Control of G protein-coupled receptor function via membrane-interacting intrinsically disordered C-terminal domains.

G protein-coupled receptors (GPCRs) control intracellular signaling cascades via agonist-dependent coupling to intracellular transducers including heterotrimeric G proteins, GPCR kinases (GRKs), and arrestins. In addition to their critical interactions with the transmembrane core of active GPCRs, all three classes of transducers have also been reported to interact with receptor C-terminal domains (CTDs). An underexplored aspect of GPCR CTDs is their possible role as lipid sensors given their proximity to the membrane. CTD-membrane interactions have the potential to control the accessibility of key regulatory CTD residues to downstream effectors and transducers. Here, we report that the CTDs of two closely related family C GPCRs, metabotropic glutamate receptor 2 (mGluR2) and mGluR3, bind to membranes and that this interaction can regulate receptor function. We first characterize CTD structure with NMR spectroscopy, revealing lipid composition-dependent modes of membrane binding. Using molecular dynamics simulations and structure-guided mutagenesis, we then identify key conserved residues and cancer-associated mutations that modulate CTD-membrane binding. Finally, we provide evidence that mGluR3 transducer coupling is controlled by CTD-membrane interactions in live cells, which may be subject to regulation by CTD phosphorylation and changes in membrane composition. This work reveals an additional mechanism of GPCR modulation, suggesting that CTD-membrane binding may be a general regulatory mode throughout the broad GPCR superfamily.

Phylogenetic and phylogeographic evidence for the colonization success of the diplochorous Astydamia latifolia across the Canary Islands.

Astydamia latifolia is the only species of the genus Astydamia, which forms an early-diverging lineage of Apiaceae, subfamily Apioideae. This species is subendemic to the Canary Islands and one of the most representative species of the coastal environments of this archipelago. Astydamia displays diplochory, that is, diaspores with two long-distance dispersal (LDD) syndromes. In particular, A. latifolia has both anemochorous and thalassochorous fruit traits (corky and winged mericarps). Although we expect this species to have a high dispersal capacity, there is no genetic study addressing it. The divergence time of this species from its sister taxon is also unknown. In this study, we aimed (i) to unveil the phylogenetic relationships and divergence times of A. latifolia; (ii) to reconstruct its phylogeographic structure across the Canary Islands; and (iii) to estimate the number of inter-island colonization events. To these ends, we first sequenced the internal transcribed spacer (ITS) region for A. latifolia, reconstructed the phylogenetic relationships of Astydamia and Apiaceae relatives and estimated divergence times. Then, two plastid DNA regions (psaI-aacD and psbK-trnS) were sequenced for 158 individuals (from 36 Canarian population and one NW African population) to reconstruct a haplotype network. The recently developed method Phylogeographic Analysis of Island Colonization Events (PAICE) was used to estimate the number of inter-island colonization events. Results show that A. latifolia is a phylogenetically isolated lineage that diverged from the most closely related genus (Molopospermum) in the Eocene-Miocene. It displays a low plastid DNA diversity (only four haplotypes detected), which is accompanied by a high degree of haplotype sharing between islands and highly linear rarefaction curves of colonization obtained in PAICE. These findings suggest a high colonization ability for this species, most likely related to the availability of two LDD syndromes.

Allostatic Load/Chronic Stress and Cardiovascular Outcomes in Patients Diagnosed With Breast, Lung, or Colorectal Cancer.

BACKGROUND: Cardiovascular disease and cancer share a common risk factor: chronic stress/allostatic load (AL). A 1-point increase in AL is linked to up to a 30% higher risk of major cardiac events (MACE) in patients with prostate cancer. However, AL's role in MACE in breast cancer, lung cancer, or colorectal cancer remains unknown. METHODS AND RESULTS: Patients ≥18 years of age diagnosed with the mentioned 3 cancers of interest (2010-2019) and followed up at a large, hybrid academic-community practice were included in this retrospective cohort study. AL was modeled as an ordinal measure (0-11). Adjusted Fine-Gray competing risks regressions estimated the impact of AL precancer diagnosis on 2-year MACE (a composite of heart failure, ischemic stroke, acute coronary syndrome, and atrial fibrillation). The effect of AL changes over time on MACE was calculated via piecewise Cox regression (before, and 2 months, 6 months, and 1 year after cancer diagnosis). Among 16 467 patients, 50.5% had breast cancer, 27.9% had lung cancer, and 21.4% had colorectal cancer. A 1-point elevation in AL before breast cancer diagnosis corresponded to a 10% heightened associated risk of MACE (adjusted hazard ratio, 1.10 [95% CI, 1.06-1.13]). Similar findings were noted in lung cancer (adjusted hazard ratio, 1.16 [95% CI, 1.12-1.20]) and colorectal cancer (adjusted hazard ratio, 1.13 [95% CI, 1.08-1.19]). When considering AL as a time-varying exposure, the peak associated MACE risk occurred with a 1-point AL rise between 6 and 12 months post- breast cancer, lung cancer, and colorectal cancer diagnosis. CONCLUSIONS: AL warrants investigation as a potential marker in these patients to identify those at elevated cardiovascular risk and intervene accordingly.

Odds of developing cancer among male and female volunteer firefighters in Florida: A case-control study design.

OBJECTIVE: Determine whether volunteer firefighters in Florida are at increased odds of developing cancer compared to non-firefighters. METHODS: A case-control study design was implemented to assess the odds of developing cancer among male and female volunteer firefighters in Florida. Gender-specific age and calendar year-adjusted odds ratios (aOR) and 95% confidence intervals (95%CI) were estimated. RESULTS: Male volunteer firefighters were at increased odds for developing prostate (aOR = 1.26; 95%CI;[1.10- 1.44]) and male genital cancers combined (1.22;[1.07-1.39]), while reduced odds for endocrine cancer (0.41;[0.17-1.00]), and all leukemias (0.55;[0.35-0.86]), including lymphocytic (0.48;[0.24-0.97]); and chronic lymphocytic (0.40;[0.17-0.97]) leukemias. Female volunteer firefighters were at increased odds of developing of kidney cancer (2.51;[1.29-4.91]). CONCLUSIONS: Male volunteer firefighters are at increased odds for prostate and overall male genital cancers, while female volunteers are increased odds of kidney cancer.

Mental Health Disorders, Organizational Stigma, and Health Service Utilization among U.S. Fire Investigators: A Cross-Sectional Survey.

OBJECTIVE: Estimate in a sample of U.S. fire investigators the: (1) prevalence of generalized anxiety disorder (GAD), depression, post-traumatic stress disorder (PTSD) risk and mental health services use; and (2) association between organizational stigma and mental health disorders. METHODS: Cross-sectional study design used to administer between November 2023 and January 2024, a 35-item behavioral/mental health survey. RESULTS: Approximately 18.0% of fire investigators had GAD, 22.8% depression, and 18.2% PTSD risk. Organizational stigma about mental health disorders was reported by 53.3% of fire investigators. The most frequently used behavioral/mental health services were cognitive behavioral therapy (40.1%) and medication management (36.1%). Organizational stigma around reporting mental health disorders was significantly associated with PTSD risk (aOR = 5.25;[2.41-11.43]). CONCLUSION: Mental health disorders are present in the fire investigator workforce and organizational stigma is associated with limited report of PTSD risk.

A Dwindling Matter: An Analysis of Medicare Reimbursement for Endocrine Surgery Procedures from 2000-23.

OBJECTIVE: To evaluate Medicare reimbursement trends for endocrine surgeries from 2000-23. BACKGROUND: As the population ages, demand for endocrine surgeries is expected to increase. Understanding reimbursement trends is essential to ensure the financial sustainability of endocrine surgery. METHODS: Data were extracted from Medicare Inpatient and Outpatient Hospital datasets, National Summary, and Physician Fee Look-up Files for nine common thyroid, parathyroid and adrenal surgeries. Data were adjusted for inflation. Descriptive statistics, compound annual growth rate (CAGR), and linear regression models were built to evaluate practice and reimbursement trends. RESULTS: From 2000-23, there was a 63.8% increase in endocrine surgery volume. However, inflation-adjusted average procedure reimbursements decreased by 43.2% from $1709 to $972 (CAGR -2.4%), which is the largest decrease for any surgical subspecialty reported in the published literature. At the current CAGR, the average estimated reimbursement is projected to decrease to $868 by 2030 (P<0.001). Average facility reimbursements for inpatient and outpatient hospitalizations increased. However, substantial practice pattern shifts in the study period led to decreased overall facility reimbursements, with a $17.9 million decrease in total inpatient reimbursements between 2016-21 that was only partially offset by a $3.2 million increase in outpatient hospital reimbursements. CONCLUSION: Medicare procedure reimbursements for endocrine surgeries have been outpaced by inflation, with large decreases since 2000. Concurrent changes in practice patterns have also resulted in markedly fewer inpatient stays leading to lower total facility reimbursements. Our data raise concern over the financial sustainability of the endocrine surgery field as the demand for endocrine surgery procedures increases.

Interplay between the Chaperone System and Gut Microbiota Dysbiosis in Systemic Lupus Erythematosus Pathogenesis: Is Molecular Mimicry the Missing Link between Those Two Factors?

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease characterized by self-immune tolerance breakdown and the production of autoantibodies, causing the deposition of immune complexes and triggering inflammation and immune-mediated damage. SLE pathogenesis involves genetic predisposition and a combination of environmental factors. Clinical manifestations are variable, making an early diagnosis challenging. Heat shock proteins (Hsps), belonging to the chaperone system, interact with the immune system, acting as pro-inflammatory factors, autoantigens, as well as immune tolerance promoters. Increased levels of some Hsps and the production of autoantibodies against them are correlated with SLE onset and progression. The production of these autoantibodies has been attributed to molecular mimicry, occurring upon viral and bacterial infections, since they are evolutionary highly conserved. Gut microbiota dysbiosis has been associated with the occurrence and severity of SLE. Numerous findings suggest that proteins and metabolites of commensal bacteria can mimic autoantigens, inducing autoimmunity, because of molecular mimicry. Here, we propose that shared epitopes between human Hsps and those of gut commensal bacteria cause the production of anti-Hsp autoantibodies that cross-react with human molecules, contributing to SLE pathogenesis. Thus, the involvement of the chaperone system, gut microbiota dysbiosis, and molecular mimicry in SLE ought to be coordinately studied.

Methodological and Practical Challenges in Synthesizing Occupational Cancer Studies.

Studies examining occupational exposures and cancer risk frequently report mixed findings; it is thus imperative for researchers to synthesize study results and identify any potential sources that explain such variabilities in study findings. However, when synthesizing study results using meta-analytic techniques, researchers often encounter a number of practical and methodological challenges. These challenges include (1) an incomparability of effect size measures due to large variations in research methodology; (2) a violation of the independence assumption for meta-analysis; (3) a violation of the normality assumption of effect size measures; and (4) a variation in cancer definitions across studies and changes in coding standards over time. In this paper, we first demonstrate these challenges by providing examples from a real dataset collected for a large meta-analysis project that synthesizes cancer mortality and incidence rates among firefighters. We summarize how each of these challenges has been handled in our meta-analysis. We conclude this paper by providing practical guidelines for handling challenges when synthesizing study findings from occupational cancer literature.

Emerging modes of regulation of neuromodulatory G protein-coupled receptors.

In the nervous system, G protein-coupled receptors (GPCRs) control neuronal excitability, synaptic transmission, synaptic plasticity, and, ultimately, behavior through spatiotemporally precise initiation of a variety of signaling pathways. However, despite their critical importance, there is incomplete understanding of how these receptors are regulated to tune their signaling to specific neurophysiological contexts. A deeper mechanistic picture of neuromodulatory GPCR function is needed to fully decipher their biological roles and effectively harness them for the treatment of neurological and psychiatric disorders. In this review, we highlight recent progress in identifying novel modes of regulation of neuromodulatory GPCRs, including G protein- and receptor-targeting mechanisms, receptor-receptor crosstalk, and unique features that emerge in the context of chemical synapses. These emerging principles of neuromodulatory GPCR tuning raise critical questions to be tackled at the molecular, cellular, synaptic, and neural circuit levels in the future.

Targeting IGF2-IGF1R Signaling to Reprogram the Tumor Microenvironment for Enhanced Viro-Immunotherapy.

BACKGROUND: The FDA approval of oncolytic herpes simplex-1 virus (oHSV) therapy underscores its therapeutic promise and safety as a cancer immunotherapy. Despite this promise, the current efficacy of oHSV is significantly limited to a small subset of patients largely due to the resistance in tumor and tumor microenvironment (TME). METHODS: RNA sequencing (RNA-Seq) was used to identify molecular targets of oHSV resistance. Intracranial human and murine glioma or breast cancer brain metastasis (BCBM) tumor-bearing mouse models were employed to elucidate the mechanism underlying oHSV therapy-induced resistance. RESULTS: Transcriptome analysis identified IGF2 as one of the top secreted proteins following oHSV treatment. Moreover, IGF2 expression was significantly upregulated in 10 out of 14 recurrent GBM patients after treatment with oHSV, rQNestin34.5v.2 (71.4%) (p=0.0020) (ClinicalTrials.gov, NCT03152318). Depletion of IGF2 substantially enhanced oHSV-mediated tumor cell killing in vitro and improved survival of mice bearing BCBM tumors in vivo. To mitigate the oHSV-induced IGF2 in the TME, we constructed a novel oHSV, oHSV-D11mt, secreting a modified IGF2R domain 11 (IGF2RD11mt) that acts as IGF2 decoy receptor. Selective blocking of IGF2 by IGF2RD11mt significantly increased cytotoxicity, reduced oHSV-induced neutrophils/PMN-MDSCs infiltration, and reduced secretion of immune suppressive/proangiogenic cytokines, while increased CD8+cytotoxic T lymphocytes (CTLs) infiltration, leading to enhanced survival in GBM or BCBM tumor-bearing mice. CONCLUSION: This is the first study reporting that oHSV-induced secreted IGF2 exerts a critical role in resistance to oHSV therapy, which can be overcome by oHSV-D11mt as a promising therapeutic advance for enhanced viro-immunotherapy.

Deuteration as a General Strategy to Enhance Azobenzene-Based Photopharmacology.

Chemical photoswitches have become a widely used approach for the remote control of biological functions with spatiotemporal precision. Several molecular scaffolds have been implemented to improve photoswitch characteristics, ranging from the nature of the photoswitch itself (e.g. azobenzenes, dithienylethenes, hemithioindigo) to fine-tuning of aromatic units and substituents. Herein, we present deuterated azobenzene photoswitches as a general means of enhancing the performance of photopharmacological molecules. Deuteration can improve azobenzene performance in terms of light sensitivity (higher molar extinction coefficient), photoswitch efficiency (higher photoisomerization quantum yield), and photoswitch kinetics (faster macroscopic rate of photoisomerization) with minimal alteration to the underlying structure of the photopharmacological ligand. We report synthesized deuterated azobenzene-based ligands for the optimized optical control of ion channel and G protein-coupled receptor (GPCR) function in live cells, setting the stage for the straightforward, widespread adoption of this approach.

A first-in-class Wiskott-Aldrich syndrome protein activator with anti-tumor activity in hematologic cancers.

Hematological cancers are among the most common cancers in adults and children. Despite significant improvements in therapies, many patients still succumb to the disease. Therefore, novel therapies are needed. The Wiskott-Aldrich syndrome protein (WASp) family regulates actin assembly in conjunction with the Arp2/3 complex, a ubiquitous nucleation factor. WASp is expressed exclusively in hematopoietic cells and exists in two allosteric conformations: autoinhibited or activated. Here, we describe the development of EG-011, a first-in-class small molecule activator of the WASp auto-inhibited form. EG-011 possesses in vitro and in vivo anti-tumor activity as a single agent in lymphoma, leukemia, and multiple myeloma, including models of secondary resistance to PI3K, BTK, and proteasome inhibitors. The in vitro activity was confirmed in a lymphoma xenograft. Actin polymerization and WASp binding was demonstrated using multiple techniques. Transcriptome analysis highlighted homology with drugs-inducing actin polymerization.

Characterization of Cellulosic Pulps Isolated from Two Widespread Agricultural Wastes: Cotton and Sunflower Stalks.

Globally, huge amounts of cotton and sunflower stalks are generated annually. These wastes are being underutilized since they are mostly burned in the fields. So, in this work, we proposed a three-step method consisting of acid pre-treatment, alkaline hydrolysis, and bleaching for the extraction of cellulose pulps. These pulps were characterized to assess their morpho-structural and thermal properties. The design of experiments and response surface methodology were used for the optimization of the acid pre-treatment in order to achieve maximum removal of non-cellulosic compounds and obtain pulps enriched in cellulose. For cotton stalks, optimal conditions were identified as a reaction time of 190 min, a reaction temperature of 96.2 °C, and an acid (nitric acid) concentration of 6.3%. For sunflower stalks, the optimized time, temperature, and acid concentration were 130 min, 73.8 °C, and 8.7%, respectively. The pulps obtained after bleaching contained more than 90% cellulose. However, special care must be taken during the process, especially in the acid pre-treatment, as it causes the solubilization of a great amount of material. The characterization revealed that the extraction process led to cellulose pulps with around 69-70% crystallinity and thermal stability in the range of 340-350 °C, ready to be used for their conversion into derivatives for industrial applications.

A cocaine-activated ensemble exerts increased control over behavior while decreasing in size.

BACKGROUND: Substance use disorder (SUD) is characterized by long-lasting changes in reward-related brain regions, such as the nucleus accumbens (NAc). Previous work has shown that cocaine exposure induces plasticity in broad, genetically-defined cell types in the NAc; however, in response to a stimulus, only a small percent of neurons are transcriptionally active - termed an ensemble. Here, we identify an Arc-expressing neuronal ensemble that has a unique trajectory of recruitment and causally controls drug self-administration after repeated, but not acute, cocaine exposure. METHOD: Using Arc-CreERT2 transgenic mice, we expressed transgenes in Arc+ ensembles activated by cocaine exposure [either acute (1 x 10mg/kg IP), or repeated (10 x 10mg/kg IP)]. Using genetic, optical, and physiological recording and manipulation strategies, we assessed the contribution of these ensembles to behaviors associated with SUD. RESULTS: Repeated cocaine exposure reduced the size of the ensemble, while simultaneously increasing its control over behavior. Neurons within the repeated cocaine ensemble were hyperexcitable and their optogenetic excitation was sufficient for reinforcement. Finally, lesioning the repeated cocaine, but not acute cocaine, ensemble blunted cocaine self-administration. Thus, repeated cocaine exposure reduced the size of the ensemble while simultaneously increasing its contributions to drug reinforcement. CONCLUSIONS: We show that repeated, but not acute, cocaine exposure induces a physiologically distinct ensemble characterized by the expression of the immediate early gene Arc, that is uniquely capable of modulating reinforcement behavior.

Co-occurrence of ST412 Klebsiella pneumoniae isolates with hypermucoviscous and non-mucoviscous phenotypes in a short-term hospitalized patient.

Hypermucoviscosity (HMV) is a phenotype that is commonly associated with hypervirulence in Klebsiella pneumoniae. The factors that contribute to the emergence of HMV subpopulations remain unclear. In this study, eight K. pneumoniae strains were recovered from an inpatient who had been hospitalized for 20 days. Three of the isolates exhibited a non-HMV phenotype, which was concomitant with higher biofilm formation than the other five HMV isolates. All eight isolates were highly susceptible to serum killing, albeit HMV strains were remarkably more infective than non-HMV counterparts in a mouse model of infection. Whole genome sequencing (WGS) showed that the eight isolates belonged to the K57-ST412 lineage. Average nucleotide identity (FastANIb) analysis indicated that eight isolates share 99.96% to 99.99% similarity and were confirmed to be the same clone. Through comparative genomics analysis, 12 non-synonymous mutations were found among these isolates, eight of which in the non-HMV variants, including rmpA (c.285delG) and wbaP (c.1305T > A), which are assumed to be associated with the non-HMV phenotype. Mutations in manB (c.1318G > A), dmsB (c.577C > T) and tkt (c.1928C > A) occurred in HMV isolates only. RNA-Seq revealed transcripts of genes involved in energy metabolism, carbohydrate metabolism and membrane transport, including cysP, cydA, narK, tktA, pduQ, aceB, metN, and lsrA, to be significantly dysregulated in the non-HMV strains, suggesting a contribution to HMV phenotype development. This study suggests that co-occurrence of HMV and non-HMV phenotypes in the same clonal population may be mediated by mutational mechanisms as well as by certain genes involved in membrane transport and central metabolism. IMPORTANCE: K. pneumoniae with a hypermucoviscosity (HMV) phenotype is a community-acquired pathogen that is associated with increased invasiveness and pathogenicity, and underlying diseases are the most common comorbid risk factors inducing metastatic complications. HMV was earlier attributed to the overproduction of capsular polysaccharide, and more data point to the possibility of several causes contributing to this bacterial phenotype. Here, we describe a unique event in which the same clonal population showed both HMV and non-HMV characteristics. Studies have demonstrated that this process is influenced by mutational processes and genes related to transport and central metabolism. These findings provide fresh insight into the mechanisms behind co-occurrence of HMV and non-HMV phenotypes in monoclonal populations as well as potentially being critical in developing strategies to control the further spread of HMV K. pneumoniae.

Evaluating an equity-focused approach to assess climate resilience and disaster priorities through a community survey.

As the Duwamish Valley community in Seattle, Washington, U.S.A. and other environmental justice communities nationally contend with growing risks from climate change, there have been calls for a more community-centered approach to understanding impacts and priorities to inform resilience planning. To engage community members and identify climate justice and resilience priorities, a partnership of community leaders, government-based practitioners, and academics co-produced a survey instrument and collected data from the community using the Seattle Assessment for Public Health Emergency Response (SASPER), an approach adapted from the Centers for Disease Control and Prevention's Community Assessment for Public Health Emergency Response (CASPER). In addition, we conducted a process and outcome project evaluation using quantitative survey data collected from volunteers and qualitative semi-structured interviews with project team members. In October and November 2022, teams of volunteers from partner organizations collected 162 surveys from households in the Duwamish Valley. Poor air quality, extreme heat, and wildfires were among the highest reported hazards of concern. Most Duwamish Valley households agreed or strongly agreed that their neighborhood has a strong sense of community (64%) and that they have people nearby to call when they need help (69%). Forty-seven percent of households indicated willingness to get involved with resilience planning, and 62% of households said that they would use a Resilience Hub during an emergency. Survey volunteers evaluated their participation positively, with over 85% agreeing or strongly agreeing that they learned new skills, were prepared for the survey, and would participate in future assessments. The evaluation interviews underscored that while the SASPER may have demonstrated feasibility in a pre-disaster phase, CASPER may not meet all community/partner needs in the immediate disaster response phase because of its lack of focus on equity and logistical requirements. Future research should focus on identifying less resource intensive data collection approaches that maintain the rigor and reputation of CASPER while enabling a focus on equity.

Gaps and Controversies in Catatonia as a Movement Disorder.

The term "catatonia" was introduced by German psychiatrist Karl Kahlbaum in 1874. Although historically tied to schizophrenia, catatonia exhibits a diverse range of phenotypes and has been observed in various medical and neuropsychiatric conditions. Its intrinsic movement characteristics and association with hypokinetic and hyperkinetic phenomenologies place catatonia within the purview of movement disorders. Despite the presence of catatonia in psychiatry literature for over 150 years, many gaps and controversies persist regarding its etiopathogenesis, phenomenology, diagnostic criteria, and treatment. The current versions of the International Classification of Diseases (ICD-11) and the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) require clinicians to identify any three signs of 15 (ICD-11) or 12 (DSM-5) for the diagnosis of catatonia. Catalepsy and waxy flexibility are the only motor features with high specificity for the diagnosis. We highlight the gaps and controversies in catatonia as a movement disorder, emphasize the lack of a clear definition, and discuss the inconsistencies in the description of various catatonic signs. We propose the exploration of a bi-axial classification framework similar to that used for dystonia and tremor to encourage the evaluation of underlying etiologies and to guide therapeutic decisions to improve the outcome of these patients. © 2024 International Parkinson and Movement Disorder Society.

Emotional State Measurement Trial (EMOPROEXE): A Protocol for Promoting Exercise in Adults and Children with Cerebral Palsy.

BACKGROUND: The protocol described in this paper is part of a research project coordinated between three Spanish universities, where a technology aimed at improving the quality of life of people with cerebral palsy will be developed. Part of the proposed technology will consist of an interface and a series of applications to increase motivation for daily physical activity. The basis of these developments is the measurement of the emotional state of the subjects. METHODS: The experimental protocol is designed with two research objectives, on the one hand to identify the emotional state through physiological signals, and on the other to determine whether music can be a motivating factor to promote physical activity. It is specifically designed for subjects with cerebral palsy, taking into account the special characteristics of this population. These are people with whom it is difficult to use questionnaires to have a basis to contrast with the measured physiological signals, so measurements must be taken in carefully chosen daily-life situations. DISCUSSION: We hope our findings show which physiological parameters are the most robust to measure the emotional state and how to design rehabilitation and physical activity promotion routines that are motivating, in addition to being able to avoid risk factors during the performance of these routines. TRIAL REGISTRATION: NCT05621057.

Higher Concentrations of Essential Trace Elements in Women Undergoing IVF May Be Associated with Poor Reproductive Outcomes Following Single Euploid Embryo Transfer.

Essential trace elements are micronutrients whose deficiency has been associated with altered fertility and/or adverse pregnancy outcomes, while surplus may be toxic. The concentrations of eight essential trace elements were measured using inductively coupled mass spectrometry (ICP-MS) and assessed with respect to clinical in vitro fertilization (IVF) outcomes in a population of 51 women undergoing IVF with intracytoplasmic sperm injection (ICSI), pre-implantation genetic screening for aneuploidy (PGT-A), and single frozen euploid embryo transfer (SET/FET). Specifically, copper (Cu), zinc (Zn), molybdenum, selenium, lithium, iron, chromium, and manganese were quantified in follicular fluid and whole blood collected the day of vaginal oocyte retrieval (VOR) and in urine collected the day of VOR and embryo transfer. We found that the whole blood Cu/Zn ratio was significantly associated with superior responses to ovarian stimulation. Conversely, the whole blood zinc and selenium concentrations were significantly associated with poor ovarian response outcomes. Higher levels of whole blood zinc and selenium, urinary selenium, lithium, and iron had significant negative associations with embryologic outcomes following IVF. Regarding clinical IVF outcomes, higher urinary molybdenum concentrations the day of VOR were associated with significantly lower odds of implantation and live birth, while higher urinary Cu/Mo ratios on the day of VOR were associated with significantly higher odds of implantation, clinical pregnancy, and live birth. Our results suggest that essential trace element levels may directly influence the IVF outcomes of Spanish patients, with selenium and molybdenum exerting negative effects and copper-related ratios exerting positive effects. Additional studies are warranted to confirm these relationships in other human populations.