Perilipin (Peri) A is a phosphoprotein located at the surface of intracellular lipid droplets in adipocytes. Activation of cyclic AMP-dependent protein kinase (PKA) results in the phosphorylation of ...Peri A and hormone-sensitive lipase (HSL), the predominant lipase in adipocytes, with concurrent stimulation of adipocyte lipolysis. To investigate the relative contributions of Peri A and HSL in basal and PKA-mediated lipolysis, we utilized NIH 3T3 fibroblasts lacking Peri A and HSL but stably overexpressing acyl-CoA synthetase 1 (ACS1) and fatty acid transport protein 1 (FATP1). When incubated with exogenous fatty acids, ACS1/FATP1 cells accumulated 5 times more triacylglycerol (TG) as compared with NIH 3T3 fibroblasts. Adenoviral-mediated expression of Peri A in ACS1/FATP1 cells enhanced TG accumulation and inhibited lipolysis, whereas expression of HSL fused to green fluorescent protein (GFPHSL) reduced TG accumulation and enhanced lipolysis. Forskolin treatment induced Peri A hyperphosphorylation and abrogated the inhibitory effect of Peri A on lipolysis. Expression of a mutated Peri AΔ3 (Ser to Ala substitutions at PKA consensus sites Ser-81, Ser-222, and Ser-276) reduced Peri A hyperphosphorylation and blocked constitutive and forskolin-stimulated lipolysis. Thus, perilipin expression and phosphorylation state are critical regulators of lipid storage and hydrolysis in ACS1/FATP1 cells.
Few studies have investigated risk factors for recurrence of blunt traumatic abdominal wall hernias (TAWH).
Twenty trauma centers identified repaired TAWH from January 2012 to December 2018. Logistic ...regression was used to investigate risk factors for recurrence.
TAWH were repaired in 175 patients with 21 (12.0%) known recurrences. No difference was found in location, defect size, or median time to repair between the recurrence and non-recurrence groups. Mesh use was not protective of recurrence. Female sex, injury severity score (ISS), emergency laparotomy (EL), and bowel resection were associated with hernia recurrence. Bowel resection remained significant in a multivariable model.
Female sex, ISS, EL, and bowel resection were identified as risk factors for hernia recurrence. Mesh use and time to repair were not associated with recurrence. Surgeons should be mindful of these risk factors but could attempt acute repair in the setting of appropriate physiologic parameters.
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•Bowel resection is a recurrence risk factor in blunt traumatic abdominal wall hernias.•Time to repair and mesh use are not associated with recurrence.•Early repair of these injuries is feasible.
Virtual encounters have experienced an exponential rise amid the current COVID-19 crisis. This abrupt change, seen in response to unprecedented medical and environmental challenges, has been forced ...upon the orthopaedic community. However, such changes to adopting virtual care and technology were already in the evolution forecast, albeit in an unpredictable timetable impeded by regulatory and financial barriers. This adoption is not meant to replace, but rather augment established, traditional models of care while ensuring patient/provider safety, especially during the pandemic. While our department, like those of other institutions, has performed virtual care for several years, it represented a small fraction of daily care. The pandemic required an accelerated and comprehensive approach to the new reality. Contemporary literature has already shown equivalent safety and patient satisfaction, as well as superior efficiency and reduced expenses with musculoskeletal virtual care (MSKVC) versus traditional models. Nevertheless, current literature detailing operational models of MSKVC is scarce. The current review describes our pre-pandemic MSKVC model and the shift to a MSKVC pandemic workflow that enumerates the conceptual workflow organization (patient triage, from timely care provision based on symptom acuity/severity to a continuum that includes future follow-up). Furthermore, specific setup requirements (both resource/personnel requirements such as hardware, software, and network connectivity requirements, and patient/provider characteristics respectively), and professional expectations are outlined. MSKVC has already become a pivotal element of musculoskeletal care, due to COVID-19, and these changes are confidently here to stay. Readiness to adapt and evolve will be required of individual musculoskeletal clinical teams as well as organizations, as established paradigms evolve.
Cite this article: Bone Joint Open 2020;1-6:272–280.
We describe a method for measuring the integrated Comptonization (Y sub(SZ)) of clusters of galaxies from measurements of the Sunyaev-Zel'dovich (SZ) effect in multiple frequency bands and use this ...method to characterize a sample of galaxy clusters detected in the South Pole Telescope (SPT) data. We use a Markov Chain Monte Carlo method to fit a beta -model source profile and integrate Y sub(SZ) within an angular aperture on the sky. In simulated observations of an SPT-like survey that include cosmic microwave background anisotropy, point sources, and atmospheric and instrumental noise at typical SPT-SZ survey levels, we show that we can accurately recover beta -model parameters for inputted clusters. We measure Y sub(SZ) for simulated semi-analytic clusters and find that Y sub(SZ) is most accurately determined in an angular aperture comparable to the SPT beam size. We demonstrate the utility of this method to measure Y sub(SZ) and to constrain mass scaling relations using X-ray mass estimates for a sample of 18 galaxy clusters from the SPT-SZ survey. Measuring Y sub(SZ) within a 0'.75 radius aperture, we find an intrinsic log-normal scatter of 21% + or - 11% in Y sub(SZ) at a fixed mass. Measuring Y sub(SZ) within a 0.3 Mpc projected radius (equivalent to 0'.75 at the survey median redshift z = 0.6), we find a scatter of 26% + or - 9%. Prior to this study, the SPT observable found to have the lowest scatter with mass was cluster detection significance. We demonstrate, from both simulations and SPT observed clusters that Y sub(SZ) measured within an aperture comparable to the SPT beam size is equivalent, in terms of scatter with cluster mass, to SPT cluster detection significance.
Nonribosomal peptide synthetases (NRPSs) are multidomain modular biosynthetic assembly lines that polymerize amino acids into a myriad of biologically active nonribosomal peptides (NRPs). NRPS ...thioesterase (TE) domains employ diverse release strategies for off-loading thioester-tethered polymeric peptides from termination modules typically via hydrolysis, aminolysis, or cyclization to provide mature antibiotics as carboxylic acids/esters, amides, and lactams/lactones, respectively. Here we report the enzyme-catalyzed formation of a highly strained β-lactone ring during TE-mediated cyclization of a β-hydroxythioester to release the antibiotic obafluorin (Obi) from an NRPS assembly line. The Obi NRPS (ObiF) contains a type I TE domain with a rare catalytic cysteine residue that plays a direct role in β-lactone ring formation. We present a detailed genetic and biochemical characterization of the entire Obi biosynthetic gene cluster in plant-associated Pseudomonas fluorescens ATCC 39502 that establishes a general strategy for β-lactone biogenesis.
A number of mutations in genes that encode ubiquitously expressed RNA-binding proteins cause tissue specific disease. Many of these diseases are neurological in nature revealing critical roles for ...this class of proteins in the brain. We recently identified mutations in a gene that encodes a ubiquitously expressed polyadenosine RNA-binding protein, ZC3H14 (Zinc finger CysCysCysHis domain-containing protein 14), that cause a nonsyndromic, autosomal recessive form of intellectual disability. This finding reveals the molecular basis for disease and provides evidence that ZC3H14 is essential for proper brain function. To investigate the role of ZC3H14 in the mammalian brain, we generated a mouse in which the first common exon of the ZC3H14 gene, exon 13 is removed (Zc3h14Δex13/Δex13) leading to a truncated ZC3H14 protein. We report here that, as in the patients, Zc3h14 is not essential in mice. Utilizing these Zc3h14Δex13/Δex13mice, we provide the first in vivo functional characterization of ZC3H14 as a regulator of RNA poly(A) tail length. The Zc3h14Δex13/Δex13 mice show enlarged lateral ventricles in the brain as well as impaired working memory. Proteomic analysis comparing the hippocampi of Zc3h14+/+ and Zc3h14Δex13/Δex13 mice reveals dysregulation of several pathways that are important for proper brain function and thus sheds light onto which pathways are most affected by the loss of ZC3H14. Among the proteins increased in the hippocampi of Zc3h14Δex13/Δex13 mice compared to control are key synaptic proteins including CaMK2a. This newly generated mouse serves as a tool to study the function of ZC3H14 in vivo.
Abstract
We derive cosmological constraints using a galaxy cluster sample selected from the 2500 deg
2
SPT-SZ survey. The sample spans the redshift range 0.25 <
z
< 1.75 and contains 343 clusters ...with SZ detection significance
ξ
> 5. The sample is supplemented with optical weak gravitational lensing measurements of 32 clusters with 0.29 <
z
< 1.13 (from Magellan and
Hubble Space Telescope
) and X-ray measurements of 89 clusters with 0.25 <
z
< 1.75 (from
Chandra
). We rely on minimal modeling assumptions: (i) weak lensing provides an accurate means of measuring halo masses, (ii) the mean SZ and X-ray observables are related to the true halo mass through power-law relations in mass and dimensionless Hubble parameter
E
(
z
) with a priori unknown parameters, and (iii) there is (correlated, lognormal) intrinsic scatter and measurement noise relating these observables to their mean relations. We simultaneously fit for these astrophysical modeling parameters and for cosmology. Assuming a flat
ν
ΛCDM model, in which the sum of neutrino masses is a free parameter, we measure Ω
m
= 0.276 ± 0.047,
σ
8
= 0.781 ± 0.037, and
σ
8
(Ω
m
/0.3)
0.2
= 0.766 ±0.025. The redshift evolutions of the X-ray
Y
X
–mass and
M
gas
–mass relations are both consistent with self-similar evolution to within 1
σ
. The mass slope of the
Y
X
–mass relation shows a 2.3
σ
deviation from self-similarity. Similarly, the mass slope of the
M
gas
–mass relation is steeper than self-similarity at the 2.5
σ
level. In a
νw
CDM cosmology, we measure the dark energy equation-of-state parameter
w
= −1.55 ± 0.41 from the cluster data. We perform a measurement of the growth of structure since redshift
z
∼ 1.7 and find no evidence for tension with the prediction from general relativity. This is the first analysis of the SPT cluster sample that uses direct weak-lensing mass calibration and is a step toward using the much larger weak-lensing data set from DES. We provide updated redshift and mass estimates for the SPT sample.
Diffuse large B‐cell lymphoma (DLBCL) is the most common haematopoietic malignancy in dogs. Recently, MYC and BCL2 expression levels determined with immunohistochemistry (IHC) were found to be ...prognostic in people with DLBCL. We hypothesized that canine DLBCL can be similarly subdivided into prognostic subtypes based on expression of MYC and BCL2. Cases of canine DLBCL treated with CHOP chemotherapy were retrospectively collected and 43 dogs had available histologic tissue and complete clinical follow‐up. Median values of percent immunoreactive versus immunonegative cells were used to determine positive or negative expression status. Completion of CHOP was significantly associated with a positive outcome. Compared with human patients, our canine DLBCL patients had high IHC expression of both MYC and BCL2, and relative expression levels of one or both markers were not associated with clinical outcome.
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