Reconstruction of single-cell lineage trajectories and identification of diversity in fates during the epithelial-to-mesenchymal transition.

Exploring the complexity of the epithelial-to-mesenchymal transition (EMT) unveils a diversity of potential cell fates; however, the exact timing and mechanisms by which early cell states diverge into distinct EMT trajectories remain unclear. Studying these EMT trajectories through single-cell RNA sequencing is challenging due to the necessity of sacrificing cells for each measurement. In this study, we employed optimal-transport analysis to reconstruct the past trajectories of different cell fates during TGF-beta-induced EMT in the MCF10A cell line. Our analysis revealed three distinct trajectories leading to low EMT, partial EMT, and high EMT states. Cells along the partial EMT trajectory showed substantial variations in the EMT signature and exhibited pronounced stemness. Throughout this EMT trajectory, we observed a consistent downregulation of the EED and EZH2 genes. This finding was validated by recent inhibitor screens of EMT regulators and CRISPR screen studies. Moreover, we applied our analysis of early-phase differential gene expression to gene sets associated with stemness and proliferation, pinpointing ITGB4, LAMA3, and LAMB3 as genes differentially expressed in the initial stages of the partial versus high EMT trajectories. We also found that CENPF, CKS1B, and MKI67 showed significant upregulation in the high EMT trajectory. While the first group of genes aligns with findings from previous studies, our work uniquely pinpoints the precise timing of these upregulations. Finally, the identification of the latter group of genes sheds light on potential cell cycle targets for modulating EMT trajectories.

Long-term efficacy, safety, and patient-reported outcomes of apitegromab in patients with spinal muscular atrophy: results from the 36-month TOPAZ study.

Background and purpose: At 12 months in the phase 2 TOPAZ study, treatment with apitegromab was associated with both an improved motor function in patients with Type 2 or 3 spinal muscular atrophy (SMA) and with a favorable safety profile. This manuscript reports the extended efficacy and safety in the nonambulatory group of the TOPAZ study at 36 months. Methods: Patients who completed the primary study (NCT03921528) could enroll in an open-label extension, during which patients received apitegromab 20 mg/kg by intravenous infusion every 4 weeks. Patients were assessed periodically via the Hammersmith Functional Motor Scale-Expanded (HFMSE), Revised Upper Limb Module (RULM), World Health Organization (WHO) motor development milestones, Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) Daily Activities and Mobility domains, and Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue questionnaire. Results: Of the 58 patients enrolled in TOPAZ, 35 were nonambulatory (mean age 7.3 years). The mean change at 36 months in HFMSE score from baseline was +4.0 (standard deviation [SD]: 7.54), and + 2.4 (3.24) for RULM score (excluding n = 7 after scoliosis surgery). Caregiver-reported outcomes (PEDI-CAT and PROMIS Fatigue) showed improvements from baseline over 36 months. In addition, most patients (28/32) improved or maintained WHO motor milestones achieved at baseline. The most frequently reported treatment-emergent adverse events were pyrexia (48.6%), nasopharyngitis (45.7%), COVID-19 infection (40.0%), vomiting (40.0%), and upper respiratory tract infection (31.4%). Conclusion: The benefit of apitegromab treatment observed at 12 months was sustained at 36 months with no new safety findings.

Evaluation of sterile glove usage on digital tactile sensitivity using the Grating Orientation Task.

Introduction: Surgical glove use may be associated with a decrease in tactile sensitivity, with thicker gloves or double-gloving techniques further altering sensation. This study evaluates digital tactile sensitivity by use of a Grating Orientation Task (GOT) with multiple sterile gloving techniques (no gloves, single standard gloving, double standard gloving, orthopedic gloves, and micro-thickness gloves). Methods: Each participant performed the GOT at increasing grating widths until correctly noting orientation in ≥8 of 10 trials with multiple glove types or double-gloving technique. Glove order was randomly assigned and participants were blinded to the orientation and dome size. Results: All gloves except micro-thickness gloves showed increased threshold sensitivity values (i.e. worse fingertip sensitivity) when compared to control (micro:control, p = 0.105, others:control, p < 0.05). Single-layer gloves showed no significant difference in sensitivity when compared to orthopedic (p = 0.06) or double-layer latex gloves (p = 0.26). Discussion: Standard latex gloves decreased fingertip sensitivity when evaluated with the GOT. Double-layer and orthopedic latex gloves do not decrease sensitivity when compared with single-layer gloving. Micro-thickness gloves may provide similar tactile sensitivity to no surgical glove.

The number of comorbidities as an important cofactor to ASA class in predicting postoperative outcome: An international multicentre cohort study.

BACKGROUND: Multimorbidity is a growing burden in our ageing society and is associated with perioperative morbidity and mortality. Despite several modifications to the ASA physical status classification, multimorbidity as such is still not considered. Thus, the aim of this study was to quantify the burden of comorbidities in perioperative patients and to assess, independent of ASA class, its potential influence on perioperative outcome. METHODS: In a subpopulation of the prospective ClassIntra® validation study from eight international centres, type and severity of anaesthesia-relevant comorbidities were additionally extracted from electronic medical records for the current study. Patients from the validation study were of all ages, undergoing any type of in-hospital surgery and were followed up until 30 days postoperatively to assess perioperative outcomes. Primary endpoint was the number of comorbidities across ASA classes. The associated postoperative length of hospital stay (pLOS) and Comprehensive Complication Index (CCI®) were secondary endpoints. On a scale from 0 (no complication) to 100 (death) the CCI® measures the severity of postoperative morbidity as a weighted sum of all postoperative complications. RESULTS: Of 1421 enrolled patients, the mean number of comorbidities significantly increased from 1.5 in ASA I (95% CI, 1.1-1.9) to 10.5 in ASA IV (95% CI, 8.3-12.7) patients. Furthermore, independent of ASA class, postoperative complications measured by the CCI® increased per each comorbidity by 0.81 (95% CI, 0.40-1.23) and so did pLOS (geometric mean ratio, 1.03; 95% CI, 1.01-1.06). CONCLUSIONS: These data quantify the high prevalence of multimorbidity in the surgical population and show that the number of comorbidities is predictive of negative postoperative outcomes, independent of ASA class.

Insights into the nature of ichthyotoxins from the Chrysochromulina leadbeateri blooms in Northern Norwegian fjords.

In May-June 2019, the microalga Chrysochromulina leadbeateri caused a massive fish-killing event in several fjords in Northern Norway, resulting in the largest direct impact ever on aquaculture in northern Europe due to toxic algae. Motivated by the fact that no algal toxins have previously been described from C. leadbeateri, we set out to investigate the chemical nature and toxicity of secondary metabolites in extracts of two strains (UIO 393, UIO 394) isolated from the 2019 bloom, as well as one older strain (UIO 035) isolated during a bloom in Northern Norway in 1991. Initial LC-DAD-MS/MS-based molecular networking analysis of the crude MeOH extracts of the cultivated strains showed that their profiles of small organic molecules, including a large number of known lipids, were very similar, suggesting that the same class of toxin(s) were likely the causative agents of the two harmful algal bloom (HAB) events. Next, bioassay-guided fractionation using the RTgill-W1 cell line and metabolomics analysis pointed to a major compound affording [M + H]+ ions at m/z 1399.8333 as a possible toxin, corresponding to a compound with the formula C67H127ClO27. Moreover, our study unveiled a series of minor analogues exhibiting distinct patterns of chlorination and sulfation, together defining a new family of compounds, which we propose to name leadbeaterins. Remarkably, these suspected toxins were detected in situ in samples collected during the 2019 bloom close to Tromsø, thereby consistent with a role in fish kills. The elemental compositions of the putative C. leadbeateri ichthyotoxins strongly indicate them to be long linear polyhydroxylated polyketides, structurally similar to sterolysins reported from a number of dinoflagellates.

Risk Factors for Cervical Cancer in Ghana.

BACKGROUND: The major burden of cervical cancer occurs in low- and middle-income countries. In Ghana, it is the second most common cancer among women. Infection with high-risk human papilloma virus (HPV) has been established as the cause of cervical cancer. As such, it is important to identify risk factors that may affect progression from HPV infection to cancer. AIMS: We assessed the risk factors assocaited with cervical cancer in Ghana. METHODS: To identify the risk factors for cervical cancer, we conducted an unmatched case-control study in two hospitals in Ghana where most cervical cancer cases are diagnosed. Women with histologically confirmed cervical cancer were the cases, whereas women without cancer seeking care at the two hospitals were controls. A structured questionnaire was administered to the women, after which cervical samples were sent for HPV deoxyribonucleic acid (DNA) testing. RESULTS: Overall, 206 cases and 230 controls were recruited. After adjusting for possible confounders, women with the highest educational level had a significantly lower risk of cervical cancer than those with no or little formal education. Parity was a major risk factor (odd ratio [OR] for five or more children = 7.9; 95% CI: 2.3-27.6), with risk increasing with increasing parity (p for trend <0.001). Women reporting the use of a homemade sanitary towel during menstruation also had an increased risk of cervical cancer compared with women who used a pad (OR: 7.3; 95% CI: 2.5-22.0). CONCLUSION: In this Ghanaian population, high parity and poor personal hygienic conditions were the main contributing factors to the risk of cervical cancer after adjustment for the presence of high-risk HPV genotypes.

Double cervical cerclage for cervical insufficiency: Case report.

Recurrent pregnancy loss devastates parents and frustrates doctors, especially when the pregnancy progresses to the second trimester. Cervical insufficiency is the most common cause of second-trimester pregnancy loss. Abdominal cerclage is the treatment option for women with failed vaginally applied cervical cerclage. We report a 33-year-old para 0 with a history of nine second-trimester pregnancy losses. She had six failed transvaginal cerclages using McDonald's procedure. A vaginal double cervical cerclage was placed in her index pregnancy. Two mersilene tape purse-string sutures were placed in the submucosal layer of the cervix; the first 1cm below and the second at the level of the internal os. Both sutures were knotted at the 12 O'Clock position on the cervix. She carried her pregnancy to almost term and delivered a healthy baby girl weighing 2.5kg. We recommend a transvaginal double cervical cerclage with mersilene tape using a modified McDonald's technique as a viable alternative to abdominal cervical cerclage. (Afr J Reprod Health 2024; 28 [6]: 117-125).

Les fausses couches récurrentes sont dévastatrices pour les parents et frustrent les médecins, surtout lorsque la grossesse progresse jusqu'au deuxième trimestre. L'insuffisance cervicale est la cause la plus fréquente de fausse couche au deuxième trimestre. Le cerclage abdominal est l'option de traitement pour les femmes dont le cerclage cervical appliqué par voie vaginale a échoué. Nous rapportons une para 0 de 33 ans avec des antécédents de neuf fausses couches au deuxième trimestre. Elle a eu six cerclages transvaginaux selon la procédure McDonald's qui ont échoué. Un double cerclage vaginal vaginal a été placé lors de sa grossesse index. Deux fils de suture en bourse en ruban de mersilène ont été placés dans la couche sous-muqueuse du col de l'utérus ; le premier 1cm en dessous et le second au niveau de l'os interne. Les deux sutures ont été nouées à la position 12 heures sur le col. Elle a mené sa grossesse presque à terme et a donné naissance à une petite fille en bonne santé pesant 2,5 kg. Nous recommandons un double cerclage cervical transvaginal avec du ruban de mersilène en utilisant une technique McDonald's modifiée comme alternative viable au cerclage cervical abdominal. (Afr J Reprod Health 2024; 28 [6]: 117-125).

"Nobody gave me information": Hospital experiences of Ghanaian families after maternal mortalities.

Background: Rates of maternal mortality are highest in low-resource settings. Family members are often involved in the critical periods surrounding a maternal death, including transportation to health centers and financial and emotional support during hospital admissions. Maternal death has devastating impacts on surviving family members, which are often overlooked and understudied. Objective: Our study aimed to explore the hospital experiences of family members surrounding a maternal death, and to define their access to and need for institutional and psychosocial support. Study Design: This mixed methods cross-sectional study was conducted at an urban tertiary hospital in Ghana. Maternal mortalities from June 2019 to December 2020 were identified using death certificates. Participants, defined as husbands or other heads of households in families affected by maternal mortality, were purposively recruited. An interview guide was developed using grounded theory. In-person semi-structured interviews were conducted in English or Twi to explore impacts of maternal mortality on family members, with a focus on hospital experiences. Surveys were administered on types of and needs for institutional support. Interviews were audio recorded, translated, transcribed, coded with an iteratively-developed codebook, and thematically analyzed. Survey data was descriptively analyzed. Results: Fifty-one participants included 26 husbands of the deceased woman, 5 parents, 12 siblings, and 8 second-degree relatives. Interviews revealed an overall negative hospital experience for surviving family members, who expressed substantial dissatisfaction and distress. Four themes regarding the hospital experience emerged from the interviews: 1) poor communication from healthcare workers and hospital personnel, which contributed to 2) limited understanding of the patient's clinical status, hospital course, and cause of death; 3) maternal death perceived as avoidable; and 4) maternal death perceived as unexpected and shocking. Survey data revealed that only 10% of participants were provided psychosocial support following the maternal death event, yet 93.3% of those who did not receive support desired this resource. Conclusion: The hospital experience was overall negative for family members and a lack of effective communication emerged as the root cause of this negative perception. Strategies to improve communication between healthcare providers and families are essential. In addition, there is an unmet need for formal mental health resources for families who experience a maternal death.

Achieving Digestive Autonomy and Gastrointestinal Continuity in a Patient with Short Bowel Syndrome Secondary to Concomitant Jejunal Atresia and Small Intestinal Hirschsprung's Disease.

Concomitant presentation of jejunal atresia and Hirschsprung's disease is rare and places children at high risk for developing short bowel syndrome and parenteral nutrition dependence, which can affect the feasibility/timing of pull-through. A patient was born with jejunal atresia with a delayed diagnosis of Hirschsprung's disease. After several procedures and bowel resections, the patient was ultimately left with an end jejunostomy and long Hartman's pouch with short bowel syndrome, dependent on parenteral nutrition. The patient initially presented to our institution at age 2 with failure to thrive secondary to an obstructed/dilated jejunostomy and mild enterocolitis of their defunctionalized segment. The patient subsequently underwent completion of subtotal colectomy and revision of jejunostomy utilizing a serial transverse enteroplasty to manage the dilated bowel and gain length. The patient was able to wean off parenteral nutrition and achieve nutritional autonomy by age 5. Following this, the patient was able to undergo an ileoanal pull-through. After the pull-through, the patient was able to pass stool independently and suffered no major complications to date. Serial transverse enteroplasty can be successfully utilized in patients with a history of Hirschsprung's disease and jejunal atresia to achieve nutritional autonomy and ultimately reestablish gastrointestinal continuity with pull-through.

High-Resolution Mass Spectrometry for Human Exposomics: Expanding Chemical Space Coverage.

In the modern "omics" era, measurement of the human exposome is a critical missing link between genetic drivers and disease outcomes. High-resolution mass spectrometry (HRMS), routinely used in proteomics and metabolomics, has emerged as a leading technology to broadly profile chemical exposure agents and related biomolecules for accurate mass measurement, high sensitivity, rapid data acquisition, and increased resolution of chemical space. Non-targeted approaches are increasingly accessible, supporting a shift from conventional hypothesis-driven, quantitation-centric targeted analyses toward data-driven, hypothesis-generating chemical exposome-wide profiling. However, HRMS-based exposomics encounters unique challenges. New analytical and computational infrastructures are needed to expand the analysis coverage through streamlined, scalable, and harmonized workflows and data pipelines that permit longitudinal chemical exposome tracking, retrospective validation, and multi-omics integration for meaningful health-oriented inferences. In this article, we survey the literature on state-of-the-art HRMS-based technologies, review current analytical workflows and informatic pipelines, and provide an up-to-date reference on exposomic approaches for chemists, toxicologists, epidemiologists, care providers, and stakeholders in health sciences and medicine. We propose efforts to benchmark fit-for-purpose platforms for expanding coverage of chemical space, including gas/liquid chromatography-HRMS (GC-HRMS and LC-HRMS), and discuss opportunities, challenges, and strategies to advance the burgeoning field of the exposome.

Ant social network structure is highly conserved across species.

The ecological success of social insects makes their colony organization fascinating to scientists studying collective systems. In recent years, the combination of automated behavioural tracking and social network analysis has deepened our understanding of many aspects of colony organization. However, because studies have typically worked with single species, we know little about interspecific variation in network structure. Here, we conduct a comparative network analysis across five ant species from five subfamilies, separated by more than 100 Myr of evolution. We find that social network structure is highly conserved across subfamilies. All species studied form modular networks, with two social communities, a similar distribution of individuals between the two communities, and equivalent mapping of task performance onto the communities. Against this backdrop of organizational similarity, queens of the different species occupied qualitatively distinct network positions. The deep conservation of the two community structure implies that the most fundamental behavioural division of labour in social insects is between workers that stay in the nest to rear brood, and those that leave the nest to forage. This division has parallels across the animal kingdom in systems of biparental care and probably represents the most readily evolvable form of behavioural division of labour.

An outbreak of renal failure in asian dogs due to s-triazine adulteration of pet food raw material: Analysis of unique, green kidney stones formed as a result.

Renoliths were removed at necropsy from dogs that had died from acute kidney injury in Asia in 2004 and submitted to our laboratories for analysis including elemental composition, mass spectrometry, and nuclear magnetic resonance spectroscopy. The presence of a mixed s-triazine matrix comprising melamine, cyanuric acid, and ammelide, but no detectable ammeline, was found in the stone samples we analyzed. The unusual and unique green coloration of these stones was determined to be due to the presence of biliverdin. The occurrence of these green stones distinguished the 2004 incident from another incident in 2007 in the USA and other reported cases. The presence of crystals was reported in renal tubules and collecting ducts in both outbreaks, but no stones were reported in the 2007 incident. This difference suggested a variation in the disease process caused by mixed s-triazine ingestion. Careful monitoring of food additives is warranted to prevent future problems in animals and humans.

Combined clinical, structural, and cellular studies discriminate pathogenic and benign TRPV4 variants.

Dominant mutations in the calcium-permeable ion channel TRPV4 (transient receptor potential vanilloid 4) cause diverse and largely distinct channelopathies, including inherited forms of neuromuscular disease, skeletal dysplasias, and arthropathy. Pathogenic TRPV4 mutations cause gain of ion channel function and toxicity that can be rescued by small molecule TRPV4 antagonists in cellular and animal models, suggesting that TRPV4 antagonism could be therapeutic for patients. Numerous variants in TRPV4 have been detected with targeted and whole exome/genome sequencing, but for the vast majority, their pathogenicity remains unclear. Here, we used a combination of clinical information and experimental structure-function analyses to evaluate 30 TRPV4 variants across various functional protein domains. We report clinical features of seven patients with TRPV4 variants of unknown significance and provide extensive functional characterization of these and an additional 17 variants, including structural position, ion channel function, subcellular localization, expression level, cytotoxicity, and protein-protein interactions. We find that gain-of-function mutations within the TRPV4 intracellular ankyrin repeat domain target charged amino acid residues important for RhoA interaction, whereas ankyrin repeat domain residues outside of the RhoA interface have normal or reduced ion channel activity. We further identify a cluster of gain-of-function variants within the intracellular intrinsically disordered region that may cause toxicity via altered interactions with membrane lipids. In contrast, assessed variants in the transmembrane domain and other regions of the intrinsically disordered region do not cause gain of function and are likely benign. Clinical features associated with gain of function and cytotoxicity include congenital onset of disease, vocal cord weakness, and motor predominant disease, whereas patients with likely benign variants often demonstrated late-onset and sensory-predominant disease. These results provide a framework for assessing additional TRPV4 variants with respect to likely pathogenicity, which will yield critical information to inform patient selection for future clinical trials for TRPV4 channelopathies.

Genomic Analysis of Aspergillus Section Terrei Reveals a High Potential in Secondary Metabolite Production and Plant Biomass Degradation.

Aspergillus terreus has attracted interest due to its application in industrial biotechnology, particularly for the production of itaconic acid and bioactive secondary metabolites. As related species also seem to possess a prosperous secondary metabolism, they are of high interest for genome mining and exploitation. Here, we present draft genome sequences for six species from Aspergillus section Terrei and one species from Aspergillus section Nidulantes. Whole-genome phylogeny confirmed that section Terrei is monophyletic. Genome analyses identified between 70 and 108 key secondary metabolism genes in each of the genomes of section Terrei, the highest rate found in the genus Aspergillus so far. The respective enzymes fall into 167 distinct families with most of them corresponding to potentially unique compounds or compound families. Moreover, 53% of the families were only found in a single species, which supports the suitability of species from section Terrei for further genome mining. Intriguingly, this analysis, combined with heterologous gene expression and metabolite identification, suggested that species from section Terrei use a strategy for UV protection different to other species from the genus Aspergillus. Section Terrei contains a complete plant polysaccharide degrading potential and an even higher cellulolytic potential than other Aspergilli, possibly facilitating additional applications for these species in biotechnology.

Comparative mitochondrial genomics in Nematoda reveal astonishing variation in compositional biases and substitution rates indicative of multi-level selection.

BACKGROUND: Nematodes are the most abundant and diverse metazoans on Earth, and are known to significantly affect ecosystem functioning. A better understanding of their biology and ecology, including potential adaptations to diverse habitats and lifestyles, is key to understanding their response to global change scenarios. Mitochondrial genomes offer high species level characterization, low cost of sequencing, and an ease of data handling that can provide insights into nematode evolutionary pressures. RESULTS: Generally, nematode mitochondrial genomes exhibited similar structural characteristics (e.g., gene size and GC content), but displayed remarkable variability around these general patterns. Compositional strand biases showed strong codon position specific G skews and relationships with nematode life traits (especially parasitic feeding habits) equal to or greater than with predicted phylogeny. On average, nematode mitochondrial genomes showed low non-synonymous substitution rates, but also high clade specific deviations from these means. Despite the presence of significant mutational saturation, non-synonymous (dN) and synonymous (dS) substitution rates could still be significantly explained by feeding habit and/or habitat. Low ratios of dN:dS rates, particularly associated with the parasitic lifestyles, suggested the presence of strong purifying selection. CONCLUSIONS: Nematode mitochondrial genomes demonstrated a capacity to accumulate diversity in composition, structure, and content while still maintaining functional genes. Moreover, they demonstrated a capacity for rapid evolutionary change pointing to a potential interaction between multi-level selection pressures and rapid evolution. In conclusion, this study helps establish a background for our understanding of the potential evolutionary pressures shaping nematode mitochondrial genomes, while outlining likely routes of future inquiry.

Sympathetic innervation of interscapular brown adipose tissue is not a predominant mediator of oxytocin-elicited reductions of body weight and adiposity in male diet-induced obese mice.

Previous studies indicate that CNS administration of oxytocin (OT) reduces body weight in high fat diet-induced obese (DIO) rodents by reducing food intake and increasing energy expenditure (EE). We recently demonstrated that hindbrain (fourth ventricular [4V]) administration of OT elicits weight loss and elevates interscapular brown adipose tissue temperature (T IBAT , a surrogate measure of increased EE) in DIO mice. What remains unclear is whether OT-elicited weight loss requires increased sympathetic nervous system (SNS) outflow to IBAT. We hypothesized that OT-induced stimulation of SNS outflow to IBAT contributes to its ability to activate BAT and elicit weight loss in DIO mice. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on the ability of 4V OT administration to increase T IBAT and elicit weight loss in DIO mice. We first determined whether bilateral surgical SNS denervation to IBAT was successful as noted by ≥ 60% reduction in IBAT norepinephrine (NE) content in DIO mice. NE content was selectively reduced in IBAT at 1-, 6- and 7-weeks post-denervation by 95.9±2.0, 77.4±12.7 and 93.6±4.6% ( P <0.05), respectively and was unchanged in inguinal white adipose tissue, pancreas or liver. We subsequently measured the effects of acute 4V OT (1, 5 µg ≈ 0.99, 4.96 nmol) on T IBAT in DIO mice following sham or bilateral surgical SNS denervation to IBAT. We found that the high dose of 4V OT (5 µg ≈ 4.96 nmol) elevated T IBAT similarly in sham mice as in denervated mice. We subsequently measured the effects of chronic 4V OT (16 nmol/day over 29 days) or vehicle infusions on body weight, adiposity and food intake in DIO mice following sham or bilateral surgical denervation of IBAT. Chronic 4V OT reduced body weight by 5.7±2.23% and 6.6±1.4% in sham and denervated mice ( P <0.05), respectively, and this effect was similar between groups ( P =NS). OT produced corresponding reductions in whole body fat mass ( P <0.05). Together, these findings support the hypothesis that sympathetic innervation of IBAT is not necessary for OT-elicited increases in BAT thermogenesis and reductions of body weight and adiposity in male DIO mice.

Healthcare resource use associated with tumor-induced osteomalacia: a literature review.

CONTEXT: Tumor-induced osteomalacia (TIO) is an ultra-rare, paraneoplastic syndrome caused by tumors that secrete fibroblast growth factor 23 (FGF23). Initial signs and musculoskeletal symptoms can be non-specific and unrecognized, leading to long delays in diagnosis and treatment, which results in severe and progressive disability in patients with TIO. This review aimed to identify published evidence on healthcare resource use in TIO to better understand the burden of the disease. EVIDENCE ACQUISITION: A targeted literature review was conducted to identify publications reporting on disease characteristics and healthcare resource use associated with TIO. EVIDENCE SYNTHESIS: In total, 414 publications were included in the review, of which 376 were case reports. From the case reports, data on 621 patients were extracted. These patients had a mean (standard deviation) age of 46.3 (15.8) years; 57.6% were male. Mean time from first symptoms to diagnosis of TIO was 4.6 (4.7) years and, in cases where imaging tests were reported, patients underwent a mean of 4.1 (2.7) procedures. Tumor resection was attempted in 81.0% of patients and successful in 67.0%. Fracture was reported in 49.3% of patients. Results from association analyses demonstrated that longer time to diagnosis was associated with poorer tumor resection outcomes and a higher probability of tumor recurrence. Unfavorable tumor resection outcomes were associated with greater use of pharmacologic treatment and a greater likelihood of orthopedic surgery. CONCLUSION: TIO is associated with a substantial healthcare resource burden. Improvements in the diagnostic process could lead to better management of TIO, thereby benefiting patients and reducing that burden.

Evolution of connectivity architecture in the Drosophila mushroom body.

Brain evolution has primarily been studied at the macroscopic level by comparing the relative size of homologous brain centers between species. How neuronal circuits change at the cellular level over evolutionary time remains largely unanswered. Here, using a phylogenetically informed framework, we compare the olfactory circuits of three closely related Drosophila species that differ in their chemical ecology: the generalists Drosophila melanogaster and Drosophila simulans and Drosophila sechellia that specializes on ripe noni fruit. We examine a central part of the olfactory circuit that, to our knowledge, has not been investigated in these species-the connections between projection neurons and the Kenyon cells of the mushroom body-and identify species-specific connectivity patterns. We found that neurons encoding food odors connect more frequently with Kenyon cells, giving rise to species-specific biases in connectivity. These species-specific connectivity differences reflect two distinct neuronal phenotypes: in the number of projection neurons or in the number of presynaptic boutons formed by individual projection neurons. Finally, behavioral analyses suggest that such increased connectivity enhances learning performance in an associative task. Our study shows how fine-grained aspects of connectivity architecture in an associative brain center can change during evolution to reflect the chemical ecology of a species.

TRPV4 neuromuscular disease registry highlights bulbar, skeletal and proximal limb manifestations.

Dominant missense mutations of the calcium-permeable cation channel TRPV4 cause Charcot-Marie-Tooth disease (CMT) type 2C and two forms of distal spinal muscular atrophy. These conditions are collectively referred to as TRPV4-related neuromuscular disease and share features of motor greater than sensory dysfunction and frequent vocal fold weakness. Pathogenic variants lead to gain of ion channel function that can be rescued by TRPV4 antagonists in cellular and animal models. As small molecule TRPV4 antagonists have proven safe in trials for other disease indications, channel inhibition is a promising therapeutic strategy for TRPV4 patients. However, the current knowledge of the clinical features and natural history of TRPV4-related neuromuscular disease is insufficient to enable rational clinical trial design. To address these issues, we developed a TRPV4 patient database and administered a TRPV4-specific patient questionnaire. Here, we report demographic and clinical information, including CMT examination scores (CMTES), from 68 patients with known pathogenic TRPV4 variants, 40 of whom also completed the TRPV4 patient questionnaire. TRPV4 patients showed a bimodal age of onset, with the largest peak occurring in the first 2 years of life. Compared to CMT1A patients, TRPV4 patients showed distinct symptoms and signs, manifesting more ambulatory difficulties and more frequent involvement of proximal arm and leg muscles. Although patients reported fewer sensory symptoms, sensory dysfunction was often detected clinically. Many patients were affected by vocal fold weakness (55%) and shortness of breath (55%), and 11% required ventilatory support. Skeletal abnormalities were common, including scoliosis (64%), arthrogryposis (33%), and foot deformities. Strikingly, patients with infantile onset of disease showed less sensory involvement and less progression of symptoms. These results highlight distinctive clinical features in TRPV4 patients, including motor-predominant disease, proximal arm and leg weakness, severe ambulatory difficulties, vocal fold weakness, respiratory dysfunction, and skeletal involvement. In addition, patients with infantile onset of disease appeared to have a distinct phenotype with less apparent disease progression based on CMTES. These collective observations indicate that clinical trial design for TRPV4-related neuromuscular disease should include outcome measures that reliably capture non-length dependent motor dysfunction, vocal fold weakness, and respiratory disease.