Compensatory changes after spinal cord injury in a remyelination deficient mouse model.

The development of therapeutic strategies to reduce impairments following spinal cord injury (SCI) motivates an active area of research, because there are no effective therapies. One strategy is to address injury-induced demyelination of spared axons by promoting endogenous or exogenous remyelination. However, previously, we showed that new myelin was not necessary to regain hindlimb stepping following moderate thoracic spinal cord contusion in 3-month-old mice. The present analysis investigated two potential mechanisms by which animals can re-establish locomotion in the absence of remyelination: compensation through intact white matter and conduction through spared axons. We induced a severe contusion injury to reduce the spared white matter rim in the remyelination deficient model, with no differences in recovery between remyelination deficient animals and injured littermate controls. We investigated the nodal properties of the axons at the lesion and found that in the remyelination deficient model, axons express the Nav1.2 voltage-gated sodium channel, a sub-type not typically expressed at mature nodes of Ranvier. In a moderate contusion injury, conduction velocities through the lesions of remyelination deficient animals were similar to those in animals with the capacity to remyelinate after injury. Detailed gait analysis and kinematics reveal subtle differences between remyelination deficient animals and remyelination competent controls, but no worse deficits. It is possible that upregulation of Nav1.2 channels may contribute to establishing conduction through the lesion. This conduction could contribute to compensation and regained motor function in mouse models of SCI. Such compensatory mechanism may have implications for interpreting efficacy results for remyelinating interventions in mice and the development of therapies for improving recovery following SCI.

The 'Prostate Embolisation AS first-line therapY compAred to meDication in treatment naïVe men with prostAte eNlargement, a randomised ControllEd trial' (P-EASY ADVANCE): a randomised controlled trial of prostate embolisation vs medication for BPH.

OBJECTIVE: To compare prostate artery embolisation (PAE) to the combination of tamsulosin and dutasteride therapy as a potential first-line therapy for obstructive benign prostatic hyperplasia (BPH) in treatment-naïve patients in the 'Prostate Embolisation AS first-line therapY compAred to meDication in treatment naïVe men with prostAte eNlargement, a randomised ControllEd trial' (P-EASY ADVANCE). PATIENTS AND METHODS: A total of 39 men with enlarged prostates, moderate-severe lower urinary tract symptoms (LUTS) and obstructed/equivocal urodynamic studies (UDS), and who had no prior treatment for BPH, were randomised to receive either combined medical therapy with tamsulosin and dutasteride (medication) or PAE. Follow-up UDS, International Prostate Symptom Score (IPSS), uroflowmetry and ultrasound were performed at short- to medium-term intervals following interventions and compared to baseline. RESULTS: The medication and PAE treatment groups had similar baseline characteristics, including prostate volumes (87.8 and 85.4 mL respectively), maximum urinary flow rate (Qmax; 6.5 and 6.6 mL/s, respectively), IPSS (19.5 and 21, respectively) and obstructed UDS (79% and 74%, respectively). Both interventions improved voiding and bladder outflow obstruction from baseline, with more patients unobstructed after PAE (63%) compared to medication (28%) (P = 0.03). PAE patients had significantly greater reductions in prostate size (P < 0.001), incomplete emptying (P = 0.002), total IPSS (P = 0.032), Qmax (P = 0.006) and quality of life (P = 0.001). Altered ejaculation, erectile dysfunction and nausea were more common in the medication group. CONCLUSION: Prostate artery embolisation was more effective than combined medical therapy at reducing urinary obstruction, decreasing prostate volume and improving LUTS in patients with BPH who had not previously been treated. This is the first randomised control study to compare PAE and combined medical therapy in exclusively treatment-naïve patients and raises the potential of PAE as an alternative early treatment option for BPH. Further randomised comparative trials are planned to further validate the role of PAE in mitigating obstructive BPH.

Comparing CB1 receptor GIRK channel responses to receptor internalization using a kinetic imaging assay.

The type 1 cannabinoid receptor (CB1R) mediates neurotransmitter release and synaptic plasticity in the central nervous system. Endogenous, plant-derived, synthetic cannabinoids bind to CB1R, initiating the inhibitory G-protein (Gi) and the ß-arrestin signaling pathways. Within the Gi signaling pathway, CB1R activates G protein-gated, inwardly-rectifying potassium (GIRK) channels. The ß-arrestin pathway reduces CB1R expression on the cell surface through receptor internalization. Because of their association with analgesia and drug tolerance, GIRK channels and receptor internalization are of interest to the development of pharmaceuticals. This research used immortalized mouse pituitary gland cells transduced with a pH-sensitive, fluorescently-tagged human CB1R (AtT20-SEPCB1) to measure GIRK channel activity and CB1R internalization. Cannabinoid-induced GIRK channel activity is measured by using a fluorescent membrane-potential sensitive dye. We developed a kinetic imaging assay that visualizes and measures CB1R internalization. All cannabinoids stimulated a GIRK channel response with a rank order potency of WIN55,212-2 > (±)CP55,940 > Δ9-THC > AEA. Efficacy was expressed relative to (±)CP55,940 with a rank order efficacy of (±)CP55,940 > WIN55, 212-2 > AEA > Δ9-THC. All cannabinoids stimulated CB1R internalization with a rank order potency of (±)CP55,940 > WIN55, 212-2 > AEA > Δ9-THC. Internalization efficacy was normalized to (±)CP55,940 with a rank order efficacy of WIN55,212-2 > AEA > (±)CP55,940 > Δ9-THC. (±)CP55,940 was significantly more potent and efficacious than AEA and Δ9-THC at stimulating a GIRK channel response; no significant differences between potency and efficacy were observed with CB1R internalization. No significant differences were found when comparing a cannabinoid's GIRK channel and CB1R internalization response. In conclusion, AtT20-SEPCB1 cells can be used to assess cannabinoid-induced CB1R internalization. While cannabinoids display differential Gi signaling when compared to each other, this did not extend to CB1R internalization.

Degree of primary care integration predicts job satisfaction and emotional exhaustion among rural medical and behavioral healthcare providers.

INTRODUCTION: Minimal research on integrated primary care (IPC) or integrated behavioral health (IBH) has examined clinics in rural communities. The relationships between provider burnout, job satisfaction, and IBH/IPC practices remain understudied, particularly in rural settings. METHOD: We employed an online survey of 147 medical and behavioral health care providers in primary care settings throughout Montana. Respondents self-identified as predominantly White/European American (89.4%) and female (76.7%). We tested whether degree of adherence to IBH/IPC practices concurrently predicted providers' reports of emotional exhaustion (EE), a dimension of burnout, and job satisfaction. Data were collected during the COVID-19 pandemic, in 2020. RESULTS: In multiple linear regression analyses, providers' reports of IBH/IPC practices significantly predicted EE (B = -0.036, p < .01) and job satisfaction (B = 0.123, p < .05), suggesting that higher levels of integration were linked to less EE and greater job satisfaction. DISCUSSION: Our findings contribute to the evidence base regarding the potential usefulness of IBH/IPC models. Specifically, because existing research links provider burnout and low job satisfaction with provider retention difficulties and diminished health, poor patient satisfaction and outcomes, and cost inefficiencies, our findings have potential to inform policy-level discussions regarding the use of IBH/IPC models in rural states like Montana. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Associations between fearlessness about death and suicidal ideation in individuals with psychosis.

BACKGROUND: Despite high rates of suicide among people with psychosis, relatively little is known about the mechanisms underlying the transition from suicidal ideation to behavior in this population. The Interpersonal Psychological Theory of Suicide (IPTS) proposes that fearlessness about death (FAD) may play a role in this relationship. The present study tested whether constructs of the IPTS [thwarted belongingness (TB), perceived burdensomeness (PB), and FAD] were associated with the severity of suicidal ideation in a sample of adults with histories of psychosis. METHOD: 261 adults with histories of psychosis completed measures of IPTS constructs, current severity of suicidal ideation, and history of suicidal attempts. We examined differences between those with past suicide attempts and those without and conducted regression analyses to evaluate the associations among TB, PB, FAD and severity of current suicidal ideation. RESULTS: Contrary to expectations, a history of suicidal behavior was not uniquely associated with FAD. Regression analyses revealed TB × PB and FAD × PB interactions emerged as significant correlates of the severity of suicidal ideation, with the relationship between PB and suicidal ideation more pronounced at higher levels of FAD and TB. Interestingly, positive symptoms of psychosis were positively associated with PB. IMPLICATIONS: This study provides support for broadening the investigation of FAD as a contributor to suicidal ideation in individuals with psychotic symptoms. Future research investigating the role of other contributors that may influence capability for suicide (e.g., impulsivity) may add additional understanding of suicide in this population.

Formylated Peptide Receptor-1-Mediated Gut Inflammation as a Therapeutic Target in Inflammatory Bowel Disease.

Background: Formylated peptide receptor (FPR)-1 is a G-coupled receptor that senses foreign bacterial and host-derived mitochondrial formylated peptides (FPs), leading to innate immune system activation. Aim: We sought to investigate the role of FPR1-mediated inflammation and its potential as a therapeutic target in inflammatory bowel disease (IBD). Methods: We characterized FPR1 gene and protein expression in 8 human IBD (~1000 patients) datasets with analysis on disease subtype, mucosal inflammation, and drug response. We performed in vivo dextran-sulfate sodium (DSS) colitis in C57/BL6 FPR1 knockout mice. In ex vivo studies, we studied the role of mitochondrial FPs and pharmacological blockade of FPR1 using cyclosporin H in human peripheral blood neutrophils. Finally, we assess mitochondrial FPs as a potential mechanistic biomarker in the blood and stools of patients with IBD. Results: Detailed in silico analysis in human intestinal biopsies showed that FPR1 is highly expressed in IBD (n = 207 IBD vs 67 non-IBD controls, P < .001), and highly correlated with gut inflammation in ulcerative colitis (UC) and Crohn's disease (CD) (both P < .001). FPR1 receptor is predominantly expressed in leukocytes, and we showed significantly higher FPR1+ve neutrophils in inflamed gut tissue section in IBD (17 CD and 24 UC; both P < .001). Further analysis in 6 independent IBD (data available under Gene Expression Omnibus accession numbers GSE59071, GSE206285, GSE73661, GSE16879, GSE92415, and GSE235970) showed an association with active gut inflammation and treatment resistance to infliximab, ustekinumab, and vedolizumab. FPR1 gene deletion is protective in murine DSS colitis with lower gut neutrophil inflammation. In the human ex vivo neutrophil system, mitochondrial FP, nicotinamide adenine dinucleotide dehydrogenase subunit-6 (ND6) is a potent activator of neutrophils resulting in higher CD62L shedding, CD63 expression, reactive oxygen species production, and chemotactic capacity; these effects are inhibited by cyclosporin H. We screened for mitochondrial ND6 in IBD (n = 54) using ELISA and detected ND6 in stools with median values of 2.2 gg/mL (interquartile range [IQR] 0.0-4.99; range 0-53.3) but not in blood. Stool ND6 levels, however, were not significantly correlated with paired stool calprotectin, C-reactive protein, and clinical IBD activity. Conclusions: Our data suggest that FPR1-mediated neutrophilic inflammation is a tractable target in IBD; however, further work is required to clarify the clinical utility of mitochondrial FPs as a potential mechanistic marker for future stratification.

Solar-induced chlorophyll fluorescence captures the effects of elevated ozone on canopy structure and acceleration of senescence in soybean.

Solar-induced chlorophyll fluorescence (SIF) provides an opportunity to rapidly and non-destructively investigate how plants respond to stress. Here, we explored the potential of SIF to detect the effects of elevated O3 on soybean in the field where soybean was subjected to ambient and elevated O3 throughout the growing season in 2021. Exposure to elevated O3 resulted in a significant decrease in canopy SIF at 760 nm (SIF760), with a larger decrease in the late growing season (36%) compared with the middle growing season (13%). Elevated O3 significantly decreased the fraction of absorbed photosynthetically active radiation by 8-15% in the middle growing season and by 35% in the late growing stage. SIF760 escape ratio (fesc) was significantly increased under elevated O3 by 5-12% in the late growth stage due to a decrease of leaf chlorophyll content and leaf area index. Fluorescence yield of the canopy was reduced by 5-11% in the late growing season depending on the fesc estimation method, during which leaf maximum carboxylation rate and maximum electron transport were significantly reduced by 29% and 20% under elevated O3. These results demonstrated that SIF could capture the elevated O3 effect on canopy structure and acceleration of senescence in soybean and provide empirical support for using SIF for soybean stress detection and phenotyping.

Patient and family perceptions of a discharge bedside board.

Objective: To explore patient and family perspectives of a discharge bedside board for supporting engagement in patient care and discharge planning to inform tool revision. Methods: This qualitative descriptive study included 45 semi-structured interviews with a purposeful sample of English-speaking patients (n = 44; mean age 58.5 years) and their family members (n = 5) across seven adult inpatient units at a tertiary acute care hospital in mid-western Canada. Thematic (interviews), content (board, organization procedure document), and framework-guided integrated (all data) analyses were performed. Results: Four themes were generated from interview data: understanding the board, included essential information to guide care, balancing information on the board, and maintaining a sense of connection. Despite application inconsistencies, documented standard procedures aligned with recommended board (re)orientation, timely patient-friendly content, attention to privacy, and patient-provider engagement strategies. Conclusion: Findings indicate the tool supported consultation and some involvement level engagement in patient care and discharge. Board information was usually valued, however, perceived procedural gaps in tool education, privacy, and the quality of tool-related communication offer opportunities to strengthen patients' and families' tool experience. Innovation: Novel application of a continuum engagement framework in the exploration of multiple data sources generated significant insights to guide tool revision.

Membrane proteome of the thermoalkaliphile Caldalkalibacillus thermarum TA2.A1.

Proteomics has greatly advanced the understanding of the cellular biochemistry of microorganisms. The thermoalkaliphile Caldalkalibacillus thermarum TA2.A1 is an organism of interest for studies into how alkaliphiles adapt to their extreme lifestyles, as it can grow from pH 7.5 to pH 11. Within most classes of microbes, the membrane-bound electron transport chain (ETC) enables a great degree of adaptability and is a key part of metabolic adaptation. Knowing what membrane proteins are generally expressed is crucial as a benchmark for further studies. Unfortunately, membrane proteins are the category of proteins hardest to detect using conventional cellular proteomics protocols. In part, this is due to the hydrophobicity of membrane proteins as well as their general lower absolute abundance, which hinders detection. Here, we performed a combination of whole cell lysate proteomics and proteomics of membrane extracts solubilised with either SDS or FOS-choline-12 at various temperatures. The combined methods led to the detection of 158 membrane proteins containing at least a single transmembrane helix (TMH). Within this data set we revealed a full oxidative phosphorylation pathway as well as an alternative NADH dehydrogenase type II (Ndh-2) and a microaerophilic cytochrome oxidase ba3. We also observed C. thermarum TA2.A1 expressing transporters for ectoine and glycine betaine, compounds that are known osmolytes that may assist in maintaining a near neutral internal pH when the external pH is highly alkaline.

Rapid and Highly Stable Membrane Reconstitution by LAiR Enables the Study of Physiological Integral Membrane Protein Functions.

Functional reintegration into lipid environments represents a major challenge for in vitro investigation of integral membrane proteins (IMPs). Here, we report a new approach, termed LMNG Auto-insertion Reintegration (LAiR), for reintegration of IMPs into lipid bilayers within minutes. The resulting proteoliposomes displayed an unprecedented capability to maintain proton gradients and long-term stability. LAiR allowed for monitoring catalysis of a membrane-bound, physiologically relevant polyisoprenoid quinone substrate by Escherichia coli cytochromes bo 3 (cbo 3) and bd (cbd) under control of the proton motive force. LAiR also facilitated bulk-phase detection and physiological assessment of the "proton leak" in cbo 3, a controversial catalytic state that previously was only approachable at the single-molecule level. LAiR maintained the multisubunit integrity and higher-order oligomeric states of the delicate mammalian F-ATP synthase. Given that LAiR can be applied to both liposomes and planar membrane bilayers and is compatible with IMPs and lipids from prokaryotic and eukaryotic sources, we anticipate LAiR to be applied broadly across basic research, pharmaceutical applications, and biotechnology.

ATP binding by an F1Fo ATP synthase ε subunit is pH dependent, suggesting a diversity of ε subunit functional regulation in bacteria.

It is a conjecture that the ε subunit regulates ATP hydrolytic function of the F1Fo ATP synthase in bacteria. This has been proposed by the ε subunit taking an extended conformation, with a terminal helix probing into the central architecture of the hexameric catalytic domain, preventing ATP hydrolysis. The ε subunit takes a contracted conformation when bound to ATP, thus would not interfere with catalysis. A recent crystallographic study has disputed this; the Caldalkalibacillus thermarum TA2.A1 F1Fo ATP synthase cannot natively hydrolyse ATP, yet studies have demonstrated that the loss of the ε subunit terminal helix results in an ATP synthase capable of ATP hydrolysis, supporting ε subunit function. Analysis of sequence and crystallographic data of the C. thermarum F1Fo ATP synthase revealed two unique histidine residues. Molecular dynamics simulations suggested that the protonation state of these residues may influence ATP binding site stability. Yet these residues lie outside the ATP/Mg2+ binding site of the ε subunit. We then probed the effect of pH on the ATP binding affinity of the ε subunit from the C. thermarum F1Fo ATP synthase at various physiologically relevant pH values. We show that binding affinity changes 5.9 fold between pH 7.0, where binding is weakest, to pH 8.5 where it is strongest. Since the C. thermarum cytoplasm is pH 8.0 when it grows optimally, this correlates to the ε subunit being down due to ATP/Mg2+ affinity, and not being involved in blocking ATP hydrolysis. Here, we have experimentally correlated that the pH of the bacterial cytoplasm is of critical importance for ε subunit ATP affinity regulated by second-shell residues thus the function of the ε subunit changes with growth conditions.

Reoperation following urgent and emergent colectomy in the State of Michigan.

BACKGROUND: Reoperation is associated with unfavorable outcomes and increased healthcare utilization. This study seeks to investigate the incidence and factors related to reoperation in patients undergoing urgent/emergent colectomies. METHODS: The Michigan Surgical Quality Collaborative (MSQC) database was used to identify patients undergoing urgent/emergent colectomies. Outcomes and risk factors of patients who underwent reoperation within 30 days were compared to those who did not. RESULTS: 16,004 patients undergoing urgent/emergent colon resection were identified. Reoperation occurred in 12.4% and was associated with increased 30-day mortality (16.7% vs. 9.6%, p < .0001), median hospital length of stay (17 vs. 10 days, p < .0001), readmission rate (21.0% vs. 12.1%, p < .001), and discharge to a location other than home (62.3% vs. 36.8%, p < .0001). Reoperation rate was highest for vascular-related indications (23.5%), and was associated with several clinical factors (male gender, low albumin, ASA classification, and presence of pre-operative sepsis, dialysis or ventilator dependence) CONCLUSIONS: Reoperation following urgent/emergent colectomy occurs frequently. Additional study into strategies to reduce reoperations in this population is warranted.

The Evolution of C4 Photosynthesis in Flaveria (Asteraceae): Insights from the Flaveria linearis Complex.

Flaveria is a leading model for C4 plant evolution due to the presence of a dozen C3-C4 intermediate species, many of which are associated with a phylogenetic complex centered around Flaveria linearis. To investigate C4 evolution in Flaveria, we updated the Flaveria phylogeny and evaluated gas exchange, starch δ13C, and activity of C4 cycle enzymes in 19 Flaveria species and 28 populations within the F. linearis complex. A principal component analysis identified six functional clusters: (1) C3, (2) sub-C2, (3) full C2, (4) enriched C2, (5) sub-C4, and (6) fully C4 species. The sub-C2 species lacked a functional C4 cycle, while a gradient was present in the C2 clusters from little to modest C4 cycle activity as indicated by δ13C and enzyme activities. Three Yucatan populations of F. linearis had photosynthetic CO2 compensation points equivalent to C4 plants but showed little evidence for an enhanced C4 cycle, indicating they have an optimized C2 pathway that recaptures all photorespired CO2 in the bundle sheath (BS) tissue. All C2 species had enhanced aspartate aminotransferase activity relative to C3 species and most had enhanced alanine aminotransferase activity. These aminotransferases form aspartate and alanine from glutamate and in doing so could help return photorespiratory nitrogen (N) from BS to mesophyll cells, preventing glutamate feedback onto photorespiratory N assimilation. Their use requires upregulation of parts of the C4 metabolic cycle to generate carbon skeletons to sustain N return to the mesophyll, and thus could facilitate the evolution of the full C4 photosynthetic pathway.

Antidepressants Trial in Parkinson's Disease (ADepT-PD): protocol for a randomised placebo-controlled trial on the effectiveness of escitalopram and nortriptyline on depressive symptoms in Parkinson's disease.

BACKGROUND: Depressive symptoms are common in patients with Parkinson's disease and depression is a significant predictor of functional impairment, reduced quality of life and general well-being in Parkinson's disease. Despite the high prevalence of depression, evidence on the effectiveness and tolerability of antidepressants in this population is limited. The primary aim of this trial is to establish the clinical and cost effectiveness of escitalopram and nortriptyline for the treatment of depression in Parkinson's disease. METHODS: This is a multi-centre, double-blind, randomised placebo-controlled trial in 408 people with Parkinson's disease with subsyndromal depression, major depressive disorder or persistent depressive disorder and a Beck Depression Inventory-II (BDI-II) score of 14 or above. Participants will be randomised into one of three groups, receiving either escitalopram, nortriptyline or placebo for 12 months. Trial participation is face-to-face, hybrid or remote. The primary outcome measure is the BDI-II score following 8 weeks of treatment. Secondary outcomes will be collected at baseline, 8, 26 and 52 weeks and following withdrawal, including severity of anxiety and depression scores as well as Parkinson's disease motor severity, and ratings of non-motor symptoms, cognitive function, health-related quality of life, levodopa-equivalence dose, changes in medication, overall clinical effectiveness, capability, health and social care resource use, carer health-related quality of life, adverse effects and number of dropouts. DISCUSSION: This trial aims to determine the effectiveness of escitalopram and nortriptyline for reducing depressive symptoms in Parkinson's disease over 8 weeks, to provide information on the effect of these medications on anxiety and other non-motor symptoms in PD and on impact on patients and caregivers, and to examine their effect on change in motor severity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03652870 Date of registration - 29th August 2018.

Multivalent viral particles elicit safe and efficient immunoprotection against Nipah Hendra and Ebola viruses.

Experimental vaccines for the deadly zoonotic Nipah (NiV), Hendra (HeV), and Ebola (EBOV) viruses have focused on targeting individual viruses, although their geographical and bat reservoir host overlaps warrant creation of multivalent vaccines. Here we explored whether replication-incompetent pseudotyped vesicular stomatitis virus (VSV) virions or NiV-based virus-like particles (VLPs) were suitable multivalent vaccine platforms by co-incorporating multiple surface glycoproteins from NiV, HeV, and EBOV onto these virions. We then enhanced the vaccines' thermotolerance using carbohydrates to enhance applicability in global regions that lack cold-chain infrastructure. Excitingly, in a Syrian hamster model of disease, the VSV multivalent vaccine elicited safe, strong, and protective neutralizing antibody responses against challenge with NiV, HeV, or EBOV. Our study provides proof-of-principle evidence that replication-incompetent multivalent viral particle vaccines are sufficient to provide protection against multiple zoonotic deadly viruses with high pandemic potential.

Positive lifestyle behaviours and emotional health factors are associated with low back pain resilience.

PURPOSE: To evaluate the relationship between lifestyle behaviours, emotional health factors, and low back pain (LBP) resilience. METHODS: This retrospective longitudinal study utilised 1,065 twins with a recent history of LBP from the Washington State Twin Registry. A lifestyle behaviour score was built using variables of body mass index, physical activity engagement, sleep quality, smoking status, and alcohol consumption. An emotional health score was built using variables of the absence of depressed mood, perceived stress, and active coping. The main outcome was LBP resilience, assessed as recovery ("bouncing back"), and sustainability (maintaining high levels of function despite LBP). RESULTS: After adjusting for covariates, there was no relationship between the lifestyle behaviour score (OR 1.05, 95% CI 0.97-1.15, p = 0.218) and the emotional health score (OR 1.08, 95% CI 0.98-1.19, p = 0.142) with the likelihood of recovering from LBP. There was however, evidence of a positive association between the lifestyle behaviour score (ß 0.20, 95% CI 0.04-0.36, p = 0.013), the emotional health score (ß 0.22, 95% CI 0.00-0.43, p = 0.049), and greater levels of sustainability. These results were confirmed by a within-pair analysis (lifestyle behaviour score: ß 1.79, 95% CI 0.05-3.53, p = 0.043) and (emotional health score: ß 0.52, 95% CI 0.09-0.96, p = 0.021) adjusting for genetic and early shared environmental confounding. CONCLUSION: Findings from this study suggest that people who adopt optimal lifestyle behaviours and positive emotional factors are more likely to be resilient and maintain high levels of function despite suffering from LBP.

Substrate Induced Movement of the Metal Cofactor between Active and Resting State.

Regulation of enzyme activity is vital for living organisms. In metalloenzymes, far-reaching rearrangements of the protein scaffold are generally required to tune the metal cofactor's properties by allosteric regulation. Here structural analysis of hydroxyketoacid aldolase from Sphingomonas wittichii RW1 (SwHKA) revealed a dynamic movement of the metal cofactor between two coordination spheres without protein scaffold rearrangements. In its resting state configuration (M2+ R ), the metal constitutes an integral part of the dimer interface within the overall hexameric assembly, but sterical constraints do not allow for substrate binding. Conversely, a second coordination sphere constitutes the catalytically active state (M2+ A ) at 2.4 Šdistance. Bidentate coordination of a ketoacid substrate to M2+ A affords the overall lowest energy complex, which drives the transition from M2+ R to M2+ A . While not described earlier, this type of regulation may be widespread and largely overlooked due to low occupancy of some of its states in protein crystal structures.

The leaf economics spectrum of triploid and tetraploid C4 grass Miscanthus x giganteus.

The leaf economics spectrum (LES) describes multivariate correlations in leaf structural, physiological and chemical traits, originally based on diverse C3 species grown under natural ecosystems. However, the specific contribution of C4 species to the global LES is studied less widely. C4 species have a CO2 concentrating mechanism which drives high rates of photosynthesis and improves resource use efficiency, thus potentially pushing them towards the edge of the LES. Here, we measured foliage morphology, structure, photosynthesis, and nutrient content for hundreds of genotypes of the C4 grass Miscanthus× giganteus grown in two common gardens over two seasons. We show substantial trait variations across M.× giganteus genotypes and robust genotypic trait relationships. Compared to the global LES, M.× giganteus genotypes had higher photosynthetic rates, lower stomatal conductance, and less nitrogen content, indicating greater water and photosynthetic nitrogen use efficiency in the C4 species. Additionally, tetraploid genotypes produced thicker leaves with greater leaf mass per area and lower leaf density than triploid genotypes. By expanding the LES relationships across C3 species to include C4 crops, these findings highlight that M.× giganteus occupies the boundary of the global LES and suggest the potential for ploidy to alter LES traits.

A qualitative study of rural healthcare providers' views of social, cultural, and programmatic barriers to healthcare access.

BACKGROUND: Ensuring access to healthcare is a complex, multi-dimensional health challenge. Since the inception of the coronavirus pandemic, this challenge is more pressing. Some dimensions of access are difficult to quantify, namely characteristics that influence healthcare services to be both acceptable and appropriate. These link to a patient's acceptance of services that they are to receive and ensuring appropriate fit between services and a patient's specific healthcare needs. These dimensions of access are particularly evident in rural health systems where additional structural barriers make accessing healthcare more difficult. Thus, it is important to examine healthcare access barriers in rural-specific areas to understand their origin and implications for resolution. METHODS: We used qualitative methods and a convenience sample of healthcare providers who currently practice in the rural US state of Montana. Our sample included 12 healthcare providers from diverse training backgrounds and specialties. All were decision-makers in the development or revision of patients' treatment plans. Semi-structured interviews and content analysis were used to explore barriers-appropriateness and acceptability-to healthcare access in their patient populations. Our analysis was both deductive and inductive and focused on three analytic domains: cultural considerations, patient-provider communication, and provider-provider communication. Member checks ensured credibility and trustworthiness of our findings. RESULTS: Five key themes emerged from analysis: 1) a friction exists between aspects of patients' rural identities and healthcare systems; 2) facilitating access to healthcare requires application of and respect for cultural differences; 3) communication between healthcare providers is systematically fragmented; 4) time and resource constraints disproportionately harm rural health systems; and 5) profits are prioritized over addressing barriers to healthcare access in the US. CONCLUSIONS: Inadequate access to healthcare is an issue in the US, particularly in rural areas. Rural healthcare consumers compose a hard-to-reach patient population. Too few providers exist to meet population health needs, and fragmented communication impairs rural health systems' ability to function. These issues exacerbate the difficulty of ensuring acceptable and appropriate delivery of healthcare services, which compound all other barriers to healthcare access for rural residents. Each dimension of access must be monitored to improve patient experiences and outcomes for rural Americans.