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Acute myeloid leukemia (AML) is a heterogeneous and deadly disease characterized by uncontrolled expansion of malignant blasts. Altered metabolism and dysregulated microRNA (miRNA) expression profiles are both characteristic of AML. However, there is a paucity of studies exploring how changes in the metabolic state of the leukemic cells regulate miRNA expression leading to altered cellular behavior. Here, we blocked pyruvate entry into mitochondria by deleting the Mitochondria Pyruvate Carrier (MPC1) gene in human AML cell lines, which decreased Oxidative Phosphorylation (OXPHOS). This metabolic shift also led to increased expression of miR-1 in the human AML cell lines tested. AML patient sample datasets showed that higher miR-1 expression correlates with reduced survival. Transcriptional and metabolic profiling of miR-1 overexpressing AML cells revealed that miR-1 increased OXPHOS, along with key metabolites that fuel the TCA cycle such as glutamine and fumaric acid. Inhibition of glutaminolysis decreased OXPHOS in miR-1 overexpressing MV4-11 cells, highlighting that miR-1 promotes OXPHOS through glutaminolysis. Finally, overexpression of miR-1 in AML cells exacerbated disease in a mouse xenograft model. Together, our work expands current knowledge within the field by uncovering novel connections between AML cell metabolism and miRNA expression that facilitates disease progression. Further, our work points to miR-1 as a potential new therapeutic target that may be used to disrupt AML cell metabolism and thus pathogenesis in the clinic.

Intercellular communication is critical for homeostasis in mammalian systems, including the gastrointestinal (GI) tract. Exosomes are nanoscale lipid extracellular vesicles that mediate communication between many cell types. Notably, the roles of immune cell exosomes in regulating GI homeostasis and inflammation are largely uncharacterized. By generating mouse strains deficient in cell-specific exosome production, we demonstrate deletion of the small GTPase Rab27A in CD11c+ cells exacerbated murine colitis, which was reversible through administration of DC-derived exosomes. Profiling RNAs within colon exosomes revealed a distinct subset of miRNAs carried by colon- and DC-derived exosomes. Among antiinflammatory exosomal miRNAs, miR-146a was transferred from gut immune cells to myeloid and T cells through a Rab27-dependent mechanism, targeting Traf6, IRAK-1, and NLRP3 in macrophages. Further, we have identified a potentially novel mode of exosome-mediated DC and macrophage crosstalk that is capable of skewing gut macrophages toward an antiinflammatory phenotype. Assessing clinical samples, RAB27A, select miRNAs, and RNA-binding proteins that load exosomal miRNAs were dysregulated in ulcerative colitis patient samples, consistent with our preclinical mouse model findings. Together, our work reveals an exosome-mediated regulatory mechanism underlying gut inflammation and paves the way for potential use of miRNA-containing exosomes as a novel therapeutic for inflammatory bowel disease.

The rising toll of cancer globally necessitates ingenuity in early detection and therapy. In the last decade, the utilization of immune signatures and immune-based therapies has made significant progress in the clinic; however, clinical standards leave many current and future patients without options. Non-coding RNAs, specifically microRNAs, have been explored in pre-clinical contexts with tremendous success. MicroRNAs play indispensable roles in programming the interactions between immune and cancer cells, many of which are current or potential immunotherapy targets. MicroRNAs mechanistically control a network of target genes that can alter immune and cancer cell biology. These insights provide us with opportunities and tools that may complement and improve immunotherapies. In this review, we discuss immune and cancer cell–derived miRNAs that regulate cancer immunity and examine miRNAs as an integral part of cancer diagnosis, classification, and therapy.

IFNy can polarize macrophages in the tumour microenvironment to an inflammatory state and thereby contributes to their anti-tumour function. Here the authors show an underlying mechanism in this process is IFNy-driven STAT1 occupancy and activation of NRE1, a regulatory region within the NAMPT gene, thereby implicating inducible NAD salvage synthesis in TAM functions.

Summary: Intestinal epithelial cells (IECs) have long been understood to express high levels of major histocompatibility complex class II (MHC class II) molecules but are not considered canonical antigen-presenting cells, and the impact of IEC-MHC class II signaling on gut homeostasis remains enigmatic. As IECs serve as the primary barrier between underlying host immune cells, we reasoned that IEC-intrinsic antigen presentation may play a role in responses toward the microbiota. Mice with an IEC-intrinsic deletion of MHC class II (IECΔMHC class II) are healthy but have fewer microbial-bound IgA, regulatory T cells (Tregs), and immune repertoire selection. This was associated with increased interindividual microbiota variation and altered proportions of two taxa in the ileum where MHC class II on IECs is highest. Intestinal mononuclear phagocytes (MNPs) have similar MHC class II transcription but less surface MHC class II and are capable of acquiring MHC class II from IECs. Thus, epithelial-myeloid interactions mediate development of adaptive responses to microbial antigens within the gastrointestinal tract.

Summary: Metabolic pathways regulate T cell development and function, but many remain understudied. Recently, the mitochondrial pyruvate carrier (MPC) was identified as the transporter that mediates pyruvate entry into mitochondria, promoting pyruvate oxidation. Here we find that deleting Mpc1, an obligate MPC subunit, in the hematopoietic system results in a specific reduction in peripheral αβ T cell numbers. MPC1-deficient T cells have defective thymic development at the β-selection, intermediate single positive (ISP)-to-double-positive (DP), and positive selection steps. We find that early thymocytes deficient in MPC1 display alterations to multiple pathways involved in T cell development. This results in preferred escape of more activated T cells. Finally, mice with hematopoietic deletion of Mpc1 are more susceptible to experimental autoimmune encephalomyelitis. Altogether, our study demonstrates that pyruvate oxidation by T cell precursors is necessary for optimal αβ T cell development and that its deficiency results in reduced but activated peripheral T cell populations. : Ramstead et al. show that mitochondrial pyruvate carrier 1, which mediates mitochondrial uptake of pyruvate, is necessary for proper development of αβ T cells. Consequently, deletion of MPC1 in early thymic development results in reduced numbers and abnormal activation of peripheral αβ T cells.

Ketamine has been found to have rapid, long-lasting antidepressant effects in treatment-resistant (TR) patients with major depressive disorder (MDD). Recently, we have also shown that ketamine acts as a prophylactic to protect against the development of stress-induced depressive-like behavior in mice, indicating that a preventative treatment against mental illness using ketamine is possible. While there is significant investigation into ketamine’s antidepressant mechanism of action, little is known about ketamine’s underlying prophylactic mechanism. More specifically, whether ketamine’s prophylactic action is molecularly similar to or divergent from its antidepressant action is entirely unknown. Here, we sought to characterize immunohistochemical signatures of cell populations governing ketamine’s antidepressant and prophylactic effects. 129S6/SvEv mice were treated with saline (Sal) or ketamine (K) either before a social defeat (SD) stressor as a prophylactic, or after SD as an antidepressant, then subsequently assessed for depressive-like behavior. Post-fixed brains were processed for doublecortin (DCX), calretinin (CR) and calbindin (CB) expression. The number of DCX+ neurons in the dentate gyrus (DG) of the hippocampus (HPC) was not affected by prophylactic or antidepressant ketamine treatment, while the number of CR+ neurons in the ventral hilus increased with antidepressant ketamine under SD conditions. Moreover, antidepressant, but not prophylactic ketamine administration significantly altered CR and CB expression in the ventral HPC (vHPC). These data show that while antidepressant ketamine treatment mediates some of its effects via adult hippocampal markers, prophylactic ketamine administration does not, at least in 129S6/SvEv mice. These data suggest that long-lasting behavioral effects of prophylactic ketamine are independent of hippocampal DCX, CR and CB expression in stress-susceptible mice.

[This corrects the article DOI: 10.1371/journal.ppat.1007474.].

Several Zika virus (ZIKV) vaccines designed to elicit protective antibody (Ab) responses are currently under rapid development, but the underlying mechanisms that control the magnitude and quality of the Ab response remain unclear. Here, we investigated the CD4+ T cell response to primary intravenous and intravaginal infection with ZIKV. Using the LysMCre+Ifnar1fl/fl (myeloid type I IFN receptor-deficient) C57BL/6 mouse models, we identified six I-Ab-restricted ZIKV epitopes that stimulated CD4+ T cells with a predominantly cytotoxic Th1 phenotype in mice primed with ZIKV. Intravenous and intravaginal infection with ZIKV effectively induced follicular helper and regulatory CD4+ T cells. Treatment of mice with a CD4+ T cell-depleting Ab reduced the plasma cell, germinal center B cell, and IgG responses to ZIKV without affecting the CD8+ T cell response. CD4+ T cells were required to protect mice from a lethal dose of ZIKV after infection intravaginally, but not intravenously. However, adoptive transfer and peptide immunization experiments showed a role for memory CD4+ T cells in ZIKV clearance in mice challenged intravenously. These results demonstrate that CD4+ T cells are required mainly for the generation of a ZIKV-specific humoral response but not for an efficient CD8+ T cell response. Thus, CD4+ T cells could be important mediators of protection against ZIKV, depending on the infection or vaccination context.

Infection with one of the four dengue virus serotypes (DENV1-4) presumably leads to lifelong immunity against the infecting serotype but not against heterotypic reinfection, resulting in a greater risk of developing Dengue Hemorrhagic Fever/Dengue Shock Syndrome (DHF/DSS) during secondary infection. Both antibodies and T cell responses have been implicated in DHF/DSS pathogenesis. According to the T cell-based hypothesis termed “original antigenic sin,” secondary DENV infection is dominated by non-protective, cross-reactive T cells that elicit an aberrant immune response. The goal of our study was to compare the roles of serotype-specific and cross-reactive T cells in protection vs. pathogenesis during DENV infection in vivo. Specifically, we utilized IFN-α/βR−/− HLA*B0702 transgenic mice in the context of peptide vaccination with relevant human CD8 T cell epitopes. IFN-α/βR−/− HLA*B0702 transgenic mice were immunized with DENV serotype 2 (DENV2)-specific epitopes or variants found in any of the other three serotypes (DENV1, DENV3 or DENV4), followed by challenge with DENV. Although cross-reactive T cell responses were lower than responses elicited by serotype-specific T cells, immunization with either serotype-specific or variant peptide epitopes enhanced viral clearance, demonstrating that both serotype-specific and cross-reactive T cells can contribute to protection in vivo against DENV infection.

Traditional Chinese medicine (TCM) has been frequently used as skin lightning agents. However, the mechanism of action of their effect is unclear. The present study aims to evaluate anti-tyrosinase activity of 10 commonly used TCM on mushroom ( ab ), human ( hs ) and mouse melanoma B16F0 ( mm ) tyrosinase (TYR) respectively. The results showed that at 1.0 mg/mL, extracts from Rosa rugosa Thumb, Morus alba L. and Paeonia lactiflora Pall were active against both ab TYR and hs TYR (>50% inhibition), extracts from Bletilla striata (Thunb.) Rchb. F. , Centella asiatica (L.) Urb , Cynanchum atratum L., Rosa canina L. , Rhus chinensis Mill. and Glycyrrhiza urolensis Fisch. Ex DC. inhibited either ab TYR or hs TYR (>50%), while extract from Tribulus terrestris L. had no/minimal activity (<10% inhibition). When treated with melanoma B16F0 cells, M. alba also significantly reduced mm TYR activity (70% at 250 μg/mL) and melanin content (50% at 250 μg/mL). These findings demonstrated inhibitory effects of 9 TCM against TYR and hence support their application as skin lightning agents. Our results also showed discrepancies in TYR activity from different sources, suggesting a testing regime of combining ab TYR, hs TYR and mm TYR when developing depigmentation agents for human application., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

The Internet of Things (IoT) has become critical to the implementation of Industry 4.0. The successful operation of smart manufacturing depends on the ability to connect everything together. In this research, we applied the TOC (Theory of Constraints) to develop a wireless Wi-Fi intelligent programmable IoT controller that can be connected to and easily control PLCs. By applying the TOC-focused thinking steps to break through their original limitations, the development process guides the user to use the powerful and simple flow language process control syntax to efficiently connect to PLCs and realize the full range of IoT applications. Finally, this research uses oil-water mixer equipment as the target of continuous improvement and verification. The verification results meet the requirements of the default function. The IoT controller developed in this research uses a marine boiler to illustrate the application. The successful development of flow control language by TOC in this research will enable academic research on PLC-derivative applications. The results of this research will help more SMEs to move into smart manufacturing and the new realm of Industry 4.0.

Two beetles, Ceratophila (Vovidesa) chipjonesi, new species, and Pharaxonotha perezi, new species, (Coleoptera: Erotylidae: Pharaxonothinae) are described from the male cones of the New World cycad Ceratozamia santillanii Prez-Farr. Vovides (Cycadales: Zamiaceae). Morphological analysis and keys are provided for distinguishing these from related beetles inhabiting Ceratozamia in Mexico.

This paper applies the modified undesirable dynamic data envelopment analysis (DEA) model by considering the role of forest carbon sinks to evaluate European countries' carbon dioxide (CO 2 ) emissions and productivity efficiency. Taking population and energy consumption as input variables, gross domestic product (GDP) as the desirable input, CO 2 as the undesirable output, and fixed assets as an inter-temporal carry-out input variable, our results suggest considering the fixed amount of the forest carbon sinks significantly affects efficiency rankings. The overall efficiency rankings for Ireland, Austria, Italy, Germany, Spain, and Belgium look to be overrated, while those of Finland, France, and Netherlands are apparently underrated. In terms of Total-Factor Efficiency analysis, countries with the best performance in efficiency ranking are Denmark, Luxembourg, Norway, Sweden, and the UK, thanks to their long-term effort at addressing the impact of forest carbon sinks and the effect of CO 2 emissions on efficiency., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In this community review report, we discuss applications and techniques for fast machine learning (ML) in science-the concept of integrating powerful ML methods into the real-time experimental data processing loop to accelerate scientific discovery. The material for the report builds on two workshops held by the Fast ML for Science community and covers three main areas: applications for fast ML across a number of scientific domains; techniques for training and implementing performant and resource-efficient ML algorithms; and computing architectures, platforms, and technologies for deploying these algorithms. We also present overlapping challenges across the multiple scientific domains where common solutions can be found. This community report is intended to give plenty of examples and inspiration for scientific discovery through integrated and accelerated ML solutions. This is followed by a high-level overview and organization of technical advances, including an abundance of pointers to source material, which can enable these breakthroughs., Competing Interests: MB was employed by the company Xilinx Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor EC is currently organizing a Research Topic with the authors JD, ML, and JN., (Copyright © 2022 Deiana, Tran, Agar, Blott, Di Guglielmo, Duarte, Harris, Hauck, Liu, Neubauer, Ngadiuba, Ogrenci-Memik, Pierini, Aarrestad, Bähr, Becker, Berthold, Bonventre, Müller Bravo, Diefenthaler, Dong, Fritzsche, Gholami, Govorkova, Guo, Hazelwood, Herwig, Khan, Kim, Klijnsma, Liu, Lo, Nguyen, Pezzullo, Rasoulinezhad, Rivera, Scholberg, Selig, Sen, Strukov, Tang, Thais, Unger, Vilalta, von Krosigk, Wang and Warburton.)

The spatio-temporal flexibility of free-floating carsharing (FFCS) fleets leads to vehicle stock imbalances across the network. One set of strategies for managing fleet distribution involves incentivising users to participate in relocating the vehicles. The objective of this study is to establish FFCS customers' preferences for each of four incentivisation mechanisms: 1) vehicle delivery, 2) paid relocation, and 3-4) incentivisation for alternate vehicle pick-up and drop-off locations. Survey data (n = 311; collected Sept. 2017) from FFCS users in Vancouver and Washington D.C. are employed to quantify willingness-to-pay/accept (WTP/WTA) for these mechanisms. We find that a majority of respondents report positive attitudes ("definitely" or "possibly" willing to use) toward each of the four incentivisation mechanisms, with alternate drop-off the highest (57%) and paid relocation the lowest (40%). Regression analysis finds that user experiences using FFCS are generally stronger predictors of WTP/WTA than socio-demographic features, with (intuitively) the frequency of FFCS unavailability the strongest predictor. Age is the strongest socio-demographic predictor, with the WTP for vehicle delivery increasing and the size of required incentives for alternate pick-up/drop-off locations decreasing with age. Finally, we performed k-means cluster analysis of respondents based on the times-of-week that they report experiencing difficulty finding an available FFCS vehicle, and identified four distinct segments of users. However, we found generally weak relationships between WTP/WTA and the specific time-of-week periods that unavailability is experienced., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 Hong Kong Society for Transportation Studies. Published by Elsevier Ltd. All rights reserved.)

Nuclear fusion power delivered by magnetic-confinement tokamak reactors holds the promise of sustainable and clean energy 1 . The avoidance of large-scale plasma instabilities called disruptions within these reactors 2,3 is one of the most pressing challenges 4,5 , because disruptions can halt power production and damage key components. Disruptions are particularly harmful for large burning-plasma systems such as the multibillion-dollar International Thermonuclear Experimental Reactor (ITER) project 6 currently under construction, which aims to be the first reactor that produces more power from fusion than is injected to heat the plasma. Here we present a method based on deep learning for forecasting disruptions. Our method extends considerably the capabilities of previous strategies such as first-principles-based 5 and classical machine-learning 7-11 approaches. In particular, it delivers reliable predictions for machines other than the one on which it was trained-a crucial requirement for future large reactors that cannot afford training disruptions. Our approach takes advantage of high-dimensional training data to boost predictive performance while also engaging supercomputing resources at the largest scale to improve accuracy and speed. Trained on experimental data from the largest tokamaks in the United States (DIII-D 12 ) and the world (Joint European Torus, JET 13 ), our method can also be applied to specific tasks such as prediction with long warning times: this opens up the possibility of moving from passive disruption prediction to active reactor control and optimization. These initial results illustrate the potential for deep learning to accelerate progress in fusion-energy science and, more generally, in the understanding and prediction of complex physical systems.

Ceratophila new genus (Erotylidae: Pharaxonothinae) inhabiting male cones of the Mesoamerican cycad genus Ceratozamia Brongniart (Zamiaceae) is described for seven new species and compared to other genera of the Pharaxonothinae. Ceratophila differs from other genera of the Pharaxonothinae in many characters, most notable of which are: lateral pronotal carina thicker anteriorly in lateral view; head with supraocular and transverse occipital lines; elytra lacking a basal bead; and stridulatory files at base of head narrowly separated. Ceratophila has the male genitalia laterally compressed with a short median lobe and flagellum, similar to other Erotylidae. In comparison, the most superficially similar pharaxonothine genus Pharaxonotha Reitter has: lateral pronotal carina thin along entire length; head lacking supraocular lines, but with transverse occipital lines; elytra with distinct basal bead; stridulatory files at base of head widely separated; and unique male genitalia that are dorsoventrally flattened with a long median lobe and flagellum. Ceratophila contains two subgenera, which differ most notably in external characters and sexual dimorphism. Members of Ceratophila (Ceratophila), the nominal subgenus, have: more cylindrical bodies, pronotum evenly convex dorsally; the pronotum lacking basal longitudinal grooves on disc; metatibiae that are distinctly triangularly dilated toward apex; and no apparent external sexual dimorphism. In comparison, members of Ceratophila (Vovidesa) new subgenus have: dorsoventrally flattened bodies; the pronotum explanate (concave) along lateral margins; the pronotum with basal longitudinal grooves on disc; metatibiae weakly or not dilated toward apex; and with all tibiae in males showing strong sexual dimorphism. Four new species are described within the subgenus Ceratophila: C. (C.) chemnicki, C. (C.) gregoryi, C. (C.) picipennis, C. (C.) sanchezae; and three new species are described within the subgenus Vovidesa: C. (V.) chiapensis, C. (V.) mixeorum, C. (V.) vazquezi. Keys to genera, subgenera and species of known adults based on morphology are provided.

Interferon-regulatory factors (IRFs) are a family of transcription factors (TFs) that translate viral recognition into antiviral responses, including type I interferon (IFN) production. Dengue virus (DENV) and other clinically important flaviviruses are suppressed by type I IFN. While mice lacking the type I IFN receptor (Ifnar1 -/- ) succumb to DENV infection, we found that mice deficient in three transcription factors controlling type I IFN production (Irf3 -/- Irf5 -/- Irf7 -/- triple knockout [TKO]) survive DENV challenge. DENV infection of TKO mice resulted in minimal type I IFN production but a robust type II IFN (IFN-γ) response. Using loss-of-function approaches for various molecules, we demonstrate that the IRF-3-, IRF-5-, IRF-7-independent pathway predominantly utilizes IFN-γ and, to a lesser degree, type I IFNs. This pathway signals via IRF-1 to stimulate interleukin-12 (IL-12) production and IFN-γ response. These results reveal a key antiviral role for IRF-1 by activating both type I and II IFN responses during DENV infection., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

The genus Cycadophila Xu, Tang & Skelley (Coleoptera: Erotylidae: Pharaxonothinae) associated with Cycas L. (Cycadacaeae) in Asia is reviewed. Strobilophila, new subgenus, with five species is described: Cycadophila (Strobilophila) assamensis new species, C. (S.) hiepi new species, C. (S.) kwaiensis new species, C. (S.) tansachai new species and C. (S.) yangi new species, all associated with Cycas. For the nominate subgenus Cycadophila eight new species are described, Cycadophila (Cycadophila) abyssa new species, C. (C.) collina new species,C. (C.) samara new species, C. (C.) convexa new species, C. (C.) cyclochasma new species, C. (C.) eurynota new species, C. (C.) papua new species, and C. (C.) torquata new species and four new generic combinations are proposed: C. (C.) vittata (Arrow) new combination, C. (C.) discimaculata (Mader) new combination, C. (C.) intermedia (Chûjô) new combination, and C. (C.) lata (Grouvelle) new combination. Only the first three listed species of the nominate subgenus have known associations with Cycas. Species are distinguished on the basis of morphology and/or by analysis of 16S rRNA gene sequences. The larva of subgenus Strobilophila is described based on individuals collected together with adults and matched with analysis of 16S rRNA gene sequences. Keys to subgenera and species of known adults and larvae are provided.

Zika virus (ZIKV)-related neuropathology is an important global health concern. Several studies have shown that ZIKV can infect neural stem cells in the developing brain, but infection in the adult brain has not been examined. Two areas in the adult mouse brain contain neural stem cells: the subventricular zone of the anterior forebrain and the subgranular zone of the hippocampus. Here, using 6-week-old mice triply deficient in interferon regulatory factor (IRF) as a model, we show that blood-borne ZIKV administration can lead to pronounced evidence of ZIKV infection in these adult neural stem cells, leading to cell death and reduced proliferation. Our data therefore suggest that adult as well as fetal neural stem cells are vulnerable to ZIKV neuropathology. Thus, although ZIKV is considered a transient infection in adult humans without marked long-term effects, there may in fact be consequences of exposure in the adult brain., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The antiviral activity of UV-4 was previously demonstrated against dengue virus serotype 2 (DENV2) in multiple mouse models. Herein, step-wise minimal effective dose and therapeutic window of efficacy studies of UV-4B (UV-4 hydrochloride salt) were conducted in an antibody-dependent enhancement (ADE) mouse model of severe DENV2 infection in AG129 mice lacking types I and II interferon receptors. Significant survival benefit was demonstrated with 10-20 mg/kg of UV-4B administered thrice daily (TID) for seven days with initiation of treatment up to 48 h after infection. UV-4B also reduced infectious virus production in in vitro antiviral activity assays against all four DENV serotypes, including clinical isolates. A set of purified enzyme, in vitro, and in vivo studies demonstrated that inhibition of endoplasmic reticulum (ER) α-glucosidases and not the glycosphingolipid pathway appears to be responsible for the antiviral activity of UV-4B against DENV. Along with a comprehensive safety package, these and previously published data provided support for an Investigational New Drug (IND) filing and Phases 1 and 2 clinical trials for UV-4B with an indication of acute dengue disease., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Asian species assigned to Pharaxonotha Reitter formed a separate clade from New World species of the genus and are distinguished on the basis of morphology and analysis of 16S rRNA gene sequences. Cycadophila, new genus, is described based on a consideration of four Asian species in comparison with New World Pharaxonotha. This new genus includes two new species (Cycadophila debaonica new species and Cycadophila fupingensis new species) and two previously described species (Cycadophila nigra (Gorham) new combination and Cycadophila yunnanensis (Grouvelle) new combination). These latter two may represent species complexes. Lectotypes are designated for Thallis nigra Gorham and Pharaxonotha yunnanensis Grouvelle. Larvae of C. debaonica and C. fupingensis are described based on individuals collected on the cones of Cycas debaoensis Y. C. Zhong & C. J. Chen (Cycadaceae), a cycad native to Guangxi and Yunnan provinces, China.

The taxonomy of the weevils inhabiting male cycad cones in the New World is reviewed. All species belong in a single subtribe, Allocorynina, of the family Belidae, subfamily Oxycoryninae and tribe Oxycorynini and are known to develop only in cones of the cycad genera Dioon and Zamia. Most species of Rhopalotria Chevrolat develop in male cones of Zamia ranging from Mexico, Belize, the Caribbean (Cuba, Isle of Youth, Cayman Islands, Jamaica and the Bahamas) to southern Florida, and one species in those of Dioon spinulosum in Mexico. Rhopalotria consists of three previously described species, two previously described genus-group names (treated herein as subgenera) and four new species described herein: subgenus Allocorynus Sharp with R. calonjei n. sp., R. furfuracea n. sp., R. mollis (Sharp) and R. vovidesi n. sp., and the nominate subgenus Rhopalotria with R. dimidiata Chevrolat, R. meerowi n. sp. and R. slossoni (Schaeffer). The species of Parallocorynus Voss develop only in cones of Dioon in Mexico, and the genus consists of one previously described species, the nominate subgenus and three new subgenera and 11 new species described herein: subgenus Dysicorynus n. subg. with P. andrewsi n. sp. and P. sonorensis n. sp., subgenus Eocorynus n. subg. with P. chemnicki n. sp. and P. schiblii n. sp., subgenus Neocorynus n. subg. with P. iglesiasi n. sp. and P. inexpectatus n. sp., and the nominate subgenus Parallocorynus with P. bicolor (Voss), P. gregoryi n. sp., P. jonesi n. sp., P. norstogi n. sp., P. perezfarrerai n. sp. and P. salasae n. sp. Two new genera are described, Protocorynus with one new species in Honduras, P. bontai, and Notorhopalotria with four new species ranging from Costa Rica to Colombia, N. montgomeryensis, N. panamensis, N. platysoma and N. taylori. Keys to genera, subgenera and species are provided. All of these weevils are believed to be involved in pollination of their host cycads.

A 2-week-old infant with normal intracardiac anatomy presented to the emergency department in a hypertensive crisis with acute cardiac failure. Despite extensive evaluation, no underlying disease was found. The patient's hypertension and cardiac dysfunction resolved after 1 week of supportive care in the PICU, and she was discharged within 2 weeks of presentation. The patient's history revealed transplacental exposure to the α-adrenergic agonist methyldopa for 10 weeks before delivery. Her age at presentation and the self-limited nature of cardiac sequelae with complete resolution of cardiac dysfunction suggest withdrawal effects from this exposure. Whereas the rebound hypertensive effects of α-adrenergic agonists are well established in the adult population, this report shows an unusual adverse outcome of in utero exposure to methyldopa., (Copyright © 2014 by the American Academy of Pediatrics.)

This paper reports the design, fabrication and simulation of a novel micromachined electrode array with a form-fitting profile for use in auditory nerve prostheses. A 10times10 electrode array is created in a 1mm 2 area using bulk micromachining technology. The space between the individual electrodes within the array is filled with a layer of SU-8 molded to conform to the curved surface of the auditory nerve. This layer enables the implant to be secured to the auditory nerve and to have a good sealing between the array and the nerve tissue after insertion. An electrical model for a single electrode is built. Both mechanical and electrochemical finite element analyses (FEA) of the array are also performed.