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Excess levels of circulating androgens during prenatal or peripubertal development are an important cause of polycystic ovary syndrome (PCOS), with the brain being a key target. Approximately half of the women diagnosed with PCOS also experience metabolic syndrome; common features including obesity, insulin resistance and hyperinsulinemia. Although a large amount of clinical and preclinical evidence has confirmed this relationship between androgens and the reproductive and metabolic features of PCOS, the mechanisms by which androgens cause this dysregulation are unknown. Neuron‐specific androgen receptor knockout alleviates some PCOS‐like features in a peripubertal dihydrotestosterone (DHT) mouse model, but the specific neuronal populations mediating these effects are undefined. A candidate population is the agouti‐related peptide (AgRP)‐expressing neurons, which are important for both reproductive and metabolic function. We used a well‐characterised peripubertal androgenized mouse model and Cre‐loxP transgenics to investigate whether deleting androgen receptors specifically from AgRP neurons can alleviate the induced reproductive and metabolic dysregulation. Androgen receptors were co‐expressed in 66% of AgRP neurons in control mice, but only in <2% of AgRP neurons in knockout mice. The number of AgRP neurons was not altered by the treatments. Only 20% of androgen receptor knockout mice showed rescue of DHT‐induced androgen‐induced anovulation and acyclicity. Furthermore, androgen receptor knockout did not rescue metabolic dysfunction (body weight, adiposity or glucose and insulin tolerance). While we cannot rule out developmental compensation in our model, these results suggest peripubertal androgen excess does not markedly influence Agrp expression and does not dysregulate reproductive and metabolic function through direct actions of androgens onto AgRP neurons. [ABSTRACT FROM AUTHOR]

An individual's nutritional status has a powerful effect on sexual maturation. Puberty onset is delayed in response to chronic energy insufficiency and is advanced under energy abundance. The consequences of altered pubertal timing for human health are profound. Late puberty increases the chances of cardiometabolic, musculoskeletal and neurocognitive disorders, whereas early puberty is associated with increased risks of adult obesity, type 2 diabetes mellitus, cardiovascular diseases and various cancers, such as breast, endometrial and prostate cancer. Kennedy and Mitra's trailblazing studies, published in 1963 and using experimental models, were the first to demonstrate that nutrition is a key factor in puberty onset. Building on this work, the field has advanced substantially in the past decade, which is largely due to the impressive development of molecular tools for experimentation and population genetics. In this Review, we discuss the latest advances in basic and translational sciences underlying the nutritional and metabolic control of pubertal development, with a focus on perspectives and future directions. Key papers on the role of nutrition and metabolic cues in puberty timing were published in 1963, and there have been many advances in this field in the subsequent 60 years. This Review discusses the latest advances in basic and translational sciences underlying the nutritional and metabolic control of pubertal development. Key points: In 1963, Kennedy and Mitra published a seminal study in rats demonstrating that body weight is a major determinant of pubertal timing. An increasing incidence of earlier ages at puberty has been documented; early pubertal timing favours the occurrence of type 2 diabetes mellitus, cardiovascular diseases and certain cancers in adulthood. Macronutrients and hormones that modulate growth and/or signal adipose tissue mass serve as metabolic cues conveying the nutritional status and stored energy available for sexual maturation, differentiation and growth. The effect of metabolic cues on puberty is mediated by neural targets upstream of GnRH neurons; considerable progress in defining the neuronal circuitry and glial components has been achieved. A number of molecular pathways and epigenetic mechanisms have been identified as primary components in the modulation of pubertal timing by hormones and nutritional cues. [ABSTRACT FROM AUTHOR]

Reproductive function is critical for species survival; however, it is energetically costly and physically demanding. Reproductive suppression is therefore a physiologically appropriate adaptation to certain ecological, environmental, and/or temporal conditions. This 'allostatic' suppression of fertility enables individuals to accommodate unfavorable reproductive circumstances and safeguard survival. The mechanisms underpinning this reproductive suppression are complex, yet culminate with the reduced secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus, which in turn suppresses gonadotropin release from the pituitary, thereby impairing gonadal function. The focus of this review will be on the role of RFamide-related peptide (RFRP) neurons in different examples of allostatic reproductive suppression. RFRP neurons release the RFRP-3 peptide, which negatively regulates GnRH neurons and thus appears to act as a 'brake' on the neuroendocrine reproductive axis. In a multitude of predictable (e.g., pre-puberty, reproductive senescence, and seasonal or lactational reproductive quiescence) and unpredictable (e.g., metabolic, immune and/or psychosocial stress) situations in which GnRH secretion is suppressed, the RFRP neurons have been suggested to act as modulators. This review examines evidence for and against these roles. [ABSTRACT FROM AUTHOR]

The article presents the results of the survey of the law of professional responsibility in Indiana from August 2021 to September 2022. Also cited are the per curiam rulings by the state's Supreme Court imposing sanctions for lawyer misconduct, the need for civility in both trials and disciplinary proceedings, and the application of the Rules of Professional Conduct to common ethical dilemmas.

Polycystic ovary syndrome (PCOS) is one of the most common causes of infertility in women. Approximately half of the diagnosed individuals also experience the metabolic syndrome. Central and peripheral resistance to the hormones insulin and leptin have been reported to contribute to both metabolic and reproductive dysregulation. In PCOS and preclinical PCOS animal models, circulating insulin and leptin levels are often increased in parallel with the development of hormone resistance; however, it remains uncertain whether these changes contribute to the PCOS state. In this study, we tested whether central actions of protein tyrosine phosphatase 1B (PTP1B) and suppressor of cytokine signaling 3 (SOCS3), negative regulators of insulin and leptin signaling pathways, respectively, play a role in the development of PCOS-like phenotype. A peripubertal dihydrotestosterone (DHT) excess PCOS-like mouse model was used, which exhibits both metabolic and reproductive dysfunction. Mice with knockout of the genes encoding PTP1B and SOCS3 from forebrain neurons were generated, and metabolic and reproductive functions were compared between knockout and control groups. DHT treatment induced mild insulin resistance but not leptin resistance, so the role of SOCS3 could not be tested. As expected, DHT excess abolished estrous cycles and corpora lutea presence and caused increased visceral adiposity and fasting glucose levels. Knockout mice did not show any rescue of reproductive dysfunction but did have reduced adiposity compared to the control DHT mice. These data suggest that negative regulation of central insulin signaling by PTP1B is not responsible for peripubertal DHT excess-induced reproductive impairments but may mediate its increased adiposity effects. [ABSTRACT FROM AUTHOR]

Objectives: To identify behavioral, preferential, and professional factors influencing the use of amalgam in private practices; and to compare the incidence of the placement of amalgam versus composite resin restorations in the province of Ontario and its pedagogical implications on dental curricula. Methods: Participants responded anonymously to a 23‐question online survey about their current use of dental amalgam and composite resins as well as their opinions regarding both dental materials. The explanatory variables were associated bivariately with the outcome variables, and the most significant predictors were identified using the multivariate analysis. Results: Higher percentages of amalgam use were reported among clinicians who trained in Canada only (P =.009), who graduated before 1980 (p = <.001) and who work outside private practice (p = <.001). Familiarity with amalgam was higher among clinicians who are female (p = <.001), older (p = <.001), trained only in Canada (p =.017), who graduated prior to 2000 (p = <.001), and who work in locations with populations over 100,000 (p =.042). Familiarity with composite resin was higher among clinicians who graduated more recently (p =.002). A higher percentage of females (p = <.001), younger clinicians (p = <.001), recent graduates (p = <.001), and clinicians who work in private practice (p =.043) suggested that over 50% of dental student training time be allocated to amalgam. Conclusions: Decreased amalgam use was reported by later dental graduates and private practitioners; this may be impacted by familiarity with dental amalgam. As amalgam remains a safe and effective dental material, its removal may not be prudent. Dental educators play a crucial role in the future of amalgam opinion and use. [ABSTRACT FROM AUTHOR]

In Fall 2020, all universities in Alberta went with remote delivery of classes due to COVID-19 restrictions. This provided not only teaching challenges, but also opportunities. Professors at three Canadian universities teaching similar undergraduate courses in international political economy decided to use the challenges/opportunities of COVID-19 restrictions to experiment with a World Trade Organization (WTO) simulation across three campuses through remote delivery. Simulations are frequently used for teaching in political science, but what was unusual was doing it through remote delivery. This paper assesses the effectiveness of the experiment. It traces the origins/evolution of the idea, learning objectives for the students, preparation by the professors to design the WTO simulation, and the experience of the actual simulation. It also addresses the challenges (technological, timing, assignments, grading, student anxiety, etc.). In addition, it identifies the steps that were taken to reduce and mitigate the challenges. It also acknowledges the mistakes that were made by the professors in designing and implementing the assignment. These observations and reflections are informed by the materials that the professors prepared, their thoughts on the experience, and the feedback from participating students (through official student evaluations as well as a special survey instrument). It provides lessons for future online simulations. [ABSTRACT FROM AUTHOR]

The RF-amide peptides comprise a family of neuropeptides that includes the kisspeptin (Kp), the natural ligand of kisspeptin receptor (Kiss1r), and the RFamide-related peptide 3 (RFRP-3) that binds preferentially to the neuropeptide FF receptor 1 (Npffr1). Kp stimulates prolactin (PRL) secretion through the inhibition of tuberoinfundibular dopaminergic (TIDA) neurons. Because Kp also has affinity to Npffr1, we investigated the role of Npffr1 in the control of PRL secretion by Kp and RFRP-3. Intracerebroventricular (ICV) injection of Kp increased PRL and LH secretion in ovariectomized, estradiol-treated rats. The unselective Npffr1 antagonist RF9 prevented these responses, whereas the selective antagonist GJ14 altered PRL but not LH levels. The ICV injection of RFRP-3 in ovariectomized, estradiol-treated rats increased PRL secretion, which was associated with a rise in the dopaminergic activity in the median eminence, but had no effect on LH levels. The RFRP-3-induced increase in PRL secretion was prevented by GJ14. Moreover, the estradiol-induced PRL surge in female rats was blunted by GJ14, along with an amplification of the LH surge. Nevertheless, whole-cell patch clamp recordings showed no effect of RFRP-3 on the electrical activity of TIDA neurons in dopamine transporter-Cre recombinase transgenic female mice. We provide evidence that RFRP-3 binds to Npffr1 to stimulate PRL release, which plays a role in the estradiol-induced PRL surge. This effect of RFRP-3 is apparently not mediated by a reduction in the inhibitory tone of TIDA neurons but possibly involves the activation of a hypothalamic PRL-releasing factor. [ABSTRACT FROM AUTHOR]

The adipose-derived hormone leptin critically modulates reproductive function, such that its absence results in hypothalamic hypogonadism. Pituitary adenylate cyclase-activating polypeptide (PACAP)-expressing neurons are potential mediators of leptin's action on the neuroendocrine reproductive axis because they are leptin-sensitive and involved in both feeding behavior and reproductive function. In the complete absence of PACAP, male and female mice exhibit metabolic and reproductive abnormalities, yet there is some sexual dimorphism in the reproductive impairments. We tested whether PACAP neurons play a critical and/or sufficient role in mediating leptin's effects on reproductive function by generating PACAP-specific leptin receptor (LepR) knockout and rescue mice, respectively. We also generated PACAP-specific estrogen receptor alpha knockout mice to determine whether estradiol-dependent regulation of PACAP was critically involved in the control of reproductive function and whether it contributed to the sexually dimorphic effects of PACAP. We showed that LepR signaling in PACAP neurons is critically involved in the timing of female, but not male, puberty onset, but not fertility. Rescuing LepR-PACAP signaling in otherwise LepR-deficient mice was unable to rescue the reproductive deficits observed in LepR null mice but led to a marginal improvement in body weight and adiposity in females. Finally, PACAP-specific estrogen receptor alpha knockout did not lead to any changes in body weight or puberty onset compared with control mice. These data highlight that PACAP is a critical mediator of some of leptin's, but not estradiol's, influence on puberty onset in females, but is not critically involved in relaying leptin's effects in males or in adult females. [ABSTRACT FROM AUTHOR]

Polycystic ovarian syndrome (PCOS) is the leading cause of anovulatory infertility and is a heterogenous condition associated with a range of reproductive and metabolic impairments. While its etiology remains unclear, hyperandrogenism and impaired steroid negative feedback have been identified as key factors underpinning the development of PCOS-like features both clinically and in animal models. We tested the hypothesis that androgen signaling in kisspeptin-expressing neurons, which are key drivers of the neuroendocrine reproductive axis, is critically involved in PCOS pathogenesis. To this end, we used a previously validated letrozole (LET)-induced hyperandrogenic mouse model of PCOS in conjunction with Cre-lox technology to generate female mice exhibiting kisspeptin-specific deletion of androgen receptor (KARKO mice) to test whether LET-treated KARKO females are protected from the development of reproductive and metabolic PCOS-like features. LET-treated mice exhibited hyperandrogenism, and KARKO mice exhibited a significant reduction in the coexpression of kisspeptin and androgen receptor mRNA compared to controls. In support of our hypothesis, LET-treated KARKO mice exhibited improved estrous cyclicity, ovarian morphology, and insulin sensitivity in comparison to LET-treated control females. However, KARKO mice were not fully protected from the effects of LET-induced hyperandrogenism and still exhibited reduced corpora lutea numbers and increased body weight gain. These data indicate that increased androgen signaling in kisspeptin-expressing neurons plays a critical role in PCOS pathogenesis but highlight that other mechanisms are also involved. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this paper is to report progress concerning the design of a computer-assisted simulation training (CAST) platform for developing decision-making skills in police students. The overarching aim is to outline a theoretical framework for the design of CAST to facilitate police students' development of search techniques in complex interactions within the built environment, learning to apply and perform the five "quick peek" techniques for information gathering, and subsequent risk evaluation. Design/methodology/approach: The paper draws on Luckin's ecology of resources model of learner context informed with perspectives on reflective thinking from John Dewey and Donald Schön. The paper discusses design issues within the ecology of resources model applied on CAST for complex police situations. Findings: It is suggested that Luckin's framework with its focus on the interaction between different elements and filters in the learner's context together with Schön's perspective on reflection challenge educational designers to look beyond the immediate development of specific tools (such as the CAST in this project) and examine how these tools will be effectively embedded in the overall learning experience. Originality/value: This paper has presented two theoretical perspectives, Luckin's ecology of resources model and Schön's perspective on reflective practice as foundations for the educational design of CAST. Applying Luckin's framework as informed by Schön helps focus attention on issues that are important in the design process in order to facilitate educational transfer.

Timing of puberty requires exquisite coordination of genes, hormones, and brain circuitry. An increasing level of body adiposity, signaled to the brain via the fat-derived hormone leptin, is recognized as a major factor controlling puberty onset. However, it is clear that leptin is not the only metabolic cue regulating puberty, and that developmental regulation of this process also involves tissues other than adipose, with muscle development potentially playing a role in the timing of puberty. The proteolytic processing of fibronectin type 3 domain-containing protein 5 (FNDC5) releases a hormone, irisin. Irisin is primarily produced by muscle and is released into circulation, where levels increase dramatically as puberty approaches. We investigated the effects of a global deletion of the Fndc5 gene on pubertal timing. The absence of irisin induced a delay in puberty onset in female knockout mice compared with controls, without affecting body weight or gonadotropin-releasing hormone (GnRH) neuronal density. We next treated pre-pubertal wild-type male and female mice with an irisin receptor antagonist, cilengitide, for 7 days and observed a delay in first estrus occurrence compared to vehicle-treated control mice. Male puberty timing was unaffected. Next, we deleted the irisin receptor (integrin subunit alpha V) in all forebrain neurons and found a delay in the occurrence of first estrus in knockout females compared to controls. Taken together, these data suggest irisin plays a role in the timing of puberty onset in female mice via a centrally mediated mechanism. [ABSTRACT FROM AUTHOR]

We describe an inexpensive device for performing capillary electrophoresis (CE) separations with fluorescence detection. As a demonstration of the device's utility we have determined the mass of riboflavin in a commercially available dietary supplement. The device allows for separation of riboflavin in [asymptotically equivalent to] 100 s with a mass limit of detection of [asymptotically equivalent to] 10 fmol. The device may be of particular interest to faculty at smaller chemistry departments that do not currently possess a CE instrument. While of limited utility, the device we describe could be used to introduce students to capillary electrophoresis despite the obstacle of limited funding. (Contains 2 figures.)

Budget pressures compel everyone in higher education to demonstrate value in IT investments, using both quantitative and qualitative information. Like many institutions, however, both Stanford and Massachusetts Institute of Technology (MIT) have found themselves forced to rely more on anecdotes than on management information to guide decisions. In response, MIT and Stanford partnered to develop meaningful comparative data and to understand each other's IT services and performance. In essence, after more than a decade of significant IT investments, both campuses asked, "How effectively are they performing? How do they compare to other universities and by what measures? How can they use their IT systems to help them manage themselves better?" When beginning this effort, both institutions knew that several aspects of the project would be critical: (1) Define data clearly; (2) Capture costs consistently for the services under study; (3) Understand each other's processes in depth; and (4) Tackle issues of a manageable scope. As a result of an 18-month effort, MIT and Stanford have learned valuable lessons about: (1) developing the methodology to conduct these comparisons; (2) defining specific metrics for IT helpdesk services; (3) creating a "dashboard" chart that summarizes important performance indicators at a glance; and (4) using data to drive cultural change in the management of a university. The efforts have been rewarded well. Each campus has seen process improvements, new abilities to handle spikes in workload due to crises (such as viruses) or plans (such as new system rollouts), and marked improvement in performance. One of the greatest outcomes of the collaborative project has been a fundamental shift in the sands of management culture. Administrators and senior officers are requiring that relevant, useful data be part of management decision making and assessment. They are shifting from management by personality and anecdote to management by fact. (Contains 2 tables, 4 figures and 7 endnotes.)

Agouti‐related peptide (AgRP) neurons are thought to indirectly regulate the activity of hypothalamic gonadotrophin‐releasing hormone neurons which control fertility. AgRP neurons also drive caloric intake and are modulated by metabolically‐relevant hormones, providing a link to the hypothalamic–pituitary‐gonadal axis. In mice expressing Cre‐dependant designer receptors (DREADDs) in AgRP neurons, we activated or silenced these neurons in vivo using the synthetic ligand clozapine‐N‐oxide (CNO) to observe the effect of AgRP neuron activity on timing of puberty. To validate these animals, we chronically treated both stimulatory (hM3Dq) and inhibitory (hM4Di) DREADD × AgRP‐Cre mice with CNO, observing a pronounced increase and decrease of food intake, respectively, consistent with the known orexigenic effects of these neurons. RNAscope was performed to visually confirm the activation of AgRP neurons. Puberty onset was assessed in males and females. There was no effect on preputial separation in males or vaginal opening and first oestrus in females after CNO treatment from day 26 to 30 to chronically modulate AgRP neurons. Next, to determine whether the delay in puberty onset occurring in response to neonatal underfeeding could be overcome by inhibiting AgRP neuronal activity, mice were raised in large (neonatally underfed) or normal litter sizes. The delay in puberty from underfeeding was completely reversed in CNO‐treated AgRP‐hM4Di male mice. These data highlight the inhibitory role of AgRP neurons to delay puberty onset when undernutrition occurs during the neonatal period, at least in male mice. Trail registration number: JNE‐22‐0081‐OA.R2 [ABSTRACT FROM AUTHOR]

I. INTRODUCTION For aspiring junior associates in most law firms, one of the more important issues they will confront is whether they will ever be made partner. Indeed, a Google [...]