Time-restricted feeding (TRF) is a form of intermittent fasting that involves having a longer daily fasting period. Preliminary studies report that TRF improves cardiometabolic health in rodents and ...humans. Here, we performed the first study to determine how TRF affects gene expression, circulating hormones, and diurnal patterns in cardiometabolic risk factors in humans. Eleven overweight adults participated in a 4-day randomized crossover study where they ate between 8 am and 2 pm (early TRF (eTRF)) and between 8 am and 8 pm (control schedule). Participants underwent continuous glucose monitoring, and blood was drawn to assess cardiometabolic risk factors, hormones, and gene expression in whole blood cells. Relative to the control schedule, eTRF decreased mean 24-hour glucose levels by 4 ± 1 mg/dl (
= 0.0003) and glycemic excursions by 12 ± 3 mg/dl (
= 0.001). In the morning before breakfast, eTRF increased ketones, cholesterol, and the expression of the stress response and aging gene
and the autophagy gene
(all
< 0.04), while in the evening, it tended to increase brain-derived neurotropic factor (BNDF;
= 0.10) and also increased the expression of
(
= 0.007), a major nutrient-sensing protein that regulates cell growth. eTRF also altered the diurnal patterns in cortisol and the expression of several circadian clock genes (
< 0.05). eTRF improves 24-hour glucose levels, alters lipid metabolism and circadian clock gene expression, and may also increase autophagy and have anti-aging effects in humans.
In market operations, distributed generators (DGs) and price-sensitive loads participate in a microgrid energy market implemented in JADE. Each DG and each price-sensitive load is represented by the ...respective agents which perform various functions such as scheduling, coordination and market clearing subject to system, DG and load constraints. Each agent is assigned to one of the several agent objectives which maximizes either DG or load surpluses or both. In simulated operation of a microgrid, hourly power reference signals and load control signals from JADE are passed to DG and load models developed in MATLAB/Simulink using MACSimJX. Simulated operation of DGs and loads are studied by performing simulations under different agent objectives. Results from simulation studies demonstrate the effectiveness of implementing multi-agent system (MAS) in the distributed management of microgrids.
Although CEO commitment is recognized as being crucial to organizational diversity efforts, we know little about how CEOs signal their priorities and mobilize key organizational actors to implement ...diversity management. We tested an integrative model in which CEO beliefs about diversity were theorized to predict the implementation of organizational diversity practices through two consecutive mediating steps—via greater CEO engagement in pro-diversity behavior, and in turn, higher perceived CEO commitment by their HR manager. In this model, we also proposed a moderating effect such that when CEOs have less positive beliefs about diversity, CEOs espousing higher moral values will display greater pro-diversity behavior. Results supported the proposed model. Taken together, our findings indicate that a CEO's words and actions alone are not sufficient for the implementation of diversity management practices. HR managers must view their CEOs as being committed to workplace diversity in order for diversity management practices to be implemented.
This research investigates how top management team national diversity (TMTND) and corporate social responsibility (CSR) institutional uncertainty affect strategic CSR focus in foreign-owned ...subsidiaries. The paper develops a theoretical framework based on institutional theory and upper echelon perspectives to test a sample of MNE subsidiaries. Survey data were collected from subsidiaries in Thailand and Taiwan. Non-symmetric analysis suggests that while TMTND plays an important role in establishing a CSR focus, it is not conducive in itself to high-performance outcomes. Performance is measured by market share, sales growth, and profitability for each subsidiary. The results also show that there are notable differences between the subsidiaries located in Thailand and Taiwan as to what extent CSR strategic focus and top management team national diversity are relevant for high-performance outcomes. The study demonstrates that the links between CSR, TMTND, and subsidiary performance are much more complex than previously assumed.
Anaphylaxis is an acute, potential life-threatening systemic allergic reaction that may have a wide range of clinical manifestations. Severe anaphylaxis and/or the need for repeated doses of ...epinephrine to treat anaphylaxis are risk factors for biphasic anaphylaxis. Antihistamines and/or glucocorticoids are not reliable interventions to prevent biphasic anaphylaxis, although evidence supports a role for antihistamine and/or glucocorticoid premedication in specific chemotherapy protocols and rush aeroallergen immunotherapy. Evidence is lacking to support the role of antihistamines and/or glucocorticoid routine premedication in patients receiving low- or iso-osmolar contrast material to prevent recurrent radiocontrast media anaphylaxis. Epinephrine is the first-line pharmacotherapy for uniphasic and/or biphasic anaphylaxis. After diagnosis and treatment of anaphylaxis, all patients should be kept under observation until symptoms have fully resolved. All patients with anaphylaxis should receive education on anaphylaxis and risk of recurrence, trigger avoidance, self-injectable epinephrine education, referral to an allergist, and be educated about thresholds for further care.
Purpose This study investigated the career expectations and priorities of members of the "millennial" generation (born in or after 1980) and explored differences among this cohort related to ...demographic factors (i. e., gender, race, and year of study) and academic performance. Design/Methodology/Approach Data were obtained from a national survey of millennial undergraduate university students from across Canada (N = 23,413). Data were analyzed using various multivariate techniques to assess the impacts of demographic variables and academic achievement on career expectations and priorities. Findings Millennial placed the greatest importance on individualistic aspects of a job. They had realistic expectations of their first job and salary but were seeking rapid advancement and the development of new skills, while also ensuring a meaningful and satisfying life outside of work. Our results suggest that Millennials' expectations and values vary by gender, visible minority status, GPA, and year of study, but these variables explain only a small proportion of variance. Implications Changing North American demographics have created a crisis in organizations as they strive to recruit and retain the millennial generation, who purportedly hold values, attitudes, and expectations that are significantly different from those of the generations of workers that preceded them. A better understanding of the Millennials' career expectations and priorities helps employers to create job offerings and work environments that are more likely to engage and retain millennial workers. Originality/Value This is a large-sample study that provides benchmark results for the millennial generation, which can be compared to results from other generational cohorts, and to millennial cohorts in the future as they progress through their life-cycle. This is one of the few studies that examines demographic heterogeneity within the millennial cohort.
Few therapeutic options exist for the highly aggressive triple negative breast cancers (TNBCs). In this study, we report that a contextual synthetic lethality can be achieved both in vitro and in ...vivo with combined EGFR and PARP inhibition with lapatinib and ABT-888, respectively. The mechanism involves a transient DNA double strand break repair deficit induced by lapatinib and subsequent activation of the intrinsic pathway of apoptosis. Further dissection of the mechanism reveals that EGFR and BRCA1 can be found in the same protein complex, which is reduced by lapatinib. Interestingly, lapatinib also increases cytosolic BRCA1 and EGFR, away from their nuclear DNA repair substrates. Taken together, these results reveal a novel regulation of homologous recombination repair involving EGFR and BRCA1 interaction and alteration of subcellular localization. Additionally, a contextual synthetic lethality may exist between combined EGFR and PARP inhibitors.
Poly(ADP-ribose) polymerases (PARPs) are DNA-dependent nuclear enzymes that transfer negatively charged ADP-ribose moieties from cellular nicotinamide-adenine-dinucleotide (NAD(+)) to a variety of ...protein substrates, altering protein-protein and protein-DNA interactions. The most studied of these enzymes is poly(ADP-ribose) polymerase-1 (PARP-1), which is an excellent therapeutic target in cancer due to its pivotal role in the DNA damage response. Clinical studies have shown susceptibility to PARP inhibitors in DNA repair defective cancers with only mild adverse side effects. Interestingly, additional studies are emerging which demonstrate a role for this therapy in DNA repair proficient tumors through a variety of mechanisms. In this review, we will discuss additional functions of PARP-1 - including regulation of inflammatory mediators, cellular energetics and death pathways, gene transcription, sex hormone- and ERK-mediated signaling, and mitosis - and the role these PARP-1-mediated processes play in oncogenesis, cancer progression, and the development of therapeutic resistance. As PARP-1 can act in both a pro- and anti-tumor manner depending on the context, it is important to consider the global effects of this protein in determining when, and how, to best use PARP inhibitors in anticancer therapy.
Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) in germline ...(g)
/
mutation carriers. Olaparib Expanded, an investigator-initiated, phase II study, assessed olaparib response in patients with MBC with somatic (s)
/
mutations or g/s mutations in homologous recombination (HR)-related genes other than
2.
Eligible patients had MBC with measurable disease and germline mutations in non-
/
HR-related genes (cohort 1) or somatic mutations in these genes or
/
(cohort 2). Prior PARPi, platinum-refractory disease, or progression on more than two chemotherapy regimens (metastatic setting) was not allowed. Patients received olaparib 300 mg orally twice a day until progression. A single-arm, two-stage design was used. The primary endpoint was objective response rate (ORR); the null hypothesis (≤ 5% ORR) would be rejected within each cohort if there were four or more responses in 27 patients. Secondary endpoints included clinical benefit rate and progression-free survival (PFS).
Fifty-four patients enrolled. Seventy-six percent had estrogen receptor-positive HER2-negative disease. Eighty-seven percent had mutations in
s
/
,
or
. In cohort 1, ORR was 33% (90% CI, 19% to 51%) and in cohort 2, 31% (90% CI, 15% to 49%). Confirmed responses were seen only with g
(ORR, 82%) and s
/
(ORR, 50%) mutations. Median PFS was 13.3 months (90% CI, 12 months to not available/computable NA) for g
and 6.3 months (90% CI, 4.4 months to NA) for s
/
mutation carriers. No responses were observed with
or
mutations alone.
PARP inhibition is an effective treatment for patients with MBC and g
or s
/
mutations, significantly expanding the population of patients with breast cancer likely to benefit from PARPi beyond g
/
mutation carriers. These results emphasize the value of molecular characterization for treatment decisions in MBC.
Purpose
– Popular literature argues that successive generations are experiencing more job changes and changes of employer. The “new careers” literature also proposes that career mobility patterns are ...becoming more diverse as people engage in more downward and lateral job changes and changes of occupation. The purpose of this paper is to test these assertions by comparing the career mobility patterns across four generations of workers.
Design/methodology/approach
– The authors analyzed the career mobility patterns of four generations of Canadian professionals (n=2,555): Matures (born prior to 1946); Baby Boomers (1946-1964); Generation Xers (1965-1979) and Millennials (1980 or later). Job mobility, organizational mobility and the direction of job moves were compared across groups through analysis of variance.
Findings
– Significant differences were observed in job mobility and organizational mobility of the various generations, with younger generations being more mobile. However, despite significant environmental shifts, the diversity of career patterns has not undergone a significant shift from generation to generation.
Originality/value
– This is the first quantitative study to examine shifting career mobility patterns across all four generations in today’s workplace. The authors extend previous research on generational differences in job mobility by using novel measures of career mobility that are more precise than extant measures.
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