Structures of wild-type and a constitutively closed mutant of connexin26 shed light on channel regulation by CO2.

Connexins allow intercellular communication by forming gap junction channels (GJCs) between juxtaposed cells. Connexin26 (Cx26) can be regulated directly by CO2. This is proposed to be mediated through carbamylation of K125. We show that mutating K125 to glutamate, mimicking the negative charge of carbamylation, causes Cx26 GJCs to be constitutively closed. Through cryo-EM we observe that the K125E mutation pushes a conformational equilibrium towards the channel having a constricted pore entrance, similar to effects seen on raising the partial pressure of CO2. In previous structures of connexins, the cytoplasmic loop, important in regulation and where K125 is located, is disordered. Through further cryo-EM studies we trap distinct states of Cx26 and observe density for the cytoplasmic loop. The interplay between the position of this loop, the conformations of the transmembrane helices and the position of the N-terminal helix, which controls the aperture to the pore, provides a mechanism for regulation.

Blood Flow Restriction Training in Nonspecific Shoulder Pain: Study Protocol of a Crossover Randomised Controlled Trial.

"Nonspecific shoulder pain" encompasses various non-traumatic musculoskeletal shoulder disorders, diverging from diagnostic terminologies that refer to precise tissue-oriented clinical diagnosis. Blood flow restriction (BFR) training, involving partial arterial inflow and complete venous outflow restriction, has exhibited acute hypoalgesic effects primarily in healthy populations by increasing their pain thresholds. This study aims to examine whether a single BFR session with low-load exercises can alleviate pain perception among nonspecific shoulder pain patients. Conducted as a single-blind crossover randomised clinical trial, 48 adults (age range: 18 to 40) presenting with nonspecific shoulder pain will partake in two trial sessions. Random assignment will place participants into BFR or sham BFR groups and ask them to perform one exercise with BFR. Subsequently, participants will complete a shoulder girdle loading regimen comprising six exercises. The second session will involve participants switching treatment groups. Pain pressure thresholds (PPTs), shoulder pain and disability via the shoulder pain and disability index (SPADI), maximal voluntary isometric contraction (MVIC) of shoulder external rotators, pain during active abduction, and peak pain during shoulder external rotation will be evaluated using the numeric pain rating scale (NPRS). Immediate post-exercise assessments will include patient-perceived pain changes using the global rating of change scale (GROC) and participant-rated perceived exertion (RPE), employing a modified Borg's scale (Borg CR10) post-BFR or sham BFR exercise session. Each session will encompass three assessment periods, and a combination of mixed-effect models and descriptive statistics will underpin the analysis. This protocol was approved by Cyprus National Bioethics Committee (ΕΕΒΚ/2023/48), and was registered in ClinicalTrials.gov (Registration number: NCT05956288). Conclusion: The anticipated outcomes of this study illuminated the acute effects of BFR training on pain perception within the context of nonspecific shoulder pain, potentially advancing strategies for managing pain intensity using BFR techniques.

The effectiveness of cognitive behavioural therapy in chronic neck pain: A systematic review with meta-analysis.

We evaluated the effects of Cognitive Behavioural Therapy (CBT) alone or with additional interventions on pain, disability, kinesiophobia, anxiety, stress, depression, quality of life, and catastrophizing of patients with chronic neck pain (CNP). Nineteen studies met the inclusion criteria, and fourteen studies were quantitatively analysed. Risk of bias was assessed using the PEDro scale and the certainty of evidence using the GRADE approach. Studies were pooled (where applicable) and subgroup analyses were performed for CNP, or whiplash associated disorders. Studies compared-directly or indirectly-CBT interventions to no treatment, conservative interventions such as exercise and/or physiotherapy, or multimodal interventions. We present effect estimates at 8-week, 12-week, 6-month, and 1-year follow-up. Low certainty evidence suggests a clinically significant pain reduction (short-term) favouring CBT with or without additional intervention compared to no intervention SMD = -0.73; 95%CI: -1.23 to -0.23). Very low and low certainty evidence suggest clinically significant improvements in kinesiophobia (very short-term SMD = -0.83; 95%CI: -1.28 to -0.39 and short-term SMD = -1.30, 95%CI: -1.60 to -0.99), depression SMD = -0.74, 95%CI: -1.35 to -0.14) and anxiety SMD = -0.76, 95%CI: -1.34 to -0.18) favouring a multimodal intervention with CBT (short-term) compared to other conservative interventions. Combining different types of CBT interventions resulted in potentially heterogeneous comparisons.

The effects of upper limb exercise training on upper limb muscle strength in people with chronic obstructive pulmonary disease: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Upper limb (UL) muscle dysfunction is a common extrapulmonary manifestation of chronic obstructive pulmonary disease (COPD). UL muscle dysfunction is associated with muscle weakness, dyspnea, and exercise intolerance. Although upper limb exercise training (ULET) is typically incorporated in pulmonary rehabilitation programs, its effects on UL muscle strength remains unclear. OBJECTIVES: The purpose of this systematic review was to investigate the effectiveness of ULET, in UL muscle strength of people with COPD. DESIGN: This is systematic review and meta-analysis study. DATA SOURCES AND METHODS: Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) Protocols 2020 guidelines were used for this study. PubMed, Cochrane, CINAHL Plus and SPORTDiscus and clinicaltrials.gov registry were searched from inception to July 2022. Included studies were randomized controlled trials, assessing the effectiveness in muscle strength of ULET, compared with other types of upper or lower limb exercise or no exercise. The quality and risk of bias were assessed using the Physiotherapy Evidence Database (PEDro) scale and certainty of evidence with the Grading of Recommendations, Assessment, Development, and Evaluations approach. Treatment effects of ULET were calculated using standardized mean differences and 95% confidence intervals. RESULTS: Twenty-four studies, with a total sample of 882 patients, were included. Most studies were of moderate quality and high risk of bias. Very low to low certainty evidence indicates a significant difference in UL muscle strength in favor of resistance ULET, compared with lower limb exercise alone or no exercise. No significant differences were found in different types of ULET comparisons. CONCLUSION: The results of this review showed that resistance ULET could improve UL muscle strength in people with COPD. Most studies, however, were of moderate quality and high risk of bias. Further studies with larger sample sizes, better methodological quality, and standardized training protocols are needed to confirm these findings.

The effects of upper body blood flow restriction training on muscles located proximal to the applied occlusive pressure: A systematic review with meta-analysis.

BACKGROUND: Blood flow restriction combined with low load resistance training (LL-BFRT) is associated with increases in upper limb muscle strength and size. The effect of LL-BFRT on upper limb muscles located proximal to the BFR cuff application is unclear. OBJECTIVE: The aim of this systematic review was to evaluate the effect of LL-BFRT compared to low load, or high load resistance training (LL-RT, HL-RT) on musculature located proximal to cuff placement. METHODS: Six electronic databases were searched for randomized controlled trials (RCTs). Two reviewers independently evaluated the risk of bias using the PEDro scale. We performed a meta-analysis using a random effects model, or calculated mean differences (fixed-effect) where appropriate. We judged the certainty of evidence using the GRADE approach. RESULTS: The systematic literature searched yielded 346 articles, of which 9 studies were eligible. The evidence for all outcomes was of very low to low certainty. Across all comparisons, a significant increase in bench press and shoulder flexion strength was found in favor of LL-BFRT compared to LL-RT, and in shoulder lean mass and pectoralis major thickness in favor of the LL-BFRT compared to LL-RT and HL-RT, respectively. No significant differences were found between LL-BFRT and HL-RT in muscle strength. CONCLUSION: With low certainty LL-BFRT appears to be equally effective to HL-RT for improving muscle strength in upper body muscles located proximal to the BFR stimulus in healthy adults. Furthermore, LL-BFRT may induce muscle size increase, but these adaptations are not superior to LL-RT or HL-RT.

Cryo-EM structure of the agonist-bound Hsp90-XAP2-AHR cytosolic complex.

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that mediates a broad spectrum of (patho)physiological processes in response to numerous substances including pollutants, natural products and metabolites. However, the scarcity of structural data precludes understanding of how AHR is activated by such diverse compounds. Our 2.85 Å structure of the human indirubin-bound AHR complex with the chaperone Hsp90 and the co-chaperone XAP2, reported herein, reveals a closed conformation Hsp90 dimer with AHR threaded through its lumen and XAP2 serving as a brace. Importantly, we disclose the long-awaited structure of the AHR PAS-B domain revealing a unique organisation of the ligand-binding pocket and the structural determinants of ligand-binding specificity and promiscuity of the receptor. By providing structural details of the molecular initiating event leading to AHR activation, our study rationalises almost forty years of biochemical data and provides a framework for future mechanistic studies and structure-guided drug design.

In vitro evolution predicts emerging SARS-CoV-2 mutations with high affinity for ACE2 and cross-species binding.

Emerging SARS-CoV-2 variants are creating major challenges in the ongoing COVID-19 pandemic. Being able to predict mutations that could arise in SARS-CoV-2 leading to increased transmissibility or immune evasion would be extremely valuable in development of broad-acting therapeutics and vaccines, and prioritising viral monitoring and containment. Here we use in vitro evolution to seek mutations in SARS-CoV-2 receptor binding domain (RBD) that would substantially increase binding to ACE2. We find a double mutation, S477N and Q498H, that increases affinity of RBD for ACE2 by 6.5-fold. This affinity gain is largely driven by the Q498H mutation. We determine the structure of the mutant-RBD:ACE2 complex by cryo-electron microscopy to reveal the mechanism for increased affinity. Addition of Q498H to SARS-CoV-2 RBD variants is found to boost binding affinity of the variants for human ACE2 and confer a new ability to bind rat ACE2 with high affinity. Surprisingly however, in the presence of the common N501Y mutation, Q498H inhibits binding, due to a clash between H498 and Y501 side chains. To achieve an intermolecular bonding network, affinity gain and cross-species binding similar to Q498H alone, RBD variants with the N501Y mutation must acquire instead the related Q498R mutation. Thus, SARS-CoV-2 RBD can access large affinity gains and cross-species binding via two alternative mutational routes involving Q498, with route selection determined by whether a variant already has the N501Y mutation. These mutations are now appearing in emerging SARS-CoV-2 variants where they have the potential to influence human-to-human and cross-species transmission.

The effectiveness of slider and tensioner neural mobilization techniques in the management of upper quadrant pain: A systematic review of randomized controlled trials.

BACKGROUND: Little attention has been given to support the use of slider and tensioner neural mobilization (NM) techniques for upper quadrant pain (UQP). The purpose of this study was to systematically review the effectiveness of these techniques in patients with UQP. METHOD: The PubMed, Cochrane Library and EBSCOhost were searched without chronological restriction to identify randomized clinical trials (RCTs) that assessed pain changes following NM in the upper quadrant. Two researchers independently performed screening, full-text assessment, data extraction and risk of bias assessment of the studies. RESULTS: A total of 974 articles were identified, of which 25 were included in this systematic review. The score for methodological quality of studies included was between 5 and 10 with a mean score of 7.96 points. Results demonstrated that slider and tensioner NM techniques are considered beneficial in pain reduction of UQP in certain musculoskeletal conditions including carpal tunnel syndrome and cervical radiculopathy. Regarding other conditions such as subacromial impingement syndrome, lateral elbow tendinopathy and cubital tunnel syndrome, due to conflicting findings, various methodological limitations and/or inadequate information, the available evidence remains uncertain. Furthermore, slider NM was found to be more effective in acute conditions compared to tensioner NM that seems to provide further analgesic effect in chronic UQP. CONCLUSIONS: This systematic review revealed that NM slider and tensioner techniques can be used as analgesic modalities for managing UQP resulting from cervical radiculopathy and carpal tunnel. There remain unanswered questions concerning other conditions, and, therefore, further well-designed RCTs are needed to examine the analgesic response of NM techniques in UQP.

Conformational changes and CO2-induced channel gating in connexin26.

Connexins form large-pore channels that function either as dodecameric gap junctions or hexameric hemichannels to allow the regulated movement of small molecules and ions across cell membranes. Opening or closing of the channels is controlled by a variety of stimuli, and dysregulation leads to multiple diseases. An increase in the partial pressure of carbon dioxide (PCO2) has been shown to cause connexin26 (Cx26) gap junctions to close. Here, we use cryoelectron microscopy (cryo-EM) to determine the structure of human Cx26 gap junctions under increasing levels of PCO2. We show a correlation between the level of PCO2 and the size of the aperture of the pore, governed by the N-terminal helices that line the pore. This indicates that CO2 alone is sufficient to cause conformational changes in the protein. Analysis of the conformational states shows that movements at the N terminus are linked to both subunit rotation and flexing of the transmembrane helices.

Effect of Strength Versus Strength and Endurance Upper Limb Exercise Training in Patients With Chronic Obstructive Pulmonary Disease: A RANDOMIZED CLINICAL TRIAL.

PURPOSE: Pulmonary rehabilitation (PR) including exercise training improves muscle strength, exercise capacity, and health-related quality of life in patients with chronic obstructive pulmonary disease (COPD). However, the evidence of the effect of upper limb exercise training (ULET) on activities of daily living (ADL) is sparse. This study investigated the effect of two different types of ULET on ADL in addition to standard PR. METHODS: Patients were randomly assigned to a strength or a combined ULET group. Both groups exercised 2 d/wk for 12 wk. Outcome measures were handgrip strength and muscle strength of biceps and triceps muscles. Moreover, health-related quality of life was assessed through the COPD assessment test (CAT) and Saint George Respiratory Questionnaire. Ability to perform ADL was evaluated through an ADL simulation test. Dyspnea was evaluated by a modified Medical Research Council scale, whereas dyspnea and fatigue perception during strength and ADL tests were measured through a modified Borg scale. RESULTS: Thirty-six patients with COPD (67.4 ± 5.3 yr) participated in the study. Significant improvements in upper limb strength and CAT were found within both groups. At the end of the study period, patients in the combined group improved time of the ADL test (P = .02) with reduced perception of fatigue (P = .03) compared with patients in the strength group. CONCLUSIONS: In addition to standard PR of patients with COPD, the combined endurance and resistance ULET program improved ADL and muscle strength, whereas resistance training only increased strength.

The effect of lumbar spine manipulation on pain and disability in Achilles tendinopathy. A case report.

BACKGROUND/PURPOSE: Cervical and thoracic spine manipulation has been found to reduce tendon pain and disability in lateral epicondylalgia and rotator cuff tendinopathy. Based on these findings, the application of lumbar spine manipulation may also provide similar improvements in Achilles tendinopathy (AT). Therefore, the purpose of this study was to evaluate the effect of lumbar spine manipulation on pain and disability in a patient experiencing AT. CASE DESCRIPTION: A 44 years old male ex-football player presented with a 20-year history of persistent Achilles tendon pain (ATP) consistent with AT diagnosis. The patient attended 12 treatment sessions receiving a high-velocity, low amplitude lumbar spine manipulation. Outcome measures were collected at baseline, 2 weeks, 4 weeks, 3 months and 6 months and included pain in visual analogue scale, the American Orthopedic Foot and Ankle Score, the 36-Item Short Form Health Survey and the Victorian Institute of Sport Assessment-Achilles questionnaire. Pressure pain threshold was also assessed using an electronic pressure algometer. OUTCOMES: Improvement in all outcome measures was noted 6-months post intervention. Outcome measures indicated substantial improvements in both the patient's pain and disability. The patient was able to perform activities of daily living without difficulties, suggesting higher level of function and quality of life at 6-months post initial evaluation. CONCLUSION: These findings have demonstrated the positive effects of lumbar spine manipulation on ATP and disability. Further studies, specifically clinical trials investigating the effect of lumbar spine manipulation or combining this technique with exercises and functional activities are suggested.

Cervical traction combined with neural mobilization for patients with cervical radiculopathy: A randomized controlled trial.

BACKGROUND: Although both neural mobilization (NM) and cervical traction (CT) are widely used interventions in cervical radiculopathy (CR), there is limited clinical data to support their use. OBJECTIVE: To evaluate the effects of CT, with or without the addition of NM, on pain, function, and disability in patients with CR. DESIGN: A randomized, double-blinded, placebo-controlled clinical trial. METHODS: 66 patients with CR were randomly allocated to: a group (n = 22) received CT combined with NM (CT + NM), a group (n = 22) received CT combined with sham NM (CT + shamNM) and a wait-list control (WLC) group (n = 22). The Neck Disability Index (NDI), the Patient-Specific Functional Scale, the Numeric Pain Rating Scale (NPRS), grip strength and cervical spine mobility were used as outcome measures. A two-way analysis of variance was used to evaluate differences between the three groups at baseline and at 4-week follow-up. RESULTS: Statistically and clinically significant between-group differences at 4-week follow-up were found between CT + NM and WLC groups in favor of CT + NM group in NDI scores (d = 1.30), NRPS (d = 1.94), and active cervical rotation towards the opposite arm (d = 1.18) and between CT + NM and CT + shamNM groups in favor of CT + NM group in NRPS (d = 1.21). No significant differences were observed between CT + shamNM and WLC groups in all outcome measures. Clinically significant within-group improvements were found only for the CT + NM group. CONCLUSION: At 4-week follow-up, CT in combination with NM resulted in improved outcomes in pain, function and disability in patients with CR.

The analgesic effect of joint mobilization and manipulation in tendinopathy: a narrative review.

Objective: To summarize the available literature with regards to the potential analgesic effect and mechanism of joint mobilization and manipulation in tendinopathy. Results: The effect of these techniques in rotator cuff tendinopathy and lateral elbow tendinopathy, applied alone, compared to a placebo intervention or along with other interventions has been reported in some randomized controlled trials which have been scrutinized in systematic reviews. Due to the small randomized controlled trials and other methodological limitations of the evidence base, including short-term follow-ups, small sample size and lack of homogenous samples further studies are needed. Literature in other tendinopathies such as medial elbow tendinopathy, de Quervain's disease and Achilles tendinopathy is limited since the analgesic effect of these techniques has been identified in few case series and reports. Therefore, the low methodological quality renders caution in the generalization of findings in clinical practice. Studies on the analgesic mechanism of these techniques highlight the activation of the descending inhibitory pain mechanism and sympathoexcitation although this area needs further investigation. Conclusion: Study suggests that joint mobilization and manipulation may be a potential contributor in the management of tendinopathy as a pre-conditioning process prior to formal exercise loading rehabilitation or other proven effective treatment approaches.

The topology of chromatin-binding domains in the NuRD deacetylase complex.

Class I histone deacetylase complexes play essential roles in many nuclear processes. Whilst they contain a common catalytic subunit, they have diverse modes of action determined by associated factors in the distinct complexes. The deacetylase module from the NuRD complex contains three protein domains that control the recruitment of chromatin to the deacetylase enzyme, HDAC1/2. Using biochemical approaches and cryo-electron microscopy, we have determined how three chromatin-binding domains (MTA1-BAH, MBD2/3 and RBBP4/7) are assembled in relation to the core complex so as to facilitate interaction of the complex with the genome. We observe a striking arrangement of the BAH domains suggesting a potential mechanism for binding to di-nucleosomes. We also find that the WD40 domains from RBBP4 are linked to the core with surprising flexibility that is likely important for chromatin engagement. A single MBD2 protein binds asymmetrically to the dimerisation interface of the complex. This symmetry mismatch explains the stoichiometry of the complex. Finally, our structures suggest how the holo-NuRD might assemble on a di-nucleosome substrate.

Test-Retest Reliability of Handgrip Strength in Patients with Chronic Obstructive Pulmonary Disease.

The purpose of this study was to investigate the intra-rater reliability and agreement of handgrip strength (HGS) measurement using a hydraulic hand dynamometer in patients with chronic obstructive pulmonary disease (COPD). A sample of 19 COPD patients (18 males and 1 female; mean ± SD age, 66.9 ± 6.3 years) was evaluated using a hand dynamometer by the same rater in two different testing sessions with a 7-d interval. During each session, patients were asked to exert three maximal isometric contractions on the dominant hand and the mean value of the 3 efforts (measured in kilogram-force [Kgf]) was used for data analysis. The intraclass correlation coefficient (ICC2,1), the standard error of measurement (SEM), the minimal detectable change (MDC), and Bland-Altman methods were used to estimate the degree of test-retest reliability and the measurement error, respectively. HGS in COPD patients revealed an ICC2,1 score of 0.99, suggesting excellent test-retest reliability. The calculated SEM was relatively small (0.59 Kgf), and the MDC presented a clinically acceptable value of 1.64 Kgf. These findings, in conjunction with the narrow width of the 95% limits of agreements (95% limits of agreement, -2.5-2.1 Kgf) in the Bland-Altman plot, reflected the measurement precision and the narrow variation of the differences during the 2 testing sessions. The results of this study demonstrated an excellent test-retest reliability of HGS measurement, indicating that this method is reliable for repeated monitoring of peripheral muscle strength in patients with COPD.

The MiDAC histone deacetylase complex is essential for embryonic development and has a unique multivalent structure.

MiDAC is one of seven distinct, large multi-protein complexes that recruit class I histone deacetylases to the genome to regulate gene expression. Despite implications of involvement in cell cycle regulation and in several cancers, surprisingly little is known about the function or structure of MiDAC. Here we show that MiDAC is important for chromosome alignment during mitosis in cancer cell lines. Mice lacking the MiDAC proteins, DNTTIP1 or MIDEAS, die with identical phenotypes during late embryogenesis due to perturbations in gene expression that result in heart malformation and haematopoietic failure. This suggests that MiDAC has an essential and unique function that cannot be compensated by other HDAC complexes. Consistent with this, the cryoEM structure of MiDAC reveals a unique and distinctive mode of assembly. Four copies of HDAC1 are positioned at the periphery with outward-facing active sites suggesting that the complex may target multiple nucleosomes implying a processive deacetylase function.

Structure of the processive human Pol δ holoenzyme.

In eukaryotes, DNA polymerase δ (Pol δ) bound to the proliferating cell nuclear antigen (PCNA) replicates the lagging strand and cooperates with flap endonuclease 1 (FEN1) to process the Okazaki fragments for their ligation. We present the high-resolution cryo-EM structure of the human processive Pol δ-DNA-PCNA complex in the absence and presence of FEN1. Pol δ is anchored to one of the three PCNA monomers through the C-terminal domain of the catalytic subunit. The catalytic core sits on top of PCNA in an open configuration while the regulatory subunits project laterally. This arrangement allows PCNA to thread and stabilize the DNA exiting the catalytic cleft and recruit FEN1 to one unoccupied monomer in a toolbelt fashion. Alternative holoenzyme conformations reveal important functional interactions that maintain PCNA orientation during synthesis. This work sheds light on the structural basis of Pol δ's activity in replicating the human genome.

Mechanism of Crosstalk between the LSD1 Demethylase and HDAC1 Deacetylase in the CoREST Complex.

The transcriptional corepressor complex CoREST is one of seven histone deacetylase complexes that regulate the genome through controlling chromatin acetylation. The CoREST complex is unique in containing both histone demethylase and deacetylase enzymes, LSD1 and HDAC1, held together by the RCOR1 scaffold protein. To date, it has been assumed that the enzymes function independently within the complex. Now, we report the assembly of the ternary complex. Using both structural and functional studies, we show that the activity of the two enzymes is closely coupled and that the complex can exist in at least two distinct states with different kinetics. Electron microscopy of the complex reveals a bi-lobed structure with LSD1 and HDAC1 enzymes at opposite ends of the complex. The structure of CoREST in complex with a nucleosome reveals a mode of chromatin engagement that contrasts with previous models.

Upper limb exercise training and activities of daily living in patients with COPD: a systematic review of randomized controlled trials / Treinamento de membros superiores e atividades da vida diária em pacientes com DPOC: revisão sistemática de ensaios controlados randomizados

ABSTRACT Objective: To investigate the efficacy of upper limb exercise training (ULExT) in improving the performance of activities of daily living (ADL) that involve the upper limbs (UL) in patients with COPD. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used in this systematic review. PubMed and EBSCOhost databases were searched to identify randomized controlled trials involving adults with COPD who underwent ULExT, compared with those who underwent other types of exercise or no exercise, in order to assess the performance of ADL that involve the UL. The methodological quality of the selected studies was assessed using the Physiotherapy Evidence Database scale. Results: Five studies, with a total sample of 173 subjects, met the inclusion criteria. The results of the selected studies showed that ULExT is safe and can significantly improve the performance of ADL that involve the UL in patients with COPD. However, there were inconsistencies in the results, especially regarding the perception of symptoms during ADL. The small number of studies included and their methodological quality do not allow for firm conclusions. Conclusions: The findings of this review revealed that ULExT is a safe therapeutic approach and can improve the performance of ADL that involve the UL in patients with COPD, but the results are unclear. Further investigation through well-designed randomized trials is warranted to determine the effectiveness of ULExT in improving the performance of ADL that involve the UL in patients with COPD.

RESUMO Objectivo: Investigar a eficácia do treinamento de membros superiores (MMSS) na melhora na execução de atividades da vida diária (AVD) que envolvem os MMSS em pacientes com DPOC. Métodos: Nesta revisão sistemática foram utilizadas as diretrizes do Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Os bancos de dados PubMed e EBSCOhost foram pesquisados para identificar ensaios controlados randomizados envolvendo adultos com DPOC submetidos a treinamento de MMSS, comparados àqueles submetidos a outros tipos de exercício ou a nenhum exercício, a fim de avaliar a execução de AVD que envolvem os MMSS. A qualidade metodológica dos estudos selecionados foi avaliada por meio da escala do Physiotherapy Evidence Database. Resultados: Cinco estudos, com uma amostra total de 173 indivíduos, preencheram os critérios de inclusão. Os resultados dos estudos selecionados mostraram que o treinamento de MMSS é seguro e pode melhorar significativamente a execução de AVD que envolvem os MMSS em pacientes com DPOC. No entanto, houve inconsistências nos resultados, especialmente em relação à percepção de sintomas durante as AVD. O pequeno número de estudos incluídos e a qualidade metodológica desses estudos não permitem conclusões firmes. Conclusões: Os achados desta revisão revelaram que o treinamento de MMSS é uma abordagem terapêutica segura e pode melhorar a execução de AVD que envolvem os MMSS em pacientes com DPOC, mas os resultados não são claros. São necessárias mais investigações, por meio de ensaios aleatorizados bem desenhados, para determinar a eficácia do treinamento de MMSS na melhora na execução de AVD que envolvem os MMSS em pacientes com DPOC.

The pore structure of Clostridium perfringens epsilon toxin.

Epsilon toxin (Etx), a potent pore forming toxin (PFT) produced by Clostridium perfringens, is responsible for the pathogenesis of enterotoxaemia of ruminants and has been suggested to play a role in multiple sclerosis in humans. Etx is a member of the aerolysin family of ß-PFTs (aß-PFTs). While the Etx soluble monomer structure was solved in 2004, Etx pore structure has remained elusive due to the difficulty of isolating the pore complex. Here we show the cryo-electron microscopy structure of Etx pore assembled on the membrane of susceptible cells. The pore structure explains important mutant phenotypes and suggests that the double ß-barrel, a common feature of the aß-PFTs, may be an important structural element in driving efficient pore formation. These insights provide the framework for the development of novel therapeutics to prevent human and animal infections, and are relevant for nano-biotechnology applications.