Translational control in the spinal cord regulates gene expression and pain hypersensitivity in the chronic phase of neuropathic pain.

Sensitization of spinal nociceptive circuits plays a crucial role in neuropathic pain. This sensitization depends on new gene expression that is primarily regulated via transcriptional and translational control mechanisms. The relative roles of these mechanisms in regulating gene expression in the clinically relevant chronic phase of neuropathic pain are not well understood. Here, we show that changes in gene expression in the spinal cord during the chronic phase of neuropathic pain are substantially regulated at the translational level. Downregulating spinal translation at the chronic phase alleviated pain hypersensitivity. Cell-type-specific profiling revealed that spinal inhibitory neurons exhibited greater changes in translation after peripheral nerve injury compared to excitatory neurons. Notably, increasing translation selectively in all inhibitory neurons or parvalbumin-positive (PV+) interneurons, but not excitatory neurons, promoted mechanical pain hypersensitivity. Furthermore, increasing translation in PV+ neurons decreased their intrinsic excitability and spiking activity, whereas reducing translation in spinal PV+ neurons prevented the nerve injury-induced decrease in excitability. Thus, translational control mechanisms in the spinal cord, particularly in inhibitory neurons, play a role in mediating neuropathic pain hypersensitivity.

Disability and long-term breathlessness: a cross-sectional, population study.

INTRODUCTION: Disability, resulting from altered interactions between individuals and their environment, is a worldwide issue causing inequities and suffering. Many diseases associated with breathlessness cause disability but the relationship between disability and the severity of breathlessness itself is unknown.This study evaluated associations between disability using the WHO's Disability Assessment Schedule (WHODAS) 2.0 and levels of long-term breathlessness limiting exertion. METHODS: This population-based, cross-sectional online survey (n=10 033) reflected the most recent national census (2016) by age, sex, state/territory of residence and rurality. Assessments included self-reported disability (WHODAS 2.0 12-item (range 12 (no disability) to 60 (most severe disability)) assessed in 6 domains) and long-term breathlessness limiting exertion (modified Medical Research Council (mMRC) breathlessness scale; 0-4 (4-most severe)). Days in the last month affected by breathlessness were reported. RESULTS: Of respondents (52% women; mean age 45), mean total disability score was 20.9 (SD 9.5). 42% (n=4245) had mMRC >0 (mMRC1 31% (n=3139); mMRC2 8% (n=806); mMRC3,4 3% (n=300)). Every level of long-term breathlessness limiting exertion was associated with greater levels of disability (total p <0.001; each domain p <0.001). The most compromised domains were Mobility and Participation.In the last 30 days, people with severe breathlessness (mMRC 3-4): experienced disability (20 days); reduced activities/work (10 days); and completely forwent activities (another 5 days). CONCLUSIONS: Disability should be in the definition of persistent breathlessness as it is systematically associated with long-term breathlessness limiting exertion in a grade-dependent, multidimensional manner. Disability should be assessed in people with long-term breathlessness to optimise their social well-being and health.

Mapping Somatosensory Afferent Circuitry to Bone Identifies Neurotrophic Signals Required for Fracture Healing.

The profound pain accompanying bone fracture is mediated by somatosensory neurons, which also appear to be required to initiate bone regeneration following fracture. Surprisingly, the precise neuroanatomical circuitry mediating skeletal nociception and regeneration remains incompletely understood. Here, we characterized somatosensory dorsal root ganglia (DRG) afferent neurons innervating murine long bones before and after experimental long bone fracture in mice. Retrograde labeling of DRG neurons by an adeno-associated virus with peripheral nerve tropism showed AAV-tdT signal. Single cell transcriptomic profiling of 6,648 DRG neurons showed highest labeling across CGRP+ neuron clusters (6.9-17.2%) belonging to unmyelinated C fibers, thinly myelinated Aδ fibers and Aß-Field LTMR (9.2%). Gene expression profiles of retrograde labeled DRG neurons over multiple timepoints following experimental stress fracture revealed dynamic changes in gene expression corresponding to the acute inflammatory ( S100a8 , S100a9 ) and mechanical force ( Piezo2 ). Reparative phase after fracture included morphogens such as Tgfb1, Fgf9 and Fgf18 . Two methods to surgically or genetically denervate fractured bones were used in combination with scRNA-seq to implicate defective mesenchymal cell proliferation and osteodifferentiation as underlying the poor bone repair capacity in the presence of attenuated innervation. Finally, multi-tissue scRNA-seq and interactome analyses implicated neuron-derived FGF9 as a potent regulator of fracture repair, a finding compatible with in vitro assessments of neuron-to-skeletal mesenchyme interactions.

Upcycling of industrial footwear waste into nonwoven fibrous structures with thermal and acoustic insulation properties.

The footwear industry significantly impacts the environment, from raw material extraction to waste disposal. Transforming waste into new products is a viable option to mitigate the environmental consequences, reducing the reliance on virgin raw materials. This work aims to develop thermal and acoustic insulation materials using polyester waste from footwear industry. Two nonwoven and two compressed nonwoven structures, comprising 80% polyester waste and 20% commercial recycled polyester (matrix), were produced. The materials were created through needle-punching and compression molding techniques. The study included the production of sandwich and monolayer nonwoven structures, which were evaluated considering area weight, thickness, air permeability, mechanical properties, morphology using field emission scanning electron microscopy, and thermal and acoustic properties. The nonwoven samples presented high tensile strength (893 kPa and 629 kPa) and the highest strain (79.7% and 73.3%) and compressed nonwoven structures showed higher tensile strength (2700 kPa and 1291 kPa) but reduced strain (25.8% and 40.8%). Nonwoven samples showed thermal conductivity of 0.041 W/K.m and 0.037 W/K.m. Compressed nonwoven samples had higher values at 0.060 W/K.m and 0.070 W/K.m. While the sample with the highest conductivity exceeds typical insulation levels, other samples are suitable for thermal insulation. Nonwoven structures exhibited good absorption coefficients (0.640-0.644), suitable for acoustic insulation. Compressed nonwoven structures had lower values (0.291-0.536), unsuitable for this purpose. In summary, this study underscores the potential of 100% recycled polyester structures derived from footwear and textile industry waste, showcasing remarkable acoustic and thermal insulation properties ideal for the construction sector.

Harmonized cross-species cell atlases of trigeminal and dorsal root ganglia.

Sensory neurons in the dorsal root ganglion (DRG) and trigeminal ganglion (TG) are specialized to detect and transduce diverse environmental stimuli to the central nervous system. Single-cell RNA sequencing has provided insights into the diversity of sensory ganglia cell types in rodents, nonhuman primates, and humans, but it remains difficult to compare cell types across studies and species. We thus constructed harmonized atlases of the DRG and TG that describe and facilitate comparison of 18 neuronal and 11 non-neuronal cell types across six species and 31 datasets. We then performed single-cell/nucleus RNA sequencing of DRG from both human and the highly regenerative axolotl and found that the harmonized atlas also improves cell type annotation, particularly of sparse neuronal subtypes. We observed that the transcriptomes of sensory neuron subtypes are broadly similar across vertebrates, but the expression of functionally important neuropeptides and channels can vary notably. The resources presented here can guide future studies in comparative transcriptomics, simplify cell-type nomenclature differences across studies, and help prioritize targets for future analgesic development.

Deciphering the molecular landscape of human peripheral nerves: implications for diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is a prevalent complication of diabetes mellitus that is caused by metabolic toxicity to peripheral axons. We aimed to gain deep mechanistic insight into the disease process using bulk and spatial RNA sequencing on tibial and sural nerves recovered from lower leg amputations in a mostly diabetic population. First, our approach comparing mixed sensory and motor tibial and purely sensory sural nerves shows key pathway differences in affected nerves, with distinct immunological features observed in sural nerves. Second, spatial transcriptomics analysis of sural nerves reveals substantial shifts in endothelial and immune cell types associated with severe axonal loss. We also find clear evidence of neuronal gene transcript changes, like PRPH, in nerves with axonal loss suggesting perturbed RNA transport into distal sensory axons. This motivated further investigation into neuronal mRNA localization in peripheral nerve axons generating clear evidence of robust localization of mRNAs such as SCN9A and TRPV1 in human sensory axons. Our work gives new insight into the altered cellular and transcriptomic profiles in human nerves in DPN and highlights the importance of sensory axon mRNA transport as an unappreciated potential contributor to peripheral nerve degeneration.

Prevalence, severity and impacts of breathlessness in Indian adults: An exploratory, nationally representative, cross-sectional online survey.

There are no known estimates of the prevalence, severity and impacts from breathlessness in low- and middle-income countries. This study aimed to explore the prevalence, severity, self-attributed underlying conditions and impacts of breathlessness limiting exertion in community-dwelling adults in India. This exploratory, population-based online survey recruited a pre-planned sample of 3,000 adult respondents stratified by age, sex and rurality (quotas as per the 2011 Indian National Census). Measures included: demographics; breathlessness limiting exertion (modified Medical Research [mMRC] scale); health-related quality of life (EQ-5D-5L); and disability (World Health Organisation's Disability Assessment Schedule 2.0 12-item questionnaire [WHODAS-12]). Respondents (n = 3,046) had a mean age of 38 years (SD 15); 57% were male, 59% lived in rural areas and 33% had completed 12th grade. Breathlessness limiting exertion (mMRC ≥1) was reported by 44%, mostly attributed to poor nutrition (28%), lung conditions excluding tuberculosis (17%) or anaemia (13%). Compared to those without breathlessness, a higher proportion of people with breathlessness (mMRC ≥1) reported problems across all EQ-5D-5L dimensions. Most people reporting breathlessness (81%) indicated the symptom had adversely affected their normal activities. Disability scores (WHODAS-12 total and individual domains) increased as breathlessness worsened. To conclude, in India, conservative estimates indicate 626 million people live with breathlessness of whom 52 million people live with severe breathlessness. The symptom is associated with poorer health-related quality of life and marked disability, including reduced ability to perform daily activities.

High-Value Compounds in Papaya By-Products (Carica papaya L. var. Formosa and Aliança): Potential Sustainable Use and Exploitation.

BACKGROUND: Food waste is a global and growing problem that is gaining traction due to its environmental, ethical, social, and economic repercussions. Between 2022 and 2027, the worldwide papaya market is expected to have a huge increase, meaning a growth in organic waste, including peels and seeds. Thus, this study evaluated the potential use of peels and seeds of two mature papaya fruits as a source of bioactive compounds, converting these by-products into value-added products. Proximate analysis (AOAC methods), mineral content (ICP-MS), free sugars (HPLC-ELSD), fatty acid composition (GC-FID), vitamin E profile (HPLC-DAD-FLD), and antioxidant activity (DPPH and FRAP assays) were evaluated. RESULTS: Both by-products showed high total protein (20-27%), and dietary fiber (32-38%) contents. Papaya peels presented a high ash content (14-16%), indicating a potential application as a mineral source. 14 fatty acids were detected, with α-linolenic acid (30%) as the most abundant in the peels and oleic acid (74%) in the seeds. Both by-products showed high antioxidant activity. CONCLUSION: Papaya by-products display great potential for industrial recovery and application, such as formulation of new functional food ingredients.

The Potential of Electrospun Membranes in the Treatment of Textile Wastewater: A Review.

Water security and industrial wastewater treatment are significant global concerns. One of the main issues with environmental contamination has been the discharge of dye wastewater from the textile and dye industries, contributing to an ever-growing problem with water pollution, poisoning water supplies, and harming the ecosystem. The traditional approach to wastewater treatment has been found to be inefficient, and biosorption techniques and mechanisms have been proven to be a successful replacement for conventional methods. Recent developments have led to the recognition of fibrous materials as an environmentally friendly option with broad application in several industries, including wastewater treatment. This review explores the potential of fibrous materials produced by the electrospinning technique as adsorbents for wastewater treatment, while at the same time, for the removal of adsorbates such as oil, dyes, heavy metals, and other substances, as reported in the literature. Textile wastewater filtering structures, produced by electrospinning, are summarized and the use of synthetic and natural polymers for this purpose is discussed. The limitations of electrospun textile wastewater filtering structures are also mentioned. Electrospun nanofibrous membranes appear to be a very promising route to filter textile wastewater and therefore contribute to water reuse and to reducing the contamination of water courses.

Extraction, characterization and properties evaluation of pineapple leaf fibers from Azores pineapple.

Pineapple leaves can provide competitive and high-quality fibers for textile purposes. Despite pineapple being cultivated in the Portugues islands there is still a technology gap for the extraction and treatment of Pineapple Leaf Fibers (PALF) in Europe. Since Azorean Pineapple differs significantly from other plants in the bromeliad family, the properties and characterization of its leaf fibers were explored for the first time. Long fibers have been extracted by hand scraping and compared to biological retting at 25 °C for different time periods. It was explored the properties of PALF from plants of different ages (11- and 18-months) and from different zones of the leaves (beginning, middle, and tip). Physical-mechanical properties of Azores PALF were determined, including diameter, linear density, strength, Young's modulus, and elongation at break and characterized by ATR-FTIR, XRD, TGA/DTG, and FESEM to understand their chemical and morphological characteristics. While slight differences were observed between different ages, variations in physical-mechanical properties were notable among fibers extracted from different leaf positions. Extraction of Azores PALF through 25 °C biological retting for 14 days effectively eliminated non-fibrous matter and produced the thinnest and strongest fibers. These fibers ranged between 34.9 and 168.3 µm in diameter, 1.39 and 7.07 tex in linear mass density, 37-993 MPa in tensile strength, 1.0-3.9 % in elongation at break, and 2.4-21.8 GPa in Young's modulus.

Limited associations between MHC diversity and reproductive success in a bird species with biparental care.

The selective pressure from pathogens on individuals can have direct consequences on reproduction. Genes from the major histocompatibility complex (MHC) are central to the vertebrate adaptive immune system and pathogen resistance. In species with biparental care, each sex has distinct reproductive roles and levels of investment, and due to a trade-off with immunity, one can expect different selective regimes acting upon the MHC of each parent. Here, we addressed whether couples combine each other's variation at MHC loci to increase their breeding success. Specifically, we used a 23-year dataset from a barn owl population (Tyto alba) to understand how MHC class Iα and IIß functional divergence and supertypes of each parent were associated with clutch size and fledging success. We did not detect associations between MHC diversity and supertypes with the clutch size or with the fledging success. In addition, to understand the relative contribution from the MHC of the genetic parents and the social parents, we analyzed the fledging success using only a cross-fostered dataset. We found several associations of weak-to-moderate effect sizes between the father's MHC and fledging success: (i) lower MHC-Iα divergence in the genetic father increases fledging success, which might improve paternal care during incubation, and (ii) one and two MHC-IIß DAB2 supertypes in the social father decrease and increase, respectively, fledging success, which may affect the paternal care after hatching. Furthermore, fledging success increased when both parents did not carry MHC-IIß DAB1 supertype 2, which could suggest conditional effects of this supertype. Although our study relied on a substantial dataset, we showed that the associations between MHC diversity and reproductive success remain scarce and of complex interpretation in the barn owl. Moreover, our results highlighted the need to incorporate more than one proxy of reproductive success and several MHC classes to capture more complex associations.

The impact of regular, low-dose, sustained-release morphine for chronic breathlessness on caregiver burden: An exploratory analysis of the BEAMS trial.

BACKGROUND: Chronic breathlessness adversely impacts people with chronic obstructive pulmonary disease and their caregivers (family and friends), who may, in turn, experience significant burden due to their caregiving role. Sustained-release morphine may reduce chronic breathlessness in some patients, which may have an impact on caregivers' perceived burden. AIM: To explore the impact on caregiver burden of active treatment of people with chronic breathlessness (modified Medical Research Council (mMRC) ⩾ 3) and chronic obstructive pulmonary disease (COPD) with regular, low-dose, sustained-release morphine within a multi-site, double-blind, randomised, placebo-controlled trial. DESIGN: Exploratory analysis of self-reported caregiver burden at baseline and end of week 3 in a randomised, double-blind, placebo-controlled study. Caregiver measures included: demographics and perceived burden (Zarit Burden Interview 12-item short-form questionnaire). Patient measures included: worst breathlessness and FitBitR-measures. SETTING/PARTICIPANTS: All consenting caregivers of trial patient participants in a multi-site study recruiting from palliative care and respiratory services. RESULTS: Caregivers (n = 49; 59% women; median age 68 years [IQR 50-75]) reported median baseline caregiver burden 12 [IQR 5-17], with 53% reporting high burden (⩾13). Eighty-four percent of caregivers reported no change in burden. In people whose worst breathlessness improved, caregiver burden moved in the same direction, though the correlation was not significant (rs = 0.25, p = 0.17). Conversely, caregiver burden worsened as patients' minutes lightly active increased, with the correlation being significant (rs = 0.56, p = 0.04). CONCLUSIONS: Caregivers reported high levels of caregiver burden, but patients' response to treatment in terms of their symptom and function may influence change in caregiver burden over a three-week period.

Prevalence and risk factors for acquired long QT syndrome in the emergency department: a retrospective observational study.

BACKGROUND: Long QT syndrome (LQTS) is a heterogeneous syndrome that may be congenital or, more frequently, acquired. The real-world prevalence of acquired LQTS (aLQTS) in the emergency department (ED) remains to be determined. The aim of this study was to determine prevalence of aLQTS and its impact on symptoms on ED admissions. METHODS: Electrocardiograms (ECG) of 5,056 consecutively patients admitted in the ED of a tertiary hospital between January 28th and March 17th of 2020 were reviewed. All patients with aLQTS were included. Clinical data with a focus on QT prolonging drugs and clinical factors were recorded. Statistical comparison was made between the groups with and without corrected QT (QTc) interval greater than 500 ms (value that is considered severely increased). RESULTS: A total of 383 ECGs with prolonged QTc were recognized, corresponding to a prevalence of aLQTS at admission of 7.82%. Patients with aLQTS were more commonly men (53.3%) with an age of (73.49±14.79) years old and QTc interval of (505.3±32.4) ms. Only 20.4% of these patients with aLQTS were symptomatic. No ventricular arrhythmias were recorded. Patients with QT interval greater than 500 ms were more frequently female (59.5%; P<0.001) and were more frequently on QT prolonging drugs (77.3%; P=0.025). Main contributing factor was intake of antibiotics (odds ratio [OR] 4.680) followed by female gender (OR 2.473) and intake of antipsychotics (OR 1.925). CONCLUSION: aLQTS is particularly prevalent in the ED. Female patients on antibiotics and antipsychotics are at particularly high risk. Efforts must be made to avoid, detect and treat aLQTS as early as possible.

Mapping the contributions of dyadic approaches to couples' psychosocial adaptation to prostate cancer: a scoping review.

INTRODUCTION: Prostate cancer is the second-most prevalent cancer diagnosis worldwide among males. Although prostate cancer affects the physical, sexual, and mental health of patients, the impact of prostate cancer on partners has also been increasingly recognized. Hence, taking a dyadic approach is of relevance. Moreover, there is evidence of the utility of dyadic approaches to the study of relational stress that chronic diseases such as prostate cancer can bring to couples, even though knowledge is sparse about prostate cancer. OBJECTIVES: This scoping review aimed to map existing dyadic studies on the psychosocial adaptation of couples to prostate cancer. METHODS: A systematic search of studies published from 2005 to November 2022 was conducted on electronic databases (PubMed, Cochrane Library, EBSCOHost, Scopus, and Web of Science) following PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-analyses-Extension for Scoping Reviews). RESULTS: The review included 25 eligible studies from the initial 2514 articles retrieved. Overall, the results emphasized the interdependency between couple members and suggested how partners' adaptation influences patients' adaptation to prostate cancer and vice versa, regarding several psychosocial dimensions (eg, intimacy, quality of life). CONCLUSIONS: This work can bring awareness to health care professionals to adopt a couples approach when managing prostate cancer whenever there is a partner, due to these interdependent influences. For researchers and future studies, this work can strengthen the relevance of dyadic approaches on how couples adapt to prostate cancer and explore which other dimensions influence these complex dynamics.

4E-BP1-dependent translation in nociceptors controls mechanical hypersensitivity via TRIM32/type I interferon signaling.

Activation of the mechanistic target of rapamycin complex 1 (mTORC1) contributes to the development of chronic pain. However, the specific mechanisms by which mTORC1 causes hypersensitivity remain elusive. The eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) is a key mTORC1 downstream effector that represses translation initiation. Here, we show that nociceptor-specific deletion of 4E-BP1, mimicking activation of mTORC1-dependent translation, is sufficient to cause mechanical hypersensitivity. Using translating ribosome affinity purification in nociceptors lacking 4E-BP1, we identified a pronounced translational up-regulation of tripartite motif-containing protein 32 (TRIM32), an E3 ubiquitin ligase that promotes interferon signaling. Down-regulation of TRIM32 in nociceptors or blocking type I interferon signaling reversed the mechanical hypersensitivity in mice lacking 4E-BP1. Furthermore, nociceptor-specific ablation of TRIM32 alleviated mechanical hypersensitivity caused by tissue inflammation. These results show that mTORC1 in nociceptors promotes hypersensitivity via 4E-BP1-dependent up-regulation of TRIM32/interferon signaling and identify TRIM32 as a therapeutic target in inflammatory pain.

Asymptomatic Elevation of Pancreatic Enzymes: A Case of Gullo's Syndrome.

Benign pancreatic hyperenzymemia (BPH) or Gullo's syndrome is a benign condition consisting of an oscillating elevation of pancreatic enzymes without the identification of pancreatic disease. Its diagnosis is usually incidental and by excluding other conditions that occur with elevated pancreatic enzymes. To the best of our knowledge, there are no reports of this diagnosis to this day in Portugal. A 65-year-old female was referred to an internal medicine consultation for complaints of xerostomia, xerophthalmia, and xeroderma with one year of evolution. From the study carried out by the patient prior to the consultation, an incidental elevation of amylase stands out. The sicca symptoms were attributed to sertraline since, after excluding other causes, its discontinuation resolved the symptoms. Regarding the elevation of pancreatic enzymes, the patient underwent an extensive diagnostic study for clarification without identifying any condition. The serial measurement of amylase and lipase revealed an oscillating increase in pancreatic enzymes with temporary normalization. After one year of follow-up, the diagnosis of Gullo's syndrome was established. The identification of Gullo's syndrome is extremely important as it avoids carrying out unnecessary tests in the future and allows the patient to be reassured in the face of this benign alteration of pancreatic enzymes. A follow-up of at least one year is crucial since some pancreatic tumors course with an asymptomatic increase in pancreatic enzymes.

Analysis of matrisome expression patterns in murine and human dorsal root ganglia.

The extracellular matrix (ECM) is a dynamic structure of molecules that can be divided into six different categories and are collectively called the matrisome. The ECM plays pivotal roles in physiological processes in many tissues, including the nervous system. Intriguingly, alterations in ECM molecules/pathways are associated with painful human conditions and murine pain models. Nevertheless, mechanistic insight into the interplay of normal or defective ECM and pain is largely lacking. The goal of this study was to integrate bulk, single-cell, and spatial RNA sequencing (RNAseq) datasets to investigate the expression and cellular origin of matrisome genes in male and female murine and human dorsal root ganglia (DRG). Bulk RNAseq showed that about 65% of all matrisome genes were expressed in both murine and human DRG, with proportionally more core matrisome genes (glycoproteins, collagens, and proteoglycans) expressed compared to matrisome-associated genes (ECM-affiliated genes, ECM regulators, and secreted factors). Single cell RNAseq on male murine DRG revealed the cellular origin of matrisome expression. Core matrisome genes, especially collagens, were expressed by fibroblasts whereas matrisome-associated genes were primarily expressed by neurons. Cell-cell communication network analysis with CellChat software predicted an important role for collagen signaling pathways in connecting vascular cell types and nociceptors in murine tissue, which we confirmed by analysis of spatial transcriptomic data from human DRG. RNAscope in situ hybridization and immunohistochemistry demonstrated expression of collagens in fibroblasts surrounding nociceptors in male and female human DRG. Finally, comparing human neuropathic pain samples with non-pain samples also showed differential expression of matrisome genes produced by both fibroblasts and by nociceptors. This study supports the idea that the DRG matrisome may contribute to neuronal signaling in both mouse and human, and that dysregulation of matrisome genes is associated with neuropathic pain.