Transcriptome analysis of the entomopathogenic oomycete Lagenidium giganteum reveals putative virulence factors.
A combination of 454 pyrosequencing and Sanger sequencing was used to sample and characterize the transcriptome of the entomopathogenic oomycete Lagenidium giganteum. More than 50,000 high-throughput reads were annotated through homology searches. Several selected reads served as seeds for the amplification and sequencing of full-length transcripts. Phylogenetic analyses inferred from full-length cellulose synthase alignments revealed that L giganteum is nested within the peronosporalean galaxy and as such appears to have evolved from a phytopathogenic ancestor. In agreement with the phylogeny reconstructions, full-length L. giganteum oomycete effector orthologs, corresponding to the cellulose-binding elicitor lectin (CBEL), crinkler (CRN), and elicitin proteins, were characterized by domain organizations similar to those of pathogenicity factors of plant-pathogenic oomycetes. Importantly, the L. giganteum effectors provide a basis for detailing the roles of canonical CRN, CBEL, and elicitin proteins in the infectious process of an oomycete known principally as an animal pathogen. Finally, phylogenetic analyses and genome mining identified members of glycoside hydrolase family 5 subfamily 27 (GH5_27) as putative virulence factors active on the host insect cuticle, based in part on the fact that GH5_27 genes are shared by entomopathogenic oomycetes and fungi but are underrepresented in nonentomopathogenic genomes. The genomic resources gathered from the L. giganteum transcriptome analysis strongly suggest that filamentous entomopathogens (oomycetes and fungi) exhibit convergent evolution: they have evolved independently from plant-associated microbes, have retained genes indicative of plant associations, and may share similar cores of virulence factors, such as GH5_27 enzymes, that are absent from the genomes of their plant-pathogenic relatives.


Treating binge eating problems in primary care.
Binge eating problems are a common source of psychiatric morbidity among young adult women. To date, the research on their treatment has been conducted almost exclusively in specialist settings. As it is unlikely there will ever be sufficient specialist resources to address a problem of this scale, a priority is to develop treatments that can be applied more generally. One option is to develop treatments suitable for use in primary care. Four such treatments are available: antidepressant drugs, brief cognitive behavior therapy, and the use of a cognitive behavioral self-help manual with or without supervision from a nonspecialist therapist. Tests of the effectiveness of these treatments are needed.


Bees may drive the reproduction of four sympatric cacti in a vanishing coastal mediterranean-type ecosystem.
Sympatric congeneric plants might share pollinators, or each species might avoid competition by evolving specialized traits that generate partitions in pollinator assemblages. In both cases, pollen limitation (a decrease in the quality and quantity of compatible reproductive pollen) can occur, driving the plant mating system to autogamy as a mechanism of reproductive assurance. We assessed the relationships between pollinator assemblages and mating systems in a group of sympatric congeneric plants. We attempted to answer the following questions: (i) How similar are pollinator assemblages among sympatric cactus species? (ii) Which mating systems do sympatric cactus species use? We studied sympatric Eriosyce taxa that inhabit a threatened coastal strip in a mediterranean-type ecosystem in central Chile. We performed field observations on four taxa and characterized pollinators during the years 2016 and 2017. We estimated differences in the pollinator assemblages using the Bray-Curtis index. To elucidate the mating systems, we conducted hand-pollination experiments using three treatments: manual cross-pollination, automatic self-pollination, and control (unmanipulated individuals). We tested differences in seed production for statistical significance using Kruskal-Wallis analysis. Eriosyce subgibbosa showed a distinctive pollinator assemblage among the sympatric species that we studied (similarity ranged from 0% to 8%); it was visited by small bees and was the only species that was visited by the giant hummingbird Patagona gigas. Pollinator assemblages were similar between E. chilensis (year 2016 = 4 species; 2017 = 8) and E. chilensis var. albidiflora (2016 = 7; 2017 = 4); however, those of E. curvispina var. mutabilis (2016 = 7; 2017 = 6) were less similar to those of the aforementioned species. E. curvispina var. mutabilis showed the highest interannual variation in its pollinator assemblage (18% similarity). Reproduction in E. subgibbosa largely depends on pollinators, although it showed some degree of autogamy. Autonomous pollination was unfeasible in E. chilensis, which depended on flower visitors for its reproductive success. Both E. chilensis var. albidiflora and E. curvispina var. mutabilis showed some degree of autogamy. We observed differences in pollinator assemblages between E. subgibbosa and the remaining Eriosyce taxa, which depend on hymenopterans for pollen transfer. Pollinator assemblages showed considerable interannual variation, especially those of E. subgibbosa (ornithophilous syndrome) and E. curvispina var. mutabilis (melitophilous syndrome). Autogamous reproduction in these taxa may act as a reproductive assurance mechanism when pollinator availability is unpredictable. Our study contributes to improving our understanding of the reproductive systems of ecological interactions between threatened species in a Chilean mediterranean-type ecosystem.


Allogeneic stem cell transplantation for patients harboring T315I BCR-ABL mutated leukemias.
T315I(+) Philadelphia chromosome-positive leukemias are inherently resistant to all licensed tyrosine kinase inhibitors, and therapeutic options remain limited. We report the outcome of allogeneic stem cell transplantation in 64 patients with documented BCR-ABL(T315I) mutations. Median follow-up was 52 months from mutation detection and 26 months from transplantation. At transplantation, 51.5% of patients with chronic myeloid leukemia were in the chronic phase and 4.5% were in advanced phases. Median overall survival after transplantation was 10.3 months (range 5.7 months to not reached [ie, still alive]) for those with chronic myeloid leukemia in the blast phase and 7.4 months (range 1.4 months to not reached [ie, still alive]) for those with Philadelphia chromosome-positive acute lymphoblastic leukemia but has not yet been reached for those in the chronic and accelerated phases of chronic myeloid leukemia. The occurrence of chronic GVHD had a positive impact on overall survival (P = .047). Transplant-related mortality rates were low. Multivariate analysis identified only blast phase at transplantation (hazard ratio 3.68, P = .0011) and unrelated stem cell donor (hazard ratio 2.98, P = .011) as unfavorable factors. We conclude that allogeneic stem cell transplantation represents a valuable therapeutic tool for eligible patients with BCR-ABL(T315I) mutation, a tool that may or may not be replaced by third-generation tyrosine kinase inhibitors.


Molecular Mechanisms of Sexually Dimorphic Nervous System Patterning in Flies and Worms.
Male and female brains display anatomical and functional differences. Such differences are observed in species across the animal kingdom, including humans, but have been particularly well-studied in two classic animal model systems, the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans. Here we summarize recent advances in understanding how the worm and fly brain acquire sexually dimorphic features during development. We highlight the advantages of each system, illustrating how the precise anatomical delineation of sexual dimorphisms in worms has enabled recent analysis into how these dimorphisms become specified during development, and how focusing on sexually dimorphic neurons in the fly has enabled an increasingly detailed understanding of sex-specific behaviors.


Detection of hepatitis E virus RNA in stools and serum by reverse transcription-PCR.
Stools and sera collected during an experimental hepatitis E virus (HEV) infection in monkeys and collected from humans with acute HEV infections during epidemic and sporadic cases were analyzed by reverse transcription-PCR. Two methods for RNA purification were compared. Proteinase K digestion and phenolchloroform extraction were more efficient than guanidinium isothiocyanate extraction in improving the sensitivity and specificity for the detection of HEV genomes.


Plasma Metabolomics Implicates Modified Transfer RNAs and Altered Bioenergetics in the Outcomes of Pulmonary Arterial Hypertension.
Pulmonary arterial hypertension (PAH) is a heterogeneous disorder with high mortality. We conducted a comprehensive study of plasma metabolites using ultraperformance liquid chromatography mass spectrometry to identify patients at high risk of early death, to identify patients who respond well to treatment, and to provide novel molecular insights into disease pathogenesis. Fifty-three circulating metabolites distinguished well-phenotyped patients with idiopathic or heritable PAH (n=365) from healthy control subjects (n=121) after correction for multiple testing (P<7.3e-5) and confounding factors, including drug therapy, and renal and hepatic impairment. A subset of 20 of 53 metabolites also discriminated patients with PAH from disease control subjects (symptomatic patients without pulmonary hypertension, n=139). Sixty-two metabolites were prognostic in PAH, with 36 of 62 independent of established prognostic markers. Increased levels of tRNA-specific modified nucleosides (N2,N2-dimethylguanosine, N1-methylinosine), tricarboxylic acid cycle intermediates (malate, fumarate), glutamate, fatty acid acylcarnitines, tryptophan, and polyamine metabolites and decreased levels of steroids, sphingomyelins, and phosphatidylcholines distinguished patients from control subjects. The largest differences correlated with increased risk of death, and correction of several metabolites over time was associated with a better outcome. Patients who responded to calcium channel blocker therapy had metabolic profiles similar to those of healthy control subjects. Metabolic profiles in PAH are strongly related to survival and should be considered part of the deep phenotypic characterization of this disease. Our results support the investigation of targeted therapeutic strategies that seek to address the alterations in translational regulation and energy metabolism that characterize these patients.


Prospective observational study in elderly patients with non-valvular atrial fibrillation: Rationale and design of the All Nippon AF In the Elderly (ANAFIE) Registry.
Although anticoagulation effectively prevents stroke in patients with atrial fibrillation (AF), it has been underused in elderly AF patients for many reasons, mainly because of knowledge gaps regarding cardiovascular treatment of these populations with multiple comorbidities and poor prognosis. The objectives of the All Nippon AF In the Elderly (ANAFIE) Registry are to collect real-world information about the clinical status of patients with non-valvular AF (NVAF) aged ≥75 years, current status of anticoagulant therapy, and prognosis with/without anticoagulation to establish a database for this specific patient population that is increasing remarkably worldwide. The ANAFIE Registry is an observational, multicenter, prospective study of Japanese patients with NVAF aged ≥75 years that will include 30,000 patients and have the primary endpoint of composite of stroke and systemic embolism over a 2-year follow-up period. In parallel with the main study, seven sub-cohort studies will be conducted with assessments including coagulation-fibrinolysis markers, echocardiography, heart rate, hypertension, cognitive function, frailty, and medication adherence. Subgroup analyses will be performed, and stratified by renal function, HbA1c, and maximum number of drugs used. The study was started in October 2016, with a planned 2-year recruitment period. As of January 31, 2018, 33,213 patients were enrolled; the recruitment was therefore ended 8 months earlier than the original plan. The ANAFIE Registry will provide a valuable database for the clinical status, management, and outcomes of mortality, stroke, systemic embolism, and hemorrhagic events with/without anticoagulation in the increasing population of elderly NVAF patients, and will identify risk factors associated with these clinical events.


The microscale Weissenberg effect for high-viscosity solution pumping at the picoliter level.
Transportation of highly viscous solutions at the picoliter level with a rapid dynamic response is paramount for micro/nano-fabrication. With the advantages of a higher length-wall (thickness) ratio and a more stable free surface compared to those of the traditional Weissenberg effect (TWE), the microscale Weissenberg effect (MWE) can continuously and controllably pump high-viscosity solutions at the picoliter scale. Some typical characteristics and behaviors of MWE are investigated as the rotation rod diameter decreases to the microscale of ∼100 μm. The pumped minimum solution volume can reach 167.5 pL per second, and the minimum response time of solution pumping is 0.3 s, which is much shorter than that of pressure driven pumping. Then, a new direct writing with an adjustable jet diameter based on the MWE is proposed to write microstructures on a substrate from a solution with a viscosity of approximately 130.1 Pa s. The stability of the as-spun jet and the deposited structures is improved when a high voltage is applied. To fully demonstrate the advantages of MWE, MWE-based direct writing is performed to successfully fabricate microfluidic channels with variable diameters. Thus, the system can overcome the problems of high transport resistance to the pumping of a high-viscosity solution.


Vascular Endothelial Over-Expression of Human Soluble Epoxide Hydrolase (Tie2-sEH Tr) Attenuates Coronary Reactive Hyperemia in Mice: Role of Oxylipins and ω-Hydroxylases.
Cytochromes P450 metabolize arachidonic acid (AA) into two vasoactive oxylipins with opposing biologic effects: epoxyeicosatrienoic acids (EETs) and omega-(ω)-terminal hydroxyeicosatetraenoic acids (HETEs). EETs have numerous beneficial physiological effects, including vasodilation and protection against ischemia/reperfusion injury, whereas ω-terminal HETEs induce vasoconstriction and vascular dysfunction. We evaluated the effect of these oxylipins on post-ischemic vasodilation known as coronary reactive hyperemia (CRH). CRH prevents the potential harm associated with transient ischemia. The beneficial effects of EETs are reduced after their hydrolysis to dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). ω-terminal HETEs are formed by ω-hydroxylase family members. The relationship among endothelial over-expression of sEH (Tie2-sEH Tr), the changes in oxylipins it may produce, the pharmacologic inhibition of ω-hydroxylases, activation of PPARγ, and CRH response to a brief ischemia is not known. We hypothesized that CRH is attenuated in isolated mouse hearts with endothelial sEH over-expression through modulation of oxylipin profiles, whereas both inhibition of ω-hydroxylases and activation of PPARγ enhance CRH. Compared to WT mice, Tie2-sEH Tr mice had decreased CRH, including repayment volume, repayment duration, and repayment/debt ratio (P < 0.05), whereas inhibition of ω-hydroxylases increased these same CRH parameters in Tie2-sEH Tr mice. Inhibition of sEH with t-AUCB reversed the decreased CRH in Tie2-sEH Tr mice. Endothelial over-expression of sEH significantly changed oxylipin profiles, including decreases in DHETs, mid-chain HETEs, and prostaglandins (P < 0.05). Treatment with rosiglitazone, PPARγ-agonist, enhanced CRH (P < 0.05) in both Tie2-sEH Tr and wild type (WT) mice. These data demonstrate that endothelial over-expression of sEH (through changing the oxylipin profiles) attenuates CRH, whereas inhibition of ω-hydroxylases and activation of PPARγ enhance it.


Effect of inelastic scattering on underwater daylight in the ocean: model evaluation, validation, and first results.
A model based on a matrix-operator theory capable of simulating underwater daylight in the ocean is presented. The main focus is on gelbstoff and chlorophyll fluorscence as well as water Raman scattering as sources of inelastic scattering and their effect on underwater daylight and relevance for the remote sensing of ocean color. Any combination of inelastic sources can be investigated, including differences in simulated underwater daylight in the absence and the presence of these sources. To our knowledge, it is the first matrix-operator model to include all these inelastic source. The model allows simulations for case 1 and case 2 waters. Calculations can be done with highly anisotropic phase functions as they are observed in the ocean, and every order of multiple scattering is considered. A detailed mathematical description of inelastic sources is given, and a special treatment of the depth dependency of these sources is presented. The model is validated by comparison with depth-dependent and spectrally resolved measurements of downward irradiance in the open ocean. The differences between measured and simulated data are within the error of the radiometric measurements. Water Raman scattering has been found to contribute significantly to water-leaving radiance. The inelastic fraction depends on the water Raman scattering coefficient, on the ratio of the total attenuation coefficient at excitation and emission wavelengths, and on the spectral course of the irradiance incident on the ocean. For clear ocean waters the inelastic fraction can reach values of more than 17% [C = 0.08 mg m(-3), a(y) (440 nm) = 0.01 m(-1)] at wavelengths relevant for the remote sensing of ocean color. The inelastic fraction of gelbstoff fluorescence can reach or even exceed the relevance of water Raman scattering atshort wavelengths. In the water column, depending on optically active substances and on actual depth, water Raman scattering can provide 100% of the light field at wavelengths greater than 580 nm. The effect of gelbstoff fluorescence on depth-dependent irradiances is less significant than the effect of water Raman scattering in all cases considered, except for near surface levels and high gelbstoff concentrations.


Part I: A Quantitative Study of Social Risk Screening Acceptability in Patients and Caregivers.
Despite recent growth in healthcare delivery-based social risk screening, little is known about patient perspectives on these activities. This study evaluates patient and caregiver acceptability of social risk screening. This was a cross-sectional survey of 969 adult patients and adult caregivers of pediatric patients recruited from 6 primary care clinics and 4 emergency departments across 9 states. Survey items included the Center for Medicare and Medicaid Innovation Accountable Health Communities' social risk screening tool and questions about appropriateness of screening and comfort with including social risk data in electronic health records. Logistic regressions evaluated covariate associations with acceptability measures. Data collection occurred from July 2018 to February 2019; data analyses were conducted in February‒March 2019. Screening was reported as appropriate by 79% of participants; 65% reported comfort including social risks in electronic health records. In adjusted models, higher perceived screening appropriateness was associated with previous exposure to healthcare-based social risk screening (AOR=1.82, 95% CI=1.16, 2.88), trust in clinicians (AOR=1.55, 95% CI=1.00, 2.40), and recruitment from a primary care setting (AOR=1.70, 95% CI=1.23, 2.38). Lower appropriateness was associated with previous experience of healthcare discrimination (AOR=0.66, 95% CI=0.45, 0.95). Higher comfort with electronic health record documentation was associated with previously receiving assistance with social risks in a healthcare setting (AOR=1.47, 95% CI=1.04, 2.07). A strong majority of adult patients and caregivers of pediatric patients reported that social risk screening was appropriate. Most also felt comfortable including social risk data in electronic health records. Although multiple factors influenced acceptability, the effects were moderate to small. These findings suggest that lack of patient acceptability is unlikely to be a major implementation barrier. This article is part of a supplement entitled Identifying and Intervening on Social Needs in Clinical Settings: Evidence and Evidence Gaps, which is sponsored by the Agency for Healthcare Research and Quality of the U.S. Department of Health and Human Services, Kaiser Permanente, and the Robert Wood Johnson Foundation.


Analysis of a zebrafish dync1h1 mutant reveals multiple functions for cytoplasmic dynein 1 during retinal photoreceptor development.
Photoreceptors of the retina are highly compartmentalized cells that function as the primary sensory neurons for receiving and initiating transmission of visual information. Proper morphogenesis of photoreceptor neurons is essential for their normal function and survival. We have characterized a zebrafish mutation, cannonball, that completely disrupts photoreceptor morphogenesis. Analysis revealed a non-sense mutation in cytoplasmic dynein heavy chain 1 (dync1h1), a critical subunit in Dynein1, to underlie the cannonball phenotypes. Dynein1 is a large minus-end directed, microtubule motor protein complex that has been implicated in multiple, essential cellular processes. In photoreceptors, Dynein1 is thought to mediate post-Golgi vesicle trafficking, while Dynein2 is thought to be responsible for outer segment maintenance. Surprisingly, cannonball embryos survive until larval stages, owing to wild-type maternal protein stores. Retinal photoreceptor neurons, however, are significantly affected by loss of Dync1h1, as transmission electron microscopy and marker analyses demonstrated defects in organelle positioning and outer segment morphogenesis and suggested defects in post-Golgi vesicle trafficking. Furthermore, dosage-dependent antisense oligonucleotide knock-down of dync1h1 revealed outer segment abnormalities in the absence of overt inner segment polarity and trafficking defects. Consistent with a specific function of Dync1h1 within the outer segment, immunolocalization showed that this protein and other subunits of Dynein1 and Dynactin localized to the ciliary axoneme of the outer segment, in addition to their predicted inner segment localization. However, knock-down of Dynactin subunits suggested that this protein complex, which is known to augment many Dynein1 activities, is only essential for inner segment processes as outer segment morphogenesis was normal. Our results indicate that Dynein1 is required for multiple cellular processes in photoreceptor neurons, including organelle positioning, proper outer segment morphogenesis, and potentially post-Golgi vesicle trafficking. Titrated knock-down of dync1h1 indicated that outer segment morphogenesis was affected in photoreceptors that showed normal inner segments. These observations, combined with protein localization studies, suggest that Dynein1 may have direct and essential functions in photoreceptor outer segments, in addition to inner segment functions.


The angiogenic process as a therapeutic target in cancer.
Angiogenesis has emerged as a critical process for tumour progression. Identifying key pathways involved in the regulation and promotion of angiogenesis has resulted in the development of numerous approaches targeting pro-angiogenic signalling pathways. The most prominent and characterised pro-angiogenic pathway is the vascular endothelial growth factor signalling pathway. This review will describe several inhibitors of angiogenesis currently in clinical trial and their various targets. Targeting pro-angiogenic pathways has improved outcome for many patients, however, the emerging problems with drug resistance with clinically approved angiogenic inhibitors will also be discussed in this review. It is hoped that identifying the causes of tumour re-growth and disease progression following treatment will enable future anti-angiogenic therapies to circumvent resistance.


A millisecond pulsar in a stellar triple system.
Gravitationally bound three-body systems have been studied for hundreds of years and are common in our Galaxy. They show complex orbital interactions, which can constrain the compositions, masses and interior structures of the bodies and test theories of gravity, if sufficiently precise measurements are available. A triple system containing a radio pulsar could provide such measurements, but the only previously known such system, PSR B1620-26 (refs 7, 8; with a millisecond pulsar, a white dwarf, and a planetary-mass object in an orbit of several decades), shows only weak interactions. Here we report precision timing and multiwavelength observations of PSR J0337+1715, a millisecond pulsar in a hierarchical triple system with two other stars. Strong gravitational interactions are apparent and provide the masses of the pulsar M[Symbol: see text](1.4378(13), where M[Symbol: see text]is the solar mass and the parentheses contain the uncertainty in the final decimal places) and the two white dwarf companions (0.19751(15)M[Symbol: see text] and 0.4101(3))M[Symbol: see text], as well as the inclinations of the orbits (both about 39.2°). The unexpectedly coplanar and nearly circular orbits indicate a complex and exotic evolutionary past that differs from those of known stellar systems. The gravitational field of the outer white dwarf strongly accelerates the inner binary containing the neutron star, and the system will thus provide an ideal laboratory in which to test the strong equivalence principle of general relativity.


Stem cells and their niche: a matter of fate.
Embryonic stem cells provide an in vitro model for developmental biologists to study cell fate decisions during ontogenesis, while somatic stem cells allow physiologists to understand tissue homeostasis in the adult. The behavior of stem cells is dependent on an intimate relationship with a supportive niche. This brief review highlights some of the most important recent trends in stem cell biology, focusing in particular on the supportive microenvironments for both embryonic and adult stem cells. Known intrinsic and extrinsic molecular players from the best-characterized stem cell types are summarized, illuminating a number of shared environmental cues among tissues originating from all three embryonic germ layers.


Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms.
Clinical genetic testing of protein-coding regions identifies a likely causative variant in only around half of developmental disorder (DD) cases. The contribution of regulatory variation in non-coding regions to rare disease, including DD, remains very poorly understood. We screened 9,858 probands from the Deciphering Developmental Disorders (DDD) study for de novo mutations in the 5' untranslated regions (5' UTRs) of genes within which variants have previously been shown to cause DD through a dominant haploinsufficient mechanism. We identified four single-nucleotide variants and two copy-number variants upstream of MEF2C in a total of ten individual probands. We developed multiple bespoke and orthogonal experimental approaches to demonstrate that these variants cause DD through three distinct loss-of-function mechanisms, disrupting transcription, translation, and/or protein function. These non-coding region variants represent 23% of likely diagnoses identified in MEF2C in the DDD cohort, but these would all be missed in standard clinical genetics approaches. Nonetheless, these variants are readily detectable in exome sequence data, with 30.7% of 5' UTR bases across all genes well covered in the DDD dataset. Our analyses show that non-coding variants upstream of genes within which coding variants are known to cause DD are an important cause of severe disease and demonstrate that analyzing 5' UTRs can increase diagnostic yield. We also show how non-coding variants can help inform both the disease-causing mechanism underlying protein-coding variants and dosage tolerance of the gene.


Interventions to improve delivery of isoniazid preventive therapy: an overview of systematic reviews.
Uptake of isoniazid preventive therapy (IPT) to prevent tuberculosis has been poor, particularly in the highest risk populations. Interventions to improve IPT delivery could promote implementation. The large number of existing systematic reviews on treatment adherence has made drawing conclusions a challenge. To provide decision makers with the evidence they need, we performed an overview of systematic reviews to compare different organizational interventions to improve IPT delivery as measured by treatment completion among those at highest risk for the development of TB disease, namely child contacts or HIV-infected individuals. We searched the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects (DARE), and MEDLINE up to August 15, 2012. Two authors used a standardized data extraction form and the AMSTAR instrument to independently assess each review. Six reviews met inclusion criteria. Interventions included changes in the setting/site of IPT delivery, use of quality monitoring mechanisms (e.g., directly observed therapy), IPT delivery integration into other healthcare services, and use of lay health workers. Most reviews reported a combination of outcomes related to IPT adherence and treatment completion rate but without a baseline or comparison rate. Generally, we found limited evidence to demonstrate that the studied interventions improved treatment completion. While most of the interventions were not shown to improve IPT completion, integration of tuberculosis and HIV services yielded high treatment completion rates in some settings. The lack of data from high burden TB settings limits applicability. Further research to assess different IPT delivery interventions, including those that address barriers to care in at-risk populations, is urgently needed to identify the most effective practices for IPT delivery and TB control in high TB burden settings.


Universal and adapted vocabularies for generic visual categorization.
Generic Visual Categorization (GVC) is the pattern classification problem which consists in assigning labels to an image based on its semantic content. This is a challenging task as one has to deal with inherent object/scene variations as well as changes in viewpoint, lighting and occlusion. Several state-of-the-art GVC systems use a vocabulary of visual terms to characterize images with a histogram of visual word counts. We propose a novel practical approach to GVC based on a universal vocabulary, which describes the content of all the considered classes of images, and class vocabularies obtained through the adaptation of the universal vocabulary using class-specific data. The main novelty is that an image is characterized by a set of histograms - one per class - where each histogram describes whether the image content is best modeled by the universal vocabulary or the corresponding class vocabulary. This framework is applied to two types of local image features: low-level descriptors such as the popular SIFT and high-level histograms of word co-occurrences in a spatial neighborhood. It is shown experimentally on two challenging datasets (an in-house database of 19 categories and the PASCAL VOC 2006 dataset) that the proposed approach exhibits state-of-the-art performance at a modest computational cost.


Drugs in development for social anxiety disorder: more to social anxiety than meets the SSRI.
Individuals with social phobia (SP) fear and avoid a wide variety of social and performance situations in which they are exposed to unfamiliar persons or to possible scrutiny by others. The lifetime prevalence of SP is estimated to be as high as 13%. It is frequently co-morbid with and usually precedes the onset of other psychiatric illnesses and is associated with significant occupational and social impairment, including academic and vocational underachievement. Fortunately, there are effective treatments for this common and debilitating condition. There is currently considerable evidence for the efficacy of pharmacotherapy and especially the monoamine oxidase inhibitors (MAOIs) and selective serotonin re-uptake inhibitors (SSRIs) in the treatment of this disorder. However, SSRIs are generally preferred as the first-line treatment of choice due to the advantages of SSRIs over MAOIs in terms of safety and tolerability. Despite encouraging results, current treatments most often produce partial symptomatic improvement, rather than high end-state functioning. While current first line treatments for social phobia target the serotonergic system, it is important to remember that different social fears are likely to have different developmental roots and may be based on quite different neurobiological systems. In this article we provide a review of current pharmacotherapeutic options for SP, current knowledge of the neurobiology of SP, and a review of new and promising directions in pharmacological research. It is increasingly clear that serotonin (5-HT) is unlikely to be the whole story in SP and that other brain chemical systems, especially the dopaminergic, noradrenaline-corticotropin releasing hormone and gamma-aminobutyric acid (GABA) dependent systems, most probably have an important role to play in a substantial percentage of cases. A number of new and novel agents, including the substance P antagonists, GABA agonists and CRF antagonists show considerable promise in the treatment of SP. However, in order to enhance the understanding of the neurobiology and treatment response of SP, we need to develop more sophisticated theory-driven typologies of SP.


Targeted overexpression of androgen receptor in osteoblasts: unexpected complex bone phenotype in growing animals.
The androgen receptor (AR), as a classic steroid receptor, generally mediates biologic responses to androgens. In bone tissue, both AR and the estrogen receptor (ER) are expressed in a variety of cell types. Because androgens can be converted into estrogen via aromatase activity, the specific role of the AR in maintenance of skeletal homoeostasis remains controversial. The goal of this study was to use skeletally targeted overexpression of AR as a means of elucidating the specific role(s) for AR transactivation in bone homeostasis. Rat AR cDNA was cloned downstream of a 3.6-kb alpha1(I)-collagen promoter fragment and used to create AR-transgenic mice. AR-transgenic males gain less weight and body and femur length is shorter than wild-type controls, whereas females are not different. AR-transgenic males also demonstrate thickened calvaria and increased periosteal but reduced endosteal labeling by fluorescent labeling and reduced osteocalcin levels. High-resolution micro-computed tomography shows normal mineral content in both male and female AR-transgenic mice, but male AR-transgenics reveal a reduction in cortical area and moment of inertia. Male AR-transgenics also demonstrate an altered trabecular morphology with bulging at the metaphysis. Histomorphometric analysis of trabecular bone parameters confirmed the increased bone volume comprised of more trabeculae that are closer together but not thicker. Biomechanical analysis of the skeletal phenotype demonstrate reduced stiffness, maximum load, post-yield deflection, and work-to-failure in male AR-transgenic mice. Steady-state levels of selected osteoblastic and osteoclastic genes are reduced in tibia from both male and female transgenics, with the exception of increased osteoprotegerin expression in male AR-transgenic mice. These results indicate that AR action is important in the development of a sexually dimorphic skeleton and argue for a direct role for androgen transactivation of AR in osteoblasts in modulating skeletal development and homeostasis.


Epidemiological impacts of the NHS COVID-19 app in England and Wales throughout its first year.
The NHS COVID-19 app was launched in England and Wales in September 2020, with a Bluetooth-based contact tracing functionality designed to reduce transmission of SARS-CoV-2. We show that user engagement and the app's epidemiological impacts varied according to changing social and epidemic characteristics throughout the app's first year. We describe the interaction and complementarity of manual and digital contact tracing approaches. Results of our statistical analyses of anonymised, aggregated app data include that app users who were recently notified were more likely to test positive than app users who were not recently notified, by a factor that varied considerably over time. We estimate that the app's contact tracing function alone averted about 1 million cases (sensitivity analysis 450,000-1,400,000) during its first year, corresponding to 44,000 hospital cases (SA 20,000-60,000) and 9,600 deaths (SA 4600-13,000).


Electrical resistivity variations associated with earthquakes on the san andreas fault.
A 24 percent precursory change in apparent electrical resistivity was observed before a magnitude 3.9 earthquake of strike-slip nature on the San Andreas fault in central California. The experimental configuration and numerical calculations suggest that the change is associated with a volume at depth rather than some near-surface phenomenon. The character and duration of the precursor period agree well with those of other earthquake studies and support a dilatant earthquake mechanism model.


Evaluation of text-mining systems for biology: overview of the Second BioCreative community challenge.
Genome sciences have experienced an increasing demand for efficient text-processing tools that can extract biologically relevant information from the growing amount of published literature. In response, a range of text-mining and information-extraction tools have recently been developed specifically for the biological domain. Such tools are only useful if they are designed to meet real-life tasks and if their performance can be estimated and compared. The BioCreative challenge (Critical Assessment of Information Extraction in Biology) consists of a collaborative initiative to provide a common evaluation framework for monitoring and assessing the state-of-the-art of text-mining systems applied to biologically relevant problems. The Second BioCreative assessment (2006 to 2007) attracted 44 teams from 13 countries worldwide, with the aim of evaluating current information-extraction/text-mining technologies developed for one or more of the three tasks defined for this challenge evaluation. These tasks included the recognition of gene mentions in abstracts (gene mention task); the extraction of a list of unique identifiers for human genes mentioned in abstracts (gene normalization task); and finally the extraction of physical protein-protein interaction annotation-relevant information (protein-protein interaction task). The 'gold standard' data used for evaluating submissions for the third task was provided by the interaction databases MINT (Molecular Interaction Database) and IntAct. The Second BioCreative assessment almost doubled the number of participants for each individual task when compared with the first BioCreative assessment. An overall improvement in terms of balanced precision and recall was observed for the best submissions for the gene mention (F score 0.87); for the gene normalization task, the best results were comparable (F score 0.81) compared with results obtained for similar tasks posed at the first BioCreative challenge. In case of the protein-protein interaction task, the importance and difficulties of experimentally confirmed annotation extraction from full-text articles were explored, yielding different results depending on the step of the annotation extraction workflow. A common characteristic observed in all three tasks was that the combination of system outputs could yield better results than any single system. Finally, the development of the first text-mining meta-server was promoted within the context of this community challenge.


[Prostate cancer surgery].
Radical prostatectomy (RP) remains the preferred treatment option for men with localised prostate cancer (PCa). Following the introduction in 1995, approximately 1,100 procedures are performed annually in Denmark. Several studies have demonstrated the Danish standard of RP to be at an international level in terms of both functional and oncological outcomes. In order to reduce the risk of overtreatment, management of localised PCa should be organised in experienced multidisciplinary teams, where a constantly growing armamentarium of diagnostic and therapeutic options can be offered.


Phosphorylation-dependent osterix degradation negatively regulates osteoblast differentiation.
Proteasome inhibitors exert an anabolic effect on bone formation with elevated levels of osteoblast markers. These findings suggest the important role of the proteasomal degradation of osteogenic regulators, while the underlying molecular mechanisms are not fully understood. Here, we report that the proteasome inhibitors bortezomib and ixazomib markedly increased protein levels of the osteoblastic key transcription factor osterix/Sp7 (Osx). Furthermore, we revealed that Osx was targeted by p38 and Fbw7 for proteasomal degradation. Mechanistically, p38-mediated Osx phosphorylation at S73/77 facilitated Fbw7 interaction to trigger subsequent Osx ubiquitination. Consistent with these findings, p38 knockdown or pharmacological p38 inhibition resulted in Osx protein stabilization. Treatment with p38 inhibitors following osteogenic stimulation efficiently induced osteoblast differentiation through Osx stabilization. Conversely, pretreatment of p38 inhibitor followed by osteogenic challenge impaired osteoblastogenesis via suppressing Osx expression, suggesting that p38 exerts dual but opposite effects in the regulation of Osx level to fine-tune its activity during osteoblast differentiation. Furthermore, Fbw7-depleted human mesenchymal stem cells and primary mouse calvarial cells resulted in increased osteogenic capacity. Together, our findings unveil the molecular mechanisms underlying the Osx protein stability control and suggest that targeting the Osx degradation pathway could help enhance efficient osteogenesis and bone matrix regeneration.


Obstructive sleep apnea is a common disorder in the population-a review on the epidemiology of sleep apnea.
The prevalence of obstructive sleep apnea (OSA) defined at an apnea-hypopnea index (AHI) ≥5 was a mean of 22% (range, 9-37%) in men and 17% (range, 4-50%) in women in eleven published epidemiological studies published between 1993 and 2013. OSA with excessive daytime sleepiness occurred in 6% (range, 3-18%) of men and in 4% (range, 1-17%) of women. The prevalence increased with time and OSA was reported in 37% of men and in 50% of women in studies from 2008 and 2013 respectively. OSA is more prevalent in men than in women and increases with age and obesity. Smoking and alcohol consumption are also suggested as risk factors, but the results are conflicting. Excessive daytime sleepiness is suggested as the most important symptom of OSA, but only a fraction of subjects with AHI >5 report daytime sleepiness and one study did not find any relationship between daytime sleepiness and sleep apnea in women. Stroke and hypertension and coronary artery disease are associated with sleep apnea. Cross-sectional studies indicate an association between OSA and diabetes mellitus. Patients younger than 70 years run an increased risk of early death if they suffer from OSA. It is concluded that OSA is highly prevalent in the population. It is related to age and obesity. Only a part of subjects with OSA in the population have symptoms of daytime sleepiness. The prevalence of OSA has increased in epidemiological studies over time. Differences and the increase in prevalence of sleep apnea are probably due to different diagnostic equipment, definitions, study design and characteristics of included subjects including effects of the obesity epidemic. Cardiovascular disease, especially stroke is related to OSA, and subjects under the age of 70 run an increased risk of early death if they suffer from OSA.


Ontology-based prediction of cancer driver genes.
Identifying and distinguishing cancer driver genes among thousands of candidate mutations remains a major challenge. Accurate identification of driver genes and driver mutations is critical for advancing cancer research and personalizing treatment based on accurate stratification of patients. Due to inter-tumor genetic heterogeneity many driver mutations within a gene occur at low frequencies, which make it challenging to distinguish them from non-driver mutations. We have developed a novel method for identifying cancer driver genes. Our approach utilizes multiple complementary types of information, specifically cellular phenotypes, cellular locations, functions, and whole body physiological phenotypes as features. We demonstrate that our method can accurately identify known cancer driver genes and distinguish between their role in different types of cancer. In addition to confirming known driver genes, we identify several novel candidate driver genes. We demonstrate the utility of our method by validating its predictions in nasopharyngeal cancer and colorectal cancer using whole exome and whole genome sequencing.


Predicting Medical Students' Current Attitudes Toward Psychiatry, Interest in Psychiatry, and Estimated Likelihood of Working in Psychiatry: A Cross-Sectional Study in Four European Countries.
Psychiatry as a medical discipline is becoming increasingly important due to the high and increasing worldwide burden associated with mental disorders. Surprisingly, however, there is a lack of young academics choosing psychiatry as a career. Previous evidence on medical students' perspectives is abundant but has methodological shortcomings. Therefore, by attempting to avoid previous shortcomings, we aimed to contribute to a better understanding of the predictors of the following three outcome variables: current medical students' attitudes toward psychiatry, interest in psychiatry, and estimated likelihood of working in psychiatry. The sample consisted of N = 1,356 medical students at 45 medical schools in Germany and Austria as well as regions of Switzerland and Hungary with a German language curriculum. We used snowball sampling via Facebook with a link to an online questionnaire as recruitment procedure. Snowball sampling is based on referrals made among people. This questionnaire included a German version of the Attitudes Toward Psychiatry Scale (ATP-30-G) and further variables related to outcomes and potential predictors in terms of sociodemography (e.g., gender) or medical training (e.g., curriculum-related experience with psychiatry). Data were analyzed by linear mixed models and further regression models. On average, students had a positive attitude to and high general interest in, but low professional preference for, psychiatry. A neutral attitude to psychiatry was partly related to the discipline itself, psychiatrists, or psychiatric patients. Female gender and previous experience with psychiatry, particularly curriculum-related and personal experience, were important predictors of all outcomes. Students in the first years of medical training were more interested in pursuing psychiatry as a career. Furthermore, the country of the medical school was related to the outcomes. However, statistical models explained only a small proportion of variance. The findings indicate that particularly curriculum-related experience is important for determining attitudes toward psychiatry, interest in the subject and self-predicted professional career choice. We therefore encourage the provision of opportunities for clinical experience by psychiatrists. However, further predictor variables need to be considered in future studies.


Metastatic prostate cancer in a transgenic mouse.
We have previously reported the development of a transgenic mouse model for prostate cancer derived from PB-Tag transgenic line 8247, henceforth designated the TRAMP (transgenic adenocarcinoma mouse prostate) model. We now describe the temporal and spatial consequences of transgene expression and report the identification and characterization of metastatic disease in the TRAMP model. TRAMP mice characteristically express the T antigen oncoprotein by 8 weeks of age and develop distinct pathology in the epithelium of the dorsolateral prostate by 10 weeks of age. Distant site metastases can be detected as early as 12 weeks of age. The common sites of metastases are the periaortic lymph nodes and lungs, with occasional metastases to the kidney, adrenal gland, and bone. By 28 weeks of age, 100% harbor metastatic prostate cancer in the lymph nodes or lungs. We have also demonstrated the loss of normal E-cadherin expression, as observed in human prostate cancer, as primary tumors become less differentiated and metastasize. The TRAMP model provides a consistent source of primary and metastatic tumors for histopathobiological and molecular analysis to further define the earliest molecular events involved in the genesis, progression, and metastasis of prostate cancer.


Medication adherence among patients with Type 2 diabetes: A mixed methods study.
Oral hypoglycemic agents (OHAs) are highly effective in managing Type 2 diabetes if taken appropriately. This study assessed adherence to OHAs among patients with Type 2 diabetes and explored factors associated with adherence behaviour. Mixed methods were used comprising a cross-sectional study using the Arabic version of the Morisky Medication Adherence Scale followed by semi-structured interviews using the Theoretical Domain Framework to explore key determinants of adherence. The cross-sectional study included 395 patients of whom 40% achieved a high level of OHA adherence. Lower adherence was associated with younger age (Odds Ratio (OR) 1.084; 95% CI 1.056 to 1.112), higher numbers of non-OHAs (OR 0.848; 95% CI 0.728 to 0.986) and higher HbA1c levels (OR 0.808; 95% CI 0.691 to 0.943). Semi structured interviews based on the Theoretical Domain Framework were completed with 20 patients and identified a wide range of factors potentially associated with OHA adherence, particularly behavioural related factors (e.g. scheduling medication intake, ability to develop a habitual behaviour), social influences (e.g. acting as a role model, the effect of family support), and gaps in knowledge about diabetes and its management with OHAs. This unique mixed-methods study has highlighted possible reasons for the low levels of OHA adherence in this patient population. Whilst the theoretically-derived determinants of behaviour illustrate the complexities associated with OHA adherence, they also provide a robust underpinning for future intervention(s) development to improve adherence and maximise patient health outcomes.


Tetralogy of Fallot.
Tetralogy of Fallot is a congenital cardiac malformation that consists of an interventricular communication, also known as a ventricular septal defect, obstruction of the right ventricular outflow tract, override of the ventricular septum by the aortic root, and right ventricular hypertrophy. This combination of lesions occurs in 3 of every 10,000 live births, and accounts for 7-10% of all congenital cardiac malformations. Patients nowadays usually present as neonates, with cyanosis of varying intensity based on the degree of obstruction to flow of blood to the lungs. The aetiology is multifactorial, but reported associations include untreated maternal diabetes, phenylketonuria, and intake of retinoic acid. Associated chromosomal anomalies can include trisomies 21, 18, and 13, but recent experience points to the much more frequent association of microdeletions of chromosome 22. The risk of recurrence in families is 3%. Useful diagnostic tests are the chest radiograph, electrocardiogram, and echocardiogram. The echocardiogram establishes the definitive diagnosis, and usually provides sufficient information for planning of treatment, which is surgical. Approximately half of patients are now diagnosed antenatally. Differential diagnosis includes primary pulmonary causes of cyanosis, along with other cyanotic heart lesions, such as critical pulmonary stenosis and transposed arterial trunks. Neonates who present with ductal-dependent flow to the lungs will receive prostaglandins to maintain ductal patency until surgical intervention is performed. Initial intervention may be palliative, such as surgical creation of a systemic-to-pulmonary arterial shunt, but the trend in centres of excellence is increasingly towards neonatal complete repair. Centres that undertake neonatal palliation will perform the complete repair at the age of 4 to 6 months. Follow-up in patients born 30 years ago shows a rate of survival greater than 85%. Chronic issues that now face such adults include pulmonary regurgitation, recurrence of pulmonary stenosis, and ventricular arrhythmias. As the strategies for surgical and medical management have progressed, the morbidity and mortality of those born with tetralogy of Fallot in the current era is expected to be significantly improved.


Traumatic brain injury and bipolar psychosis in the Genomic Psychiatry Cohort.
Approximately three million individuals in the United States sustain traumatic brain injury (TBI) every year, with documented impact on a range of neurological and psychiatric disturbances including mania, depression, and psychosis. Identification of subsets of individuals that may demonstrate increased propensity for posttraumatic symptoms and who may share genetic vulnerabilities for gene-environment interactions can enhance efforts to understand, predict, and prevent these phenomena. A sample of 11,489 cases from the Genomic Psychiatry Cohort (GPC), a NIMH-managed data repository for the investigation of schizophrenia and bipolar disorder, was used for this study. Cases were excluded if TBI was deemed causal to their mental illness. A k-means clustering algorithm was used to probe differences between schizophrenia and bipolar disorder associated with variables including onset age, hallucinations, delusions, head injury, and TBI. Cases were separated into an optimum number of seven clusters, with two clusters including all cases with brain injury. Bipolar disorder with psychosis and TBI were significantly correlated in one cluster in which 72% of cases were male and 99.2% sustained head injury. This cluster also carried the longest average period of unconsciousness. This study demonstrates an association of TBI with psychosis in a subset of bipolar cases, suggesting that traumatic stressors may have the ability to impact gene expression in a vulnerable population, and/or there is a heightened occurrence of TBI in individuals with underlying psychosis. Further studies should more closely examine the interplay between genetic variation in bipolar disorder and susceptibility to psychosis following TBI. © 2015 Wiley Periodicals, Inc.


Global effects of the CSR-1 RNA interference pathway on the transcriptional landscape.
Argonaute proteins and their small RNA cofactors short interfering RNAs are known to inhibit gene expression at the transcriptional and post-transcriptional levels. In Caenorhabditis elegans, the Argonaute CSR-1 binds thousands of endogenous siRNAs (endo-siRNAs) that are antisense to germline transcripts. However, its role in gene expression regulation remains controversial. Here we used genome-wide profiling of nascent RNA transcripts and found that the CSR-1 RNA interference pathway promoted sense-oriented RNA polymerase II transcription. Moreover, a loss of CSR-1 function resulted in global increase in antisense transcription and ectopic transcription of silent chromatin domains, which led to reduced chromatin incorporation of centromere-specific histone H3. On the basis of these findings, we propose that the CSR-1 pathway helps maintain the directionality of active transcription, thereby propagating the distinction between transcriptionally active and silent genomic regions.


Cryptococcus neoformans and Cryptococcus gattii, the etiologic agents of cryptococcosis.
Cryptococcus neoformans and Cryptococcus gattii are the two etiologic agents of cryptococcosis. They belong to the phylum Basidiomycota and can be readily distinguished from other pathogenic yeasts such as Candida by the presence of a polysaccharide capsule, formation of melanin, and urease activity, which all function as virulence determinants. Infection proceeds via inhalation and subsequent dissemination to the central nervous system to cause meningoencephalitis. The most common risk for cryptococcosis caused by C. neoformans is AIDS, whereas infections caused by C. gattii are more often reported in immunocompetent patients with undefined risk than in the immunocompromised. There have been many chapters, reviews, and books written on C. neoformans. The topics we focus on in this article include species description, pathogenesis, life cycle, capsule, and stress response, which serve to highlight the specializations in virulence that have occurred in this unique encapsulated melanin-forming yeast that causes global deaths estimated at more than 600,000 annually.


Simultaneous characterization of tumor cellularity and the Warburg effect with PET, MRI and hyperpolarized 13C-MRSI.
Modern oncology aims at patient-specific therapy approaches, which triggered the development of biomedical imaging techniques to synergistically address tumor biology at the cellular and molecular level. PET/MR is a new hybrid modality that allows acquisition of high-resolution anatomic images and quantification of functional and metabolic information at the same time. Key steps of the Warburg effect-one of the hallmarks of tumors-can be measured non-invasively with this emerging technique. The aim of this study was to quantify and compare simultaneously imaged augmented glucose uptake and LDH activity in a subcutaneous breast cancer model in rats (MAT-B-III) and to study the effect of varying tumor cellularity on image-derived metabolic information. Methods: For this purpose, we established and validated a multimodal imaging workflow for a clinical PET/MR system including proton magnetic resonance (MR) imaging to acquire accurate morphologic information and diffusion-weighted imaging (DWI) to address tumor cellularity. Metabolic data were measured with dynamic [18F]FDG-PET and hyperpolarized (HP) 13C-pyruvate MR spectroscopic imaging (MRSI). We applied our workflow in a longitudinal study and analyzed the effect of growth dependent variations of cellular density on glycolytic parameters. Results: Tumors of similar cellularity with similar apparent diffusion coefficients (ADC) showed a significant positive correlation of FDG uptake and pyruvate-to-lactate exchange. Longitudinal DWI data indicated a decreasing tumor cellularity with tumor growth, while ADCs exhibited a significant inverse correlation with PET standard uptake values (SUV). Similar but not significant trends were observed with HP-13C-MRSI, but we found that partial volume effects and point spread function artifacts are major confounders for the quantification of 13C-data when the spatial resolution is limited and major blood vessels are close to the tumor. Nevertheless, analysis of longitudinal data with varying tumor cellularity further detected a positive correlation between quantitative PET and 13C-data. Conclusions: Our workflow allows the quantification of simultaneously acquired PET, MRSI and DWI data in rodents on a clinical PET/MR scanner. The correlations and findings suggest that a major portion of consumed glucose is metabolized by aerobic glycolysis in the investigated tumor model. Furthermore, we conclude that variations in cell density affect PET and 13C-data in a similar manner and correlations of longitudinal metabolic data appear to reflect both biochemical processes and tumor cellularity.


Elastic fingering in rotating Hele-Shaw flows.
The centrifugally driven viscous fingering problem arises when two immiscible fluids of different densities flow in a rotating Hele-Shaw cell. In this conventional setting an interplay between capillary and centrifugal forces makes the fluid-fluid interface unstable, leading to the formation of fingered structures that compete dynamically and reach different lengths. In this context, it is known that finger competition is very sensitive to changes in the viscosity contrast between the fluids. We study a variant of such a rotating flow problem where the fluids react and produce a gellike phase at their separating boundary. This interface is assumed to be elastic, presenting a curvature-dependent bending rigidity. A perturbative weakly nonlinear approach is used to investigate how the elastic nature of the interface affects finger competition events. Our results unveil a very different dynamic scenario, in which finger length variability is not regulated by the viscosity contrast, but rather determined by two controlling quantities: a characteristic radius and a rigidity fraction parameter. By properly tuning these quantities one can describe a whole range of finger competition behaviors even if the viscosity contrast is kept unchanged.


Reprogramming the genetic code: The emerging role of ribosomal frameshifting in regulating cellular gene expression.
Reading frame maintenance is a critical property of ribosomes. However, a number of genetic elements have been described that can induce ribosomes to shift on mRNAs, the most well understood of which are a class that directs ribosomal slippage by one base in 5' (-1) direction. This is referred to as programmed -1 ribosomal frameshifting (-1 PRF). Recently, a new -1 PRF promoting element was serendipitously discovered in a study examining the effects of stretches of adenosines in the coding sequences of mRNAs. Here, we discuss this finding, recent studies describing how -1 PRF is used to control gene expression in eukaryotes, and how -1 PRF is itself regulated. The implications of dysregulation of -1 PRF on human health are examined, as are possible new areas in which novel -1 PRF promoting elements might be discovered. Also watch the Video Abstract.


The role of melanin concentrating hormone (MCH) in the central chemoreflex: a knockdown study by siRNA in the lateral hypothalamus in rats.
Melanin concentrating hormone (MCH), a neuropeptide produced mainly in neurons localized to the lateral hypothalamic area (LHA), has been implicated in the regulation of food intake, energy balance, sleep state, and the cardiovascular system. Hypothalamic MCH neurons also have multisynaptic connections with diaphragmatic motoneurons and project to many central chemoreceptor sites. However, there are few studies of MCH involvement in central respiratory control. To test the hypothesis that MCH plays a role in the central chemoreflex, we induced a down regulation of MCH in the central nervous system by knocking down the MCH precursor (pMCH) mRNA in the LHA using a pool of small interfering RNA (siRNA), and measured the resultant changes in breathing, metabolic rate, body weight, and blood glucose levels in conscious rats. The injections of pMCH-siRNA into the LHA successfully produced a ∼ 62% reduction of pMCH mRNA expression in the LHA and a ∼ 43% decrease of MCH levels in the cerebrospinal fluid relative to scrambled-siRNA treatment (P = 0.006 and P = 0.02 respectively). Compared to the pretreatment baseline and the scrambled-siRNA treated control rats, knockdown of MCH resulted in: 1) an enhanced hypercapnic chemoreflex (∼ 42 & 47% respectively; P < 0.05) only in wakefulness; 2) a decrease in body weight and basal glucose levels; and 3) an unchanged metabolic rate. Our results indicate that MCH participates not only in the regulation of glucose and sleep-wake homeostasis but also the vigilance-state dependent regulation of the central hypercapnic chemoreflex and respiratory control.


A nicotinic acetylcholine receptor agonist affects honey bee sucrose responsiveness and decreases waggle dancing.
A nicotinic acetylcholine receptor agonist, imidacloprid, impairs memory formation in honey bees and has general effects on foraging. However, little is known about how this agonist affects two specific aspects of foraging: sucrose responsiveness (SR) and waggle dancing (which recruits nestmates). Using lab and field experiments, we tested the effect of sublethal doses of imidacloprid on (1) bee SR with the proboscis extension response assay, and (2) free-flying foragers visiting and dancing for a sucrose feeder. Bees that ingested imidacloprid (0.21 or 2.16 ng bee(-1)) had higher sucrose response thresholds 1 h after treatment. Foragers that ingested imidacloprid also produced significantly fewer waggle dance circuits (10.5- and 4.5-fold fewer for 50% and 30% sucrose solutions, respectively) 24 h after treatment as compared with controls. However, there was no significant effect of imidacloprid on the sucrose concentrations that foragers collected at a feeder 24 h after treatment. Thus, imidacloprid temporarily increased the minimum sucrose concentration that foragers would accept (short time scale, 1 h after treatment) and reduced waggle dancing (longer time scale, 24 h after treatment). The effect of time suggests different neurological effects of imidacloprid resulting from the parent compound and its metabolites. Waggle dancing can significantly increase colony food intake, and thus a sublethal dose (0.21 ng bee(-1), 24 p.p.b.) of this commonly used pesticide may impair colony fitness.


Effective strategies for the management of pyoderma gangrenosum: a comprehensive review.
Pyoderma gangrenosum (PG) is an inflammatory disease characterized by painful skin ulcerations with undermined and erythematous borders. The etiology of PG is not well understood, but it is generally considered to be an aberrant immune response characterized by a dermal neutrophilc infiltrate. Given the existence of only a few PG clinical trials, treatment options are largely based upon anecdotal data and small case studies. In addition to classic immunosuppressive medications, PG has been reported to respond well to the anti-TNF agents, infliximab, etanercept, adalimumab. Newer biologics such as ustekinumab (anti-IL-23), ixekizumab (anti-IL-17) and brodalumab (anti-IL-17R) are promising given the effect of IL-17 on neutrophil migration. However, the effectiveness of these newer agents remains to be rigorously evaluated. Multi-drug regimens have not been well described in the literature but are an excellent alternative for patients with refractory disease. Herein, we provide a comprehensive review of the pathophysiology of PG and of the different treatments available for managing PG patients, including the theoretical benefit of initiating multidrug regimens. We also provide one possible treatment algorithm for patients with refractory disease and give examples of refractory PG cases successfully treated with multidrug regimens.


An annotated checklist of the Branchiopoda (Crustacea) of the Dutch Caribbean islands.
The launch of the Dutch Caribbean Species Register by Naturalis Biodiversity Center (2017)-https://www.dutchcaribbeanspecies.org/-raised the question of which branchiopods originate from this part of the Netherlands. To answer this question, surveys of literature and of the Naturalis collection were conducted. The additional samples (collected in 2003-2005 and 2008) were analyzed. We present an annotated checklist of the Branchiopoda of the Dutch Caribbean. The Kingdom of the Netherlands includes the Dutch mainland and six Caribbean islands. From the Caribbean part of the kingdom, an annotated list of all known species is given. Fifteen taxa and three genera have been encountered and the species are discussed. To date, six species of large branchiopods and nine species of cladocerans are known. Two more genera of cladocerans have been found. One species is endemic to Bonaire.


[¹⁸F]THK5351 PET Imaging in Patients with Mild Cognitive Impairment.
Mild cognitive impairment (MCI) is a condition with diverse clinical outcomes and subgroups. Here we investigated the topographic distribution of tau in vivo using the positron emission tomography (PET) tracer [¹⁸F]THK5351 in MCI subgroups. This study included 96 participants comprising 38 with amnestic MCI (aMCI), 21 with nonamnestic MCI (naMCI), and 37 with normal cognition (NC) who underwent 3.0-T MRI, [¹⁸F]THK5351 PET, and detailed neuropsychological tests. [¹⁸F]flutemetamol PET was also performed in 62 participants. The aMCI patients were further divided into three groups: 1) verbal-aMCI, only verbal memory impairment; 2) visual-aMCI, only visual memory impairment; and 3) both-aMCI, both visual and verbal memory impairment. Voxel-wise statistical analysis and region-of-interest -based analyses were performed to evaluate the retention of [¹⁸F]THK5351 in the MCI subgroups. Subgroup analysis of amyloid-positive and -negative MCI patients was also performed. Correlations between [¹⁸F]THK5351 retention and different neuropsychological tests were evaluated using statistical parametric mapping analyses. [¹⁸F]THK5351 retention in the lateral temporal, mesial temporal, parietal, frontal, posterior cingulate cortices and precuneus was significantly greater in aMCI patients than in NC subjects, whereas it did not differ significantly between naMCI and NC participants. [¹⁸F] THK5351 retention was greater in the both-aMCI group than in the verbal-aMCI and visualaMCI groups, and greater in amyloid-positive than amyloid-negative MCI patients. The cognitive function scores were significantly correlated with cortical [¹⁸F]THK5351 retention. [¹⁸F]THK5351 PET might be useful for identifying distinct topographic patterns of [¹⁸F]THK5351 retention in subgroups of MCI patients who are at greater risk of the progression to Alzheimer's dementia.


MP3 player listening sound pressure levels among 10 to 17 year old students.
Using a manikin, equivalent free-field sound pressure level measurements were made from the portable digital audio players of 219 subjects, aged 10 to 17 years (93 males) at their typical and "worst-case" volume levels. Measurements were made in different classrooms with background sound pressure levels between 40 and 52 dBA. After correction for the transfer function of the ear, the median equivalent free field sound pressure levels and interquartile ranges (IQR) at typical and worst-case volume settings were 68 dBA (IQR = 15) and 76 dBA (IQR = 19), respectively. Self-reported mean daily use ranged from 0.014 to 12 h. When typical sound pressure levels were considered in combination with the average daily duration of use, the median noise exposure level, Lex, was 56 dBA (IQR = 18) and 3.2% of subjects were estimated to exceed the most protective occupational noise exposure level limit in Canada, i.e., 85 dBA Lex. Under worst-case listening conditions, 77.6% of the sample was estimated to listen to their device at combinations of sound pressure levels and average daily durations for which there is no known risk of permanent noise-induced hearing loss, i.e., ≤ 75 dBA Lex. Sources and magnitudes of measurement uncertainties are also discussed.


Randomized comparison of two interventions to enhance understanding during the informed consent process for research.
Many investigators have tested interventions to improve research participant understanding of information shared during the informed consent process, using a variety of methods and with mixed results. A valid criticism of most consent research is that studies are often conducted in simulated research settings rather than ongoing clinical studies. The present study rigorously tested two simple and easily adoptable strategies for presenting key consent information to participants eligible to enroll in six actual clinical trials (i.e. six parent studies). In collaboration with the study team from each parent study, we developed two consent interventions: a fact sheet and an interview-style video. The content of each of the intervention was based on the information shared in the consent form approved for each parent study. Participants were randomized to the standard consent process, or to one of the two interventions. Once exposed to the assigned consent mode, participants were asked to complete an assessment of understanding. The study was powered to determine whether those exposed to the fact sheet or video performed better on the consent assessment compared to those exposed to the standard consent. We also assessed participant satisfaction with the consent process. A total of 284 participants were randomized to one of the three consent arms. Assessments of understanding were completed with a total of 273 participants from July 2017 to April 2019. Participants exposed to the video had better understanding scores compared to those exposed to the standard consent form process (p value = 0.020). Participants were more satisfied with the video when compared to the standard consent. Participants who received the fact sheet did not achieve higher overall understanding or satisfaction scores when compared to the standard consent process. This randomized study of two novel consent interventions across six different clinical trials demonstrated a statistically significant difference in participant understanding based on overall scores among those exposed to the video intervention compared to those exposed to the standard consent.


Adaptive activation of thyroid hormone and energy expenditure.
The mechanisms by which thyroid hormone accelerates energy expenditure are poorly understood. In the brown adipose tissue (BAT), activation of thyroid hormone by type 2 iodothyronine deiodinase (D2) has been known to play a role in adaptive energy expenditure during cold exposure in human newborns and other small mammals. Although BAT is not present in significant amounts in normal adult humans, recent studies have found substantial amounts of D2 in skeletal muscle, a metabolically relevant tissue in humans. This article reviews current biological knowledge about D2 and adaptive T3 production and their roles in energy expenditure.


Distinctive Effects of Aerobic and Resistance Exercise Modes on Neurocognitive and Biochemical Changes in Individuals with Mild Cognitive Impairment.
Decreased levels of the neuroprotective growth factors, low-grade inflammation, and reduced neurocognitive functions during aging are associated with neurodegenerative diseases, such as Alzheimer's disease. Physical exercise modifies these disadvantageous phenomena while a sedentary lifestyle promotes them. The purposes of the present study included investigating whether both aerobic and resistance exercise produce divergent effects on the neuroprotective growth factors, inflammatory cytokines, and neurocognitive performance, and further exploring whether changes in the levels of these molecular biomarkers are associated with alterations in neurocognitive performance. Fifty-five older adults with amnestic MCI (aMCI) were recruited and randomly assigned to an aerobic exercise (AE) group, a resistance exercise (RE) group, or a control group. The assessment included neurocognitive measures [e.g., behavior and event-related potential (ERP)] during a task-switching paradigm, as well as circulating neuroprotective growth factors (e.g., BDNF, IGF-1, VEGF, and FGF-2) and inflammatory cytokine (e.g., TNF-α, IL-1β, IL-6, IL-8, and IL-15) levels at baseline and after either a 16-week aerobic or resistance exercise intervention program or a control period. Aerobic and resistance exercise could effectively partially facilitate neurocognitive performance [e.g., accuracy rates (ARs), reaction times during the heterogeneous condition, global switching cost, and ERP P3 amplitude] when the participants performed the task switching paradigm although the ERP P2 components and P3 latency could not be changed. In terms of the circulating molecular biomarkers, the 16-week exercise interventions did not change some parameters (e.g., leptin, VEGF, FGF-2, IL-1β, IL-6, and IL-8). However, the peripheral serum BDNF level was significantly increased, and the levels of insulin, TNF-α, and IL-15 levels were significantly decreased in the AE group, whereas the RE group showed significantly increased IGF-1 levels and decreased IL-15 levels. The relationships between the changes in neurocognitive performance (AR and P3 amplitudes) and the changes in the levels of neurotrophins (BDNF and IGF-1)/inflammatory cytokines (TNF-α) only approached significance. These findings suggested that in older adults with aMCI, not only aerobic but also resistance exercise is effective with regard to increasing neurotrophins, reducing some inflammatory cytokines, and facilitating neurocognitive performance. However, the aerobic and resistance exercise modes likely employed divergent molecular mechanisms on neurocognitive facilitation.


Structural biology of Tat protein transport.
The Tat protein transport system is found in the cytoplasmic membrane of prokaryotes and the thylakoid membrane of plant chloroplasts. Unusually, the Tat system translocates proteins only after they have folded. Proteins are targeted to the Tat system by specific N-terminal signal peptides. High resolution structures have recently been determined for the TatA and TatC proteins that form the Tat translocation site. These structures provide a molecular framework for understanding the mechanism of Tat transport. The interactions between TatC and the signal peptide of the substrate protein can be provisionally modelled. However, the way that TatA and TatC combine in the active translocation site remains to be definitively established.


Modulation of the bitterness of pea and potato proteins by a complex coacervation method.
The incorporation of novel plant-based proteins into foods is often challenging due to an unacceptable bitter sensation. Typically, a combination of electrostatic and hydrophobic forces contributes to the proteins' bitterness. The current study therefore focuses on the development of electrical properties on cationic plant proteins to reduce their overall bitterness in order to improve the perceived sensorial acceptance. As such, we utilized a simple mixing process to induce complex coacervation of oppositely charged biopolymers under acidic conditions. Pea and potato protein stock solutions were mixed with apple pectin (DE 71%) solutions at various biopolymer ratios to modulate the electrical, rheological, and sensorial properties of the complexes. Whey protein hydrolyzate was used as a control sample. Surface charge measurements revealed a transition from positive to negative values as the pectin concentration was increased regardless of the plant protein, whereas stable dispersions without sedimentation were observed above a critical pectin : protein ratio of 1. Low and intermediate biopolymer ratios (<1) promoted aggregation and led to rapid sedimentation. Sensory evaluation showed that bitterness scores depended on protein type and decreased from pea protein > potato protein > whey protein. Moreover, bitter off-notes were increasingly reduced with increasing pectin : protein ratios; however, high dispersion viscosities above 0.05 Pa s led to undesirable texture and mouthfeel of the biopolymer dispersions. Our results might have important implications for the utilization of novel plant proteins in food and beverage applications.


Genetic modification of mesenchymal stem cells in spinal cord injury repair strategies.
Spinal cord injury (SCI) is a serious injury of the central nervous system and up until now there is no evident effective treatment for SCI. Axonal regeneration is the only way to restore functions after serious SCI that interrupt the long tracts mediating motor and sensory function. The hurdles for axonal regeneration in SCI include: glial scar tissue and molecular barriers, the inhibiting microenvironment, and the lack of sufficient neurotrophic support. Therefore, the key point of applying stem cells to treat SCI is to build a microenvironment conducive to the survival and differentiation of stem cells and regulate neurotrophic factor expression. Adult mesenchymal stem cells (MSCs) have been applied in experimental animal models and clinical trials of SCI. Genetic modification of MSCs can increase secretion of peptides or total length proteins with potential to repair SCI and promote survival of themselves and survival or regeneration of neurons. There are many proteins that have been applied to modified MSCs, such as neurotrophic factors (neurotrophin 3, brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, nerve growth factor, and MNTS1), receptor tyrosine kinases (tropomyosin-related kinase C), and hepatocyte growth factor. In the future, there will be more molecules acting as transgenes in MSCs for treatment of SCI.


Variations in water status, gas exchange, and growth in Rosmarinus officinalis plants infected with Glomus deserticola under drought conditions.
The influence of the arbuscular mycorrhizal fungus Glomus deserticola on the water relations, gas exchange parameters, and vegetative growth of Rosmarinus officinalis plants under water stress was studied. Plants were grown with and without the mycorrhizal fungus under glasshouse conditions and subjected to water stress by withholding irrigation water for 14 days. Along the experimental period, a significant effect of the fungus on the plant growth was observed, and under water stress, mycorrhizal plants showed an increase in aerial and root biomass compared to non-mycorrhizal plants. The decrease in the soil water potential generated a decrease in leaf water potential (psi(l)) and stem water potential (psi(x)) of mycorrhizal and non-mycorrhizal plants, with this decrease being lower in mycorrhizal water-stressed plants. Mycorrhization also had positive effects on the root hydraulic conductivity (Lp) of water stressed plants. Furthermore, mycorrhizal-stressed plants showed a more important decrease in osmotic potential at full turgor (psi(os)) than did non-mycorrhizal-stressed plants, indicating the capacity of osmotic adjustment. Mycorrhizal infection also improved photosynthetic activity (Pn) and stomatal conductance (g(s)) in plants under water stress compared to the non-mycorrhizal-stressed plants. A similar behaviour was observed in the photochemical efficiency of PSII (Fv/Fm) with this parameter being lower in non-mycorrhizal plants than in mycorrhizal plants under water stress conditions. In the same way, under water restriction, mycorrhizal plants showed higher values of chlorophyll content than did non-mycorrhizal plants. Thus, the results obtained indicated that the mycorrhizal symbiosis had a beneficial effect on the water status and growth of Rosmarinus officinalis plants under water-stress conditions.


Genome-wide analysis of selection on the malaria parasite Plasmodium falciparum in West African populations of differing infection endemicity.
Locally varying selection on pathogens may be due to differences in drug pressure, host immunity, transmission opportunities between hosts, or the intensity of between-genotype competition within hosts. Highly recombining populations of the human malaria parasite Plasmodium falciparum throughout West Africa are closely related, as gene flow is relatively unrestricted in this endemic region, but markedly varying ecology and transmission intensity should cause distinct local selective pressures. Genome-wide analysis of sequence variation was undertaken on a sample of 100 P. falciparum clinical isolates from a highly endemic region of the Republic of Guinea where transmission occurs for most of each year and compared with data from 52 clinical isolates from a previously sampled population from The Gambia, where there is relatively limited seasonal malaria transmission. Paired-end short-read sequences were mapped against the 3D7 P. falciparum reference genome sequence, and data on 136,144 single nucleotide polymorphisms (SNPs) were obtained. Within-population analyses identifying loci showing evidence of recent positive directional selection and balancing selection confirm that antimalarial drugs and host immunity have been major selective agents. Many of the signatures of recent directional selection reflected by standardized integrated haplotype scores were population specific, including differences at drug resistance loci due to historically different antimalarial use between the countries. In contrast, both populations showed a similar set of loci likely to be under balancing selection as indicated by very high Tajima's D values, including a significant overrepresentation of genes expressed at the merozoite stage that invades erythrocytes and several previously validated targets of acquired immunity. Between-population FST analysis identified exceptional differentiation of allele frequencies at a small number of loci, most markedly for five SNPs covering a 15-kb region within and flanking the gdv1 gene that regulates the early stages of gametocyte development, which is likely related to the extreme differences in mosquito vector abundance and seasonality that determine the transmission opportunities for the sexual stage of the parasite.


Benign ethnic neutropenia in a South African population, and its association with HIV acquisition and adverse event reporting in an HIV vaccine clinical trial.
Benign ethnic neutropenia (BEN) is defined as a neutrophil count of <1.5×109 cells/L in healthy individuals and is more common in populations of certain ethnicities, e.g. African or Middle Eastern ethnicity. Neutrophil values are commonly included in eligibility criteria for research participation, but little is known about the relationship between BEN, HIV acquisition, and the occurrence of adverse events during clinical trials. We investigated these relationships using data from an HIV vaccine efficacy trial of healthy adults from 5 South African sites. We analysed data from the double-blind, placebo-controlled, randomized trial HVTN 503, and its follow-on study HVTN 503-S to assess the prevalence of BEN, its association with HIV infection, and adverse event reporting. These data were then compared with a time- and age-matched, non-pregnant cohort from the National Health and Nutrition Examination Survey (NHANES) conducted between 2007-2008 in the United States (US). The 739 South African participants had a median age of 22.0 years (interquartile range = 20-26) and 56% (n = 412) were male. Amongst the US cohort of 845 participants, the median age was 26 (IQR: 21-30) and the majority (54%, 457/745) were also male. BEN was present at enrolment in 7.0% (n = 52) of South African participants (6% in the placebo group versus 8% in the vaccine group); 81% (n = 42) of those with BEN were male. Pretoria North had the highest prevalence of BEN (11.6%, 5/43), while Cape Town had the lowest (0.7%, 1/152). Participants with BEN had a lower median neutrophil count (1.3 vs. 3.2x109 cells/L; p<0.001) and BMI (20.8 vs. 22.3 kg/m2; p<0.001) when compared to those without BEN. A greater proportion of Black South Africans had neutrophil counts <1.5×109 cells/L compared to US non-Hispanic Whites from the NHANES cohort (7% [52/739] vs. 0.6% [3/540]; p<0.001). BEN did not increase the odds for HIV infection (adjusted odds ratio [aOR]: 1.364, 95% confidence interval [95% CI]: 0.625-2.976; p = 0.4351). However, female gender (aOR: 1.947, 95% CI: 1.265-2.996; p = 0.0025) and cannabis use (aOR: 2.192, 95% CI: 1.126-4.266; p = 0.0209) increased the odds of HIV acquisition. The incidence rates of adverse events were similar between participants in the placebo group with BEN, and those without: 12.1 (95% CI: 7.3-20.1) vs. 16.5 (95% CI: 14.6-18.7; p = 0.06) events per 100 person-years (py) were noted in the infections and infestations system organ class, respectively. The vaccine group had an event incidence rate of 19.7 (95% CI: 13.3-29.2) vs. 14.8 (95% CI: 13.0-16.8; p = 0.07) events per 100py in the group with, and without BEN, respectively. BEN is more prevalent in Black South Africans compared to US Non-Hispanic Whites. Our data do not support excluding populations from HIV vaccine trials because of BEN. BEN was not associated with increased risk for HIV infection or Adverse events on a vaccine trial. Predictors of HIV infection risk were females and cannabis use, underlying the continued importance of prevention programmes in focusing on these populations.


The value of magnetic resonance imaging of the lumbar spine to predict low-back pain in asymptomatic subjects : a seven-year follow-up study.
In 1989, a group of sixty-seven asymptomatic individuals with no history of back pain underwent magnetic resonance imaging of the lumbar spine. Twenty-one subjects (31%) had an identifiable abnormality of a disc or of the spinal canal. In the current study, we investigated whether the findings on the scans of the lumbar spine that had been made in 1989 predicted the development of low-back pain in these asymptomatic subjects. A questionnaire concerning the development and duration of low-back pain over a seven-year period was sent to the sixty-seven asymptomatic individuals from the 1989 study. A total of fifty subjects completed and returned the questionnaire. A repeat magnetic resonance scan was made for thirty-one of these subjects. Two neuroradiologists and one orthopaedic spine surgeon interpreted the original and repeat scans in a blinded fashion, independent of clinical information. At each disc level, any radiographic abnormality, including bulging or degeneration of the disc, was identified. Radiographic progression was defined as increasing severity of an abnormality at a specific disc level or the involvement of additional levels. Of the fifty subjects who returned the questionnaire, twenty-nine (58%) had no back pain. Low-back pain developed in twenty-one subjects during the seven-year study period. The 1989 scans of these subjects demonstrated normal findings in twelve, a herniated disc in five, stenosis in three, and moderate disc degeneration in one. Eight individuals had radiating leg pain; four of them had had normal findings on the original scans, two had had spinal stenosis, one had had a disc protrusion, and one had had a disc extrusion. In general, repeat magnetic resonance imaging scans revealed a greater frequency of disc herniation, bulging, degeneration, and spinal stenosis than did the original scans. The findings on magnetic resonance scans were not predictive of the development or duration of low-back pain. Individuals with the longest duration of low-back pain did not have the greatest degree of anatomical abnormality on the original, 1989 scans. Clinical correlation is essential to determine the importance of abnormalities on magnetic resonance images.


Applications of nanotechnology for melanoma treatment, diagnosis, and theranostics.
Melanoma is the most aggressive type of skin cancer and has very high rates of mortality. An early stage melanoma can be surgically removed, with a survival rate of 99%. However, metastasized melanoma is difficult to cure. The 5-year survival rates for patients with metastasized melanoma are still below 20%. Metastasized melanoma is currently treated by chemotherapy, targeted therapy, immunotherapy and radiotherapy. The outcome of most of the current therapies is far from optimistic. Although melanoma patients with a mutation in the oncogene v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) have an initially higher positive response rate to targeted therapy, the majority develop acquired drug resistance after 6 months of the therapy. To increase treatment efficacy, early diagnosis, more potent pharmacological agents, and more effective delivery systems are urgently needed. Nanotechnology has been extensively studied for melanoma treatment and diagnosis, to decrease drug resistance, increase therapeutic efficacy, and reduce side effects. In this review, we summarize the recent progress on the development of various nanoparticles for melanoma treatment and diagnosis. Several common nanoparticles, including liposome, polymersomes, dendrimers, carbon-based nanoparticles, and human albumin, have been used to deliver chemotherapeutic agents, and small interfering ribonucleic acids (siRNAs) against signaling molecules have also been tested for the treatment of melanoma. Indeed, several nanoparticle-delivered drugs have been approved by the US Food and Drug Administration and are currently in clinical trials. The application of nanoparticles could produce side effects, which will need to be reduced so that nanoparticle-delivered drugs can be safely applied in the clinical setting.


Deep Learning for Understanding Satellite Imagery: An Experimental Survey.
Translating satellite imagery into maps requires intensive effort and time, especially leading to inaccurate maps of the affected regions during disaster and conflict. The combination of availability of recent datasets and advances in computer vision made through deep learning paved the way toward automated satellite image translation. To facilitate research in this direction, we introduce the Satellite Imagery Competition using a modified SpaceNet dataset. Participants had to come up with different segmentation models to detect positions of buildings on satellite images. In this work, we present five approaches based on improvements of U-Net and Mask R-Convolutional Neuronal Networks models, coupled with unique training adaptations using boosting algorithms, morphological filter, Conditional Random Fields and custom losses. The good results-as high as A P = 0.937 and A R = 0.959 -from these models demonstrate the feasibility of Deep Learning in automated satellite image annotation.


Differential organ phenotypes after postnatal Igf1r gene conditional deletion induced by tamoxifen in UBC-CreERT2; Igf1r fl/fl double transgenic mice.
Insulin-like growth factor type 1 receptor (IGF1R) is a ubiquitously expressed tyrosine kinase that regulates cell proliferation, differentiation and survival. It controls body growth and organ homeostasis, but with specific functions depending on developmental time and cell type. Human deficiency in IGF1R is involved in growth failure, microcephaly, mental retardation and deafness, and its overactivation is implicated in oncogenesis. Igf1r-deficient mice die at birth due to growth retardation and respiratory failure. Although multiple Igf1r tissue-specific mutant lines have been analyzed postnatally, using Igf1r-floxed (Igf1r (fl/fl) ) mice mated with diverse cell-type recombinase Cre-expressing transgenics, no mouse models for the study of generalized Igf1r deficiency in adults have been reported. To this end we generated UBC-CreERT2; Igf1r (fl/fl) transgenic mice with an inducible deletion of Igf1r activated by tamoxifen. Tamoxifen administration to 4 week-old prepuberal male mice delayed their growth, producing a distinct impact on organ size 4 weeks later. Whereas testes were smaller, spleen and heart showed an increased organ to body weight ratio. Mosaic Igf1r genomic deletions caused a significant reduction in Igf1r mRNA in all organs analyzed, resulting in diverse phenotypes. While kidneys, spleen and cochlea had unaltered gross morphology, testes revealed halted spermatogenesis, and liver and alveolar lung parenchyma showed increased cell proliferation rates without affecting apoptosis. We demonstrate that UBC-CreERT2 transgenic mice efficiently delete Igf1r upon postnatal tamoxifen treatment in multiple mouse organs, and corroborate that IGF1R function is highly dependent on cell, tissue and organ type.


Night-Time Shift Work and Related Stress Responses: A Study on Security Guards.
Work-related stress can induce a break in homeostasis by placing demands on the body that are met by the activation of two different systems, the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Night-shift work alters the body's exposure to the natural light-dark schedule and disrupts circadian (daily) rhythms. The greatest effect of night-shift work is the disruption of circadian rhythms. The impact that these disruptions may have on the pathogenesis of many diseases, including cancer, is unknown. This study aims to discover the relationship among three different job activities of security guards and their stress-related responses by evaluating salivary cortisol levels and blood pressure. Ninety security guards, including night-time workers and night-time and daily-shift workers, were recruited for this study. Each security guard provided two saliva samples before and after three scheduled time points: (i) at 22:00, (ii) at 06:30, and (iii) at 14:00. The results of the study showed a significant alteration in cortisol levels. Night-time shift cortisol levels significantly increased before and after the work shifts. A physiological prevalence of the vagal tone on the cardiocirculatory activity was found during night-shift work. This study indicates that cortisol levels and blood pressure are sensitive markers of biological responses to severe work stress. Shift-change consequences may occur at the end of the night shift when there is a significant increase in the cortisol level and a significant variation in cardiovascular parameters.