We conducted a systematic review and meta‐analysis analysing the existing data on transcutaneous electrical nerve stimulation (TENS) or interferential current (IFC) for chronic low back pain (CLBP) ...and/or neck pain (CNP) taking into account intensity and timing of stimulation, examining pain, function and disability. Seven electronic databases were searched for TENS or IFC treatment in non‐specific CLBP or CNP. Four reviewers independently selected randomized controlled trials (RCTs) of TENS or IFC intervention in adult individuals with non‐specific CLBP or CNP. Primary outcomes were for self‐reported pain intensity and back‐specific disability. Two reviewers performed quality assessment, and two reviewers extracted data using a standardized form. Nine RCTs were selected (eight CLBP; one CNP), and seven studies with complete data sets were included for meta‐analysis (655 participants). For CLBP, meta‐analysis shows TENS/IFC intervention, independent of time of assessment, was significantly different from placebo/control (p < 0.02). TENS/IFC intervention was better than placebo/control, during therapy (p = 0.02), but not immediately after therapy (p = 0.08), or 1–3 months after therapy (p = 0.99). Analysis for adequate stimulation parameters was not significantly different, and there was no effect on disability. This systematic review provides inconclusive evidence of TENS benefits in low back pain patients because the quality of the studies was low, and adequate parameters and timing of assessment were not uniformly used or reported. Without additional high‐quality clinical trials using sufficient sample sizes and adequate parameters and outcome assessments, the outcomes of this review are likely to remain unchanged.
Significance
These data highlight the need for additional high‐quality RCTs to examine the effects of TENS in CLBP. Trials should consider intensity of stimulation, timing of outcome assessment and assessment of pain, disability and function.
Centromeres are defined by the presence of chromatin containing the histone H3 variant, CENP-A, whose assembly into nucleosomes requires the chromatin assembly factor HJURP. We find that whereas ...surface-exposed residues in the CENP-A targeting domain (CATD) are the primary sequence determinants for HJURP recognition, buried CATD residues that generate rigidity with H4 are also required for efficient incorporation into centromeres. HJURP contact points adjacent to the CATD on the CENP-A surface are not used for binding specificity but rather to transmit stability broadly throughout the histone fold domains of both CENP-A and H4. Furthermore, an intact CENP-A/CENP-A interface is a requirement for stable chromatin incorporation immediately upon HJURP-mediated assembly. These data offer insight into the mechanism by which HJURP discriminates CENP-A from bulk histone complexes and chaperones CENP-A/H4 for a substantial portion of the cell cycle prior to mediating chromatin assembly at the centromere.
► The CENP-A targeting domain (CATD) houses the residues that confer HJURP binding ► HJURP transmits stability to CENP-A/H4 prior to chromatin assembly ► CENP-A hydrophobic stitch residues are required for incorporation at centromeres ► CENP-A assembly at centromeres requires an intact CENP-A/CENP-A interface
Using a combination of cell-based and biophysical approaches, Bassett et al. show that HJURP, the chromatin assembly factor for centromere-specifying histone H3 variant CENP-A, recognizes specific discontinuous surface residues on the histone. HJURP binding confers stability to CENP-A/histone H4 and, together with an intact CENP-A/CENP-A interface, allows for centromere assembly.
The initial and the terminal three enzymes of the mammalian haem biosynthetic pathway are nuclear encoded, cytoplasmically synthesized and post-translationally translocated into the mitochondrion. ...The first enzyme, ALAS (5-aminolaevulinate synthase), occurs as an isoenzyme encoded on different chromosomes and is synthesized either as a housekeeping protein (ALAS-1) in all non-erythroid cell types, or only in differentiating erythroid precursor cells (ALAS-2). Both ALAS proteins possess mitochondrial targeting sequences that have putative haem-binding motifs. In the present study, evidence is presented demonstrating that two haem-binding motifs in the leader sequence, as well as one present in the N-terminus of the mature ALAS-1 function in vivo in the haem-regulated translocation of ALAS-1. Coproporphyrinogen oxidase, the antepenultimate pathway enzyme, possesses a leader sequence that is approx. 120 residues long. In contrast with an earlier report suggesting that only 30 residues were required for translocation of the coproporphyrinogen oxidase, we report that the complete leader is necessary for translocation and that this process is not haem-sensitive in vivo. PPO (protoporphyrinogen oxidase) lacks a typical mitochondrial targeting leader sequence and was found to be effectively targeted by just 17 N-terminal residues. Bacillus subtilis PPO, which is very similar to human PPO at its N-terminal end, is not targeted to the mitochondrion when expressed in mammalian cells, demonstrating that the translocation is highly specific with regard to both the length and spacing of charged residues in this targeting region. Ferrochelatase, the terminal enzyme, possesses a typical N-terminal leader sequence and no evidence of a role for the C-terminus was found in mitochondrial targeting.
Achieving a quantitative and predictive understanding of 3D genome architecture remains a major challenge, as it requires quantitative measurements of the key proteins involved. Here, we report the ...quantification of CTCF and cohesin, two causal regulators of topologically associating domains (TADs) in mammalian cells. Extending our previous imaging studies (Hansen et al., 2017), we estimate bounds on the density of putatively DNA loop-extruding cohesin complexes and CTCF binding site occupancy. Furthermore, co-immunoprecipitation studies of an endogenously tagged subunit (Rad21) suggest the presence of cohesin dimers and/or oligomers. Finally, based on our cell lines with accurately measured protein abundances, we report a method to conveniently determine the number of molecules of any Halo-tagged protein in the cell. We anticipate that our results and the established tool for measuring cellular protein abundances will advance a more quantitative understanding of 3D genome organization, and facilitate protein quantification, key to comprehend diverse biological processes.
The 2020–2021 academic year brought numerous challenges to teachers across the country as they worked to educate students amidst the COVID-19 pandemic. The current study is a secondary data analysis ...of qualitative responses collected as part of a teacher survey to evaluate a social emotional learning curriculum implemented during the 2020–2021 academic year. The lived experiences of teachers (
N
= 52) across 11 elementary schools in the Great Plains region were captured through open-ended questions as the teachers transitioned from in-person to remote learning. A phenomenological approach was utilized to analyze the challenges expressed by teachers as they faced instability and additional professional demands. Given that stress and other factors that strain mental health exist within multiple layers of an individual's social ecology, a modified social-ecological framework was used to organize the results and themes. Findings suggest that during the academic year, teachers experienced stressors related to their personal and professional roles, concerns for students’ well-being which extended beyond academics, and frustrations with administration and other institutional entities around COVID safety measures. Without adequate support and inclusion of teacher perspectives, job-related stress may lead to teacher shortages, deterioration of teacher mental health, and ultimately worse outcomes for students. Implications for policy, research, and practice are discussed.
The FHWA laboratory also plans to test technologies developed through the Connected Vehicle Program sponsored by the U.S. Department of Transportation's Intelligent Transportation Systems Joint ...Program Office.
The epigenetic mark of the centromere is thought to be a unique centromeric nucleosome that contains the histone H3 variant, centromere protein‐A (CENP‐A). The deposition of new centromeric ...nucleosomes requires the CENP‐A‐specific chromatin assembly factor HJURP (Holliday junction recognition protein). Crystallographic and biochemical data demonstrate that the Scm3‐like domain of HJURP binds a single CENP‐A–histone H4 heterodimer. However, several lines of evidence suggest that HJURP forms an octameric CENP‐A nucleosome. How an octameric CENP‐A nucleosome forms from individual CENP‐A/histone H4 heterodimers is unknown. Here, we show that HJURP forms a homodimer through its C‐terminal domain that includes the second HJURP_C domain. HJURP exists as a dimer in the soluble preassembly complex and at chromatin when new CENP‐A is deposited. Dimerization of HJURP is essential for the deposition of new CENP‐A nucleosomes. The recruitment of HJURP to centromeres occurs independent of dimerization and CENP‐A binding. These data provide a mechanism whereby the CENP‐A pre‐nucleosomal complex achieves assembly of the octameric CENP‐A nucleosome through the dimerization of the CENP‐A chaperone HJURP.
Whether centromeric nucleosomes are hemisomes, or consist of canonical histone octamers with two CENP‐A subunits, is still unresolved. Obligatory dimerization of the CENP‐A assembly chaperone HJURP now provides support for the latter possibility.
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