bluuebunny/crossref_metadata_2025 huggingface dataset:
Histological Aspects of a Novel Technique Used for the Management of Infections Secondary to Sinus Bone Grafting
Authors: Ayna Mustafa , Açil Yahya , Wiltfang Jörg , Gülses Aydin
Published: June 2020

Recently, a technical note describing a promising method for the management of infections after sinus bone grafting by irrigating the corresponding area with hydrogen peroxide based solution with an aid of a drain has been published. The aim of this paper was to present the histological and radiological results of the above mentioned technique. A total of 17 patients who have presented with infections secondary to sinus bone grafting enrolled in the study. During implant placement, bone was collected from the originally grafted site with a trephine burr for radiological examination via micro-computed tomography and histological examination. According to the results of the current study, Bio-Oss acted as a scaffold, and mature fibrous bone formed trabeculae, which assembled to an interlinked trabecular structure. Average results obtained from the microradiography confirmed the higher percentage of Bio-Oss (27.21% ± 3.31%) at the corresponding area; whereas the amount of newly formed bone was slightly lower (6.79% ± 1.13%) As a conclusion, this simple and minimally invasive technique might be beneficial in avoiding removal of bone graft material and could help in rescuing the former laborious procedure.
Convolutional Neural Networks for Immediate Surgical Needle Automatic Detection in Craniofacial X-Ray Images
Authors: Liang Zhuangzhuang , Liao Qian , Chen Sheng , Qian Qingyu , Zhu Lin , Yang Hui , Gui Haijun
Published: June 2020

Purpose:

Immediate X-ray examination is necessary while the surgical needle falls off during operation. In this study, one convolutional neural network (CNN) model was introduced for automatically surgical needle detection in craniofacial X-ray images.

Materials and Methods:

The craniofacial surgical needle (5–0, ETHICON, USA) was localized in 8 different anatomic regions of 2 pig heads for bilateral X-ray examination separately. Thirty-two images were obtained finally which were cropped into fragmented images and divided into the training dataset and the test dataset. Then, one immediate needle detection CNN model was developed and trained. Its performance was quantitatively evaluated using the precision rate, the recall rate, and the f2-score. One 8-fold cross-validation experiment was performed. The detection rate and the time it took were calculated to quantify the degree of difference between the automatic detection and the manual detection by 3 experienced clinicians.

Results:

The precision rate, the recall rate, and the f2-score of the CNN model on fragmented images were 98.99%, 92.67%, and 93.85% respectively. For the 8-fold cross-validation experiments, 26 cases of all the 32 X-ray images were automatically marked the right position of the needle (detection rate of 81.25%). The average time of automatically detecting one image was 5.8 seconds. For the 3 clinicians, 65 images of all the 32× 3 images were checked right (detection rate of 67.7%) with the average time-consuming of 33 seconds.

Conclusion:

In summary, after training with a large dataset, the CNN model showed potential for immediate surgical needle automatic detection in craniofacial X-ray images with better detection accuracy and efficiency than the conventional manual method.
Geographic Variation in the Utilization of and Mortality After Emergency General Surgery Operations in the Northeastern and Southeastern United States
Authors: Becher Robert D. , Jin Lan , Warren Joshua L. , Gill Thomas M. , DeWane Michael P. , Davis Kimberly A. , Zhang Yawei
Published: June 2020

Objective:

To define geographic variations in emergency general surgery (EGS) care, we sought to determine how much variability exists in the rates of EGS operations and subsequent mortality in the Northeastern and Southeastern United States (US).

Summary Background Data:

While some geographic variations in healthcare are normal, unwarranted variations raise questions about the quality, appropriateness, and cost-effectiveness of care in different areas.

Methods:

Patients ≥18 years who underwent 1 of 10 common EGS operations were identified using the State Inpatient Databases (2011–2012) for 6 states, representing Northeastern (New York) and Southeastern (Florida, Georgia, Kentucky, North Carolina, Mississippi) US. Geographic unit of analysis was the hospital service area (HSA). Age-standardized rates of operations and in-hospital mortality were calculated and mapped. Differences in rates across geographic areas were compared using the Kruskal–Wallis test, and variance quantified using linear random-effects models. Variation profiles were tabulated via standardized rates of utilization and mortality to compare geographically heterogenous areas.

Results:

227,109 EGS operations were geospatially analyzed across the 6 states. Age-standardized EGS operation rates varied significantly by region (Northeast rate of 22.7 EGS operations per 10,000 in population versus Southeast 21.9; P < 0.001), state (ranging from 9.9 to 29.1; P < 0.001), and HSA (1.9–56.7; P < 0.001). The geographic variability in age-standardized EGS mortality rates was also significant at the region level (Northeast mortality rate 7.2 per 1000 operations vs Southeast 7.4; P < 0.001), state-level (ranging from 5.9 to 9.0 deaths per 1000 EGS operations; P < 0.001), and HSA-level (0.0–77.3; P < 0.001). Maps and variation profiles visually exhibited widespread and substantial differences in EGS use and morality.

Conclusions:

Wide geographic variations exist across 6 Northeastern and Southeastern US states in the rates of EGS operations and subsequent mortality. More detailed geographic analyses are needed to determine the basis of these variations and how they can be minimized.
Octopamine increases individual and collective foraging in a neotropical stingless bee
Authors: Peng Tianfei , Schroeder Maximilian , Grüter Christoph
Published: June 2020

The biogenic amine octopamine (OA) is a key modulator of individual and social behaviours in honeybees, but its role in the other group of highly eusocial bees, the stingless bees, remains largely unknown. In honeybees, OA mediates reward perception and affects a wide range of reward-seeking behaviours. Thus, we tested the hypothesis that OA increases individual foraging effort and collective food source exploitation in the neotropical stingless bee
Plebeia droryana
. OA treatment caused a significant increase in the number of bees at artificial sucrose feeders and a 1.73-times higher individual foraging frequency. This effect can be explained by OA lowering the sucrose response threshold and, thus, increasing the perceived value of the food source. Our results demonstrate that, similar to its effects on honeybees, OA increases both individual and collective food source exploitation in
P. droryana
. This suggests that, despite having evolved many complex behaviours independently, OA might have similar regulatory effects on foraging behaviours in the two groups of highly eusocial bees.
Post-activation muscle potentiation and its relevance to cyclical behaviours
Authors: Taylor-Burt Kari R. , Konow Nicolai , Biewener Andrew A.
Published: June 2020

Muscle can experience post-activation potentiation (PAP), a temporary increase in force and rate of force development, when contractions are closely timed; therefore, cyclical behaviours are likely affected by PAP, as succeeding contraction cycles can lead to potentiation over several subsequent cycles. Here, we examined PAP duringin situcyclical contractions of the mallard lateral gastrocnemius (LG). Surface swimming, a cyclical behaviour, was mimicked with work-loops usingin vivoLG length change and stimulation parameters. Tests were performed at mallards' preferred cycle frequency as well as at lower and higher frequencies. Like muscles from mammals, anurans and arthropods, the mallard LG exhibited PAP with increases in peak force, average force rate and net work. Staircase potentiation occurred over two or more work-loop cycles, resulting in gradual increases in PAP. The number of cycles needed to reach maximum work varied with cycle frequency, requiring more cycles at higher cycle frequencies. PAP occurred underin vivo-like stimulation parameters, suggesting a potentially important role of PAP in animal locomotion, especially in cyclical behaviours.
The centromere comes into focus: from CENP-A nucleosomes to kinetochore connections with the spindle
Authors: Kixmoeller Kathryn , Allu Praveen Kumar , Black Ben E.
Published: June 2020

Eukaryotic chromosome segregation relies upon specific connections from DNA to the microtubule-based spindle that forms at cell division. The chromosomal locus that directs this process is the centromere, where a structure called the kinetochore forms upon entry into mitosis. Recent crystallography and single-particle electron microscopy have provided unprecedented high-resolution views of the molecular complexes involved in this process. The centromere is epigenetically specified by nucleosomes harbouring a histone H3 variant, CENP-A, and we review recent progress on how it differentiates centromeric chromatin from the rest of the chromosome, the biochemical pathway that mediates its assembly and how two non-histone components of the centromere specifically recognize CENP-A nucleosomes. The core centromeric nucleosome complex (CCNC) is required to recruit a 16-subunit complex termed the constitutive centromere associated network (CCAN), and we highlight recent structures reported of the budding yeast CCAN. Finally, the structures of multiple modular sub-complexes of the kinetochore have been solved at near-atomic resolution, providing insight into how connections are made to the CCAN on one end and to the spindle microtubules on the other. One can now build molecular models from the DNA through to the physical connections to microtubules.
Peer-to-peer loan acceptance and default prediction with artificial intelligence
Authors: Turiel J. D. , Aste T.
Published: June 2020

Logistic regression (LR) and support vector machine algorithms, together with linear and nonlinear deep neural networks (DNNs), are applied to lending data in order to replicate lender acceptance of loans and predict the likelihood of default of issued loans. A two-phase model is proposed; the first phase predicts loan rejection, while the second one predicts default risk for approved loans. LR was found to be the best performer for the first phase, with test set recall macro score of

77.4
%

. DNNs were applied to the second phase only, where they achieved best performance, with test set recall score of

72
%

, for defaults. This shows that artificial intelligence can improve current credit risk models reducing the default risk of issued loans by as much as

70
%

. The models were also applied to loans taken for small businesses alone. The first phase of the model performs significantly better when trained on the whole dataset. Instead, the second phase performs significantly better when trained on the small business subset. This suggests a potential discrepancy between how these loans are screened and how they should be analysed in terms of default prediction.
RevisedCornechiniscus(Heterotardigrada) and new phylogenetic analyses negate echiniscid subfamilies and tribes
Authors: Gąsiorek Piotr , Michalczyk Łukasz
Published: June 2020

Echiniscidae are undoubtedly the most thoroughly studied lineage of the class Heterotardigrada. Recently, new subfamilies and tribes grouping echiniscid genera based on traditionally recognized morphological clues have been proposed. Here, by integrative analyses of morphology and DNA sequences of numerous populations of a rare genusCornechiniscus, we show that this hypothesized classification is artificial. Specifically, we demonstrate that Echiniscinae are diphyletic, asBryodelphaxforms a distinct phyletic lineage within Echiniscidae, and Pseudechiniscinae are polyphyletic, withMopsechiniscusbeing indirectly related toPseudechiniscus, which is closer to theEchiniscus-like genera than to other genera with pseudosegmental plates. Consequently, the subfamilies and tribes are considered as unsupported from the phylogenetic and morphological point of view. The genusCornechiniscusis revised, and the phenotypic diagnoses of several species are updated thanks to new rich material from Africa, Asia and Europe.Cornechiniscus imperfectussp. nov. is described from mountains of Kyrgyzstan, being the second appendaged species within the genus and the third known to exhibit dioecy. A taxonomic key to the genus is provided. Systematic positions ofAcanthechiniscusandMultipseudechiniscusare also discussed.Acanthechiniscus goedeniis confirmed to be a member of the genusAcanthechiniscus.
Presence of mismatches between diagnostic PCR assays and coronavirus SARS-CoV-2 genome
Authors: Khan Kashif Aziz , Cheung Peter
Published: June 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; initially named as 2019-nCoV) is responsible for the recent COVID-19 pandemic and polymerase chain reaction (PCR) is the current standard method for its diagnosis from patient samples. This study conducted a reassessment of published diagnostic PCR assays, including those recommended by the World Health Organization (WHO), through the evaluation of mismatches with publicly available viral sequences. An exhaustive evaluation of the sequence variability within the primer/probe target regions of the viral genome was performed using more than 17 000 viral sequences from around the world. The analysis showed the presence of mutations/mismatches in primer/probe binding regions of 7 assays out of 27 assays studied. A comprehensive bioinformatics approach for
in silico
inclusivity evaluation of PCR diagnostic assays of SARS-CoV-2 was validated using freely available software programs that can be applied to any diagnostic assay of choice. These findings provide potentially important information for clinicians, laboratory professionals and policy-makers.
Therapeutic effectiveness of interferon-alpha 2b against COVID-19: the Cuban experience
Authors: Pereda R , González D , Rivero HB , Rivero JC , Pérez A , López LR , Mezquia N , Venegas R , Betancourt JR , Domínguez RE
Published: June 2020

Background

Effective therapies are needed to control the SARS-Cov-2 infection pandemic and reduce mortality associated with COVID-19. Several clinical studies have provided evidence for the antiviral effects of type I interferons (IFNs) in patients with respiratory coronaviruses. This study assessed the therapeutic efficacy of IFN-α2b in patients infected with SARS-CoV-2 during the first month after the outbreak began in Cuba.

Method

This multicenter prospective observational study was conducted in 16 hospitals in 8 Cuban provinces. Participants were patients with confirmed SARS-CoV-2 infection detected from throat swab specimens by real time RT-PCR who gave informed consent and had no contraindications for IFN treatment. Patients received therapy as per the Cuban COVID protocol, that included a combination of oral antivirals (lopinavir/ritonavir and chloroquine) with intramuscular administration of IFN-α2b (Heberon® Alpha R, Center for Genetic Engineering and Biotechnology, Havana), 3 times per week, for 2 weeks. The primary endpoint was the proportion of patients discharged from hospital (without clinical and radiological symptoms and non-detectable virus by RT-PCR). The secondary endpoint was the case fatality rate (CFR), defined as the number of confirmed deaths divided by the number of confirmed cases.

Results

From March 11th to April 14th, 814 patients were confirmed SARS-CoV-2 positive in Cuba, 761 (93.4%) were treated with Heberon® Alpha R and 53 received the approved protocol without IFN treatment. The proportion of fully recovered patients was higher in the IFN-treated compared with non-IFN treated group (95.4% vs 26.1%, p<0.01). The CFR for all patients was 2.95%, and for those patients who received IFN-α2b the CFR was reduce to 0.92. The estimated global CFR is 6.34% and 4.05% for the Americas reported by WHO and PAHO, respectively. In this study, 82 patients (10.1%) required intensive care and, of these, 42 (5.5%) were treated with IFN.

Conclusions

This report provides preliminary evidence for the therapeutic effectiveness of IFNα-2b for COVID-19 and suggests that the use of Heberon® Alpha R may contribute to complete recovery.
The First Complete Zoroastrian-Parsi Mitochondrial Reference Genome and genetic signatures of an endogamous non-smoking population
Authors: Patell Villoo Morawala , Pasha Naseer , Krishnasamy Kashyap , Mittal Bharti , Gopalakrishnan Chellappa , Mugasimangalam Raja , Sharma Naveen , Gupta Arati-Khanna , Bhote-Patell Perviz , Rao Sudha , Jain Renuka ,   The Avestagenome Project
Published: June 2020

The present-day Zoroastrian-Parsis have roots in ancient pastoralist migrations from circumpolar regions leading to their settlement on the Eurasian Steppes and later, as Indo-Iranians in the Fertile Crescent. After migrating from the Persian province of Pars to India, the Zoroastrians from Pars (“Parsis”) practiced endogamy, thereby preserving their genetic identity and social practices. The study was undertaken to gain an insight into the genetic consequences of migration on the community, the practice of endogamy, to decipher the phylogenetic relationships with other groups, and elucidate the disease linkages to their individual haplotypes

We generated thede novothe Zoroastrian-Parsi Mitochondrial Reference Genome (AGENOME-ZPMS-HV2a-1), which is the first complete mitochondrial reference genome assembled for this group. Phylogenetic analysis of an additional 99 Parsi mitochondrial genome sequences showed the presence of HV, U, T, A and F (belonging to the macrohaplogroup N) and Z and other M descendents of the macrohaplogroup M (M5, M39, M33, M44’52, M24, M3, M30, M2, M4’30, M2, M35 and M27) and a largely Persian origin for the Parsi community. We assembled individual reference genomes for each major haplogroup and the Zoroastrian-Parsi Mitochondrial Consensus Genome (AGENOME-ZPMCG V1.0), which is the first consensus genome assembled for this group. We report the existence of 420 mitochondrial genetic variants, including 12 unique variants, in the 100 Zoroastrian-Parsi mitochondrial genome sequences. Disease association mapping showed 217 unique variants linked to longevity and 41 longevity-associated disease phenotypes across the majority of haplogroups.

Analysis of the coding genes, tRNA genes, and the D-loop region revealed haplogroup-specific disease associations for Parkinson’s disease, Alzheimer’s disease, cancers, and rare diseases. No known mutations linked to lung cancer were found in our study. Mutational signatures linked to tobacco carcinogens, specifically, the C>A and G>T transitions, were observed at extremely low frequencies in the Parsi cohort, suggestive of an association between the cultural norm prohibiting smoking and its reflection in the genetic signatures. In sum, the Parsi mitochondrial genome provides an exceptional resource for determining details of their migration and uncovering novel genetic signatures for wellness and disease.
Evidence for reduced long-term potentiation-like visual cortical plasticity in schizophrenia and bipolar disorder
Authors: Valstad Mathias , Roelfs Daniël , Slapø Nora B. , Timpe Clara M.F. , Rai Ahsan , Matziorinis Anna Maria , Beck Dani , Richard Geneviève , Sæther Linn Sofie , Haatveit Beathe , Nordvik Jan Egil , Hatlestad-Hall Christoffer , Einevoll Gaute T. , Mäki-Marttunen Tuomo , Haram Marit , Ueland Torill , Lagerberg Trine V. , Steen Nils Eiel , Melle Ingrid , Westlye Lars T. , Jönsson Erik G. , Andreassen Ole A. , Moberget Torgeir , Elvsåshagen Torbjørn
Published: June 2020

Background

Several lines of research suggest that impairments in long-term potentiation (LTP)-like synaptic plasticity might be a key pathophysiological mechanism in schizophrenia (SZ) and bipolar disorder type I (BDI) and II (BDII). Using modulations of visually evoked potentials (VEP) of the electroencephalogram, impaired LTP-like visual cortical plasticity has been implicated in patients with BDII, while there has been conflicting evidence in SZ, a lack of research in BDI, and mixed results regarding associations with symptom severity, mood states, and medication.

Methods

We measured the VEP of patients with SZ spectrum disorders (n=31), BDI (n=34), BDII (n=33), and other BD spectrum disorders (n=2), and age-matched healthy control participants (n=200) before and after prolonged visual stimulation.

Results

Compared to healthy controls, modulation of VEP component N1b, but not C1 or P1, was impaired both in patients within the SZ spectrum (χ2=35.1, p=3.1×10−9) and BD spectrum (χ2=7.0, p=8.2×10−3), including BDI (χ2=6.4, p=0.012), but not BDII (χ2=2.2, p=0.14). N1b modulation was also more severely impaired in SZ spectrum than BD spectrum patients (χ2=14.2, p=1.7×10−4). The reduction in N1b modulation was related to PANSS total scores (χ2=10.8, p=1.0×10−3), and nominally to number of psychotic episodes (χ2=4.9, p=0.027).Conclusions.These results suggest that LTP-like plasticity is impaired in SZ and BDI, but not BDII, and related to psychotic symptom severity. Adding to previous genetic, pharmacological, and anatomical evidence, these results implicate aberrant synaptic plasticity as a mechanism underlying SZ and BD.
Analysis of single-cell RNA-seq data from ovarian cancer samples before and after chemotherapy links stress-related transcriptional profile with chemotherapy resistance
Authors: Zhang Kaiyang , Erkan Erdogan Pekcan , Dai Jun , Andersson Noora , Kaipio Katja , Lamminen Tarja , Mansuri Naziha , Huhtinen Kaisa , Carpén Olli , Hynninen Johanna , Hietanen Sakari , Oikkonen Jaana , Häkkinen Antti , Hautaniemi Sampsa , Vähärautio Anna
Published: June 2020

Chemotherapy resistance is the greatest contributor to cancer mortality and the most urgent unmet challenge in oncology. In order to reveal transcriptomics changes due to platinum-based chemotherapy we analyzed single-cell RNA-seq data from fresh tissue samples taken at the time of diagnosis and after neoadjuvant chemotherapy from 11 high-grade serous ovarian cancer (HGSOC) patients. With a novel clustering method accounting for patient-specific variability and technical confounders, we identified 12 clusters. Of these, a stress-related transcriptional profile was enriched during chemotherapy and associated significantly to poor progression-free survival (PFS) and disease-free interval (DFI) in deconvoluted bulk RNA-seq data analysis of treatment-naive samples in TCGA cohort. Pan-cancer cell line analysis suggests that patients with high stress-related transcriptional profile may benefit from MEK1/2 inhibitors instead of platinum. Further, high proportion of stromal components and high interaction score between tumor and stromal suggest the tumor cells with high-stress profile actively interact with and potentially recruit stromal cells to their microenvironment already prior to chemotherapy, potentially facilitating protection from chemotherapeutic treatments. In summary, we have identified a stress-related transcriptional profile, which is present at the time of diagnosis, enriched during platinum treatment, independent predictor for poor PFS and DFI, and, based onin vitrodata, targetable with MEK1/2 inhibitors.

Translational relevance

We discovered a stress-related transcriptional profile that is significantly enriched in fresh tissue samples after chemotherapy and is significantly associated with poor progression-free survival in an independent patient cohort. The survival association is independent of age, tumor purity or BRCAness. Therefore, this chemotherapy resistance associated profile is intrinsic and could thus be targeted already in treatment-naive patients. The translation potential of the stress-related transcriptomics profile was further supported by pan-cancer cell line analysis that showed that cell lines with high stress-related transcriptional profile are not affected by platinum, corroborating our results, whereas they were more sensitive to MEK1/2 inhibitors. Taken together, the stress-related transcriptional profile, quantifiable with a set of 35 marker genes, provides a basis for improved prediction of platinum response as well as novel avenues to treat this patient group more effectively.
Identification of Wee1 as Target in Combination with Avapritinib for the Treatment of Gastrointestinal Stromal Tumor
Authors: Ye Shuai , Sharipova Dinara , Kozinova Marya , Klug Lilli , D’Souza Jimson , Belinsky Martin G. , Johnson Katherine J. , Einarson Margret B. , Devarajan Karthik , Zhou Yan , Litwin Samuel , Heinrich Michael C. , DeMatteo Ronald , von Mehren Margaret , Duncan James S. , Rink Lori
Published: June 2020

Management of gastrointestinal stromal tumor (GIST) has been revolutionized by the identification of activating mutations in KIT and PDGFRA, and the clinical application of receptor tyrosine kinase (RTK) inhibitors in the advanced disease setting. Stratification of GIST into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in the majority of GIST, resistance to these agents remains a significant clinical problem. Development of effective treatment strategies for refractory GIST subtypes requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has the potential to identify critical signaling networks and reveal protein kinases that are essential in GIST. Using Multiplexed Inhibitor Beads and Mass Spectrometry, we explored the majority of the kinome in GIST specimens from the three most common molecular subtypes to identify novel kinase targets. Kinome profiling revealed distinct signatures in GIST subtypes and identified kinases that are universally activated in all GIST, as well as kinases that are unique to each subtype. Kinome profiling in combination with loss-of-function assays identified a significant role for the G2-M tyrosine kinase, Wee1, in GIST cell survival.In vitroandin vivostudies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib inKITandPDGFRA-mutant GIST cell lines, and notable efficacy of MK-1775 as a single agent in thePDGFRA-mutant line. These studies provide strong preclinical justification for the use of MK-1775 in GIST.
Swine viral detection by adapted Next-Generation Sequencing (NGS) for RNA and DNA species reveals first detection of porcine circovirus type 3 (PCV3) in Chile
Authors: Rubilar Paulina S. , Tognarelli Javier , Fernández Jorge , Valdés Cristóbal , Broitman Felipe , Mandakovic Dinka , Pulgar Rodrigo
Published: June 2020

The outbreak and propagation of COVID-19 have posed a significant challenge to our society, highlighting the relevance of epidemiological monitoring of animal pathogens closely related to humans due to potential zoonosis. To find previously undetected viruses inside Chilean swine farms, we collected non-invasive samples from animals suspected to undergo any viral disease. After screening by Next Generation Sequencing (NGS) adapted to identify viral species with RNA and DNA genomes simultaneously, different viral species were successfully detected. Among viruses with an RNA genome, Porcine Rotavirus A (RVA), Porcine Astrovirus type 5 (PAstV-5) and Porcine Feces-Associated IASV-like virus (PfaIV) were identified; whereas among viruses with DNA genome, Porcine Parvovirus 1 (PPV1), Porcine Circovirus type 1 (PCV1) and Porcine Circovirus type 3 (PCV3) were found. PCV3, a recently described pathogenic virus, was detected for the first time in Chile in different samples from mummified tissue of stillbirths. The whole genome sequence of PCV3 was completed using conventional PCR and Sanger sequencing and compared with previously reported genomes. To the best of our knowledge, this is the first time that an adapted NGS system is used for the screening of DNA and RNA viral species simultaneously inside the Chilean swine industry. This adapted NGS system might be useful for the detection of swine viral emerging diseases worldwide.
Altered Thalamocortical Connectivity in Six-Week Old Infants at High Familial Risk for Autism Spectrum Disorder
Authors: Nair Aarti , Jalal Rhideeta , Liu Janelle , Tsang Tawny , McDonald Nicole M. , Jackson Lisa , Ponting Carolyn , Jeste Shafali S. , Bookheimer Susan Y. , Dapretto Mirella
Published: June 2020

Converging evidence from neuroimaging studies has revealed altered connectivity in cortical-subcortical networks in youth and adults with autism spectrum disorder (ASD). Comparatively little is known about the development of cortical-subcortical connectivity in infancy, before the emergence of overt ASD symptomatology. Here we examined early functional and structural connectivity of thalamocortical networks in infants at high familial risk for ASD (HR) and lowrisk controls (LR). Resting-state functional connectivity (rs-fcMRI) and diffusion tensor imaging (DTI) data were acquired 52 six-week-old infants. Functional connectivity was examined between six cortical seeds –prefrontal, motor, somatosensory, temporal, parietal, and occipital regions– and bilateral thalamus. We found significant thalamic-prefrontal underconnectivity, as well as thalamic-occipital and thalamic-motor overconnectivity in HR infants, relative to LR infants. Subsequent structural connectivity analyses also revealed atypical white matter integrity in thalamic-occipital tracts in HR infants, compared to LR infants. Notably, aberrant rs-fcMRI and DTI connectivity indices at 6 weeks predicted atypical social development between 6 and 36 months of age, as assessed with eye-tracking and diagnostic measures. These findings indicate that thalamocortical connectivity is disrupted at both the functional and structural level in HR infants as early as six weeks of age, providing a possible early marker of risk for ASD.
Structural basis for polyglutamate chain initiation and elongation by TTLL family enzymes
Authors: Mahalingan Kishore K. , Keenen E. Keith , Strickland Madeleine , Li Yan , Liu Yanjie , Ball Haydn L. , Tanner Martin E. , Tjandra Nico , Roll-Mecak Antonina
Published: June 2020

Glutamylation, introduced by TTLL enzymes, is the most abundant modification of brain tubulin. Essential effector proteins read the tubulin glutamylation pattern, and its misregulation causes neurodegeneration. TTLL glutamylases posttranslationally add glutamates to internal glutamates in tubulin C-terminal tails (branch initiation, through an isopeptide bond), and additional glutamates can extend these (elongation). TTLLs are thought to specialize for initiation or elongation, but the mechanistic basis for regioselectivity is unknown. We present cocrystal structures of murine TTLL6 bound to tetrahedral intermediate analogs that delineate key active-site residues that make this an elongase. We show that TTLL4 is exclusively an initiase, and through combined structural and phylogenetic analyses, engineer TTLL6 into a branch-initiating enzyme. TTLL glycylases add glycines posttranslationally to internal glutamates, and we find that the same active-site residues discriminate between initiase and elongase glycylases. These active-site specializations of TTLL glutamylases and glycylases ultimately yield the chemical complexity of cellular microtubules.
Predictive usefulness of PCR testing in different patterns of Covid-19 symptomatology - Analysis of a French cohort of 12,810 outpatients
Authors:   AP-HP / Universities / Inserm COVID-19 research collaboration members, Caroline Apra , Charlotte Caucheteux , Arthur Mensch , Jenny Mansour , Mélodie Bernaux , Agnès Dechartres , Erwan Debuc , Xavier Lescure , Aurélien Dinh , Youri Yordanov , Patrick Jourdain , Arthur Mensch , Charlotte Caucheteux , Caroline Apra , Jenny Mansour , Nicolas Paris , Alexandre Gramfort
Published: June 2020

Polymerase Chain reaction (PCR) is a key tool to diagnose Covid-19. Yet access to PCR is often limited. In this paper, we develop a clinical strategy for prescribing PCR to patients based on data from COVIDOM, a French cohort of 54,000 patients with clinically suspected Covid-19 including 12,810 patients tested by PCR. Using a machine learning algorithm (a decision tree), we show that symptoms alone are sufficient to predict PCR outcome with a mean average precision of 86%. We identify combinations of symptoms that are predictive of PCR positivity (90% for anosmia/ageusia) or negativity (only 30% of PCR+ for a subgroup with cardiopulmonary symptoms): in both cases, PCR provides little added diagnostic value. We deduce a prescribing strategy based on clinical presentation that can improve the global efficiency of PCR testing.
Covid-19 Incidence Rate Evolution Modeling using Dual Wave Gaussian-Lorentzian Composite Functions
Authors: Poomari Radhakrishnan
Published: June 2020

Modeling the evolution of Covid-19 incidence rate is critical to deciding and assessing non-medical intervention strategies that can lead to successful containment of the pandemic. This research presents a mathematical model to empirically assess measures related to various pandemic containment strategies, their similarities and a probabilistic estimate on the evolution of Covid-19 incidence rates. The model is built on the principle that, the exponential rise and decay of the number of confirmed Covid-19 infections can be construed as a set of concurrent non-linear waves. These waves can be characterized by a linear combination of Gaussian and Cauchy Lorentz functions collectively termed as Gaussian-Lorentzian Composite (GLC) function. The GLC function is used for non-linear approximation of officially confirmed Covid-19 incidence rates in each country. Results of fitting GLC based models to incidence rate trends of 20 different countries proves that the models can empirically explain the growth and decay trajectory Covid-19 infections in a given population.
The CBP KIX domain regulates long-term memory and circadian activity
Authors: Chatterjee Snehajyoti , Angelakos Christopher C. , Bahl Ethan , Hawk Joshua D. , Gaine Marie E. , Poplawski Shane G. , Schneider-Anthony Anne , Yadav Manish , Porcari Giulia S. , Cassel Jean-Christophe , Giese K. Peter , Michaelson Jacob J. , Lyons Lisa C. , Boutillier Anne-Laurence , Abel Ted
Published: June 2020

CREB-dependent transcription necessary for long-term memory is driven by interactions with CREB-binding protein (CBP), a multi-domain protein that binds numerous transcription factors. Identifying specific domain functions for multi-action proteins is essential to understand processes necessary for healthy living including cognitive function and a robust circadian clock. We investigated the function of the CBP KIX domain in hippocampal memory and gene expression using CBPKIX/KIXmice with mutations that prevent phospho-CREB (Ser133) binding. We found that CBPKIX/KIXmice were impaired in long-term, but not short-term spatial memory in the Morris water maze. Using an unbiased analysis of gene expression after training for hippocampus-dependent memory, we discovered dysregulation of CREB and CLOCK target genes and downregulation of circadian genes in CBPKIX/KIXmice. With our finding that the CBP KIX domain was important for transcription of circadian genes, we profiled circadian activity in CBPKIX/KIXmice. CBPKIX/KIXmice exhibited delayed activity peaks after light offset and longer free-running periods in constant dark, although phase resetting to light was comparable to wildtype. These studies provide insight into the significance of the CBP KIX domain by defining targets of CBP transcriptional co-activation in memory and the role of the CBP KIX domainin vivoon circadian rhythms.
Cancer cells depend on environmental lipids for proliferation when electron acceptors are limited
Authors: Li Zhaoqi , Ji Brian W. , Dixit Purushottam D. , Lien Evan C. , Tchourine Konstantine , Hosios Aaron M. , Abbott Keene L. , Westermark Anna M. , Gorodetsky Elizabeth F. , Sullivan Lucas B. , Vander Heiden Matthew G. , Vitkup Dennis
Published: June 2020

It is not well understood how physiological environmental conditions and nutrient availability influence cancer cell proliferation. Production of oxidized biomass, which requires regeneration of the cofactor NAD+, can limit cancer cell proliferation1-5. However, it is currently unclear which specific metabolic processes are constrained by electron acceptor availability, and how they affect cell proliferation. Here, we use computational and experimental approaches to demonstrate thatde novolipid biosynthesis can impose an increased demand for NAD+ in proliferating cancer cells. While some cancer cells and tumors synthesize a substantial fraction of their lipidsde novo6, we find that environmental lipids are crucial for proliferation in hypoxia or when the mitochondrial electron transport chain is inhibited. Surprisingly, we also find that even the reductive glutamine carboxylation pathway to produce fatty acids is impaired when cancer cells are limited for NAD+. Furthermore, gene expression analysis of 34 heterogeneous tumor types shows that lipid biosynthesis is strongly and consistently negatively correlated with hypoxia, whereas expression of genes involved in lipid uptake is positively correlated with hypoxia. These results demonstrate that electron acceptor availability and access to environmental lipids can play an important role in determining whether cancer cells engage inde novolipogenesis to support proliferation.
Isoform-specific aPKC renders primary cilia dispensable for Hedgehog signaling and basal cell carcinoma growth
Authors: Nguyen Tuyen T. L. , Wong Kirsten N. , Jeon Ung Seop , Jhumkhawala Vama , Luy Daniel , Tan Kevin C. , Wickramatunga Ishini , Kumar Vinay , England Whitney E. , Doan Linda T. , Spitale Robert C. , Atwood Scott X.
Published: June 2020

Primary cilia loss is a common feature of advanced cancers. While primary cilia are necessary to initiate Hedgehog (HH)-driven cancers, how HH pathway activity is maintained in advanced cancers devoid of primary cilia is unclear. Here, we find that HH-driven basal cell carcinoma (BCC) accumulates mutations in Alström and Usher syndrome genes. Loss of Alström and Usher syndrome gene expression, which are common underlying causes of deafness and blindness, suppresses primary ciliogenesis and HH signaling but enhances expression of atypical protein kinase C iota/lambda (aPKC), a GLI1 kinase necessary for advanced BCC growth. We show that aPKC expression is inversely correlated with primary ciliogenesis and that superficial BCCs display less primary cilia and higher aPKC expression, with the opposite trend in nodular BCC subtypes. Surprisingly, a constitutively active isoform of aPKC but not full-length protein drives HH pathway activity. Overexpression of the constitutively active aPKC variant can maintain HH pathway activity and tumor growth in the absence of primary cilia. Our results suggest tumors enhance isoform-specific expression of aPKC to prevent mutation-induced cessation of tumor growth.
A new method for distinguishing human and mouse cellsin situ
Authors: Wang Yongqiang , Huang Zixian , Hu Kaishun , Peng Jiangyun , Yao Weicheng , Deng Weixi , Zuo Jiyuan , Zhang Yin , Yin Dong
Published: June 2020

The mouse xenograft model is one of the most widely used animal model for biomedicine research. It is vital to distinguish the cells from different species, especially for the spatial distribution information. However, the available strategies of species-specific detection are either inapplicablein situor of low specificity. Here, we reported a method based on DAPI staining, which offers an effective, convenient way that accurately identifies human and mouse nuclei at single-cell levelin situ. This method was proven to be effective in cell co-culture and tumor xenograft tissue section. Microscopic imaging results shows obvious DAPI plaques-like structures in mouse nuclei, but absent in human nuclei. Moreover, we found these structures are co-localized with mouse major satellite DNA, which is located pericentromere in mouse, but absent in human. Our study provides a high-performance method that can be widely used for distinguish human and mouse cellin situ.
Engineering of Phytosterol-Producing Yeast Platforms for Functional Reconstitution of Downstream Biosynthetic Pathways
Authors: Xu Shanhui , Chen Curtis , Li Yanran
Published: June 2020

As essential structural molecules for plant plasma membranes, phytosterols are key intermediates for the synthesis of many downstream specialized metabolites of pharmaceutical or agricultural significance, such as brassinosteroids and withanolides.Saccharomyces cerevisiaehas been widely used as an alternative producer for plant secondary metabolites. Establishment of heterologous sterol pathways in yeast, however, has been challenging due to either low efficiency or structural diversity, likely a result of crosstalk between the heterologous phytosterol and the endogenous ergosterol biosynthesis. For example, in this study, we engineered campesterol production in yeast using plant enzymes; although we were able to enhance the titer of campesterol to ~40mg/L by upregulating the mevalonate pathway, no conversion to downstream products was detected upon the introduction of downstream plant enzymes. Further investigations uncovered two interesting observations about sterol engineering in yeast. First, many heterologous sterols tend to be efficiently and intensively esterified in yeast, which drastically impedes the function of downstream enzymes. Second, yeast can overcome the growth deficiency caused by altered sterol metabolism through repeated culture. By employing metabolic engineering, strain evolution, fermentation engineering, and pathway reconstitution, we were able to establish a set of phytosterol-producing yeast strains with decent growth and titer of campesterol (~ 7mg/L), β-sitosterol (~2mg/L), 22-hydroxycampesterol (~1mg/L), and 22-hydroxycampest-4-en-3-one (~4mg/L). This work resolves the technical bottlenecks in phytosterol-derived pathway reconstitution in the backer’s yeast and opens up opportunities for efficient bioproduction and pathway elucidation of this group of phytochemicals.
Neural systems underlying the learning of cognitive effort costs
Authors: Sayali Ceyda , Badre David
Published: June 2020

People balance the benefits of cognitive work against the costs of cognitive effort. Models that incorporate prospective estimates of the costs of cognitive effort into decision making require a mechanism by which these costs are learned. However, it remains open what brain systems are important for this learning, particularly when learning is not tied explicitly to a decision about what task to perform. In this fMRI experiment, we parametrically manipulated the level of effort a task requires by increasing task switching frequency across six task contexts. In a scanned learning phase, participants implicitly learned about the task switching frequency in each context. In a subsequent test phase, participants made selections between pairs of these task contexts. We modeled learning within a reinforcement learning framework, and found that effort expectations that derived from task-switching probability and response time (RT) during learning were the best predictors of later choice behavior. Prediction errors (PE) from these two models were associated with FPN during distinct learning epochs. Specifically, PE derived from expected RT was most correlated with the fronto-parietal network early in learning, whereas PE derived from expected task switching frequency was correlated with the fronto-parietal network late in learning. These results suggest that multiple task-related factors are tracked by the brain while performing a task that can drive subsequent estimates of effort costs.
Evolutionary and demographic consequences of temperature-induced masculinization under climate warming: the effects of mate choice
Authors: Nemesházi Edina , Kövér Szilvia , Bókony Veronika
Published: June 2020

Background

One of the dangers of global climate change to wildlife is distorting sex ratios by temperature-induced sex reversals in populations where sex determination is not exclusively genetic, potentially leading to population collapse and/or sex-determination system transformation. Here we introduce a new concept on how these outcomes may be altered by mate choice if sex-chromosome-linked phenotypic traits allow females to choose between normal and sex-reversed (genetically female) males.

Results

We developed a theoretical model to investigate if preference for sex-reversed males would spread and affect demographic and evolutionary processes under climate warming. We found that preference for sex-reversed males 1) more likely spread in ZW/ZZ than in XX/XY sex-determination systems, 2) in populations starting with ZW/ZZ system, it significantly hastened the transitions between different sex-determination systems and maintained more balanced adult sex ratio for longer compared to populations where all females preferred normal males; and 3) in ZZ/ZW systems with low but nonzero viability of WW individuals, a widespread preference for sex-reversed males saved the populations from early extinction.

Conclusions

Our results suggest that climate change may affect the evolution of mate choice, which in turn may influence the evolution of sex-determination systems, sex ratios, and thereby adaptive potential and population persistence.
Suppression of pyramidal neuron G protein-gated inwardly rectifying K+ channel signaling impairs prelimbic cortical function and underlies stress-induced deficits in cognitive flexibility
Authors: Anderson Eden M , Loke Steven , Wrucke Benjamin , Engelhardt Annabel , Hess Evan , Wickman Kevin , Hearing Matthew C
Published: June 2020

Background

Imbalance in prefrontal cortical (PFC) pyramidal neuron excitation:inhibition is thought to underlie symptomologies shared across stress-related disorders and neuropsychiatric disease, including dysregulation of emotion and cognitive function. G protein-gated inwardly rectifying K+(GIRK/Kir3) channels mediate excitability of medial PFC pyramidal neurons, however the functional role of these channels in mPFC-dependent regulation of affect, cognition, and cortical dynamics is unknown.

Methods

In mice harboring a ‘floxed’ version of the kcnj3 (Girk1) gene, we used a viral-cre approach to disrupt GIRK1-containing channel expression in pyramidal neurons within the prelimbic (PL) or infralimbic (IL) cortices. Additional studies used a novel model of chronic unpredictable stress (CUS) to determine the impact on PL GIRK-dependent signaling and cognitive function.

Results

In males, loss of pyramidal GIRK-dependent signaling in the PL, but not IL, differentially impacted measures of affect and motivation, and impaired working memory and cognitive flexibility. CUS produced similar deficits in affect and cognition that paralleled a reduction in PL pyramidal GIRK-dependent signaling akin to viral approaches. Viral- and stress-induced behavioral deficits were rescued by systemic injection of a novel, GIRK1-selective agonist, ML-297. Unexpectedly, neither ablation of PL GIRK-dependent signaling or exposure to the CUS regimen impacted affect or cognition in female mice.

Conclusions

GIRK-dependent signaling in male mice, but not females, is critical for maintaining optimal PL function and behavioral control. Disruption of this inhibition may underlie stress-related dysfunction of the PL and represent a therapeutic target for treating stress-induced deficits in affect regulation and impaired cognition that reduce quality of life.