Peripheral myelin protein 22 (PMP22) is highly expressed in myelinating Schwann cells of the peripheral nervous system.
genetic alterations cause the most common forms of Charcot-Marie-Tooth disease ...(CMTD), which is characterized by severe dysmyelination in the peripheral nerves. However, the functions of PMP22 in Schwann cell membranes remain unclear. We demonstrate that reconstitution of purified PMP22 into lipid vesicles results in the formation of compressed and cylindrically wrapped protein-lipid vesicles that share common organizational traits with compact myelin of peripheral nerves in vivo. The formation of these myelin-like assemblies depends on the lipid-to-PMP22 ratio, as well as on the PMP22 extracellular loops. Formation of the myelin-like assemblies is disrupted by a CMTD-causing mutation. This study provides both a biochemical assay for PMP22 function and evidence that PMP22 directly contributes to membrane organization in compact myelin.
KCNQ1 (also known as KV7.1 or KVLQT1) is a voltage-gated potassium channel modulated by members of the KCNE protein family. Among multiple functions, KCNQ1 plays a critical role in the cardiac action ...potential. This channel is also subject to inherited mutations that cause certain cardiac arrhythmias and deafness. In this study, we report the overexpression, purification, and preliminary structural characterization of the voltage-sensor domain (VSD) of human KCNQ1 (Q1-VSD). Q1-VSD was expressed in Escherichia coli and purified into lyso-palmitoylphosphatidylglycerol micelles, conditions under which this tetraspan membrane protein yields excellent nuclear magnetic resonance (NMR) spectra. NMR studies reveal that Q1-VSD shares a common overall topology with other channel VSDs, with an S0 helix followed by transmembrane helices S1–S4. The exact sequential locations of the helical spans do, however, show significant variations from those of the homologous segments of previously characterized VSDs. The S4 segment of Q1-VSD was seen to be α-helical (with no 310 component) and underwent rapid backbone amide H–D exchange over most of its length. These results lay the foundation for more advanced structural studies and can be used to generate testable hypotheses for future structure–function experiments.
Full text
Available for:
IJS, KILJ, NUK, PNG, UL, UM
KCNQ1 (Q1) is a voltage-gated potassium channel that is modulated by members of the KCNE family, the best-characterized being KCNE1 (E1) and KCNE3 (E3). The Q1/E1 complex generates a channel with ...delayed activation and increased conductance. This complex is expressed in cardiomyocytes where it provides the I
Ks
current that is critical for the repolarization phase of the cardiac action potential. The Q1/E3 complex, on the other hand, is expressed in epithelial cells of the colon and stomach, where it serves as a constitutively active leak channel to help maintain water and ion homeostasis. Studies show the single transmembrane segments (TMS) present in both E1 and E3 are essential to their distinct functions. More specifically, residues FTL located near the middle of the E1 TMS are essential for the delayed activation of Q1, while the corresponding TVG sites in E3 are critical for constitutive activation of the channel. Swapping these three residues leads to the switching of the functional properties for both Q1/E1
FTL→TVG
and Q1/E3
TVG→FTL
complexes. This work details the backbone assignments and chemical shifts for the E1
FTL→TVG
mutant, as determined using a suite of 3D NMR experiments along with specific and inverse amino acid isotopic labeling. The completed assignments can be used, in conjunction with other NMR experiments, to generate a 3D structure of E1
FTL→TVG
. The results of TALOS-N analysis of the chemical shifts are reported here. The E1
FTL→TVG
structure will be compared to the already available E1 and E3 structures to determine the roles that their TMS triplet motifs play in each protein to dictate their distinct channel-modulatory functions.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
As a steady source of juvenile delinquents and an incubator for future adult offenders, the youth gang has long been a focus of attention, from their origins and prevalence to intervention and ...prevention strategies. But while delinquent youth form gangs worldwide, youth gang research has generally focused on the U.S. Youth Gangs in International Perspective provides a needed corrective by offering significant studies from across Europe, as well as Trinidad-Tobago and Israel. The book spans the diversity of the field in the cultural and scholarly traditions represented and methods used, analyzing not only the social processes under which gangs operate and cohere, but also the evolution of the research base, starting with the Eurogang Programs definition of the term youth gang. Cross-national and gender issues are discussed, as are measurement concerns and the possibility that the American conception of the youth gang is impeding European understanding of these groups. Among the topics covered: Gang dynamics through the lens of social identity theory.Defining gangs in youth correctional settings.Gang gender composition and youth delinquency.From Stockholm: a holistic approach to gang intervention.Gang membership as a turning point in the life course.The impact of globalization, immigration, and social process on neo-Nazi youth gangs. Filling a critical gap in the literature, Youth Gangs in International Perspective will find a wide audience among criminologists, policymakers specializing in youth crime, and researchers and graduate students in criminology, political science, and youth studies.
Full text
Available for:
FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
IMPORTANCE: Ocular hypertension is an important risk factor for the development of primary open-angle glaucoma (POAG). Data from long-term follow-up can be used to inform the management of patients ...with ocular hypertension. OBJECTIVE: To determine the cumulative incidence and severity of POAG after 20 years of follow-up among participants in the Ocular Hypertension Treatment Study. DESIGN, SETTING, AND PARTICIPANTS: Participants in the Ocular Hypertension Treatment Study were followed up from February 1994 to December 2008 in 22 clinics. Data were collected after 20 years of follow-up (from January 2016 to April 2019) or within 2 years of death. Analyses were performed from July 2019 to December 2020. INTERVENTIONS: From February 28, 1994, to June 2, 2002 (phase 1), participants were randomized to receive either topical ocular hypotensive medication (medication group) or close observation (observation group). From June 3, 2002, to December 30, 2008 (phase 2), both randomization groups received medication. Beginning in 2009, treatment was no longer determined by study protocol. From January 7, 2016, to April 15, 2019 (phase 3), participants received ophthalmic examinations and visual function assessments. MAIN OUTCOMES AND MEASURES: Twenty-year cumulative incidence and severity of POAG in 1 or both eyes after adjustment for exposure time. RESULTS: A total of 1636 individuals (mean SD age, 55.4 9.6 years; 931 women 56.9%; 1138 White participants 69.6%; 407 Black/African American participants 24.9%) were randomized in phase 1 of the clinical trial. Of those, 483 participants (29.5%) developed POAG in 1 or both eyes (unadjusted incidence). After adjusting for exposure time, the 20-year cumulative incidence of POAG in 1 or both eyes was 45.6% (95% CI, 42.3%-48.8%) among all participants, 49.3% (95% CI, 44.5%-53.8%) among participants in the observation group, and 41.9% (95% CI, 37.2%-46.3%) among participants in the medication group. The 20-year cumulative incidence of POAG was 55.2% (95% CI, 47.9%-61.5%) among Black/African American participants and 42.7% (95% CI, 38.9%-46.3%) among participants of other races. The 20-year cumulative incidence for visual field loss was 25.2% (95% CI, 22.5%-27.8%). Using a 5-factor baseline model, the cumulative incidence of POAG among participants in the low-, medium-, and high-risk tertiles was 31.7% (95% CI, 26.4%-36.6%), 47.6% (95% CI, 41.6%-53.0%), and 59.8% (95% CI, 53.1%-65.5%), respectively. CONCLUSIONS AND RELEVANCE: In this study, only one-fourth of participants in the Ocular Hypertension Treatment Study developed visual field loss in either eye over long-term follow-up. This information, together with a prediction model, may help clinicians and patients make informed personalized decisions about the management of ocular hypertension. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00000125.
Comparison of the genomes and proteomes of the two diptera Anopheles gambiae and Drosophila melanogaster, which diverged about 250 million years ago, reveals considerable similarities. However, ...numerous differences are also observed; some of these must reflect the selection and subsequent adaptation associated with different ecologies and life strategies. Almost half of the genes in both genomes are interpreted as orthologs and show an average sequence identity of about 56%, which is slightly lower than that observed between the orthologs of the pufferfish and human (diverged about 450 million years ago). This indicates that these two insects diverged considerably faster than vertebrates. Aligned sequences reveal that orthologous genes have retained only half of their intron/exon structure, indicating that intron gains or losses have occurred at a rate of about one per gene per 125 million years. Chromosomal arms exhibit significant remnants of homology between the two species, although only 34% of the genes colocalize in small "microsyntenic" clusters, and major interarm transfers as well as intra-arm shuffling of gene order are detected.
Full text
Available for:
BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
PDF
