Biology subjects

Lordan, R.

Publications and source records attributed to Lordan, R..

3 recordsLinked to original sources

bioRxiv2024

A survey of the mentor-mentee relationship in early career research (ECR): Implications for publishing and career advancement in the STEMM disciplines

Early career researchers (ECRs) are the most abundant workforce in the fields of science, technology, engineering, mathematics, and medicine (STEMM). ECRs are generally mentored by experienced principal investigators (PIs) who direct the research objectives. The ECR mentee- mentor partnership can be mutually beneficial, but it is a critical relationship for ECRs with implications for publishing and career development. In this study, a mixed methods approach involving a survey, X polls (formally Twitter), and semi-structured interviews were used to determine how the ECR mentor-mentee relationship affects ECRs and their perceptions of career development in STEMM. To address this aim, two main research questions were developed: (1) Who do the STEMM ECR mentees and mentors currently perceive to be ECRs? and (2) What characteristics of the ECR mentee-mentor relationship are perceived to be important for ECR publishing practices and career progression? The main survey findings indicate that respondents largely from the life sciences and health field and they consider Ph.D. researchers and postdoctoral researchers as ECRs, but mentors also to a greater extent than mentees perceive new PIs (< 2 years experiences) as ECRs. Survey respondents also mostly agree on publishing practices regarding journal selection criteria such as journal scope and impact factor, although mentees appear to favor journal prestige and open access publishing more than mentors. This is likely due to the importance of visibility early in ones career. Mentees take the lead in preparing manuscripts for submission, although a minority have described issues regarding authorship disputes. Finally, setting clear expectations, being collegial, mutually respectful, and having regular communication was identified by survey respondents and interviewees as integral features of a healthy ECR mentee- mentor relationship. In conclusion, the mentee-mentor relationship is critically important for ECR career development, and the findings of this study have wider implications for the development of effective ECR mentee and mentor training programs across the STEMM disciplines.

scientific communication and education↗

bioRxiv2024

Brown adipose tissue thermogenesis rhythms are driven by the SCN independent of adipocyte clocks

Circadian misalignment has been associated with obesity both in rodents and humans. Brown adipose tissue (BAT) thermogenesis contributes to energy expenditure and can be activated in adults to reduce body weight. Although previous studies suggest control of BAT thermogenesis by the circadian clock, the site and mechanisms of regulation remain unclear. We used mice with genetic disruption of the circadian clock in the suprachiasmatic nucleus (SCN) and peripheral tissues to delineate their role in BAT thermogenesis. Global post-natal deletion of Bmal1 in adult mice (Bmal1-/-) abolishes the rhythms of interscapular BAT temperature, a measure of thermogenesis, while normal locomotor activity rhythms are maintained under a regular 12h light-12h dark schedule. Activation of thermogenesis either by exposure to cold or adrenergic stimulation of BAT displays a diurnal rhythm with higher activation during the active period. Both the rhythm and the magnitude of the thermogenic response is preserved in Bmal1-/- mice. In contrast to mice with global deletion of Bmal1, mice with brown adipocyte (Ucp1-Bmal1-/-) or brown and white adipocyte (Ad-Bmal1-/-) deletion of Bmal1 show intact rhythms of BAT thermogenic activity. The capacity of Ucp1-Bmal1-/- mice to activate thermogenesis in response to exposure to cold is identical to WT mice, independent of time of stimulation. Circadian rhythmicity of interscapular BAT temperature is lost in mice with SCN deletion of Bmal1 (SCN-Bmal1-/-), indicating control of BAT thermogenesis rhythms by the SCN. Control mice exhibit rhythmic BAT glucose and fatty acid uptake - a rhythm that is not recapitulated in Bmal1-/- and SCN-Bmal1-/- mice but is present in Ucp1-Bmal1-/- and Ad-Bmal1-/- mice. BAT cAMP and phosphorylated hormone-sensitive lipase (pHSL) is reduced during the active period in Bmal1-/- and SCN-Bmal1-/- mice consistent with reduced sympathetic tone. Furthermore, sympathetic denervation of BAT ablates BAT temperature rhythms in WT mice. Taken together, our findings suggest that the SCN drives rhythms of BAT thermogenesis through adipocyte clock-independent, sympathetic signaling to the BAT.

physiology↗

bioRxiv2024

Disruption of the PGE2 synthesis / response pathway restrains atherogenesis in programmed cell death-1 (Pd-1) deficient hyperlipidemic mice

Immune checkpoint inhibitors (ICIs) that target programmed cell death 1 (PD-1) have revolutionized cancer treatment by enabling the restoration of suppressed T-cell cytotoxic responses. However, resistance to single-agent ICIs limits their clinical utility. Combinatorial strategies enhance their antitumor effects, but may also enhance the risk of immune related adverse effects of ICIs. Prostaglandin (PG) E2, formed by the sequential action of the cyclooxygenase (COX) and microsomal PGE synthase (mPGES-1) enzymes, acting via its E prostanoid (EP) receptors, EPr2 and EPr4, promotes lymphocyte exhaustion, revealing an additional target for ICIs. Thus, COX inhibitors and EPr4 antagonists are currently being combined with ICIs potentially to enhance antitumor efficacy in clinical trials. However, given the cardiovascular (CV) toxicity of COX inhibitors, such combinations may increase the risk particularly of CV AEs. Here, we compared the impact of distinct approaches to disruption of the PGE2 synthesis /response pathway - global or myeloid cell specific depletion of mPges-1 or global depletion of Epr4 - on the accelerated atherogenesis in Pd-1 deficient hyperlipidemic (Ldlr-/-) mice. All strategies restrained the atherogenesis. While depletion of mPGES-1 suppresses PGE2 biosynthesis, reflected by its major urinary metabolite, PGE2 biosynthesis was increased in mice lacking EPr4, consistent with enhanced expression of aortic Cox-1 and mPges-1. Deletions of mPges-1 and Epr4 differed in their effects on immune cell populations in atherosclerotic plaques; the former reduced neutrophil infiltration, while the latter restrained macrophages and increased the infiltration of T-cells. Consistent with these findings, chemotaxis by bone-marrow derived macrophages from Epr4-/- mice was impaired. Epr4 depletion also resulted in extramedullary lymphoid hematopoiesis and inhibition of lipoprotein lipase activity (LPL) with coincident spelenomegaly, leukocytosis and dyslipidemia. Targeting either mPGES-1 or EPr4 may restrain lymphocyte exhaustion while mitigating CV irAEs consequent to PD-1 blockade.

pharmacology and toxicology↗