Explore the vast range of titles available.

ObjectivesThe aim of the study was to assess the feasibility of conducting a definitive multicentre randomised controlled trial (RCT) testing an online exercise rehabilitation and behavioural/motivational support intervention for people with postural tachycardia syndrome (PoTS).DesignFeasibility RCT.SettingTwo secondary care centres.ParticipantsAdults aged 18 to 60 years with PoTS. Exclusions were serious mental health/cognitive problem preventing safe participation; currently undertaking physical activity equivalent to the Chief Medical Officer guidelines; pregnancy.InterventionsParticipants were randomly assigned (1:1) to best-practice usual care (a single 1:1 session of advice) or the ‘postural tachycardia syndrome exercise’ (PULSE) intervention: (1) individual online consultation, (2) 12 weeks of supervised online group exercise and behavioural/motivational support, and (3) home exercise programme with recumbent exercise bike.OutcomesThe primary outcome was feasibility: (1) patients screened, eligible, recruited, randomised, withdrawn; (2) adherence; (3) physiological, clinical and patient-reported outcomes (4 and 7 months); and (4) embedded qualitative study to evaluate acceptability.Results209 patients screened between 5 May 2021 and 1 December 2022, 44 (female 98%; age 29.9 SD, 7.5) were randomised to usual care (n=21) or PULSE (n=23) (71% of target). Follow-up at 4 months was n=12 and n=17 respectively (66% of target). Median live exercise/support session attendance was 15 (IQR 12 to 17) of 18 sessions. Home exercise bike usage was highly variable. There were two serious adverse events in each treatment arm, both unrelated to the trial. Exercise rehabilitation was considered important by participants, and trial procedures, outcomes and interventions were acceptable.ConclusionsThe PULSE trial procedures and interventions were acceptable, and important design considerations were identified. A definitive RCT testing a remotely supervised exercise rehabilitation and behavioural/motivational support intervention for people with PoTS is feasible in the UK National Health Service.Trial registration number ISRCTN45323485.

Heart-rate variability (HRV) is a low-cost marker of autonomic regulation and a potential prognostic biomarker in psychosis. We hypothesized that HRV markers recorded at admission are associated with remission at discharge in patients with suspected first-episode psychosis. In this retrospective study, 78 inpatients (mean age: 30.8 years; 45% female) admitted to the Psychiatric University Hospital Zurich between 2018 and 2024 underwent a 2-min electrocardiogram on admission. Frequency-domain indices (log-transformed high-frequency [HF] and low-frequency [LF] power) and the linear slope of heart rate over time (beats per minute [BPM] slope) were extracted. Remission status at discharge was determined from clinician-rated scales and clinical evaluation. Binomial logistic regression with 5-fold stratified cross-validation assessed predictive accuracy (area under the receiver operating curve, AUC). Twenty-six patients (33.3 %) remitted. Sex was not associated with outcome. In the initial model, log HF (P = .011) and BPM slope (P = .014) predicted remission, whereas log LF and mean BPM did not. The final model retaining log HF and BPM slope achieved an AUC of 0.714. Lower log HF and more rapidly declining BPM slope at admission were linked to higher odds of remission. An HRV profile combining low vagally mediated HF power with rapid heart rate decrease predicted short-term remission, supporting the autonomic-flexibility framework. HRV may aid early treatment stratification, but findings require prospective validation with larger samples, respiratory monitoring, and standardized interventions.

A rendszerváltás éveiben újra indított falusi turizmus meghatározásában, vonzerőjében fontos szerepet kapott a magyar falvak néphagyományt felelevenítő törekvése. A falvak élelmiszertermelő tevékenységéhez olyan események kapcsolódtak, amelyek megismerése a városi emberek számára turisztikai vonzerőt jelentettek. A társadalmi, gazdasági fejlődés azonban mára jelentős változást eredményezett és mind az árutermelésben mind az ehhez kapcsolható hagyományőrzésben teljes átalakulás figyelhető meg. A falvak földtulajdona néhány gazda birtokába koncentrálódott, míg a termesztett növényi kultúrák száma drasztikusan csökkent. Ezzel együtt a gazdálkodáshoz köthető néphagyományok száma is fogyóban van. Indokolt tehát, hogy a falusi hagyományokra épülő, közösségformáló falusi turizmus újragondolását a figyelem központjába állítsuk. Az elmúlt 30 év kutatási eredményei azt mutatják, hogy a falusi turizmus népi értékeinek megőrzése nem kapott elegendő figyelmet. A fejlesztések elsősorban a szállásfejlesztést preferálták és a hagyományápolás háttérbe szorult. Fontos tehát, hogy az újragondolást tettek kövessék és az elődeink által ránk hagyott természeti, szellemi, kulturális örökségünket megőrizzük. A kutatás azoknak a hiányosságoknak a feltárását tartotta szem előtt, amelyek a jelen helyzet kialakulásához vezettek és igyekezett megoldást találni a sikeresen újra indított falusi turizmus túlélési esélyeinek növelésére. A még élő hagyományok megóvása nemzeti kincsként kezelendő, amely biztosítani tudja a falvak turisztikai vonzerőjét, a közös gondolkodáson alapuló falusi közösségek továbbélését! A falusi turizmus kínálatának tematizálása, és egy eredményesebb marketing tevékenység nagyobb turistaérkezést generálna, hozzájárulhatna a hátrányos helyzetű vidéki térségek felzárkóztatásához, a fenntarthatósági célok eléréséhez.

The evening routine In plants, the circadian clock functions as an endogenous pacemaker that anticipates and responds to a changing environment in order to optimize the timing of physiological and developmental events. Nusinow et al . elucidate the mechanism by which the circadian clock controls growth of the model plant Arabidopsis thaliana . A novel trimeric complex called the evening complex is regulated by the clock and has a peak of expression at dusk. The complex represses the expression of two transcription factors, PIF4 and PIF5, which are part of a light-signalling cascade that controls the timing of plant growth in response to light conditions. The circadian clock is required for adaptive responses to daily and seasonal changes in environmental conditions 1 , 2 , 3 . Light and the circadian clock interact to consolidate the phase of hypocotyl cell elongation to peak at dawn under diurnal cycles in Arabidopsis thaliana 4 , 5 , 6 , 7 . Here we identify a protein complex (called the evening complex)—composed of the proteins encoded by EARLY FLOWERING 3 ( ELF3 ), ELF4 and the transcription-factor-encoding gene LUX ARRHYTHMO ( LUX ; also known as PHYTOCLOCK 1 )—that directly regulates plant growth 8 , 9 , 10 , 11 , 12 . ELF3 is both necessary and sufficient to form a complex between ELF4 and LUX, and the complex is diurnally regulated, peaking at dusk. ELF3 , ELF4 and LUX are required for the proper expression of the growth-promoting transcription factors encoded by PHYTOCHROME INTERACTING FACTOR 4 ( PIF4 ) and PIF5 (also known as PHYTOCHROME INTERACTING FACTOR 3-LIKE 6 ) under diurnal conditions 4 , 6 , 13 . LUX targets the complex to the promoters of PIF4 and PIF5 in vivo . Mutations in PIF4 and/or PIF5 are epistatic to the loss of the ELF4–ELF3–LUX complex, suggesting that regulation of PIF4 and PIF5 is a crucial function of the complex. Therefore, the evening complex underlies the molecular basis for circadian gating of hypocotyl growth in the early evening.

The main organelles of the secretory and endocytic pathways—the endoplasmic reticulum (ER) and endosomes, respectively—are connected through contact sites whose numbers increase as endosomes mature 1 , 2 , 3 . One function of such sites is to enable dephosphorylation of the cytosolic tails of endosomal signalling receptors by an ER-associated phosphatase 4 , whereas others serve to negatively control the association of endosomes with the minus-end-directed microtubule motor dynein 5 or mediate endosome fission 6 . Cholesterol transfer and Ca 2+ exchange have been proposed as additional functions of such sites 2 , 3 . However, the compositions, activities and regulations of ER–endosome contact sites remain incompletely understood. Here we show in human and rat cell lines that protrudin, an ER protein that promotes protrusion and neurite outgrowth 7 , forms contact sites with late endosomes (LEs) via coincident detection of the small GTPase RAB7 and phosphatidylinositol 3-phosphate (PtdIns(3)P). These contact sites mediate transfer of the microtubule motor kinesin 1 from protrudin to the motor adaptor FYCO1 on LEs. Repeated LE–ER contacts promote microtubule-dependent translocation of LEs to the cell periphery and subsequent synaptotagmin-VII-dependent fusion with the plasma membrane. Such fusion induces outgrowth of protrusions and neurites, which requires the abilities of protrudin and FYCO1 to interact with LEs and kinesin 1. Thus, protrudin-containing ER–LE contact sites are platforms for kinesin-1 loading onto LEs, and kinesin-1-mediated translocation of LEs to the plasma membrane, fuelled by repeated ER contacts, promotes protrusion and neurite outgrowth. Repeated contacts between the endoplasmic reticulum (ER) and a subset of endosomes called late endosomes (LEs) is shown to promote microtubule-dependent translocation of LEs to the cell periphery and their subsequent fusion with the plasma membrane to induce outgrowth of neuronal protrusions. Role of endosomes in neuronal protrusion outgrowth The endoplasmic reticulum (ER) makes contact with various other cellular organelles including endosomes. Although the functional significance of ER–endosome contact sites is known, the composition, activity and regulation of these sites is poorly explored. Harald Stenmark and co-workers provide a glimpse into these enigmatic aspects. They show that the ER protein protrudin makes contact with the small GTPase RAB7 and phosphatidylinositol 3-phosphate (PtdIns(3)P) on a subset of endosomes called late endosomes (LEs). This allows transfer of the microtubule motor protein kinesin-1 from protrudin to the motor adaptor FYCO1 on LEs. Thus repeated ER–LE contacts promote microtubule-dependent translocation of LEs to the cell periphery and their subsequent fusion with the plasma membrane to induce neurite outgrowth of neuronal protrusions.

The endosomal sorting complex required for transport (ESCRT) machinery mediates cargo sorting, membrane deformation and membrane scission on the surface of endosomes, generating intraluminal vesicles (ILVs) to degrade signaling receptors. By live-cell imaging of individual endosomes in human cells, we find that ESCRT proteins are recruited in a repetitive pattern: ESCRT-0 and -I show a gradual and linear recruitment and dissociation, whereas ESCRT-III and its regulatory ATPase VPS4 display fast and transient dynamics. Electron microscopy shows that ILVs are formed consecutively, starting immediately after endocytic uptake of cargo proteins and correlating with the repeated ESCRT recruitment waves, unraveling the timing of ILV formation. Clathrin, recruited by ESCRT-0, is required for timely ESCRT-0 dissociation, efficient ILV formation, correct ILV size and cargo degradation. Thus, cargo sorting and ILV formation occur by concerted, coordinated and repetitive recruitment waves of individual ESCRT subcomplexes and are controlled by clathrin. Intraluminal vesicles are formed by the endosomal sorting complex required for transport (ESCRT) machinery. Here, the authors unravel the timing of vesicle budding, and that endosomal clathrin regulates concerted recruitment of ESCRT subcomplexes, required for efficient membrane remodeling.

Most animal studies using passive administration of HIV broadly neutralizing monoclonal antibodies (bnMAbs) have associated protection against high-dose mucosal viral challenge with relatively high serum concentrations of antibody. We recently identified several bnMAbs remarkable for their in vitro potency against HIV. Of these bnMAbs, PGT121 is one of the most broad and potent antibodies isolated to date and shows 10- to 100-fold higher neutralizing activity than previously characterized bnMAbs. To evaluate the protective potency of PGT121 in vivo, we performed a protection study in rhesus macaques. Animals were i.v. administered 5 mg/kg, 1 mg/kg, or 0.2 mg/kg PGT121 24 h before being vaginally challenged with a single high dose of chimeric simian-human immunodeficiency virus (SHIV) SF₁₆₂P₃. Sterilizing immunity was achieved in all animals administered 5 mg/kg and 1 mg/kg and three of five animals administered 0.2 mg/kg PGT121, with corresponding average antibody serum concentrations of 95 µg/mL, 15 µg/mL, and 1.8 µg/mL, respectively. The results suggest that a protective serum concentration for PGT121 is in the single-digit µg/mL for SHIV SF₁₆₂P₃, showing that PGT121 can mediate sterilizing immunity at serum concentrations that are significantly lower than those observed in previous studies and that may be achievable through vaccination with the development of a suitable immunogen.

Infection with Asian-lineage Zika virus (ZIKV) has been associated with Guillain–Barré syndrome and fetal abnormalities, but the underlying mechanisms remain poorly understood. Animal models of infection are thus urgently needed. Here we show that rhesus macaques are susceptible to infection by an Asian-lineage ZIKV closely related to strains currently circulating in the Americas. Following subcutaneous inoculation, ZIKV RNA is detected in plasma 1 day post infection (d.p.i.) in all animals ( N =8, including 2 pregnant animals), and is also present in saliva, urine and cerebrospinal fluid. Non-pregnant and pregnant animals remain viremic for 21 days and for up to at least 57 days, respectively. Neutralizing antibodies are detected by 21 d.p.i. Rechallenge 10 weeks after the initial challenge results in no detectable virus replication, indicating protective immunity against homologous strains. Therefore, Asian-lineage ZIKV infection of rhesus macaques provides a relevant animal model for studying pathogenesis and evaluating potential interventions against human infection, including during pregnancy. Animal models of infection with Zika virus (ZIKV) are urgently needed for a better understanding of pathogenesis and for testing potential therapies. Here, the authors describe infection of rhesus macaques with an Asian-lineage ZIKV strain as a relevant animal model for studying ZIKV pathogenesis.

As part of the lysosomal degradation pathway, the endosomal sorting complexes required for transport (ESCRT-0 to -III/VPS4) sequester receptors at the endosome and simultaneously deform the membrane to generate intraluminal vesicles (ILVs). Whereas ESCRT-III/VPS4 have an established function in ILV formation, the role of upstream ESCRTs (0 to II) in membrane shape remodeling is not understood. Combining experimental measurements and electron microscopy analysis of ESCRT-III–depleted cells with a mathematical model, we show that upstream ESCRT-induced alteration of the Gaussian bending rigidity and their crowding in concert with the transmembrane cargo on the membrane induce membrane deformation and facilitate ILV formation: Upstream ESCRT-driven budding does not require ATP consumption as only a small energy barrier needs to be overcome. Our model predicts that ESCRTs do not become part of the ILV, but localize with a high density at the membrane neck, where the steep decline in the Gaussian curvature likely triggers ESCRT-III/VPS4 assembly to enable neck constriction and scission.

If replication forks are perturbed, a multifaceted response including several DNA repair and cell cycle checkpoint pathways is activated to ensure faithful DNA replication. Here, we show that poly(ADP‐ribose) polymerase 1 (PARP1) binds to and is activated by stalled replication forks that contain small gaps. PARP1 collaborates with Mre11 to promote replication fork restart after release from replication blocks, most likely by recruiting Mre11 to the replication fork to promote resection of DNA. Both PARP1 and PARP2 are required for hydroxyurea‐induced homologous recombination to promote cell survival after replication blocks. Together, our data suggest that PARP1 and PARP2 detect disrupted replication forks and attract Mre11 for end processing that is required for subsequent recombination repair and restart of replication forks.