Specific forms of the lipid ceramide, synthesized by the ceramide synthase enzyme family, are believed to regulate metabolic physiology. Genetic mouse models have established C16 ceramide as a driver ...of insulin resistance in liver and adipose tissue. C18 ceramide, synthesized by ceramide synthase 1 (CerS1), is abundant in skeletal muscle and suggested to promote insulin resistance in humans. We herein describe the first isoform-specific ceramide synthase inhibitor, P053, which inhibits CerS1 with nanomolar potency. Lipidomic profiling shows that P053 is highly selective for CerS1. Daily P053 administration to mice fed a high-fat diet (HFD) increases fatty acid oxidation in skeletal muscle and impedes increases in muscle triglycerides and adiposity, but does not protect against HFD-induced insulin resistance. Our inhibitor therefore allowed us to define a role for CerS1 as an endogenous inhibitor of mitochondrial fatty acid oxidation in muscle and regulator of whole-body adiposity.
Submandibular Gland Biopsy for the Diagnosis of Parkinson Disease Beach, Thomas G; Adler, Charles H; Dugger, Brittany N ...
Journal of neuropathology and experimental neurology,
2013-February, 2013-Feb, 2013-02-00, 20130201, Letnik:
72, Številka:
2
Journal Article
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ABSTRACTThe clinical diagnosis of Parkinson disease (PD) is incorrect in 30% or more of subjects particularly at the time of symptom onset. Because Lewy-type α-synucleinopathy is present in the ...submandibular glands of PD patients, we assessed the feasibility of submandibular gland biopsy for diagnosing PD. We performed immunohistochemical staining for Lewy-type α-synucleinopathy in sections of large segments (simulating open biopsy) and needle cores of submandibular glands from 128 autopsied and neuropathologically classified subjects, including 28 PD, 5 incidental Lewy body disease, 5 progressive supranuclear palsy (3 with concurrent PD), 3 corticobasal degeneration, 2 multiple system atrophy, 22 Alzheimer disease with Lewy bodies, 16 Alzheimer disease without Lewy bodies, and 50 normal elderly. Immunoreactive nerve fibers were present in large submandibular gland sections of all 28 PD subjects (including 3 that also had progressive supranuclear palsy); 3 Alzheimer disease with Lewy bodies subjects were also positive, but none of the other subjects were positive. Cores from frozen submandibular glands taken with 18-gauge needles (total length, 15–38 mm; between 10 and 118 sections per subject examined) were positive for Lewy-type α-synucleinopathy in 17 of 19 PD patients. These results suggest that biopsy of the submandibular gland may be a feasible means of improving PD clinical diagnostic accuracy. This would be particularly advantageous for subject selection in early-stage clinical trials for invasive therapies or for verifying other biomarker studies.
Through its frequent use, a pattern has emerged showing psychometric limitations of the Difficulties in Emotion Regulation Scale (DERS; Gratz & Roemer,
2004
). This 3-part study sought to (a) ...determine whether these limitations are due to a method effect by rewording all reverse-coded items in a straightforward manner and submitting them to exploratory factor analysis (EFA), and (b) examine the tenability of an adaptation of the original measure. EFA results from Study 1 (N = 743) supported retention of 29 modified items across 5 factors. Consistent with the original theoretical underpinnings of the DERS, Awareness and Clarity items loaded on the same factor. In Study 2 (N = 738), confirmatory factor analysis (CFA) was used to examine the factor structure of the pool of items identified in Study 1. All of the modified subscales clustered strongly with one another and evidenced large loadings on a higher-order emotion regulation construct. These results were replicated in Study 3 (N = 918). Results from Study 3 also provided support for the reliability and validity of scores on the modified version of the DERS (i.e., internal consistency, convergent and criterion-related validity). These findings provide psychometric support for a modified version of the DERS.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, FSPLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Subfertility is one challenge facing the dairy industry as the average Holstein heifer conception rate (HCR), the proportion of heifers that conceive and maintain a pregnancy per breeding, is ...estimated at 55-60%. Of the loci associated with HCR, few have been validated in an independent cattle population, limiting their usefulness for selection or furthering our understanding of the mechanisms involved in successful pregnancy. Therefore, the objectives here were to identify loci associated with HCR: 1) to the first artificial insemination (AI) service (HCR1), 2) to repeated AI services required for a heifer to conceive (TBRD) and 3) to validate loci previously associated with fertility. Breeding and health records from 3359 Holstein heifers were obtained after heifers were bred by AI at observed estrus, with pregnancy determined at day 35 via palpation. Heifer DNA was genotyped using the Illumina BovineHD BeadChip, and genome-wide association analyses (GWAA) were performed with additive, dominant and recessive models using the Efficient Mixed Model Association eXpedited (EMMAX) method with a relationship matrix for two phenotypes. The HCR1 GWAA compared heifers that were pregnant after the first AI service (n = 497) to heifers that were open following the first AI service (n = 405), which included those that never conceived. The TBRD GWAA compared only those heifers which did conceive, across variable numbers of AI service (n = 712). Comparison of loci previously associated with fertility, HCR1 or TBRD were considered the same locus for validation when in linkage disequilibrium (D' > 0.7).
The HCR1 GWAA identified 116, 187 and 28 loci associated (P < 5 × 10
) in additive, dominant and recessive models, respectively. The TBRD GWAA identified 235, 362, and 69 QTL associated (P < 5 × 10
) with additive, dominant and recessive models, respectively. Loci previously associated with fertility were in linkage disequilibrium with 22 loci shared with HCR1 and TBRD, 5 HCR1 and 19 TBRD loci.
Loci associated with HCR1 and TBRD that have been identified and validated can be used to improve HCR through genomic selection, and to better understand possible mechanisms associated with subfertility.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: Chemical toxicity testing is being transformed by advances in biology and computer modeling, concerns over animal use, and the thousands of environmental chemicals lacking toxicity data. ...The U.S. Environmental Protection Agency's ToxCast program aims to address these concerns by screening and prioritizing chemicals for potential human toxicity using in vitro assays and in silico approaches. Objectives: This project aims to evaluate the use of in vitro assays for understanding the types of molecular and pathway perturbations caused by environmental chemicals and to build initial prioritization models of in vivo toxicity. Methods: We tested 309 mostly pesticide active chemicals in 467 assays across nine technologies, including high-throughput cell-free assays and cell-based assays, in multiple human primary cells and cell lines plus rat primary hepatocytes. Both individual and composite scores for effects on genes and pathways were analyzed. Results: Chemicals displayed a broad spectrum of activity at the molecular and pathway levels. We saw many expected interactions, including endocrine and xenobiotic metabolism enzyme activity. Chemicals ranged in promiscuity across pathways, from no activity to affecting dozens of pathways. We found a statistically significant inverse association between the number of pathways perturbed by a chemical at low in vitro concentrations and the lowest in vivo dose at which a chemical causes toxicity. We also found associations between a small set of in vitro assays and rodent liver lesion formation. Conclusions: This approach promises to provide meaningful data on the thousands of untested environmental chemicals and to guide targeted testing of environmental contaminants.
Subfertility is a major issue facing the dairy industry as the average US Holstein cow conception rate (CCR) is approximately 35%. The genetics underlying the physiological processes responsible for ...CCR, the proportion of cows able to conceive and maintain a pregnancy at each breeding, are not well characterized. The objectives of this study were to identify loci, positional candidate genes, and transcription factor binding sites (TFBS) associated with CCR and determine if there was a genetic correlation between CCR and milk production in primiparous Holstein cows. Cows were bred via artificial insemination (AI) at either observed estrus or timed AI and pregnancy status was determined at day 35 post-insemination. Additive, dominant, and recessive efficient mixed model association expedited (EMMAX) models were used in two genome-wide association analyses (GWAA). One GWAA focused on CCR at first service (CCR1) comparing cows that conceived and maintained pregnancy to day 35 after the first AI (n = 494) to those that were open after the first AI (n = 538). The second GWAA investigated loci associated with the number of times bred (TBRD) required for conception in cows that either conceived after the first AI (n = 494) or repeated services (n = 472).
The CCR1 GWAA identified 123, 198, and 76 loci associated (P < 5 × 10
) in additive, dominant, and recessive models, respectively. The TBRD GWAA identified 66, 95, and 33 loci associated (P < 5 × 10
) in additive, dominant, and recessive models, respectively. Four of the top five loci were shared in CCR1 and TBRD for each GWAA model. Many of the associated loci harbored positional candidate genes and TFBS with putative functional relevance to fertility. Thirty-six of the loci were validated in previous GWAA studies across multiple breeds. None of the CCR1 or TBRD associated loci were associated with milk production, nor was their significance with phenotypic and genetic correlations to 305-day milk production.
The identification and validation of loci, positional candidate genes, and TFBS associated with CCR1 and TBRD can be utilized to improve, and further characterize the processes involved in cattle fertility.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Lewy body (LB) diseases, characterized by the aggregation of misfolded α-synuclein proteins, exhibit notable clinical heterogeneity. This may be due to variations in accumulation patterns of ...LB neuropathology. Here we apply a data-driven disease progression model to regional neuropathological LB density scores from 814 brain donors with Lewy pathology. We describe three inferred trajectories of LB pathology that are characterized by differing clinicopathological presentation and longitudinal antemortem clinical progression. Most donors (81.9%) show earliest pathology in the olfactory bulb, followed by accumulation in either limbic (60.8%) or brainstem (21.1%) regions. The remaining donors (18.1%) initially exhibit abnormalities in brainstem regions. Early limbic pathology is associated with Alzheimer’s disease-associated characteristics while early brainstem pathology is associated with progressive motor impairment and substantial LB pathology outside of the brain. Our data provides evidence for heterogeneity in the temporal spread of LB pathology, possibly explaining some of the clinical disparities observed in Lewy body disease.
Employment theoretically serves as a source of informal social control that can promote desistance from crime (Sampson & Laub, 1993). Findings from studies assessing the effects of employment, ...however, have been mixed. In a seminal study, Uggen (2000) reanalyzed data from the National Supported Work (NSW) Demonstration Project and found that employment significantly reduced the rate of recidivism among individuals aged 27 and older but had no impact on younger individuals. We reproduce and replicate Uggen's (2000) findings with data from four distinct employment programs: The National Supported Work Program (1975–1979), the Transitional Aid Research Project (1976–1977), the Employment Services for Ex‐Offenders (1981–1984), and the Enhanced Services for the Hard‐to‐Employ Center for Employment Opportunities (2004–2008). We closely reproduced Uggen's original findings in the NSW but found evidence that the statistically significant interaction between age and employment in the NSW was only present at the year 3 follow‐up and the observed effect is highly sensitive to minor threats to internal validity. Furthermore, a significant age–employment interaction was not observed in the three other data sources. These findings should encourage scholars to continue to investigate the age‐graded nature of employment and crime, especially through a sociohistorical lens.
IMPORTANCE: In most patients, a prodromal period precedes the onset of schizophrenia. Although clinical criteria for identifying the psychosis risk syndrome (PRS) show promising predictive validity, ...assessment of neurophysiologic abnormalities in at-risk individuals may improve clinical prediction and clarify the pathogenesis of schizophrenia. OBJECTIVE: To determine whether P300 event-related potential amplitude, which is deficient in schizophrenia, is reduced in the PRS and associated with clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS: Auditory P300 data were collected as part of the multisite, case-control North American Prodrome Longitudinal Study (NAPLS-2) at 8 university-based outpatient programs. Participants included 552 individuals meeting PRS criteria and 236 healthy controls with P300 data. Auditory P300 data of participants at risk who converted to psychosis (n = 73) were compared with those of nonconverters who were followed up for 24 months and continued to be symptomatic (n = 135) or remitted from the PRS (n = 90). Data were collected from May 27, 2009, to September 17, 2014, and were analyzed from December 3, 2015, to May 1, 2019. MAIN OUTCOMES AND MEASURES: Baseline electroencephalography was recorded during an auditory oddball task. Two P300 subcomponents were measured: P3b, elicited by infrequent target stimuli, and P3a, elicited by infrequent nontarget novel stimuli. RESULTS: This study included 788 participants. The PRS group (n = 552) included 236 females (42.8%) (mean SD age, 19.21 4.38 years), and the healthy control group (n = 236) included 111 females (47.0%) (mean SD age, 20.44 4.73 years). Target P3b and novelty P3a amplitudes were reduced in at-risk individuals vs healthy controls (d = 0.37). Target P3b, but not novelty P3a, was significantly reduced in psychosis converters vs nonconverters (d = 0.26), and smaller target P3b amplitude was associated with a shorter time to psychosis onset in at-risk individuals (hazard ratio, 1.45; 95% CI, 1.04-2.00; P = .03). Participants with the PRS who remitted had baseline target P3b amplitudes that were similar to those of healthy controls and greater than those of converters (d = 0.51) and at-risk individuals who remained symptomatic (d = 0.41). CONCLUSIONS AND RELEVANCE: In this study, deficits in P300 amplitude appeared to precede psychosis onset. Target P3b amplitudes, in particular, may be sensitive to clinical outcomes in the PRS, including both conversion to psychosis and clinical remission. Auditory target P3b amplitude shows promise as a putative prognostic biomarker of clinical outcome in the PRS.
To update the ASCO adjuvant endocrine therapy guideline based on emerging data concerning the benefits and risks of ovarian suppression in addition to standard adjuvant therapy in premenopausal women ...with estrogen receptor-positive breast cancer.
ASCO convened an Update Panel and conducted a systematic review of randomized clinical trials investigating ovarian suppression.
Two trials investigating the addition of ovarian suppression to tamoxifen did not show an overall clinical benefit for ovarian suppression. Nonetheless, the addition of ovarian suppression to standard adjuvant therapy with tamoxifen or with an aromatase inhibitor improved disease-free survival and improved freedom from breast cancer and distant recurrence compared with tamoxifen alone among the subset of patients who were at sufficient risk for recurrence such that adjuvant chemotherapy was warranted. Compared with tamoxifen alone, ovarian suppression was associated with a substantial increase in menopausal symptoms, sexual dysfunction, and diminished quality of life.
The Panel recommends that higher-risk patients should receive ovarian suppression in addition to adjuvant endocrine therapy, whereas lower-risk patients should not. Women with stage II or III breast cancers who would ordinarily be advised to receive adjuvant chemotherapy should receive ovarian suppression with endocrine therapy. The panel recommends that some women with stage I or II breast cancers at higher risk of recurrence who might consider chemotherapy may also be offered ovarian suppression with endocrine therapy. Women with stage I breast cancers not warranting chemotherapy should not receive ovarian suppression, nor should women with node-negative cancers 1 cm or less. Ovarian suppression may be administered with either tamoxifen or an aromatase inhibitor. Additional information is available at www.asco.org/guidelines/endocrinebreast and www.asco.org/guidelineswiki.
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