Taxonomy of introns and the evolution of minor introns.

Classification of introns, which is crucial to understanding their evolution and splicing, has historically been binary and has resulted in the naming of major and minor introns that are spliced by their namesake spliceosome. However, a broad range of intron consensus sequences exist, leading us to here reclassify introns as minor, minor-like, hybrid, major-like, major and non-canonical introns in 263 species across six eukaryotic supergroups. Through intron orthology analysis, we discovered that minor-like introns are a transitory node for intron conversion across evolution. Despite close resemblance of their consensus sequences to minor introns, these introns possess an AG dinucleotide at the -1 and -2 position of the 5' splice site, a salient feature of major introns. Through combined analysis of CoLa-seq, CLIP-seq for major and minor spliceosome components, and RNAseq from samples in which the minor spliceosome is inhibited we found that minor-like introns are also an intermediate class from a splicing mechanism perspective. Importantly, this analysis has provided insight into the sequence elements that have evolved to make minor-like introns amenable to recognition by both minor and major spliceosome components. We hope that this revised intron classification provides a new framework to study intron evolution and splicing.

Examining Demand and Substitutability of Usual Brand Little Cigars/Cigarillos and Cigarettes in Young Adults Who Dual Use.

INTRODUCTION: Cigarette and little cigar/cigarillo (LCC) dual use is popular among young people and poses a substantial health risk. What remains unclear is the abuse liability of LCCs vs. cigarettes, LCCs' substitutability for cigarettes, and the influence of flavors on the abuse liability and substitutability of LCCs. METHODS: Sixty-five young adults (18-34 years) who dual use completed hypothetical purchase tasks to measure consumption of usual brand cigarettes and LCCs in 24 hours at increasing prices (demand), and LCC consumption at increasing cigarette prices (substitution). Three demand indices were calculated from raw data: breakpoint (price after which consumption reaches 0), Omax (maximum daily expenditure), and Pmax (price at maximum expenditure). Two indices were estimated using nonlinear mixed-effects modeling: intensity (consumption when free) and price-sensitivity (rate of decline in consumption as price increases). Substitution, and associations of flavored use with demand and substitution, were estimated using linear mixed models. RESULTS: Results indicated similar abuse liability for LCCs and cigarettes. Intensity was greater for cigarettes, but price-sensitivity was similar. Flavored LCC use was associated with lower price-sensitivity and greater intensity than unflavored. LCCs were significant substitutes for cigarettes, but the effect was small. Flavored use was not associated with substitution. CONCLUSIONS: Among young adults who dual use, LCCs and cigarettes had similar abuse liability, and those who used flavored had higher demand for their LCCs. A flavored cigar ban, as well as targeted prevention and cessation services for those who smoke flavored LCCs, may be important for reducing dual use in young adults. IMPLICATIONS: Cigarette and LCC dual use remains high among young adults. Using hypothetical purchase tasks with young adults who dual use, LCCs had abuse liability similar to cigarettes, but were only modest substitutes for cigarettes. Participants who used flavored LCCs reported greater abuse liability than those who used unflavored, but not greater substitution for cigarettes. Prevention and cessation services are needed to target LCCs in young people, particularly those smoking flavored products. A flavored cigar ban may help to reduce their demand.

The Influence of Kynurenine Metabolites on Neurodegenerative Pathologies.

As the kynurenine pathway's links to inflammation, the immune system, and neurological disorders became more apparent, it attracted more and more attention. It is the main pathway through which the liver breaks down Tryptophan and the initial step in the creation of nicotinamide adenine dinucleotide (NAD+) in mammals. Immune system activation and the buildup of potentially neurotoxic substances can result from the dysregulation or overactivation of this pathway. Therefore, it is not shocking that kynurenines have been linked to neurological conditions (Depression, Parkinson's, Alzheimer's, Huntington's Disease, Schizophrenia, and cognitive deficits) in relation to inflammation. Nevertheless, preclinical research has demonstrated that kynurenines are essential components of the behavioral analogs of depression and schizophrenia-like cognitive deficits in addition to mediators associated with neurological pathologies due to their neuromodulatory qualities. Neurodegenerative diseases have been extensively associated with neuroactive metabolites of the kynurenine pathway (KP) of tryptophan breakdown. In addition to being a necessary amino acid for protein synthesis, Tryptophan is also transformed into the important neurotransmitters tryptamine and serotonin in higher eukaryotes. In this article, a summary of the KP, its function in neurodegeneration, and the approaches being used currently to target the route therapeutically are discussed.

Prescription of panoramic radiographs in children using age-based prevalence of dental anomalies and pathologies.

BACKGROUND: Panoramic radiographs (PRs) are used in the detection and diagnosis of developmental dental anomalies and pathologies (DDAPs) in children. AIM: The primary objective of this observational cohort study was to evaluate the age-based prevalence of DDAP on PRs, whereas the secondary objective was to determine a threshold age for the detection of DDAP to provide supportive evidence for the prescription of PR in paediatric dental practice. DESIGN: The study examined diagnostic PRs from 581 subjects aged 6 to 19 years. All PRs were reviewed by experienced, calibrated, masked examiners for the identification or presence of anomalies in size, shape, position, structure, and other developmental anomalies and pathologies (ODAP) of the face-neck region in a standardized condition. The data were statistically analyzed for interpretation. RESULTS: Overall, 74% (n = 411) of the cohort had at least one anomaly (shape anomaly: 12%, number anomaly: 17%, positional anomaly: 28%, structural anomaly: 0%, and ODAP: 63%). The optimal Youden index cutoff for any anomaly was 9 years. Twelve and 15 years also showed predictive ability. CONCLUSION: The results suggest that PRs should be prescribed at ages 9, 12, and 15 years for the diagnosis of DDAP.

Tunable assembly of host-guest colloidal crystals.

Entropy compartmentalization provides new self-assembly routes to colloidal host-guest (HG) structures. Leveraging host particle shape to drive the assembly of HG structures has only recently been proposed and demonstrated. However, the extent to which the guest particles can dictate the structure of the porous network of host particles has not been explored. In this work, by modifying only the guest shape, we show athermal, binary mixtures of star-shaped host particles and convex polygon-shaped guest particles assemble as many as five distinct crystal structures, including rotator and discrete rotator guest crystals, two homoporous host crystals, and one heteroporous host crystal. Edge-to-edge alignment of neighboring stars results in the formation of three distinct pore motifs, whose preferential formation is controlled by the size and shape of the guest particles. Finally, we confirm, via free volume calculations, that assembly is driven by entropy compartmentalization, where the hosts and guests contribute differently to the free energy of the system; free volume calculations also explain differences in assembly based on guest shape. These results provide guest design rules for assembling colloidal HG structures, especially on surfaces and interfaces.

Inverse design of triblock Janus spheres for self-assembly of complex structures in the crystallization slot via digital alchemy.

The digital alchemy framework is an extended ensemble simulation technique that incorporates particle attributes as thermodynamic variables, enabling the inverse design of colloidal particles for desired behavior. Here, we extend the digital alchemy framework for the inverse design of patchy spheres that self-assemble into target crystal structures. To constrain the potentials to non-trivial solutions, we conduct digital alchemy simulations with constant second virial coefficient. We optimize the size, range, and strength of patchy interactions in model triblock Janus spheres to self-assemble the 2D kagome and snub square lattices and the 3D pyrochlore lattice, and demonstrate self-assembly of all three target structures with the designed models. The particles designed for the kagome and snub square lattices assemble into high quality clusters of their target structures, while competition from similar polymorphs lower the yield of the pyrochlore assemblies. We find that the alchemically designed potentials do not always match physical intuition, illustrating the ability of the method to find nontrivial solutions to the optimization problem. We identify a window of second virial coefficients that result in self-assembly of the target structures, analogous to the crystallization slot in protein crystallization.

Oxidative stress and COVID-19-associated neuronal dysfunction: mechanisms and therapeutic implications.

Severe acute respiratory syndrome (SARS)-CoV-2 virus causes novel coronavirus disease 2019 (COVID-19), and there is a possible role for oxidative stress in the pathophysiology of neurological diseases associated with COVID-19. Excessive oxidative stress could be responsible for the thrombosis and other neuronal dysfunctions observed in COVID-19. This review discusses the role of oxidative stress associated with SARS-CoV-2 and the mechanisms involved. Furthermore, the various therapeutics implicated in treating COVID-19 and the oxidative stress that contributes to the etiology and pathogenesis of COVID-19-induced neuronal dysfunction are discussed. Further mechanistic and clinical research to combat COVID-19 is warranted to understand the exact mechanisms, and its true clinical effects need to be investigated to minimize neurological complications from COVID-19.

Role of cGAS-Sting Signaling in Alzheimer's Disease.

There is mounting evidence that the development of Alzheimer's disease (AD) interacts extensively with immunological processes in the brain and extends beyond the neuronal compartment. Accumulation of misfolded proteins can activate an innate immune response that releases inflammatory mediators and increases the severity and course of the disease. It is widely known that type-I interferon-driven neuroinflammation in the central nervous system (CNS) accelerates the development of numerous acute and chronic CNS diseases. It is becoming better understood how the cyclic GMP-AMP synthase (cGAS) and its adaptor protein Stimulator of Interferon Genes (STING) triggers type-I IFN-mediated neuroinflammation. We discuss the principal elements of the cGAS-STING signaling pathway and the mechanisms underlying the association between cGAS-STING activity and various AD pathologies. The current understanding of beneficial and harmful cGAS-STING activity in AD and the current treatment pathways being explored will be discussed in this review. The cGAS-STING regulation offers a novel therapeutic opportunity to modulate inflammation in the CNS because it is an upstream regulator of type-I IFNs.

Tuning Stoichiometry to Promote Formation of Binary Colloidal Superlattices.

The self-assembly of binary nanoparticle superlattices from colloidal mixtures is a promising method for the fabrication of complex colloidal cocrystal structures. However, binary mixtures often form amorphous or metastable phases instead of the thermodynamically stable phase. Here we show that in binary mixtures of differently sized spherical particles, an excess of the smaller component can promote-and, in some cases, may be necessary for-the self-assembly of a binary cocrystal. Using computer simulations, we identify two mechanisms responsible for this phenomenon. First, excess small particles act like plasticizers and enable systems to reach a greater supersaturation before kinetic arrest occurs. Second, they can disfavor competing structures that may interfere with the growth of the target structure. We find the phase behavior of simulated mixtures of nearly hard spheres closely matches published experimental results. We demonstrate the generality of our findings for mixtures of particles of arbitrary shape by presenting a binary mixture of hard shapes that only self-assembles with an excess of the smaller component.

Multiscale Simulation of Ternary Stratum Corneum Lipid Mixtures: Effects of Cholesterol Composition.

Molecular dynamics simulations of mixtures of the ceramide nonhydroxy-sphingosine (NS), cholesterol, and a free fatty acid are performed to gain molecular-level understanding of the structure of the lipids found in the stratum corneum layer of skin. A new coarse-grained force field for cholesterol was developed using the multistate iterative Boltzmann inversion (MS-IBI) method. The coarse-grained cholesterol force field is compatible with previously developed coarse-grained force fields for ceramide NS, free fatty acids, and water and validated against atomistic simulations of these lipids using the CHARMM force field. Self-assembly simulations of multilayer structures using these coarse-grained force fields are performed, revealing that a large fraction of the ceramides adopt extended conformations, which cannot occur in the single bilayer in water structures typically studied using molecular simulation. Cholesterol fluidizes the membrane by promoting packing defects, and an increase in cholesterol content is found to reduce the bilayer thickness due to an increase in interdigitation of the C24 lipid tails, consistent with experimental observations. Using a reverse-mapping procedure, a self-assembled coarse-grained multilayer system is used to construct an equivalent structure with atomistic resolution. Simulations of this atomistic structure are found to closely agree with experimentally derived neutron scattering length density profiles. Significant interlayer hydrogen bonding is observed in the inner layers of the atomistic multilayer structure that are not found in the outer layers in contact with water or in equivalent bilayer structures. This work highlights the importance of simulating multilayer structures, as compared to the more commonly studied bilayer systems, to enable more appropriate comparisons with multilayer experimental membranes. These results also provide validation of the efficacy of the MS-IBI derived coarse-grained force fields and the framework for multiscale simulation.

Health influence of SARS-CoV-2 (COVID-19) on cancer: a review.

The novel coronavirus, namely, SARS-CoV-2 (COVID-19), broke out two years ago and has caused major global health issues. Adequate treatment options are still lacking for the management of COVID-19 viral infections. Many patients afflicted with COVID-19 may range from asymptomatic to severe symptomatic, triggering poor clinical outcomes, morbidity, and mortality. Cancer is one of the leading causes of death worldwide. It is pertinent to re-examine cancer prevalence during the COVID-19 pandemic to prevent mortality and complications. Understanding the impact of SARS-CoV-2 on cancer is key to appropriate healthcare measures for the treatment and prevention of this vulnerable population. Data was acquired from PubMed using key search terms. Additional databases were utilized, such as the Centers for Disease Prevention and Control, American Cancer Society (ACS), and National Cancer Institute (NCI). Cancer patients are more prone to SARS-CoV-2 infection and exhibit poor health outcomes, possibly due to a chronic immunosuppressive state and anticancer therapies. Male sex, older age, and active cancer disease or previous cancer are risk factors for COVID-19 infection, leading to possible severe complications, including morbidity or mortality. The speculated mechanism for potentially higher mortality or COVID-19 complications is through reduced immune system function and inflammatory processes through cancer disease, anticancer therapy, and active COVID-19 infection. This review includes prostate, breast, ovarian, hematologic, lung, colorectal, esophageal, bladder, pancreatic, cervical, and head and neck cancers. This review should help better maintain the health of cancer patients and direct clinicians for COVID-19 prevention to improve the overall health outcomes.

Shape-driven entropic self-assembly of an open, reconfigurable, binary host-guest colloidal crystal.

Entropically driven self-assembly of hard anisotropic particles, where particle shape gives rise to emergent valencies, provides a useful perspective for the design of nanoparticle and colloidal systems. Hard particles self-assemble into a rich variety of crystal structures, ranging in complexity from simple close-packed structures to structures with 432 particles in the unit cell. Entropic crystallization of open structures, however, is missing from this landscape. Here, we report the self-assembly of a two-dimensional binary mixture of hard particles into an open host-guest structure, where nonconvex, triangular host particles form a honeycomb lattice that encapsulates smaller guest particles. Notably, this open structure forms in the absence of enthalpic interactions by effectively splitting the structure into low- and high-entropy sublattices. This is the first such structure to be reported in a two-dimensional athermal system. We discuss the observed compartmentalization of entropy in this system, and show that the effect of the size of the guest particle on the stability of the structure gives rise to a reentrant phase behavior. This reentrance suggests the possibility for a reconfigurable colloidal material, and we provide a proof-of-concept by showing the assembly behavior while changing the size of the guest particles in situ. Our findings provide a strategy for designing open colloidal crystals, as well as binary systems that exhibit co-crystallization, which have been elusive thus far.

More 'milk' than 'psychology or tablets': Mental health professionals' perspectives on the value of peer support workers.

BACKGROUND: Though growing numbers of peer support workers are employed in the UK National Health Service (NHS), conflicts persist between core values of peer support and values which exert power within these services. OBJECTIVES: To explore what NHS mental health professionals value about the peer support worker role. DESIGN: Five professionals from different professions and mental health settings were interviewed twice. The first interviews explored their experiences of working with peers. Transcripts were analysed using discourse analysis and psychosocial theory. Second interviews allowed participants to respond to the analysis and influence subsequent analysis. RESULTS: Mental health professionals valued peers for the deeply empathic, relational approach they brought, based in their subjective experience. Peer work was also valued for the affect-focused quality of this work, and the challenge peers pose to existing values in mental health services. The values of peer support troubled dominant ways of working based in forms of knowledge that favour objectivity and hence encountered challenges. CONCLUSIONS: Peers fulfil the role of amplifying the status of diverse forms of knowledge, values and related ways of working that have become marginalized in NHS mental health services. It is important that peers are not seen as an isolated solution to the marginalization of these forms of knowledge and values, but that their way of working becomes reflected in other roles whilst evoking change throughout these services. PATIENT OR PUBLIC CONTRIBUTION: Patient and Public Involvement groups were consulted both in the design and analysis stages of the study.

ß-hydroxybutyric acid attenuates oxidative stress and improves markers of mitochondrial function in the HT-22 hippocampal cell line.

Ketone bodies have been the topic of research for their possible therapeutic neurotropic effects in various neurological diseases such as Parkinson's disease, dementia, and seizures. However, continuing research on ketone bodies as a prophylactic agent for decreasing the risk for various neurodegenerative diseases is currently required. In this paper, hippocampal HT-22 cells were treated with ß-hydroxybutyric acid at different doses to elucidate the neurotropic effects. In addition, markers of oxidative stress, mitochondrial function, and apoptosis were investigated. As a result, the ketone body (ß-hydroxybutyric acid) showed a significant increase in hippocampal neuronal viability at a moderate dose. Results show that ß-hydroxybutyric acid exhibited antioxidant effect by decreasing prooxidant oxidative stress markers such as reactive oxygen species, nitrite content, and increasing glutathione content leading to decreased lipid peroxidation. Results show that ß-hydroxybutyric acid improved mitochondrial functions by increasing Complex-I and Complex-IV activities and showing that ß-hydroxybutyric acid significantly reduces caspase-1 and caspase-3 activities. Finally, using computational pharmacokinetics and molecular modeling software, we validated the pharmacokinetic effects and pharmacodynamic (N-Methyl-D-aspartic acid and acetylcholinesterase) interactions of ß-hydroxybutyric acid. The computational studies demonstrate that ß-hydroxybutyric acid can interact with N-Methyl-D-aspartic acid receptor and cholinesterase enzyme (the prime pharmacodynamic targets for cognitive impairment) and further validates its oral absorption, distribution into the central nervous system. Therefore, this work highlights the neuroprotective potential of ketone bodies in cognitive-related neurodegenerative diseases.

Optical backscattering and linear polarization properties of the colony forming cyanobacterium Microcystis.

Light scattering characteristics of the cyanobacterium Microcystis are investigated with numerical models for sphere aggregates. During summer bloom seasons, Microcystis is prevalent in many inland waters across the globe. Monitoring concentrations with remote sensing techniques requires knowledge of the inherent optical properties (IOPs), especially the backscattering properties of Microcystis cells and colonies in natural settings. In situ measurements in waters dominated by Microcystis blooms have previously detected extremely high backscattering ratios, i.e., bb/b>0.043 at 443 nm [1], the highest to our knowledge in the natural environment. These highbb/bvalues could hold promise as a diagnostic tool in identifying and monitoring Microcystis using optical approaches. However, it has been unclear how this type of optically 'soft' organic particle can generate such highbb/bvalues. In this study, the Multiple Sphere T-matrix (MSTM) model is used to calculate the IOPs of model colonies, including bb/b. Colony sizes in the model ranged from several cells to several hundred and both colony packing density and cell gas vacuole content were varied. Results are compared with model results for equivalent-volume spheres (EVS) and direct in situ measurements. Colony formation was required in the modeling to reproduce the high bb/bconsistent with in situ measurements. The combination of moderate to very dense colony (packing density >30%) and high gas vacuole content in individual cells (volume percentage >20%) was the most favorable condition leading to rapid increases in bb/bwith increasing number of cells Ncell of the colony. Significant linear correlations were observed betweenbb/b and Ncell1/3 for these colonies, wherebb/b increased beyond 0.04 once cell number reached about 1000 cells in the case with the most densely packed cells and highest gas vacuole content. Within commonly observed colony sizes (Ncell <106), colonies with high gas vacuole content exhibited bb/bvalues up to 0.055, consistent with direct measurements from Lake Erie. Polarized scattering was also of interest as a diagnostic tool, particularly with future Earth-orbiting polarimeters being deployed for the NASA Plankton, Aerosols, Cloud, ocean Ecosystem (PACE) mission. The Degree of Linear Polarization (DoLP), expressed by the ratio of two Mueller matrix elements-P12/P11, decreased with increasing colony cell number for Microcystis. Another ratio of two Mueller matrix elementsP22/P11, an index for nonsphericity, also decreased with increasing colony size. In addition to higher relative backscattering, greater colony packing density and larger gas vacuole sizes both led to lower DoLP peak magnitude and lowerP22/P11. An optical opposition feature due to constructive phase interference that was observed previously for cosmic dusts is also present for these modeled colonies, manifested by a narrow intensity peak and negative polarization dip near exact backscattering direction, gradually forming as colony size increases.

Accelerating the development of innovative cellular therapy products for the treatment of cancer.

The field of cell therapy is rapidly emerging as a priority area for oncology research and drug development. Currently, two chimeric antigen receptor T-cell therapies are approved by the US Food and Drug Administration and other agencies worldwide for two types of hematologic cancers. To facilitate the development of these therapies for patients with life-threatening cancers with limited or no therapeutic options, science- and risk-based approaches will be critical to mitigating and balancing any potential risk associated with either early clinical research or more flexible manufacturing paradigms. Friends of Cancer Research and the Parker Institute for Cancer Immunotherapy convened an expert group of stakeholders to develop specific strategies and proposals for regulatory opportunities to accelerate the development of cell therapies as promising new therapeutics. This meeting took place in Washington, DC on May 17, 2019. As academia and industry expand research efforts and cellular product development pipelines, this report summarizes opportunities to accelerate entry into the clinic for exploratory studies and optimization of cell products through manufacturing improvements for these promising new therapies.

Leaf margins in a deciduous lineage from the Greater Cape Floristic Region track climate in unexpected directions.

PREMISE: The functional significance of leaf margins has long been debated. In this study, we explore influences of climate, leaf lobing, woodiness, and shared evolutionary history on two leaf margin traits within the genus Pelargonium. METHODS: Leaves from 454 populations of Pelargonium (161 species) were collected in the Greater Cape Floristic Region and scored for tooth presence/absence and degree of lobing. Tooth density (number of teeth per interior perimeter distance) was calculated for a subset of these. We compared five hypotheses to explain tooth presence and density using mixed effect models. RESULTS: Tooth presence/absence was best predicted by the interaction of leaf lobing and mean annual temperature (MAT), but often in patterns opposite those previously reported: species were more likely to be toothed with warmer temperatures, particularly for unlobed and highly lobed leaves. In contrast, tooth density was best predicted by the interaction of MAT and the season of most rain; density declines with temperature as consistent with expectations, but only in winter-rain dominated areas. Woody and nonwoody species within Pelargonium have similar associations between tooth presence/absence and MAT, contrary to the expectation that patterns within nonwoody species would be insignificant. CONCLUSIONS: We conclude Pelargonium leaf margins show predictable responses to climate, but these responses are complex and can contradict those found for global patterns across plant communities.

Predictable hematological markers associated with cognitive decline in valid rodent models of cognitive impairment.

Endogenous (hyperglycemia) and exogenous (therapeutic, prophylactic, street drugs) factors can considerably contribute to cognitive impairment (CI). Currently, there are few invasive and/or noninvasive markers that correlate with CI and those that do exist require expensive or invasive techniques to predict and accurately measure the cognitive decline. Therefore, we sought to determine hematological markers as predictors of CI in two different chemically induced valid rodent models of CI (streptozotocin induced hyperglycemic model and chemotherapy [doxorubicin/cyclophosphamide] treated rodent model). Hematological markers were analyzed in the above rodent models of CI CI and compared to their respective control groups. There was a significant increase in creatinine kinase, lactate dehydrogenase and aspartate aminotransferase (AST) in the chemotherapy group. Blood urea nitrogen (BUN), alkaline phosphatase (ALP), bilirubin, creatinine and glucose levels were significantly increased in the streptozotocin group. Interestingly, triglycerides were significantly elevated in both the streptozotocin and chemotherapy groups. Previous studies with human subjects have shown a potential link between the increase in triglyceride levels and CI. Likewise, our data indicate a notable correlation with an increase in triglycerides to cognitive impairment in the rodent models. This suggests elevated levels of triglycerides could prove to be a potential noninvasive hematological marker for the increased risk of CI. Further studies are warranted to determine the causal relationship between elevated triglyceride levels and CI.

Assessing Residents' Skills in Psychiatric Reasoning: the Tufts Test of Formulation and Treatment Planning.

OBJECTIVE: The authors aimed to develop an easily administered and scored written test of clinical reasoning for psychiatry residents and to explore its internal reliability and correlation with parameters of training. METHODS: The authors developed a case-based, multiple-choice test comprising 83 questions related to data gathering and interpretation, diagnosis, hypothesis generation and testing, and treatment planning. Postgraduate years 1-4 residents at 18 diverse residency programs, along with their Program Directors and/or Associate Program Directors, took the test. Outcome measures included internal reliability statistics, performance across levels of training, performance in different test categories, performance in programs with high vs. low emphasis on integrative case formulation, and performance in native English speakers vs. others. RESULTS: A total of 359 residents and 23 faculty members participated. The KR-20 statistic of 0.78 indicated that the test was internally reliable. Faculty performed better than residents, who began to approach faculty level only in their fourth year. Residents in programs with high emphasis on formulation and treatment planning tended to score better than those from low emphasis programs on hypothesis generation and testing, but not other categories of question. There was no evidence that non-native English speakers were at a disadvantage on the test. CONCLUSIONS: A novel test of formulation and treatment planning has met criteria for internal reliability and provided preliminary data about development of reasoning skills in residents. The authors hope that taking and discussing it will also be useful as a training exercise in integrative case formulation.

Estrogen receptor α protects pancreatic ß-cells from apoptosis by preserving mitochondrial function and suppressing endoplasmic reticulum stress.

Estrogen receptor α (ERα) action plays an important role in pancreatic ß-cell function and survival; thus, it is considered a potential therapeutic target for the treatment of type 2 diabetes in women. However, the mechanisms underlying the protective effects of ERα remain unclear. Because ERα regulates mitochondrial metabolism in other cell types, we hypothesized that ERα may act to preserve insulin secretion and promote ß-cell survival by regulating mitochondrial-endoplasmic reticulum (EndoRetic) function. We tested this hypothesis using pancreatic islet-specific ERα knockout (PERαKO) mice and Min6 ß-cells in culture with Esr1 knockdown (KD). We found that Esr1-KD promoted reactive oxygen species production that associated with reduced fission/fusion dynamics and impaired mitophagy. Electron microscopy showed mitochondrial enlargement and a pro-fusion phenotype. Mitochondrial cristae and endoplasmic reticulum were dilated in Esr1-KD compared with ERα replete Min6 ß-cells. Increased expression of Oma1 and Chop was paralleled by increased oxygen consumption and apoptosis susceptibility in ERα-KD cells. In contrast, ERα overexpression and ligand activation reduced both Chop and Oma1 expression, likely by ERα binding to consensus estrogen-response element sites in the Oma1 and Chop promoters. Together, our findings suggest that ERα promotes ß-cell survival and insulin secretion through maintenance of mitochondrial fission/fusion-mitophagy dynamics and EndoRetic function, in part by Oma1 and Chop repression.