Freedmannorup3714

Collectively, these data highlight the critical nature of glutamine transport for WNT-induced osteoblast differentiation.This article has an associated First Person interview with the joint first authors of the paper.Defective intracellular trafficking and export of microRNAs (miRNAs) have been observed in growth-retarded mammalian cells having impaired mitochondrial potential and dynamics. selleck products Here, we found that uncoupling protein 2 (Ucp2)-mediated depolarization of mitochondrial membrane also results in progressive sequestration of miRNAs within polysomes and lowers their release via extracellular vesicles. Interestingly, the impaired miRNA-trafficking process in growth-retarded human cells could be reversed in the presence of Genipin, an inhibitor of Ucp2. Mitochondrial detethering of endoplasmic reticulum (ER), observed in cells with depolarized mitochondria, was found to be responsible for defective compartmentalization of translation initiation factor eIF4E to polysomes attached to ER. This caused a retarded translation process accompanied by enhanced retention of miRNAs and target mRNAs within ER-attached polysomes to restrict extracellular export of miRNAs. Reduced compartment-specific activity of the mammalian target of rapamycin complex 1 (mTORC1), the master regulator of protein synthesis, in cells with defective mitochondria or detethered ER, caused reduced phosphorylation of eIF4E-BP1 and prevented eIF4E targeting to ER-attached polysomes and miRNA export. These data suggest how mitochondrial membrane potential and dynamics, by affecting mTORC1 activity and compartmentalization, determine the subcellular localization and export of miRNAs.The ability of a mother to produce a nutritionally complete neonatal food source has provided a powerful evolutionary advantage to mammals. Milk production by mammary epithelial cells is adaptive, its release is exquisitely timed, and its own glandular stagnation with the permanent cessation of suckling triggers the cell death and tissue remodeling that enables female mammals to nurse successive progeny. Chemical and mechanical signals both play a role in this process. However, despite this duality of input, much remains unknown about the nature and function of mechanical forces in this organ. Here, we characterize the force landscape in the functionally mature gland and the capacity of luminal and basal cells to experience and exert force. We explore molecular instruments for force-sensing, in particular channel-mediated mechanotransduction, revealing increased expression of Piezo1 in mammary tissue in lactation and confirming functional expression in luminal cells. We also reveal, however, that lactation and involution proceed normally in mice with luminal-specific Piezo1 deletion. These findings support a multifaceted system of chemical and mechanical sensing in the mammary gland, and a protective redundancy that ensures continued lactational competence and offspring survival.Misassembled nuclear pore complexes (NPCs) are removed by sealing off the surrounding nuclear envelope (NE), which is conducted by the endosomal sorting complexes required for transport (ESCRT) machinery. Recruitment of ESCRT proteins to the NE is mediated by the interaction between the ESCRT member Chm7 and the inner nuclear membrane protein Heh1, which belongs to the conserved LEM family. Increased ESCRT recruitment results in excessive membrane scission at damage sites but its regulation remains poorly understood. Here, we show that Hub1-mediated alternative splicing of HEH1 pre-mRNA, resulting in production of its shorter form Heh1-S, is critical for the integrity of the NE in Saccharomyces cerevisiae ESCRT-III mutants lacking Hub1 or Heh1-S display severe growth defects and accumulate improperly assembled NPCs. This depends on the interaction of Chm7 with the conserved MSC domain, which is only present in the longer variant Heh1-L. Heh1 variants assemble into heterodimers, and we demonstrate that a unique splice segment in Heh1-S suppresses growth defects associated with the uncontrolled interaction between Heh1-L and Chm7. Together, our findings reveal that Hub1-mediated splicing generates Heh1-S to regulate ESCRT recruitment to the NE.This article has an associated First Person interview with the first author of the paper.In invertebrates, UNC-45 regulates myosin stability and functions. Vertebrates have two distinct isoforms of the protein UNC-45B, expressed in muscle cells only, and UNC-45A, expressed in all cells and implicated in regulating both non-muscle myosin II (NMII)- and microtubule (MT)-associated functions. Here, we show that, in vitro and in human and rat cells, UNC-45A binds to the MT lattice, leading to MT bending, breakage and depolymerization. Furthermore, we show that UNC-45A destabilizes MTs independent of its C-terminal NMII-binding domain and even in the presence of the NMII inhibitor blebbistatin. These findings identified UNC-45A as a novel type of MT-severing protein with a dual non-mutually exclusive role in regulating NMII activity and MT stability. Because many human diseases, from cancer to neurodegenerative diseases, are caused by or associated with deregulation of MT stability, our findings have profound implications in the biology of MTs, as well as the biology of human diseases and possible therapeutic implications for their treatment.This article has an associated First Person interview with the joint first authors of the paper.Golgi stacks are the basic structural units of the Golgi. Golgi stacks are separated from each other and scattered in the cytoplasm of Drosophila cells. Here, we report that the ARF-GEF inhibitor Brefeldin A (BFA) induces the formation of BFA bodies, which are aggregates of Golgi stacks, trans-Golgi networks and recycling endosomes. Recycling endosomes are located in the centers of BFA bodies, while Golgi stacks surround them on their trans sides. link2 Live imaging of S2 cells revealed that Golgi stacks repeatedly merged and separated on their trans sides, and BFA caused successive merger by inhibiting separation, forming BFA bodies. S2 cells carrying genome-edited BFA-resistant mutant Sec71M717L did not form BFA bodies at high concentrations of BFA; S2 cells carrying genome-edited BFA-hypersensitive mutant Sec71F713Y produced BFA bodies at low concentrations of BFA. These results indicate that Sec71 is the sole BFA target for BFA body formation and controls Golgi stack separation. Finally, we showed that impairment of Sec71 in fly photoreceptors induces BFA body formation, with accumulation of both apical and basolateral cargoes, resulting in inhibition of polarized transport.

The Childhood Health Assessment Questionnaire (CHAQ), though widely used for assessments in pediatric rheumatology, has drawbacks, including low correlation to disease activity and ceiling effects. We sought to determine if any tools from the Patient Reported Outcomes Measurement Information System (PROMIS) improve on these shortcomings and/or are preferred by patients.

Patients 5-17 years of age, with childhood arthritis (JIA) or juvenile dermatomyositis (JDM) were recruited from the rheumatology clinics at a Canadian children's hospital. Participants completed the CHAQ, 3 PROMIS measures (pain interference, mobility, and physical activity), and underwent a standard clinical assessment.

52 patients participated, 25 with JIA and 27 with JDM. None of the PROMIS measures suffered from ceiling effects, while the CHAQ disability index (DI) and pain visual analog scales both did, with 50% and 20% of patients achieving the best possible scores respectively. The PROMIS mobility was moderately correlated CHAQ DI (r

= -0.60, 95%CI = -0.75--0.40) and the PROMIS pain interference was strongly correlated to the CHAQ pain score (r

= 0.65, 95%CI = 0.43-0.80). No measures correlated with disease activity. Patients preferred the PROMIS to the CHAQ.

The PROMIS pain interference, mobility and physical activity measures improve in some areas where the CHAQ is weak they do not suffer from ceiling effects and patients prefer the PROMIS tools. More work is needed to determine the correlation and responsiveness of the PROMIS tools to changes in disease activity over time before they should be widely adopted for clinical use.

The PROMIS pain interference, mobility and physical activity measures improve in some areas where the CHAQ is weak they do not suffer from ceiling effects and patients prefer the PROMIS tools. More work is needed to determine the correlation and responsiveness of the PROMIS tools to changes in disease activity over time before they should be widely adopted for clinical use.We sincerely thank Dr. Masi, et al for their comments in response to our manuscript, "Entheseal Changes in Response to Age, Body Mass Index and Physical Activity An Ultrasound (US) study in Healthy People"1,2 Our study had demonstrated that US changes within the enthesis are associated with older age, higher BMI, physical activity, and male sex.

Patient self-report scales are invaluable in psoriatic arthritis (PsA), as they allow physicians to rapidly assess patient perspectives of disease activity. We aimed to assess the agreement of the visual analog scale (VAS), a 100-mm horizontal line, and the numerical rating scale (NRS), a 21-point scale ranging from 0 to 10 in increments of 0.5, in patients with PsA.

Data were collected prospectively across 3 UK hospital trusts from 2018 to 2019. All patients completed the VAS and NRS for pain, arthritis, skin psoriasis (PsO), and global disease activity. A subset completed an identical pack 1 week later. Demographic and clinical data were also collected. Agreement was assessed using medians and the Bland-Altman method. Intraclass correlation coefficients (ICCs) were used to assess test-retest reliability. Spearman rank correlation coefficients were used to assess dependency between scale scores and clinical variables.

Two hundred ten patients completed the study; 1 withdrew consent. Thus, 209 were analyzed. For pain, arthritis, skin PsO, and global disease activity, the difference between the VAS and NRS lay mostly within 1.96 SD of the mean, suggesting reasonable agreement between the 2 scales. Among the patients, 64.1% preferred the NRS. The ICCs demonstrated excellent test-retest reliability for both VAS and NRS. Higher VAS and NRS scores were associated with increased tender/swollen joint count, poorer functional status, and greater life impact.

The VAS and NRS show reasonable agreement in key patient-reported outcomes in PsA. link3 Results from both scales are correlated with disease severity and life impact.

The VAS and NRS show reasonable agreement in key patient-reported outcomes in PsA. Results from both scales are correlated with disease severity and life impact.

RA patients with diabetes might have worse clinical outcomes and adverse events compared to non-diabetes patients. We evaluated the effects of diabetes on HAQ (Health Assessment Questionnaire) change and outpatient infection in RA patients.

Using the ACR's Rheumatology Informatics System for Effectiveness (RISE) EHR-based registry, we identified RA patients who had ≥1 rheumatologist visit with a HAQ measured (index visit) in 2016, ≥1 previous visit, and a subsequent outcome visit with same HAQ measured at 12 months (± 3 months). We identified diabetes by diagnosis codes, medications, or lab values. Outpatient infection was defined by diagnosis codes or anti-infective medications. We calculated mean HAQ change and incidence rate (IR) of outpatient infections among patients with and without diabetes. Generalized linear models and Cox regression were used to calculate the adjusted mean HAQ change and hazard ratios (HR).

We identified 3,853 RA patients with diabetes and 18,487 without diabetes. The mean HAQ change between index and outcome visit among diabetes patients was 0.