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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.

Being truthful with patients is a critical foundation of the doctorpatient relationship and is fundamental to development of trust. A professional commitment to truth telling may sometimes contradict other principles of bioethics, which may challenge decision-making for the doctor and/or the treatment team. Practitioners may fail to address all ethical or legal aspects of a case and therefore make inappropriate decisions. [ABSTRACT FROM AUTHOR]

A professional commitment to patient confidentiality may sometimes contradict other principles of bioethics. Decisionmaking for doctors and their team can be challenging amidst such conflicting principles, and despite the practitioner's best intentions, withholding information can result in potential consequences such as harm to others. [ABSTRACT FROM AUTHOR]

Reproductive function in mammals is energetically costly and therefore tightly regulated by nutritional status. To enable this integration of metabolic and reproductive function, information regarding peripheral nutritional status must be relayed centrally to the gonadotropin-releasing hormone (GNRH) neurons that drive reproductive function. The metabolically relevant hormones leptin, insulin and ghrelin have been identified as key mediators of this 'metabolic control of fertility'. However, the neural circuitry through which they act to exert their control over GNRH drive remains incompletely understood. With the advent of Cre-LoxP technology, it has become possible to perform targeted gene-deletion and gene-rescue experiments and thus test the functional requirement and sufficiency, respectively, of discrete hormone-neuron signaling pathways in the metabolic control of reproductive function. This review discusses the findings from these investigations, and attempts to put them in context with what is known from clinical situations and wild-type animal models. What emerges from this discussion is clear evidence that the integration of nutritional signals on reproduction is complex and highly redundant, and therefore, surprisingly difficult to perturb. Consequently, the deletion of individual hormone-neuron signaling pathways often fails to cause reproductive phenotypes, despite strong evidence that the targeted pathway plays a role under normal physiological conditions. Although transgenic studies rarely reveal a critical role for discrete signaling pathways, they nevertheless prove to be a good strategy for identifying whether a targeted pathway is absolutely required, critically involved, sufficient or dispensable in the metabolic control of fertility. [ABSTRACT FROM AUTHOR]

Introduction: Conditionally immortalised human neural progenitor cells (hNPCs) represent a robust source of native neural cells to investigate physiological mechanisms in both health and disease. However, in order to recognise the utility of such cells, it is critical to determine whether they retain characteristics of their tissue of origin and generate appropriate neural cell types upon differentiation. To this end, we have characterised the conditionally immortalised, cortically-derived, human NPC line, CTX0E16, investigating the molecular and cellular phenotype of differentiated neurons to determine whether they possess characteristics of cortical glutamatergic neurons. Methods: Differentiated CTX0E16 cells were characterised by assessing expression of several neural fates markers, and examination of developing neuronal morphology. Expression of neurotransmitter receptors, signalling proteins and related proteins were assessed by q- and RT-PCR and complemented by Ca2+ imaging, electrophysiology and assessment of ERK signalling in response to neurotransmitter ligand application. Finally, differentiated neurons were assessed for their ability to form putative synapses and to respond to activity-dependent stimulation. Results: Differentiation of CTX0E16 hNPCs predominately resulted in the generation of neurons expressing markers of cortical and glutamatergic (excitatory) fate, and with a typical polarized neuronal morphology. Gene expression analysis confirmed an upregulation in the expression of cortical, glutamatergic and signalling proteins following differentiation. CTX0E16 neurons demonstrated Ca2+ and ERK1/2 responses following exogenous neurotransmitter application, and after 6 weeks displayed spontaneous Ca2+ transients and electrophysiological properties consistent with that of immature neurons. Differentiated CTX0E16 neurons also expressed a range of pre- and post-synaptic proteins that co-localized along distal dendrites, and moreover, displayed structural plasticity in response to modulation of neuronal activity. Conclusions: Taken together, these findings demonstrate that the CTX0E16 hNPC line is a robust source of cortical neurons, which display functional properties consistent with a glutamatergic phenotype. Thus CTX0E16 neurons can be used to study cortical cell function, and furthermore, as these neurons express a range of disease-associated genes, they represent an ideal platform with which to investigate neurodevelopmental mechanisms in native human cells in health and disease. [ABSTRACT FROM AUTHOR]

Introduction: Conditionally immortalised human neural progenitor cells (hNPCs) represent a robust source of native neural cells to investigate physiological mechanisms in both health and disease. However, in order to recognise the utility of such cells, it is critical to determine whether they retain characteristics of their tissue of origin and generate appropriate neural cell types upon differentiation. To this end, we have characterised the conditionally immortalised, cortically-derived, human NPC line, CTX0E16, investigating the molecular and cellular phenotype of differentiated neurons to determine whether they possess characteristics of cortical glutamatergic neurons. Methods: Differentiated CTX0E16 cells were characterised by assessing expression of several neural fates markers, and examination of developing neuronal morphology. Expression of neurotransmitter receptors, signalling proteins and related proteins were assessed by q- and RT-PCR and complemented by Ca2+ imaging, electrophysiology and assessment of ERK signalling in response to neurotransmitter ligand application. Finally, differentiated neurons were assessed for their ability to form putative synapses and to respond to activity-dependent stimulation. Results: Differentiation of CTX0E16 hNPCs predominately resulted in the generation of neurons expressing markers of cortical and glutamatergic (excitatory) fate, and with a typical polarized neuronal morphology. Gene expression analysis confirmed an upregulation in the expression of cortical, glutamatergic and signalling proteins following differentiation. CTX0E16 neurons demonstrated Ca2+ and ERK1/2 responses following exogenous neurotransmitter application, and after 6 weeks displayed spontaneous Ca2+ transients and electrophysiological properties consistent with that of immature neurons. Differentiated CTX0E16 neurons also expressed a range of pre- and post-synaptic proteins that co-localized along distal dendrites, and moreover, displayed structural plasticity in response to modulation of neuronal activity. Conclusions: Taken together, these findings demonstrate that the CTX0E16 hNPC line is a robust source of cortical neurons, which display functional properties consistent with a glutamatergic phenotype. Thus CTX0E16 neurons can be used to study cortical cell function, and furthermore, as these neurons express a range of disease-associated genes, they represent an ideal platform with which to investigate neurodevelopmental mechanisms in native human cells in health and disease. [ABSTRACT FROM AUTHOR]

Abstract: A fundamental result of free probability theory due to Voiculescu and subsequently refined by many authors states that conjugation by independent Haar-distributed random unitary matrices delivers asymptotic freeness. In this paper we exhibit many other systems of random unitary matrices that, when used for conjugation, lead to freeness. We do so by first proving a general result asserting “asymptotic liberation” under quite mild conditions, and then we explain how to specialize these general results in a striking way by exploiting Hadamard matrices. In particular, we recover and generalize results of the second-named author and of Tulino, Caire, Shamai and Verdú. [Copyright &y& Elsevier]

Fast track procedures have been key institutional mechanisms for U.S. trade policy making for nearly three decades. In April 2008, the U.S. House of Representatives made a small change to rules for considering the U.S.-Colombia Free Trade Agreement that significantly undermined fast track. However, these actions are really the culmination of the erosion of the utility of fast track in managing U.S. trade policy in the context of the challenges brought by increased openness in the global economy. Those challenges were laid bare with the first major bilateral agreement considered under fast track rules, the Canada-U.S. Free Trade Agreement in the late 1980s. [ABSTRACT FROM AUTHOR]

The article studies the Indiana Law of Professional Responsibility appealed by the Indiana Trial Lawyers Association (ITLA) in 2006 to the Indiana Supreme Court for reconsideration. It notes the decisions of the Supreme Court on several cases involving regulated attorney's fees, judicial misconduct, criminal conduct of lawyers, improper trial strategies used by lawyers and neglect of judiciary on a case.

Abstract: Let X be a nonsingular projective curve of genus one defined over an algebraically closed field of characteristic 0. Let D be a divisor of X of degree and let O be a (closed) point of X. As is well known, there exists a unique morphism such that if and only if the divisor is principal. Our main result is a simple explicit description of the map in terms of Wronskians and certain Wronskian-like determinants lacunary in the sense that derivatives of some orders are skipped. Further, for we interpret our main result as a syzygy from classical invariant theory, thus reconciling our work with a circle of ideas treated in two papers by Weil and a recent paper by An, Kim, Marshall, Marshall, McCallum and Perlis. [Copyright &y& Elsevier]

According to classical and postclassical sources, the early Greek "turannoi" were, by definition,. illegitimate rulers who overturned existing political arrangements and installed rogue monarchic regimes in their place. And on this one fundamental point at least, modern observers of archaic "turannides" seem to have little quarrel with their ancient informants. To this day, it remains axiomatic that Cypselus, Peisistratus, and the rest were autocrats who gained power by usurpation. Whatever their individual accomplishments, they were still, in a word, "tyrants." Relying mostly on evidence from the contemporary literary and material records, the paper questions this time-honored commonplace. Prior to the late sixth century, I contend, there was in fact no absolute distinction between "turannoi" and orthodox leaders in Greek poleis. The former aimed to dominate established oligarchies, not to subvert them. A "turannis" was not yet a species of political regime, illegitimate or otherwise. Rather, it was mainstream oligarchic leadership in its most amplified form, conventional de facto authority writ large. [ABSTRACT FROM AUTHOR]

The expansion in Schur functions of the product ∏i is well known. It is more or less equivalent to Weyl''s identity for root-systems of type Dn. In this paper we obtain the expansion in Schur functions of the product ∏i0aℓxixj(xiℓ-xjℓ)/(xi-xj)), thus generalizing Weyl''s identity. We obtain this result by systematic calculation in fermionic Fock space. But familiarity with the latter is not a prerequisite for reading this paper. We develop from scratch the modest amount of theory that we need in elementary and purely algebraic fashion, taking pains to integrate the theory with classical symmetric function theory. The tools developed in this paper ought to have many further applications, e.g., to random matrix theory and to computational abelian function theory. [Copyright &y& Elsevier]

Faults in complex tectonic environments interact in various ways, including triggered rupture of one fault by another, that may increase seismic hazard in the surrounding region. We model static and dynamic fault interactions between the strike-slip and thrust fault systems in southern California. We find that rupture of the Sierra Madre-Cucamonga thrust fault system is unlikely to trigger rupture of the San Andreas or San Jacinto strike-slip faults. However, a large northern San Jacinto fault earthquake could trigger a cascading rupture of the Sierra Madre-Cucamonga system, potentially causing a moment magnitude 7.5 to 7.8 earthquake on the edge of the Los Angeles metropolitan region. [ABSTRACT FROM AUTHOR]

The abeliant is a polynomial rule which to each n×n by n+2 array with entries in a commutative ring with unit associates an n×n matrix with entries in the same ring. The theory of abeliants, first introduced in an earlier paper of the author, is simplified and extended here. Now let J be the Jacobian of a nonsingular projective algebraic curve defined over an algebraically closed field. With the aid of the theory of abeliants we obtain explicit defining equations for J and its group law. [Copyright &y& Elsevier]

The neuronal ceroid lipofuscinoses (NCLs or Batten disease) are a group of inherited, fatal neurodegenerative disorders of childhood. In these disorders, glial (microglial and astrocyte) activation typically occurs early in disease progression and predicts where neuron loss subsequently occurs. We have found that in themost common juvenile form of NCL (CLN3 disease or JNCL) this glial response is less pronounced in both mouse models and human autopsy material, with the morphological transformation of both astrocytes and microglia severely attenuated or delayed. To investigate their properties, we isolated glia and neurons from Cln3-deficient mice and studied their basic biology in culture. Upon stimulation, both Cln3-deficient astrocytes and microglia also showed an attenuated ability to transform morphologically, and an altered protein secretion profile. These defects were more pronounced in astrocytes, including the reduced secretion of a range of neuroprotective factors, mitogens, chemokines and cytokines, in addition to impaired calcium signalling and glutamate clearance. Cln3-deficient neurons also displayed an abnormal organization of their neurites. Most importantly, using a co-culture system, Cln3-deficient astrocytes and microglia had a negative impact on the survival and morphology of both Cln3-deficient and wildtype neurons, but these effects were largely reversed by growing mutant neurons with healthy glia. These data provide evidence that CLN3 disease astrocytes are functionally compromised. Together with microglia, they may play an active role in neuron loss in this disorder and can be considered as potential targets for therapeutic interventions. [ABSTRACT FROM AUTHOR]

The Navy has a need for monitoring conditions and gathering information in marine environments. Sensors can monitor and report environmental parameters and potential activities such as animal movements, ships, or personnel. However, there has to be a means to power these sensors. One promising enabling technology that has been shown to provide long-term power production in underwater environments is the benthic microbial fuel cells (BMFC). BMFCs are devices that generate energy by coupling bioanodes and biocathodes through an external energy harvester. Recent studies have demonstrated success for usage of BMFCs in powering small instruments and other devices on the seafloor over limited periods of time. In this effort, a seven-stranded BMFC linear array of 30 m was designed to power a seafloor magnetometer to detect passing ship movements through Pearl Harbor, Hawaii. The BMFC system was connected to a flyback energy harvesting circuit that charged the battery powering the magnetometer. The deployment was demonstrated the BMFC supplied power to the battery for approximately 38 days. This is the first large-scale demonstration system for usage of the SeptiStrand BMFC technology to power a relevant sensor. [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. [ABSTRACT FROM AUTHOR]

The adipocyte-derived 'satiety promoting' hormone, leptin, has been identified as a key central regulator of body weight and fertility, such that its absence leads to obesity and infertility. Plasma leptin levels reflect body adiposity, and therefore act as an 'adipostat', whereby low leptin levels reflect a state of low body adiposity (under-nutrition/starvation) and elevated leptin levels reflect a state of high body adiposity (over-nutrition/obesity). While genetic leptin deficiency is rare, obesity-related leptin resistance is becoming increasingly common. In the absence of adequate leptin sensitivity, leptin is unable to exert its 'anti-obesity' effects, thereby exacerbating obesity. Furthermore, extreme leptin resistance and consequent low or absent leptin signalling resembles a state of starvation and can thus lead to infertility. However, leptin resistance occurs on a spectrum, and it is possible to be resistant to leptin's metabolic effects while retaining leptin's permissive effects on fertility. This may be because leptin exerts its modulatory effects on energy homeostasis and reproductive function through discrete intracellular signalling pathways, and these pathways are differentially affected by the molecules that promote leptin resistance. This review discusses the potential mechanisms that enable leptin to exert differential control over metabolic and reproductive function in the contexts of healthy leptin signalling and of diet-induced leptin resistance. [ABSTRACT FROM AUTHOR]

Background: Organizations of all types require the use of teams. Poor team member engagement costs billions of US dollars annually. Objective: This study aimed to explain how team building can be accomplished with team video gaming based on a team cohesion model enhanced by team flow theory. Methods: In this controlled experiment, teams were randomly assigned to a team video gaming treatment or a control treatment. Team productivity was measured during both pretreatment and posttreatment team tasks. After the pretest, teams who were involved in the team video gaming treatment competed against other teams by playing the Halo or Rock Band video game for 45 minutes. After the pretest, teams in the control treatment worked alone for 45 minutes. Then, all teams completed the posttest team activity. This same experimental protocol was conducted on 2 different team tasks. Results: For both tasks, teams in the team video gaming treatment increased their productivity significantly more (F1=8.760, P=.004) on the posttest task than teams in the control treatment. Our flow-based theoretical model explained team performance improvement more than twice as well (R²=40.6%) than prior related research (R²=18.5%). Conclusions: The focused immersion caused by team video gaming increased team performance while the enjoyment component of flow decreased team performance on the posttest. Both flow and team cohesion contributed to team performance, with flow contributing more than cohesion. Team video gaming did not increase team cohesion, so team video gaming effects are independent of cohesion. Team video gaming is a valid practical method for developing and improving newly formed teams. [ABSTRACT FROM AUTHOR]

We use Global Positioning System (GPS) velocities and stress orientations inferred from seismicity to invert for the distribution of slip on faults in the southern California plate-boundary region. Of particular interest is how long-term slip rates are partitioned between the Indio segment of the San Andreas fault (SAF), the San Jacinto fault (SJF) and the San Bernardino segment of the SAF. We use two new sets of constraints to address this problem. The first is geodetic velocities from the Southern California Earthquake Center's (SCEC) Crustal Motion Map (version 3 by Shenet al.), which includes significantly more data than previous models. The second is a regional model of stress-field orientations at seismogenic depths, as determined from earthquake focal mechanisms. While GPS data have been used in similar studies before, this is the first application of stress-field observations to this problem. We construct a simplified model of the southern California fault system, and estimate the interseismic surface velocities using a backslip approach with purely elastic strain accumulation, following Meadeet al.In addition, we model the stress orientations at seismogenic depths, assuming that crustal stress results from the loading of active faults. The geodetically derived stressing rates are found to be aligned with the stress orientations from seismicity. We therefore proceed to invert simultaneously GPS and stress observations for slip rates of the faults in our network. We find that the regional patterns of crustal deformation as imaged by both data sets can be explained by our model, and that joint inversions lead to better constrained slip rates. In our preferred model, the SJF accommodatesand the Indio segment of the SAFof right-lateral motion, accompanied by a low slip rate on the San Bernardino segment of the SAF.‘Anomalous’ fault segments such as around the 1992Landers surface rupture can be detected. There, observed stresses deviate strongly from the long-term loading as predicted by our simple model. Evaluation of model misfits together with information from palaeoseismology may provide further insights into the time dependence of strain accumulation along the San Andreas system. [ABSTRACT FROM AUTHOR]

RF-amide related peptide 3 (RFRP-3) is a neuropeptide thought to inhibit central regulation of fertility. We investigated whether alterations in RFRP neuronal activity led to changes in puberty onset, fertility, and stress responses, including stress and glucocorticoid-induced suppression of pulsatile luteinizing hormone secretion. We first validated a novel RFRP-Cre mouse line, which we then used in combination with Cre-dependent neuronal ablation and DREADD technology to selectively ablate, stimulate, and inhibit RFRP neurons to interrogate their physiological roles in the regulation of fertility and stress responses. Chronic RFRP neuronal activation delayed male puberty onset and female reproductive cycle progression, but RFRP-activated and ablated mice exhibited apparently normal fertility. When subjected to either restraint- or glucocorticoid-induced stress paradigms. However, we observed a critical sex-specific role for RFRP neurons in mediating acute and chronic stress-induced reproductive suppression. Female mice exhibiting RFRP neuron ablation or silencing did not exhibit the stress-induced suppression in pulsatile luteinizing hormone secretion observed in control mice. Furthermore, RFRP neuronal activation markedly stimulated glucocorticoid secretion, demonstrating a feedback loop whereby stressful stimuli activate RFRP neurons, which in turn further activate the stress axis. These data provide evidence for a neuronal link between the stress and reproductive axes. [ABSTRACT FROM AUTHOR]

Female reproductive success relies on proper integration of circadian- and ovarian- signals to the hypothalamic-pituitary-gonadal axis in order to synchronize the preovulatory LH surge at the end of the ovarian follicular stage with the onset of the main active period. In this study, we used a combination of neuroanatomical and electrophysiological approaches to assess whether the hypothalamic neurons expressing Arg-Phe amide- related peptide (RFRP-3), a gonadotropin inhibitory peptide, exhibit daily and estrous stage dependent variations in female mice. Furthermore, we investigated whether arginine vasopressin (AVP), a circadian peptide produced by the suprachiamatic nucleus regulates RFRP-3 neurons. The number of c-Fos-positive RFRP-3 immunoreactive neurons is significantly reduced at the day-to-night transition with no difference between diestrus and proestrus. Contrastingly, RFRP neuron firing rate is higher in proestrus as compared to diestrus, independently of the time of the day. AVP immunoreactive fibers contact RFRP neurons with the highest density observed during the late afternoon of diestrus and proestrus. Application of AVP increases RFRP neurons firing in the afternoon (ZT6-10) of diestrus, but not at the same time point of proestrus, indicating that AVP signaling on RFRP neurons may depend on circulating ovarian steroids. Together, these studies show that RFRP neurons integrate both daily and estrogenic signals, which downstream may help to properly time the preovulatory LH surge. [ABSTRACT FROM AUTHOR]

Objective: There is an increased incidence of some mental health disorders such as post-traumatic stress disorder (PTSD) in some members of the military and in some public safety personnel (PSP) such as firefighters, police officers, paramedics, and dispatchers. Upon retirement from the armed forces, many individuals go on to second careers as PSP. Individuals with prior military experience may be at even greater risk than nonveterans for developing mental health disorders. The present study was designed to examine the relationship between prior military service and symptoms of mental health disorders in PSP.Methods: This is a cross-sectional, observational study. Data for this study were collected from an anonymous, web-based, self-report survey of PSP in Canada. Invitations to participate were sent to PSP via their professional organizations. Indications of mental disorder(s) and symptom severity were assessed using well-validated self-report screening measures.Results: Of the survey respondents who provided this information, 631 (6.8%) had prior armed forces experience; however, not all responses were complete. Ex-military PSP reported significantly more exposure to traumatic events and were approximately 1.5 times more likely to screen positive for indications of PTSD, mood, anxiety, or acute stress disorders and to have contemplated suicide than those without prior armed forces experience.Conclusions: In our study, individuals in PSP with prior service experience in the armed forces were more likely to screen positive for indicators of some mental health disorders. Accordingly, mental health practitioners should inquire about previous service in the armed forces when screening, assessing, and treating PSP. [ABSTRACT FROM AUTHOR]

The cellular processes that cause high caloric diet (HCD)-induced infertility are poorly understood but may involve upregulation of suppressor of cytokine signaling (SOCS-3) proteins that are associated with hypothalamic leptin resistance. Deletion of SOCS-3 from brain cells is known to protect mice from diet-induced obesity, but the effects on HCD-induced infertility are unknown. We used neuron-specific SOCS3 knock-out mice to elucidate this and the effects on regional hypothalamic leptin resistance. As expected, male and female neuron-specific SOCS3 knock-out mice were protected from HCD-induced obesity. While female wild-type mice became infertile after 4 months of HCD feeding, infertility onset in knock-out females was delayed by 4 weeks. Similarly, knock-out mice had delayed leptin resistance development in the medial preoptic area and anteroventral periventricular nucleus, regions important for generation of the surge of GnRH and LH that induces ovulation. We therefore tested whether the suppressive effects of HCD on the estradiol-induced GnRH/LH surge were overcome by neuron-specific SOCS3 knock-out. Although only 20% of control HCD-mice experienced a preovulatory-like LH surge, LH surges could be induced in almost all neuron-specific SOCS3 knock-out mice on this diet. In contrast to females, HCD-fed male mice did not exhibit any fertility decline compared with low caloric diet-fed males despite their resistance to the satiety effects of leptin. These data show that deletion of SOCS3 delays the onset of leptin resistance and infertility in HCD-fed female mice, but given continued HCD feeding this state does eventually occur, presumably in response to other mechanisms inhibiting leptin signal transduction. [ABSTRACT FROM AUTHOR]

The adipocyte-derived hormone leptin acts in the brain to modulate the central driver of fertility: the gonadotropin releasing hormone (GnRH) neuronal system. This effect is indirect, as GnRH neurons do not express leptin receptors (LEPRs). Here we test whether GABAergic or glutamatergic neurons provide the intermediate pathway between the site of leptin action and the GnRH neurons. Leptin receptors were deleted from GABA and glutamate neurons using Cre-Lox transgenics, and the downstream effects on puberty onset and reproduction were examined. Both mouse lines displayed the expected increase in body weight and region-specific loss of leptin signaling in the hypothalamus. The GABA neuron-specific LEPR knock-out females and males showed significantly delayed puberty onset. Adult fertility observations revealed that these knock-out animals have decreased fecundity. In contrast, glutamate neuron-specific LEPR knock-out mice displayed normal fertility. Assessment of the estrogenic hypothalamic-pituitary-gonadal axis regulation in females showed that leptin action on GABA neurons is not necessary for estradiol-mediated suppression of tonic luteinizing hormone secretion (an indirect measure of GnRH neuron activity) but is required for regulation of a full preovulatory-like luteinizing hormone surge. In conclusion, leptin signaling in GABAergic (but not glutamatergic neurons) plays a critical role in the timing of puberty onset and is involved in fertility regulation throughout adulthood in both sexes. These results form an important step in explaining the role of central leptin signaling in the reproductive system. Limiting the leptin-to-GnRH mediators to GABAergic cells will enable future research to focus on a few specific types of neurons. [ABSTRACT FROM AUTHOR]

Obesity is associated with resistance to the actions of both leptin and insulin via mechanisms that remain incompletely understood. To investigate whether leptin resistance per se contributes to insulin resistance and impaired glucose homeostasis, we investigated the effect of acute leptin administration on glucose homeostasis in normal as well as leptin- or leptin receptor-deficient mice. In hyperglycemic, leptin-deficient Lepob/ob mice, leptin acutely and potently improved glucose metabolism, before any change of body fat mass, via a mechanism involving the p110α and β isoforms of phosphatidylinositol-3-kinase (PI3K). Unlike insulin, however, the anti-diabetic effect of leptin occurred independently of phospho-AKT, a major downstream target of PI3K, and instead involved enhanced sensitivity of the hypothalamus to insulin action upstream of PI3K, through modulation of IRS1 (insulin receptor substrate 1) phosphorylation. These data suggest that leptin resistance, as occurs in obesity, reduces the hypothalamic response to insulin and thereby impairs peripheral glucose homeostasis, contributing to the development of type 2 diabetes. [ABSTRACT FROM AUTHOR]

We describe two homologues of the mammalian divalent metal transporter (DMTI) for Schistosoma mansoni, a pathogenic intravascular parasite of humans. Schistosomes have a high nutritional and metabolic demand for iron. Nucleotide sequences of the parasite homologues, designated SmDMT1A and -B, are identical in all but the 5′-regions. The predicted amino acid sequences share at least 60% identity with DMT1 (=Nramp2) of humans, mice, and rats, and at least 55% identity with Nramp1 from mice, humans and Caenorhabditis elegans. SmDMT1A is expressed in differentiating eggs, miracidia, cercariae, schistosomula, and adults, whereas SmDMT1B is expressed in all but the miracidium and occurs at lower levels than SmDMT1A in differentiating eggs and cercariae. An iron-responsive element, present at the 3′-untranslated region of many DMT1 molecules, is not present in schistosome mRNAs studied here. A Western blot analysis of adult worm preparations using a homologous rabbit serum raised against a schistosome DMT1 peptide and a heterologous serum raised against mammalian DMT1, revealed a band approximating 115 kDa. By immunofluorescence microscopy, the schistosome DMT1s localize primarily to the tegument. Iron uptake assays demonstrated that SmDMT1s were able to rescue yeast growth in ferrous iron-transport deficient yeast (fet3fet4). The results suggest that schistosomes express molecules for ferrous iron transport in their tegument, suggesting trans-tegumental transport as one means of iron acquisition for these parasites. [ABSTRACT FROM AUTHOR]

The scope of the present work is to highlight the effects stemming from different C[sub 60]/exTTF linkages (exTTF = 9,10-bis(1,3-dithiol-2-ylidene)-9,10-dihydroanthracene)—either via an anthracene unit or a dithiole ring. Particular emphasis is placed on photoinduced electron-transfer features. Therefore, we devised a new series of C[sub 60]-exTTF ensembles, synthesized via 1,3-dipolar cycloaddition and Diels-Alder cycloaddition reactions, in which exTTF units are separated from C[sub 60] by two single bonds (3a-c, 4), one vinylene unit (5a), or two vinylene units (5b). The cyclic voltammetry reveals an amphoteric redox behavior with remarkably strong electron-donor ability of the trimethylsubstituted exTTF moiety in 4 and 5a,b. Steady-state and time-resolved photolytic techniques show that the fullerene singlet excited state in (3a-c, 4, and 5a,b) is subject to a rapid electron-transfer quenching. The resulting charge-separated states, that is C[sub 60[sup •-]]-exTTF[sup •+], were identified by transient absorption spectroscopy. We determined radical pair lifetimes of the order of 200 ns in benzonitrile. This suggests (i) that the positive charge of the exTTF[sup •+] is delocalized over the entire donor rather than localized on one of the 1,3-dithiole rings and (ii) that linking exTTF via the anthracene or 1,3-dithiole ring has no appreciable influence. Increasing the donor-acceptor separation via implementing one or two vinylene units as spacers led to improved radical pair lifetimes (5a: τ = 725 ns; 5b: τ = 1465 ns). [ABSTRACT FROM AUTHOR]

Systemic iron overload is multifactorial in patients suffering from myelodysplastic syndrome (MDS). Disease-immanent ineffective erythropoiesis together with chronic red blood cell transfusion represent the main underlying reasons. However, like the genetic heterogeneity of MDS, iron homeostasis is also diverse in different MDS subtypes and can no longer be generalized. While a certain amount of iron and reactive oxygen species (ROS) are indispensable for proper hematological output, both are harmful if present in excess. Consequently, iron overload has been increasingly recognized as an important player in MDS, which is worth paying attention to. This review focuses on iron- and ROS-mediated effects in the bone marrow niche, their implications for hematopoiesis and their yet unclear involvement in clonal evolution. Moreover, we provide recent insights into hepcidin regulation in MDS and its interaction between erythropoiesis and inflammation. Based on Tet methylcytosine dioxygenase 2 (TET2), representing one of the most frequently mutated genes in MDS, leading to disturbances in both iron homeostasis and hematopoiesis, we highlight that different genetic alteration may have different implications and that a comprehensive workup is needed for a complete understanding and development of future therapies. [ABSTRACT FROM AUTHOR]

HFE-related hereditary hemochromatosis (HH) is characterized by marked phenotypic heterogeneity. Homozygosity for p.C282Y is a low penetrance genotype suggesting that the HFE-HH is a multifactorial disease resulting from a complex interaction involving a major gene defect, genetic background and environmental factors. We performed a targeted NGS-based gene panel to identify new candidate modifiers by using an extreme phenotype sampling study based on serum ferritin and iron removed/age ratio. We found an increased prevalence of the HIF1A p.Phe582Ser and p.Ala588Thr variants in patients with a severe iron and clinical phenotype. Accordingly, Huh-7 cells transfected with both variants showed significantly lower HAMP promoter activity by luciferase assay. The qRT-PCR assays showed a downregulation of hepcidin and an upregulation of the HIF1A target genes (VEGF, HMOX, FUR, TMPRSS6) in cells transfected with the HIF1A-P582S vector. We identified mutations in other genes (e.g., Serpina1) that might have some relevance in single cases in aggravating or mitigating disease manifestation. In conclusion, the present study identified HIF1A as a possible modifier of the HFE-HH phenotype cooperating with the genetic defect in downregulating hepcidin synthesis. In addition, this study highlights that an NGS-based approach could broaden our knowledge and help in characterizing the genetic complexity of HFE-HH patients with a severe phenotype expression. [ABSTRACT FROM AUTHOR]