CENTROSOMAL TBC1D31 INTEGRATES cAMP SIGNALING AND OFD1 UBIQUITYLATION TO CONTROL CILIOGENESIS

The primary cilium is a microtubule-based organelle that regulates growth and development. Defects in ciliogenesis can lead to a group of genetic syndromes known as ciliopathies. The Oro-facial digital syndrome 1 (OFD1) is a X-linked ciliopathy caused by mutation in OFD1 gene, whose role in ciliogenesis is well established. Additionally, cAMP and ubiquitin pathway play a role in ciliogenesis. In mammals, most of the effects elicited by cAMP are mediated by protein kinase A (PKA). The cAMP-PKA pathway can induce activation of praja2, a RING E3-ubiquitin ligase of the ubiquitin-proteasome system (UPS). By a yeast two-hybrid screening, we identified TBC1D31 as a novel interactor of praja2. TBC1D31 is a protein localized at the centrosome and basal body, whose function is unknown. Given the role of centrosome in the control of primary cilia formation, the aim of my study was to investigate the role of TBC1D31 in ciliogenesis and evaluate the impact of cAMP and praja2 in TBC1D31-mediated ciliary functions. We identified a scaffold complex assembled by TBC1D31 at centrosome that includes the ubiquitin ligase praja2, protein kinase A (PKA) and OFD1. We show that TBC1D31 is essential for ciliogenesis and for Medaka fish development. Upon cAMP stimulation, PKA phosphorylates OFD1 at ser735. Phosphorylation primes OFD1 to praja2-mediated ubiquitylation and proteasomal degradation. Removal of OFD1 promotes primary cilia resorption. Altogether, our findings indicate that TBC1D31 is a novel centrosomal scaffold protein that physically and functionally links the activation of the cAMP signalling to the regulation of primary cilium biology and development

Robot-assisted upper limb training for patients with multiple sclerosis: an evidence-based review of clinical applications and effectiveness

Upper extremities limitation is a common functional impairment in patients with Multiple Sclerosis (PwMS). Novel technological devices are increasingly used in neurorehabilitation to support motor function improvement and the quantitative assessment of motor performance during training in patients with neurological diseases. In this review, we systematically report the evidence on clinical applications and robotic-assisted arm training (RAT) in functional recovery in PwMS. PubMed/MEDLINE, the Cochrane Library, and the Physiotherapy Evidence Database (PEDro) databases were systematically searched from inception to March 2021. The 10-item PEDro scale assessed the study quality for the RCT, and the AMSTAR-2 was used to assess the quality of the systematic review. The 5-item Oxford CEBM scale was used to rate the level of evidence. A total of 10 studies (161 subjects) were included. The selected studies included one systematic review, four RCTs, one randomized crossover, and four case series. The RCTs were scored as high-quality studies, while the systematic review was determined to be of low quality. Shoulder range of motion, handgrip strength, and proximal arm impairment improved after RAT. Manual dexterity, arm function, and use in daily life also ameliorated arm function. The high clinical heterogeneity of treatment programs and the variety of robot devices affects the generalizability of the study results; therefore, we emphasize the need to standardize the intervention type in future studies that evaluate the role of robotic-assisted training in PwMS. Robot-assisted treatment seems safe and useful to increase manual dexterity and the quality of movement execution in PwMS with moderate to severe disability. Additional studies with an adequate sample size and methodological rigour are warranted to drive definite conclusion

Upper limb robotic rehabilitation for patients with cervical spinal cord injury: a comprehensive review

The upper extremities limitation represents one of the essential functional impairments in patients with cervical spinal cord injury. Electromechanics assisted devices and robots are increasingly used in neurorehabilitation to help functional improvement in patients with neurological diseases. This review aimed to systematically report the evidence-based, state-of-art on clinical applications and robotic-assisted arm training (RAT) in motor and functional recovery in subjects affected by cervical spinal cord injury. The present study has been carried out within the framework of the Italian Consensus Conference on "Rehabilitation assisted by robotic and electromechanical devices for persons with disability of neurological origin" (CICERONE). PubMed/MEDLINE, Cochrane Library, and Physiotherapy Evidence Database (PEDro) databases were systematically searched from inception to September 2021. The 10-item PEDro scale assessed the study quality for the RCT and the AMSTAR-2 for the systematic review. Two different authors rated the studies included in this review. If consensus was not achieved after discussion, a third reviewer was interrogated. The five-item Oxford CEBM scale was used to rate the level of evidence. A total of 11 studies were included. The selected studies were: two systematic reviews, two RCTs, one parallel-group controlled trial, one longitudinal intervention study and five case series. One RCT was scored as a high-quality study, while the systematic review was of low quality. RAT was reported as feasible and safe. Initial positive effects of RAT were found for arm function and quality of movement in addition to conventional therapy. The high clinical heterogeneity of treatment programs and the variety of robot devices could severely affect the generalizability of the study results. Therefore, future studies are warranted to standardize the type of intervention and evaluate the role of robotic-assisted training in subjects affected by cervical spinal cord injury

Effects of robotic upper limb treatment after stroke on cognitive patterns: A systematic review

Background: Robotic therapy (RT) has been internationally recognized for the motor rehabilitation of the upper limb. Although it seems that RT can stimulate and promote neuroplasticity, the effectiveness of robotics in restoring cognitive deficits has been considered only in a few recent studies. Objective: To verify whether, in the current state of the literature, cognitive measures are used as inclusion or exclusion criteria and/or outcomes measures in robotic upper limb rehabilitation in stroke patients. Methods: The systematic review was conducted according to PRISMA guidelines. Studies eligible were identified through PubMed/MEDLINE and Web of Science from inception to March 2021. Results: Eighty-one studies were considered in this systematic review. Seventy-three studies have at least a cognitive inclusion or exclusion criteria, while only seven studies assessed cognitive outcomes. Conclusion: Despite the high presence of cognitive instruments used for inclusion/exclusion criteria their heterogeneity did not allow the identification of a guideline for the evaluation of patients in different stroke stages. Therefore, although the heterogeneity and the low percentage of studies that included cognitive outcomes, seemed that the latter were positively influenced by RT in post-stroke rehabilitation. Future larger RCTs are needed to outline which cognitive scales are most suitable and their cut-off, as well as what cognitive outcome measures to use in the various stages of post-stroke rehabilitation

Acute Delta Hepatitis in Italy spanning three decades (1991–2019): Evidence for the effectiveness of the hepatitis B vaccination campaign

Updated incidence data of acute Delta virus hepatitis (HDV) are lacking worldwide. Our aim was to evaluate incidence of and risk factors for acute HDV in Italy after the introduction of the compulsory vaccination against hepatitis B virus (HBV) in 1991. Data were obtained from the National Surveillance System of acute viral hepatitis (SEIEVA). Independent predictors of HDV were assessed by logistic-regression analysis. The incidence of acute HDV per 1-million population declined from 3.2 cases in 1987 to 0.04 in 2019, parallel to that of acute HBV per 100,000 from 10.0 to 0.39 cases during the same period. The median age of cases increased from 27 years in the decade 1991-1999 to 44 years in the decade 2010-2019 (p < .001). Over the same period, the male/female ratio decreased from 3.8 to 2.1, the proportion of coinfections increased from 55% to 75% (p = .003) and that of HBsAg positive acute hepatitis tested for by IgM anti-HDV linearly decreased from 50.1% to 34.1% (p < .001). People born abroad accounted for 24.6% of cases in 2004-2010 and 32.1% in 2011-2019. In the period 2010-2019, risky sexual behaviour (O.R. 4.2; 95%CI: 1.4-12.8) was the sole independent predictor of acute HDV; conversely intravenous drug use was no longer associated (O.R. 1.25; 95%CI: 0.15-10.22) with this. In conclusion, HBV vaccination was an effective measure to control acute HDV. Intravenous drug use is no longer an efficient mode of HDV spread. Testing for IgM-anti HDV is a grey area requiring alert. Acute HDV in foreigners should be monitored in the years to come

Towards a muon collider

A muon collider would enable the big jump ahead in energy reach that is needed for a fruitful exploration of fundamental interactions. The challenges of producing muon collisions at high luminosity and 10 TeV centre of mass energy are being investigated by the recently-formed International Muon Collider Collaboration. This Review summarises the status and the recent advances on muon colliders design, physics and detector studies. The aim is to provide a global perspective of the field and to outline directions for future work

Towards a Muon Collider

A muon collider would enable the big jump ahead in energy reach that is needed for a fruitful exploration of fundamental interactions. The challenges of producing muon collisions at high luminosity and 10 TeV centre of mass energy are being investigated by the recently-formed International Muon Collider Collaboration. This Review summarises the status and the recent advances on muon colliders design, physics and detector studies. The aim is to provide a global perspective of the field and to outline directions for future work.Comment: 118 pages, 103 figure

Probing the inflationary particle content: extra spin-2 field

We study how inflationary observables associated with primordial tensor modes are affected by coupling the minimal field content with an extra spin-2 particle during inflation. We work with a model that is ghost-free at the fully non-linear level and show how the new degrees of freedom modify standard consistency relations for the tensor bispectrum. The extra interacting spin-2 field is necessarily massive and unitarity dictates its mass be in the $m \gtrsim H$ range. Despite the fact that this bound selects a decaying solution for the corresponding tensor mode, cosmological correlators still carry the imprints of such "fossil" fields. Remarkably, fossil(s) of spin $\geq 1$ generate distinctive anisotropies in observables such as the tensor power spectrum. We show how this plays out in our set-up.Comment: 25 pages, 3 figure

Erratum: Towards a muon collider

The original online version of this article was revised: The additional reference [139] has been added. Tao Han’s ORICD ID has been incorrectly assigned to Chengcheng Han and Chengcheng Han’s ORCID ID to Tao Han. Yang Ma’s ORCID ID has been incorrectly assigned to Lianliang Ma, and Lianliang Ma’s ORCID ID to Yang Ma. The original article has been corrected