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Ion transport is a critical phenomenon underpinning numerous biological, physical, and chemical systems. Proton transistors leveraging proton transport face significant limitations, such as a low on-off ratio and deficient carrier mobility, which restrict their applicability in biological and other scenarios. This study explores the use of two-dimensional (2D) vacancy-residing transition metal phosphorus trichallcogenide-based membranes as the active layer for proton field-effect transistors. The synthesized Cd0.85PS3Li0.15H0.15 membrane exhibits a well-organized layered structure and high hydrophilicity, with nanometer-sized interlayers containing interconnected water networks. These distinct features facilitate proton conduction, leading to a high proton conductivity value of 0.83 S cm-1 at 98% relative humidity and 90 °C, with an activation energy of 0.26 eV. The Cd0.85PS3Li0.15H0.15-based proton transistor demonstrates tunability via gate voltage, thereby enabling effective modulation of proton flow across source and drain electrodes. The transistor notably showcases superior switching characteristics, with an on/off ratio surpassing 5.51 and a carrier mobility of 8.84 × 10-2 cm2 V-1 s-1. The underlying mechanism for this performance enhancement is attributed to electric-field-induced switching in Cd vacancies. This research boosts the development of highly versatile ionotropic devices by introducing advanced 2D ion-conductive membranes.
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BACKGROUND: Knee osteoarthritis negatively affects the gait of patients, especially that of elderly people. However, the assessment of wearable sensors in knee osteoarthritis patients has been under-researched. During clinical assessments, patients may change their gait patterns under the placebo effect, whereas wearable sensors can be used in any environment. METHODS: Sixty patients with knee osteoarthritis and 20 control subjects were included in the study. Wearing shoes with an IMU sensor embedded in the insoles, the participants were required to walk along a walkway. The sensor data were collected during the gait. To discriminate between healthy and knee osteoarthritis patients and to classify different subgroups of knee osteoarthritis patients (patients scheduled for surgery vs. patients not scheduled for surgery; bilateral knee osteoarthritis diagnosis vs. unilateral knee osteoarthritis diagnosis), we used a machine learning approach called the support vector machine. A total of 88 features were extracted and used for classification. FINDINGS: The patients vs. healthy participants were classified with 71% accuracy, 85% sensitivity, and 56% specificity. The "patients scheduled for surgery" vs. "patients not scheduled for surgery" were classified with 83% accuracy, 83% sensitivity, and 81% specificity. The bilateral knee osteoarthritis diagnosis vs. unilateral knee osteoarthritis diagnosis was classified with 81% accuracy, 75% sensitivity, and 79% specificity. INTERPRETATION: Gait analysis using wearable sensors and machine learning can discriminate between healthy and knee osteoarthritis patients and classify different subgroups with reasonable accuracy, sensitivity, and specificity. The proposed approach requires no complex gait factors and is not limited to controlled laboratory settings.
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Marcha , Osteoartrite do Joelho , Sapatos , Humanos , Osteoartrite do Joelho/fisiopatologia , Osteoartrite do Joelho/diagnóstico , Osteoartrite do Joelho/classificação , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Análise da Marcha/métodos , Análise da Marcha/instrumentação , Dispositivos Eletrônicos Vestíveis , Aprendizado de Máquina , Máquina de Vetores de Suporte , Sensibilidade e Especificidade , Reprodutibilidade dos TestesRESUMO
The endoplasmic reticulum (ER) membrane protein complex (EMC) is a conserved, multi-subunit complex acting as an insertase at the ER membrane. Growing evidence shows that the EMC is also involved in stabilizing and trafficking membrane proteins. However, the structural basis and regulation of its multifunctionality remain elusive. Here, we report cryo-electron microscopy structures of human EMC in apo- and voltage-dependent anion channel (VDAC)-bound states at resolutions of 3.47 Å and 3.32 Å, respectively. We discovered a specific interaction between VDAC proteins and the EMC at mitochondria-ER contact sites, which is conserved from yeast to humans. Moreover, we identified a gating plug located inside the EMC hydrophilic vestibule, the substrate-binding pocket for client insertion. Conformation changes of this gating plug during the apo-to-VDAC-bound transition reveal that the EMC unlikely acts as an insertase in the VDAC1-bound state. Based on the data analysis, the gating plug may regulate EMC functions by modifying the hydrophilic vestibule in different states. Our discovery offers valuable insights into the structural basis of EMC's multifunctionality.
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Retículo Endoplasmático , Canais de Ânion Dependentes de Voltagem , Humanos , Microscopia Crioeletrônica , Canais de Ânion Dependentes de Voltagem/metabolismo , Retículo Endoplasmático/metabolismo , Saccharomyces cerevisiaeRESUMO
BACKGROUND: An inertial measurement unit is small and lightweight, allowing patient measurements without physical constraints. This study aimed to determine the differences in kinematic parameters during gait using an insole with a single inertial measurement unit in healthy controls and on both sides in patients with knee osteoarthritis. METHODS: Twenty patients with knee osteoarthritis and 13 age-matched controls were included in this study. The participants walked at a self-selected speed and foot kinematics were measured during gait using an insole with a single inertial measurement unit. The right side of the healthy controls and both the affected and contralateral sides of patients with KOA were analyzed separately. FINDINGS: The foot extension angular velocity at toe-off was significantly reduced on the affected side than on the contralateral side (P < 0.001) and in healthy controls (P < 0.001). During the swing phase, foot posterior-anterior acceleration was significantly lower on the affected side than on the healthy controls (P = 0.005). Furthermore, despite a decrease in walking speed, foot superior-inferior acceleration at initial contact in patients was significantly lower on the contralateral side than in healthy controls (P = 0.0167), but not on the affected side (P = 0.344). INTERPRETATION: An insole with a single inertial measurement unit can detect differences in foot kinematics during gait between healthy controls and patients with knee osteoarthritis. Our findings indicate that patients with knee osteoarthritis exhibit dysfunction of push-off at toe-off and shock absorption at initial contact on the affected side.
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Osteoartrite do Joelho , Humanos , Articulação do Joelho , Fenômenos Biomecânicos , Estudos de Casos e Controles , Marcha , CaminhadaRESUMO
Interface modification plays an important role in improving the power conversion efficiency (PCE) of organic solar cells (OSCs). However, the low non-covalent interaction between the cathode interface layer (CIL) and nonfullerene acceptor (NFA) directly affects the charge collection of OSCs. Here, the non-covalent interaction between the CIL and NFA is enhanced by introducing the 2D vermiculite (VML) in the poly(9,9-bis(3'-(N,N-dimethyl)-Nethylammonium-propyl-2,7-fluorene)-alt-2,7-(9,9-dioctylfluorene)) dibromide (PFN-Br) interface layer to form an efficient electron transport channel. As a result, the electron extraction efficiency from the active layer to the CIL is increased, and the PCE of OSCs based on PBDB-T:ITIC is boosted from 10.87% to 12.89%. In addition, the strategy of CIL doping VML is proven to be universal in different CIL materials, for which the PCE is boosted from 10.21% to 11.57% for OSCs based on PDINN and from 9.82% to 11.27% for OSCs based on PNDIT-F3N. The results provide a viable option for designing efficient CIL for high-performance non-fullerene OSCs, which may promote the commercialization of OSCs.
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Glycoprotein (GP) Ib-IX-V is the second most abundant platelet receptor for thrombin and other ligands crucial for hemostasis and thrombosis. Its activity is involved in platelet adhesion to vascular injury sites and thrombin-induced platelet aggregation. GPIb-IX-V is a heteromeric complex composed of four subunits, GPIbα, GPIbß, GPV and GPIX, in a stoichiometric ratio that has been wildly debated. Despite its important physiological roles, the overall structure and molecular arrangement of GPIb-IX-V are not yet fully understood. Here, we purify stable and functional human GPIb-IX-V complex from reconstituted EXPi293F cells in high homogeneity, and perform biochemical and structural characterization of this complex. Single-particle cryo-electron microscopy structure of GPIb-IX-V is determined at â¼11 Å resolution, which unveils the architecture of GPIb-IX-V and its subunit organization. Size-exclusion chromatography-multi-angle static light scattering analysis reveals that GPIb-IX-V contains GPIb-IX and GPV at a 1:1 stoichiometric ratio and surface plasmon resonance assays show that association of GPV leads to slow kinetics of thrombin binding to GPIb-IX-V. Taken together, our results provide the first three-dimensional architecture of the intact GPIb-IX-V complex, which extends our understanding of the structure and functional mechanism of this complex in hemostasis and thrombosis.
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Complexo Glicoproteico GPIb-IX de Plaquetas , Trombose , Humanos , Complexo Glicoproteico GPIb-IX de Plaquetas/química , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Trombina/metabolismo , Microscopia Crioeletrônica , Plaquetas/metabolismo , Trombose/metabolismoRESUMO
Lower extremity strength (LES) is essential to support activities in daily living. To extend healthy life expectancy of elderly people, early detection of LES weakness is important. In this study, we challenge to develop a method for LES assessment in daily living via an in-shoe motion sensor (IMS). To construct the estimation model, we collected data from 62 subjects. We used the outcome of the five-times-sit-to-stand test to represent the performance of LES as the target variable. Predictors were constructed from the subjects' foot motions measured by the IMS during straight path walking. We used the leave-one-subject-out least absolute shrinkage and selection operator algorithm to select features and construct respective models for the males and females. As a result, the models achieved fair and a good intra-class correlation coefficient agreement between the true and estimation values, with mean absolute errors of 2.14 and 1.21 s (variation of 23.6 and 16.0%), respectively. To validate the models, we separately collected data from 45 subjects. The models successfully predicted 100% and 90% of the male and female subjects' data, respectively, which suggests the robustness of the constructed estimation models. The results suggested that LES can be identified more effectively in daily living by wearing an IMS, and the use of an IMS has the potential for future frailty and fall risk assessment applications.
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Extremidade Inferior , Força Muscular , Tecnologia de Sensoriamento Remoto , Sapatos , Idoso , Feminino , Humanos , Masculino , Pé , Movimento (Física) , Caminhada , Tecnologia de Sensoriamento Remoto/instrumentação , Tecnologia de Sensoriamento Remoto/métodosRESUMO
With the widespread use of sulfonamide antibiotics (SAs), SAs are detected as residues in aquatic environments, posing a serious threat to human life and safety. Because of their high water solubility, fast transmission rate, and strong antibacterial properties, the safe disposal of SAs has become a key constraint for water quality assurance. Therefore, an ultrasound (US)-assisted zero-valent iron (ZVI)/persulfate (PS) system was proposed to explore the rapid and effective degradation of SAs. Comparative experiments were performed to study the removal of sulfadiazine (SDZ) by US, ZVI, PS, US/ZVI, US/PS, ZVI/PS, and US-ZVI/PS systems, respectively. Experimental results indicated that the highest removal efficiency of SDZ was ahieved in US-ZVI/PS system (97.4%), which were 2-44 times higher than that in other systems. Furthermore, the degradation efficiency of five typical SAs was achieved over 95%, demonstrating the effectiveness of the US ZVI/PS system for SAs removal. Also, quantum chemical computations for potential reactive sites of SAs and intermediate product detection by HPLCâMS/MS were performed. The radical attack on active sites of SAs, such as N atom (number 7), was the main reason for SAs removal in US-ZVI/PS system. Besides, the common degradation pathways of six typical SAs were defined as S-N bond cleavage, C-N bond cleavage, benzene ring hydroxylation, aniline oxidation, and R substituent oxidation. Interestingly, the unique pathway of "SO2 group extraction" was observed in the degradation of six-membered ring SAs. Therefore, the US-ZVI/PS system is a promising and cost-effective method for the removal of SAs and other refractory pollutants.
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Antibacterianos , Espectrometria de Massas em Tandem , Humanos , Sulfanilamida , Sulfadiazina , Sulfonamidas , FerroRESUMO
Background: Both the Sport Education (SE) model and Teaching Games for Understanding (TGfU) have been connected to the theory of situated learning, which is a game-centered curricular model. TGfU emphasizes tactical awareness, decision making, and skill execution. The SE model provides a complete season during physical education (PE) lessons. Therefore, it is worth exploring the integration of TGfU with SE (TGfU-SE) model in PE courses, and whether the hybrid TGfU-SE model can achieve better learning effects for students than the TGfU model alone. Purpose: The purpose of the study was to compare the difference in learning effects between the TGfU-SE model and the TGfU model on students' learning motivation, sport enjoyment, responsibility, and game performance. Methods: This study used a quasi-experimental design to compare different learning effects between the experimental group (TGfU-SE) and the control group (TGfU). The participants lived in Taiwan, including two junior high school PE teachers and four PE classes with a total of 90 students (TGfU-SE group, n = 46; TGfU group, n = 44). Each teacher taught two PE classes, one with an experimental group and one with a control group. This study used four research instruments, including the Responsibility Scale in Physical Education (RSPE), Learning Motivation Scale in Physical Education (LMSPE), Sport Enjoyment Scale in Physical Education (SESPE), and Game Performance assessment instrument (GPAI). Analysis of covariance (ANCOVA) and the independent t-test were used to analyze the data. Results: The results of this study showed that the TGfU-SE model had more positive learning effects on students' learning motivation, sport enjoyment, responsibility, and game performance than the TGfU model. Conclusion: we concluded that the TGfU-SE model had a more positive influence on students' learning performance than the TGfU model. It is suggested that the hybrid TGfU-SE model could be implemented effectively in the PE curriculum.
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Frailty poses a threat to the daily lives of healthy older adults, highlighting the urgent need for technologies that can monitor and prevent its progression. Our objective is to demonstrate a method for providing long-term daily frailty monitoring using an in-shoe motion sensor (IMS). We undertook two steps to achieve this goal. Firstly, we used our previously established SPM-LOSO-LASSO (SPM: statistical parametric mapping; LOSO: leave-one-subject-out; LASSO: least absolute shrinkage and selection operator) algorithm to construct a lightweight and interpretable hand grip strength (HGS) estimation model for an IMS. This algorithm automatically identified novel and significant gait predictors from foot motion data and selected optimal features to construct the model. We also tested the robustness and effectiveness of the model by recruiting other groups of subjects. Secondly, we designed an analog frailty risk score that combined the performance of the HGS and gait speed with the aid of the distribution of HGS and gait speed of the older Asian population. We then compared the effectiveness of our designed score with the clinical expert-rated score. We discovered new gait predictors for HGS estimation via IMSs and successfully constructed a model with an "excellent" intraclass correlation coefficient and high precision. Moreover, we tested the model on separately recruited subjects, which confirmed the robustness of our model for other older individuals. The designed frailty risk score also had a large effect size correlation with clinical expert-rated scores. In conclusion, IMS technology shows promise for long-term daily frailty monitoring, which can help prevent or manage frailty for older adults.
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Fragilidade , Humanos , Idoso , Fragilidade/diagnóstico , Sapatos , Idoso Fragilizado , Força da Mão , Marcha , Avaliação Geriátrica/métodosRESUMO
Objectives: This study aimed to investigate the relationship between frailty and all-cause mortality in hypertensive population. Methods: We used data from the National Health and Nutrition Examination Survey (NHANES) 1999-2002 and mortality data from the National Death Index. Frailty was assessed using the revised version of the Fried frailty criteria (weakness, exhaustion, low physical activity, shrinking, and slowness). This study aimed to evaluate the association between frailty and all-cause mortality. Cox proportional hazard models were used to evaluate the association between frailty category and all-cause mortality, adjusted for age, sex, race, education, poverty-income ratio, smoking, alcohol, diabetes, arthritis, congestive heart failure, coronary heart disease, stroke, overweight, cancer or malignancy, chronic obstructive pulmonary disease, chronic kidney disease, and taking medicine for hypertension. Results: We gathered data of 2,117 participants with hypertension; 17.81%, 28.77%, and 53.42% were classified as frail, pre-frail, and robust, respectively. We found that frail [hazard ratio (HR) = 2.76, 95% confidence interval (CI) = 2.33-3.27] and pre-frail (HR = 1.38, 95% CI = 1.19-1.59] were significantly associated with all-cause mortality after controlling for variables. We found that frail (HR = 3.02, 95% CI = 2.50-3.65) and pre-frail (HR = 1.35, 95% CI = 1.15-1.58) were associated with all-cause mortality in the age group ≥65â years. For the frailty components, weakness (HR = 1.77, 95% CI = 1.55-2.03), exhaustion (HR = 2.25, 95% CI = 1.92-2.65), low physical activity (HR = 2.25, 95% CI = 1.95-2.61), shrinking (HR = 1.48, 95% CI = 1.13-1.92), and slowness (HR = 1.44, 95% CI = 1.22-1.69) were associated with all-cause mortality. Conclusion: This study demonstrated that frailty and pre-frailty were associated with an increased risk of all-cause mortality in patients with hypertension. More attention should be paid to frailty in hypertensive patients, and interventions to reduce the burden of frailty may improve outcomes in these patients.
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Lack of time, lack of access to equipment, and environmental constraints are generally perceived as barriers to regular physical activity. Moreover, insufficient activity is known to promote sedentary behavior, which is a factor in many chronic diseases, negatively affects mental health, and reduces quality of life. Exercise snacks, defined as short and efficient bursts of exercise, are convenient and easy to implement, reduce sedentary time, increase physical activity, and promote the development of good exercise habits. Previous studies have found exercise snacks to be safe and feasible for the elderly, promoting physical function and reducing the incidence of falls and metabolic diseases. Exercise snacks have also been found to be effective in healthy adults as well as in patients with obesity and diabetes, helping decrease blood sugar and promoting cardiorespiratory fitness. Depending on the participant's age and tolerance, exercise snack patterns may be extended and distinguished into two forms: 10-minute bouts of gentle intermittent exercise twice a day and 60-second bouts of vigorous exercise 3 to 8 times a day. The main considerations for exercise snacks include: multi-joint exercise is better than single-joint exercise, lower body exercise is better than upper body exercise, and dynamic and rapid movement that pushes away from the ground promotes osteogenesis and helps prevent osteoporosis and fractures. Exercise snacks may be applied in healthcare practice and related research to promote health and improve quality of life for all.
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Promoção da Saúde , Lanches , Adulto , Humanos , Idoso , Qualidade de Vida , Exercício Físico , Comportamento SedentárioRESUMO
Intraflagellar transport (IFT) trains, the polymers composed of two multi-subunit complexes, IFT-A and IFT-B, carry out bidirectional intracellular transport in cilia, vital for cilia biogenesis and signaling. IFT-A plays crucial roles in the ciliary import of membrane proteins and the retrograde cargo trafficking. However, the molecular architecture of IFT-A and the assembly mechanism of the IFT-A into the IFT trains in vivo remains elusive. Here, we report the cryo-electron microscopic structures of the IFT-A complex from protozoa Tetrahymena thermophila. We find that IFT-A complexes present two distinct, elongated and folded states. Remarkably, comparison with the in situ cryo-electron tomography structure of the anterograde IFT train unveils a series of adjustments of the flexible arms in apo IFT-A when incorporated into the anterograde train. Our results provide an atomic-resolution model for the IFT-A complex and valuable insights into the assembly mechanism of anterograde IFT trains.
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Cílios , Transdução de Sinais , Cílios/metabolismo , Transporte Biológico , Microscopia Crioeletrônica , Tomografia com Microscopia Eletrônica , Flagelos/metabolismoRESUMO
Identifying the characteristics of fallers is important for preventing falls because such events may reduce quality of life. It has been reported that several variables related to foot positions and angles during gait (e.g., sagittal foot angle and minimum toe clearance) differ between fallers and non-fallers. However, examining such representative discrete variables may not be sufficient to detect crucial information, which may be contained in the large portions of unanalyzed data. Therefore, we aimed to identify the comprehensive characteristics of foot position and angle during the swing phase of gait in non-fallers and fallers using principal component analysis (PCA). Thirty non-fallers and 30 fallers were recruited for this study. We performed PCA to reduce the dimensions of foot positions and angles during the swing phase and obtained principal component scores (PCSs) for each principal component vector (PCV), which were then compared between groups. The results revealed that the PCS of PCV3 in fallers was significantly larger than that in non-fallers (p = 0.003, Cohen's d = 0.80). We reconstructed waveforms of foot positions and angles during the swing phase using PCV3 and our main findings can be summarized as follows. Compared to non-fallers, fallers have a 1) low average foot position in the z-axis (i.e., height) during the initial swing phase 2) small average foot angle in the x-axis (i.e., rotation in the sagittal plane), during the initial swing phase, and 3) large variability in foot position in the y-axis (i.e., anterior/posterior position) during the initial swing phase. We can conclude that these are characteristics of gait related to fallers. Therefore, our findings may be beneficial for evaluating fall risk during gait using a device such as a shoe- or insole-embedded inertial measurement unit.
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Porous titanium interbody scaffolds are growing in popularity due to their appealing advantages for bone ingrowth. This study aimed to investigate the biomechanical effects of scaffold materials in both normal and osteoporotic lumbar spines using a finite element (FE) model. Four scaffold materials were compared: Ti6Al4V (Ti), PEEK, porous titanium of 65% porosity (P65), and porous titanium of 80% porosity (P80). In addition, the range of motion (ROM), endplate stress, scaffold stress, and pedicle screw stress were calculated and compared. The results showed that the ROM decreased by more than 96% after surgery, and the solid Ti scaffold provided the lowest ROM (1.2-3.4% of the intact case) at the surgical segment among all models. Compared to solid Ti, PEEK decreased the scaffold stress by 53-66 and the endplate stress by 0-33%, while porous Ti decreased the scaffold stress by 20-32% and the endplate stress by 0-32%. Further, compared with P65, P80 slightly increased the ROM (<0.03°) and pedicle screw stress (<4%) and decreased the endplate stress by 0-13% and scaffold stress by approximately 18%. Moreover, the osteoporotic lumbar spine provided higher ROMs, endplate stresses, scaffold stresses, and pedicle screw stresses in all motion modes. The porous Ti scaffolds may offer an alternative for lateral lumbar interbody fusion.
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EDA is a tumor necrosis factor (TNF) family member, which functions together with its cognate receptor EDAR during ectodermal organ development. Mutations of EDA have long been known to cause X-linked hypohidrotic dysplasia in humans characterized by primary defects in teeth, hair and sweat glands. However, the structural information of EDA interaction with EDAR is lacking and the pathogenic mechanism of EDA variants is poorly understood. Here, we report the crystal structure of EDA C-terminal TNF homology domain bound to the N-terminal cysteine-rich domains of EDAR. Together with biochemical, cellular and mouse genetic studies, we show that different EDA mutations lead to varying degrees of ectodermal developmental defects in mice, which is consistent with the clinical observations on human patients. Our work extends the understanding of the EDA signaling mechanism, and provides important insights into the molecular pathogenesis of disease-causing EDA variants.
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Displasia Ectodérmica Anidrótica Tipo 1 , Displasia Ectodérmica , Humanos , Camundongos , Animais , Displasia Ectodérmica Anidrótica Tipo 1/genética , Ectodisplasinas/genética , Ectodisplasinas/metabolismo , Displasia Ectodérmica/genética , Transdução de Sinais , Ectoderma/metabolismo , Mutação , Receptor Edar/genéticaRESUMO
AIMS: To determine factors associated with poor sleep quality among patients with pre-dialysis chronic kidney disease. DESIGN: This is a systematic review study guided by Preferred Reporting Items for Systematic Reviews and Meta-Analyses statements and checklist. DATA SOURCES: Empirical evidence was sought in major electronic databases, including Embase, MEDLINE, CINAHL and Airiti library from March to September 2022. REVIEW METHODS: Studies investigating factors associated with poor sleep quality among adult patients with chronic kidney disease were included. Study participants who received renal replacement therapy and had sleep disorders and serious illnesses such as cancer were excluded. Of the 526 studies that resulted from the search after removing duplicate articles, 20 studies were assessed for quality by using Joanna Briggs Institute and Newcastle-Ottawa Scale by two doctorial prepared nursing scientists. RESULTS: A total of 20 studies were included in this review. The prevalence of poor sleep quality in these studies ranged from 11% to 97.5%. Demographics (older age and female), physiological conditions (higher body mass index, higher hip circumferences, higher systolic blood pressure, poor cardiovascular function, dyspnoea, pain, cramps, itchiness or moderate to extreme pruritus, lower fasting plasma glucose, electrolyte imbalance, higher total cholesterol and gastrointestinal symptoms), depression, smoking, arousal-related and cognitive arousal behaviours were associated with poor sleep quality. CONCLUSION: Poor sleep quality was prevalent and influenced kidney function, increased mortality as well as decreased quality of life in patients with pre-dialysis chronic kidney disease. This review synthesizes factors associated with poor sleep quality. Managing these factors can mitigate and prevent poor sleep quality. IMPACT: Healthcare providers, especially nurses, can assess the risk factors of poor sleep quality and reinforce patients' self-management. Future research should elucidate the assessment and management of risk factors and transfer these into widespread use in the routine care of patients with chronic kidney disease.
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Insuficiência Renal Crônica , Qualidade do Sono , Adulto , Humanos , Feminino , Qualidade de Vida , Diálise/efeitos adversos , Insuficiência Renal Crônica/complicações , Diálise Renal/psicologiaRESUMO
Telomerase is crucial for telomere maintenance and genome integrity. The most salient feature of Tetrahymena telomerase is that its CST subcomplex (p75-p45-p19) is tethered to the telomerase catalytic core by interacting with the hub p50. Although the cryoelectron microscopy (cryo-EM) structures of Tetrahymena telomerase have recently been reported, the mechanisms of how and why p50 bridges the CST subcomplex to the telomerase catalytic core remain unclear. Here, we present the nuclear magnetic resonance (NMR) structure of the p75OB1-p50PBM complex. Loss of the interaction between p75 and p50 detaches the CST subcomplex from the telomerase catalytic core in Tetrahymena. The tethering of the CST subcomplex to telomerase is required for telomere homeostasis. However, the detached CST subcomplex is still capable of facilitating the telomeric complementary-strand (C-strand) fill in similar to the non-tethered CST complexes in other organisms. These results expand our understanding of telomere synthesis in Tetrahymena.
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Telomerase , Tetrahymena thermophila , Microscopia Crioeletrônica , Telômero , Domínio CatalíticoRESUMO
Teratozoospermia is usually associated with defective spermiogenesis and is a disorder with considerable genetic heterogeneity. Although previous studies have identified several teratozoospermia-associated genes, the etiology remains unknown for a majority of affected men. Here, we identified a homozygous missense mutation and a compound heterozygous mutation of CCIN in patients suffering from teratozoospermia. CCIN encodes the cytoskeletal protein Calicin that is involved in the formation and maintenance of the highly regular organization of the calyx of mammalian spermatozoa, and has been proposed to play a role in sperm head structure remodeling during the process of spermiogenesis. Our morphological and ultrastructural analyses of the spermatozoa obtained from all three men harboring deleterious CCIN mutants reveal severe head malformation. Further immunofluorescence assays unveil markedly reduced levels of Calicin in spermatozoa. These patient phenotypes are successfully recapitulated in mouse models expressing the disease-associated variants, confirming the role of Calicin in male fertility. Notably, all mutant spermatozoa from mice and human patients fail to adhere to the zona mass, which likely is the major mechanistic reason for CCIN-mutant sperm-derived infertility. Finally, the use of intra-cytoplasmic sperm injections (ICSI) successfully makes mutated mice and two couples with CCIN variants have healthy offspring. Taken together, our findings identify the role of Calicin in sperm head shaping and male fertility, providing important guidance for genetic counseling and assisted reproduction treatments.