Meiotic recombination starts with the formation of DNA double-strand breaks (DSBs) at specific genomic locations that correspond to PRDM9-binding sites. The molecular steps occurring from PRDM9 ...binding to DSB formation are unknown. Using proteomic approaches to find PRDM9 partners, we identified HELLS, a member of the SNF2-like family of chromatin remodelers. Upon functional analyses during mouse male meiosis, we demonstrated that HELLS is required for PRDM9 binding and DSB activity at PRDM9 sites. However, HELLS is not required for DSB activity at PRDM9-independent sites. HELLS is also essential for 5-hydroxymethylcytosine (5hmC) enrichment at PRDM9 sites. Analyses of 5hmC in mice deficient for SPO11, which catalyzes DSB formation, and in PRDM9 methyltransferase deficient mice reveal that 5hmC is triggered at DSB-prone sites upon PRDM9 binding and histone modification, but independent of DSB activity. These findings highlight the complex regulation of the chromatin and epigenetic environments at PRDM9-specified hotspots.
Background: Neurogenic thoracic outlet syndrome typically presents with paresthesia, pain, and impaired strength in the neck, shoulder, and arm, and is typically a diagnosis of exclusion. This ...condition is caused by compression of the brachial plexus, typically by a bony or soft tissue anomaly present congenitally and influenced by repetitive motion or significant trauma. Treatment typically involves removal of the first rib and anterior scalene to decompress the thoracic outlet and relieve stress to the brachial plexus if the patient has failed conservative treatment with physical therapy and lifestyle modifications. Case Presentation: We present a case of neurogenic thoracic outlet syndrome with arterial compression treated surgically via a transaxillary first rib and cervical rib resection in a patient with bilateral cervical ribs and osteochondromas of the ribs.
Purpose
Adrenocortical carcinoma (ACC) is a rare, aggressive cancer; complete surgical resection offers the best chance for long-term survival. The impact of surgical margin status on survival is ...poorly understood. Our objective was to determine the association of margin status with survival.
Methods
Patients with ACC were identified from the National Cancer Data Base, 1998–2012, and stratified based on surgical margin status (negative vs. microscopically positive + vs. macroscopically +). Univariate/multivariate regression/survival analyses were utilized to determine factors associated with margin status and overall survival (OS).
Results
A total of 1553 patients underwent surgery at 589 institutions: 86% had negative, 12% microscopically (+), and 2% macroscopically (+) margins. Those with microscopically (+) and macroscopically (+) margins more often received adjuvant chemotherapy (39.4% macroscopically (+) vs. 38.5% microscopically (+) vs. 25.2% negative margins,
p
< 0.001). For unadjusted analysis, there was a significant difference in OS between the groups (log-rank
p
< 0.001), with median survival times of 58 months (95% confidence interval CI 49–66) for those with negative margins, 22 months (95% CI 18–34) microscopically (+), and 14 months (95% CI 6–27) macroscopically (+) margins. After adjustment, both microscopically (+) (HR 1.76,
p
< 0.001) and macroscopically (+) (HR 2.10,
p
= 0.0019) margin status were associated with compromised survival.
Conclusions
Having micro- or macroscopically (+) margin status after ACC resection is associated with dose-dependent compromised survival. These results underscore the importance of achieving negative surgical margins for optimizing long-term patient outcomes.
This study sought to measure the impact on all-cause death or readmission of adding center-based exercise training (ET) to disease management programs for patients with a recent acute heart failure ...(HF) hospitalization.
ET is recommended for patients with HF, but evidence is based mainly on ET as a single intervention in stable outpatients.
A randomized, controlled trial with blinded outcome assessor, enrolling adult participants with HF discharged from 5 hospitals in Queensland, Australia. All participants received HF-disease management program plus supported home exercise program; intervention participants were offered 24 weeks of supervised center-based ET. Primary outcome was all-cause 12-month death or readmission. Pre-planned subgroups included age (<70 years vs. older), sex, left ventricular ejection fraction (≤40% vs. >40%), and exercise adherence.
Between May 2008 and July 2013, 278 participants (140 intervention, 138 control) were enrolled: 98 (35.3%) age ≥70 years, 71 (25.5%) females, and 62 (23.3%) with a left ventricular ejection fraction of >40%. There were no adverse events associated with ET. There was no difference in primary outcome between groups (84 of 140 60.0% intervention vs. 90 of 138 65.2% control; p = 0.37), but a trend toward greater benefit in participants age <70 years (OR: 0.56 95% CI: 0.30 to 1.02 vs. OR: 1.56 95% CI: 0.67 to 3.64; p for interaction = 0.05). Participants who exercised to guidelines (72 of 101 control and 92 of 117 intervention at 3 months) had a significantly lower rate of death and readmission (91 of 164 55.5% vs. 41 of 54 75.9%; p = 0.008).
Supervised center-based ET was a safe, feasible addition to disease management programs with supported home exercise in patients recently hospitalized with acute HF, but did not reduce combined end-point of death or readmission. (A supervised exercise programme following hospitalisation for heart failure: does it add to disease management?; ACTRN12608000263392).
Host restriction factors play key roles in innate antiviral defense, but it remains poorly understood which of them restricts HIV-1 in vivo. Here, we used single-cell transcriptomic analysis to ...identify host factors associated with HIV-1 control during acute infection by correlating host gene expression with viral RNA abundance within individual cells. Wide sequencing of cells from one participant with the highest plasma viral load revealed that intracellular viral RNA transcription correlates inversely with expression of the gene
, which encodes prothymosin α. This association was genome-wide significant (
< 0.05) and was validated in 28 additional participants from Thailand and the Americas with HIV-1 CRF01_AE and subtype B infections, respectively. Overexpression of prothymosin α in vitro confirmed that this cellular factor inhibits HIV-1 transcription and infectious virus production. Our results identify prothymosin α as a host factor that restricts HIV-1 infection in vivo, which has implications for viral transmission and cure strategies.
Treatment for HIV has relied on the use of antiretroviral agents that can be subject to the development of resistant viruses. The study of inhibitors directed against cellular proteins required for ...HIV replication is therefore of growing interest. Inducible T cell kinase (ITK) is a Tec family tyrosine kinase that regulates T cell receptor (TCR)-induced activation of PLCγ-1, Ca²⁺ mobilization and transcription factor activation, and actin rearrangement downstream of both TCR and chemokine receptors. Because productive infection of T cells with HIV requires T cell activation, chemokine receptors and actin reorganization, we asked whether ITK affects HIV infection using ITK-specific siRNA, a kinase-inactive ITK mutant or an ITK inhibitor. We demonstrate that loss of ITK function resulted in marked reductions in intracellular p24 levels upon HIV infection. Loss of ITK function after establishment of HIV infection also decreased virus spread within the culture. Inhibition of ITK did not affect expression of the HIV coreceptors CD4 or CXCR4 but partially blocked HIV viral entry, an effect that correlated with decreased actin polarization to gp120. Additionally, ITK was required for efficient HIV transcription, and overexpression of ITK increased both viral transcription and virus-like particle formation. Our data suggest that inhibition of ITK blocks HIV infection by affecting multiple steps of HIV replication.
Striacosta albicosta is a crop pest that causes economic damage in the United States and Canada. Only maize and dry beans are shown to be suitable hosts, since larval development is incomplete on ...other hosts. The objective of this study was to describe the developmental parameters of immature stages of S. albicosta feeding on dry beans, non-Bt, Cry1F, and Vip3A maize. For Vip3A, mortality was 100% after 24 h. Larvae feeding on non-Bt maize had the highest larval survival (70.6%) compared to the other hosts. Maize expressing Cry1F had higher survival (31.3%) than dry beans (26.0%). Larvae feeding on dry beans had a significantly faster total development time (74.8 days), compared to 92.5 days for non-Bt and 96.2 days for Cry1F. All larvae developed through seven instars. Pupae from larvae that had fed on non-Bt maize were significantly heavier than pupae from other hosts. An understanding of S. albicosta immature development on various host plants is needed to improve recommendations for effective scouting, treatment timing, and economic thresholds. Differential development can result in an extended adult emergence period, and possibly result in assortative mating between Bt susceptible and resistant populations, which violates the assumption of random mating necessary for current resistance management strategies for Bt maize. Therefore, understanding the impact of host plant and transgenic traits on aspects of pest biology will aid in developing effective integrated pest management and insect resistance management strategies for this pest.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Background
The rates of overweight and obesity are high among United States Veterans, necessitating the development of accessible weight reduction interventions.
Purpose
This observational study ...evaluated the efficacy of a novel home-based telehealth weight loss intervention (TeleMOVE) for Veterans with obesity.
Methods
We obtained weight measures of 171 patients before and after one and two 90-day cycles of TeleMOVE.
Results
Enrollment in the first 90-day cycle of TeleMOVE was associated with significant weight loss (M = 8.62 lbs, SD = 9.85). Those who subsequently enrolled in the second, identical, cycle lost significantly more weight overall (M = 11.68 lbs, SD = 12.53) than those who only enrolled in the first cycle (M = 5.55 lbs, SD = 8.23). However, this difference was due to two-cycle participants losing significantly more weight during the first cycle alone (M = 10.52, SD = 10.32).
Conclusions
TeleMOVE is a promising intervention, warranting a further investigation of its efficacy.
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