcome (AUC=0.75). The LASSO and machine learning approaches had similar performance. Advanced age and a history of fracture due to orthopedic devices are among the top predictors of hospital readmissions and other adverse outcomes. The score range for hospital readmission and an adverse postoperative outcome was 0 to 48 and 0 to 79, respectively. The cutoff points for the low, medium, and high-risk categories are 0-9, 10-14, ≥15 for hospital readmissions, and 0-11, 12-16, ≥17 for the composite outcome. CONCLUSION: Based on Medicare fee-for-service claims data, this study presents a preoperative risk stratification tool to assess hospital readmission or adverse surgical outcomes following TSA. Further investigation is warranted to validate these tools in a variety of diverse demographic settings and improve their predictive performance.

Racial and Gender Disparities in Utilization of Outpatient Total Shoulder Arthroplasties.

BACKGROUND: Utilization in outpatient total shoulder arthroplasties (TSAs) has increased significantly in recent years. It remains largely unknown whether utilization of outpatient TSA differs across gender and racial groups. This study aimed to quantify racial and gender disparities both nationally and by geographic regions. METHODS: 168,504 TSAs were identified using Medicare fee-for-service (FFS) inpatient and outpatient claims data and beneficiary enrollment data from 2020 to 2022Q4. The percentage of outpatient cases, defined as cases discharged on the same day of surgery, was evaluated by racial and gender groups and by different census divisions. A multivariate logistics regression model controlling for patient socio-demographic information (white vs. non-white race, age, gender, and dual eligibility for both Medicare and Medicaid), hierarchical condition category (HCC) score, hospital characteristics, year fixed effects, and patient residency state fixed effects was performed. RESULTS: The TSA volume per 1000 beneficiaries was 2.3 for the White population compared to 0.8, 0.6 and 0.3 for the Black, Hispanic, and Asian population, respectively. A higher percentage of outpatient TSAs were in White patients (25.6%) compared to Black patients (20.4%) (p < 0.001). The Black TSA patients were also younger, more likely to be female, more likely to be dually eligible for Medicaid, and had higher HCC risk scores. After controlling for patient socio-demographic characteristics and hospital characteristics, the odds of receiving outpatient TSAs were 30% less for Black than the White group (OR 0.70). Variations were observed across different census divisions with South Atlantic (0.67, p < 0.01), East North Central (0.56, p < 0.001), and Middle Atlantic (0.36, p < 0.01) being the four regions observed with significant racial disparities. Statistically significant gender disparities were also found nationally and across regions, with an overall odds ratio of 0.75 (p < 0.001). DISCUSSION: Statistically significant racial and gender disparities were found nationally in outpatient TSAs, with Black patients having 30% (p < 0.001) fewer odds of receiving outpatient TSAs than white patients, and female patients with 25% (p < 0.001) fewer odds than male patients. Racial and gender disparities continue to be an issue for shoulder arthroplasties after the adoption of outpatient TSAs.

Developmental and therapeutic implications of IL4ra expression for rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is a solid tumor whose metastatic progression can be accelerated through interleukin-4 receptor alpha (Il4ra) mediated interaction with normal muscle stem cells (satellite cells). To understand the function of Il4ra in this tumor initiation phase of RMS, we conditionally deleted Il4ra in genetically-engineered RMS mouse models. Nullizygosity of Il4ra altered the latency, site and/or stage distribution of RMS tumors compared to IL4RA intact models. Primary tumor cell cultures taken from the genetically-engineered models then used in orthotopic allografts further defined the interaction of satellite cells and RMS tumor cells in the context of tumor initiation: in alveolar rhabdomyosarcoma (ARMS), satellite cell co-injection was necessary for Il4ra null tumor cells engraftment, whereas in embryonal rhabdomyosarcoma (ERMS), satellite cell co-injection decreased latency of engraftment of Il4ra wildtype tumor cells but not Il4ra null tumor cells. When refocusing on Il4ra wildtype tumors by single cell sequencing and cytokine studies, we have uncovered a putative signaling interplay of Il4 from T-lymphocytes being received by Il4ra + rhabdomyosarcoma tumor cells, which in turn express Ccl2, the ligand for Ccr2 and Ccr5. Taken together, these results suggest that mutations imposed during tumor initiation have different effects than genetic or therapeutic intervention imposed once tumors are already formed. We also propose that CCL2 and its cognate receptors CCR2 and/or CCR5 are potential therapeutic targets in Il4ra mediated RMS progression.

Reuniens thalamus recruits recurrent excitation in medial prefrontal cortex.

Medial prefrontal cortex (mPFC) and hippocampus are critical for memory retrieval, decision making and emotional regulation. While ventral CA1 (vCA1) shows direct and reciprocal connections with mPFC, dorsal CA1 (dCA1) forms indirect pathways to mPFC, notably via the thalamic Reuniens nucleus (Re). Neuroanatomical tracing has documented structural connectivity of this indirect pathway through Re however, its functional operation is largely unexplored. Here we used in vivo and in vitro electrophysiology along with optogenetics to address this question. Whole-cell patch-clamp recordings in acute mouse brain slices revealed both monosynaptic excitatory responses and disynaptic feedforward inhibition for both Re-mPFC and Re-dCA1 pathways. However, we also identified a novel biphasic excitation of mPFC by Re, but not dCA1. These early monosynaptic and late recurrent components are in marked contrast to the primarily feedforward inhibition characteristic of thalamic inputs to neocortex. Local field potential recordings in mPFC brain slices revealed that this biphasic excitation propagates throughout all cortical lamina, with the late excitation specifically enhanced by GABAAR blockade. In vivo Neuropixels recordings in head-fixed awake mice revealed a similar biphasic excitation of mPFC units by Re activation. In summary, Re output produces recurrent feed-forward excitation within mPFC suggesting a potent amplification system in the Re-mPFC network. This may facilitate amplification of dCA1->mPFC signals for which Re acts as the primary conduit, as there is little direct connectivity. In addition, the capacity of mPFC neurons to fire bursts of action potentials in response to Re input suggests that these synapses have a high gain. Significance statement: The interactions between medial prefrontal cortex and hippocampus are crucial for memory formation and retrieval. Yet, it is still poorly understood how the functional connectivity of direct and indirect pathways underlies these functions. This research explores the synaptic connectivity of the indirect pathway through the Reuniens nucleus of the thalamus using electrophysiological recordings and optogenetic manipulations. The study found that Reuniens stimulation recruits recurrent and long-lasting activity in mPFC - a phenomenon not previously recorded. This recurrent activity might create a temporal window ideal for coincidence detection and be an underlying mechanism for memory formation and retrieval.

Genetic parameters for novel climatic resilience indicators derived from automatically-recorded vaginal temperature in lactating sows under heat stress conditions.

BACKGROUND: Longitudinal records of automatically-recorded vaginal temperature (TV) could be a key source of data for deriving novel indicators of climatic resilience (CR) for breeding more resilient pigs, especially during lactation when sows are at an increased risk of suffering from heat stress (HS). Therefore, we derived 15 CR indicators based on the variability in TV in lactating sows and estimated their genetic parameters. We also investigated their genetic relationship with sows' key reproductive traits. RESULTS: The heritability estimates of the CR traits ranged from 0.000 ± 0.000 for slope for decreased rate of TV (SlopeDe) to 0.291 ± 0.047 for sum of TV values below the HS threshold (HSUB). Moderate to high genetic correlations (from 0.508 ± 0.056 to 0.998 ± 0.137) and Spearman rank correlations (from 0.431 to 1.000) between genomic estimated breeding values (GEBV) were observed for five CR indicators, i.e. HS duration (HSD), the normalized median multiplied by normalized variance (Nor_medvar), the highest TV value of each measurement day for each individual (MaxTv), and the sum of the TV values above (HSUA) and below (HSUB) the HS threshold. These five CR indicators were lowly to moderately genetically correlated with shoulder skin surface temperature (from 0.139 ± 0.008 to 0.478 ± 0.048) and respiration rate (from 0.079 ± 0.011 to 0.502 ± 0.098). The genetic correlations between these five selected CR indicators and sow reproductive performance traits ranged from - 0.733 to - 0.175 for total number of piglets born alive, from - 0.733 to - 0.175 for total number of piglets born, and from - 0.434 to - 0.169 for number of pigs weaned. The individuals with the highest GEBV (most climate-sensitive) had higher mean skin surface temperature, respiration rate (RR), panting score (PS), and hair density, but had lower mean body condition scores compared to those with the lowest GEBV (most climate-resilient). CONCLUSIONS: Most of the CR indicators evaluated are heritable with substantial additive genetic variance. Five of them, i.e. HSD, MaxTv, HSUA, HSUB, and Nor_medvar share similar underlying genetic mechanisms. In addition, individuals with higher CR indicators are more likely to exhibit better HS-related physiological responses, higher body condition scores, and improved reproductive performance under hot conditions. These findings highlight the potential benefits of genetically selecting more heat-tolerant individuals based on CR indicators.