bluuebunny/crossref_metadata_2025 huggingface dataset:
ML-18 Clinical diagnosis for suspected primary central nervous system lymphoma patients without histopathological confirmation
Authors: Osawa Sho , Horiguchi Keishi , Tosaka Masahiko , Yoshimoto Yuhei
Published: November 2020

Background: The gold standard of the diagnosis of primary central nervous system lymphoma (PCNSL) is the histopathological diagnosis by biopsy surgery. However, we experience some cases with a high risk of biopsy surgery or difficulty in general anesthesia. We perform radiation and chemotherapy without histopathological confirmation for such patients based on imaging findings, ophthalmological evaluation, and cerebrospinal fluid examinations. In this study, we investigated clinical diagnosis and outcomes for patients suspected PCNSL.

Method: From April 2016 to December 2019, all adult brain tumor patients that were diagnosed with PCNSL without histopathological confirmation and underwent radiation and/or chemotherapy were included. The following criteria were retrospectively analyzed. 1) Intraorbital lymphoma, 2) SUVmax>12 in 18F FDG-PET, 3) ADCmean<0.98×10–3 mm2/s in MRI diffusion-weighted images, 4) tumor to normal ratio >1 in late phase of 123I IMP SPECT, 5) CSF β2 microglobulin >2.1 mg/l, 6) CSF sIL2R >77 U/ml, 7) Improvement of imaging findings or clinical symptoms by steroid.

Result: 9 suspected PCNSL patients were included. 8 patients were positive for 3 or more above criteria. All these patients achieved CR by initial treatment with radiation or chemotherapy which indicated appropriate diagnosis for PCNSL. The remaining 1 patient was SD by radiotherapy, which was an atypical clinical course of PCNSL. The above criteria were positive in 2 and negative in 3. There were no examinations that could be performed in all cases before the treatment.

Conclusion: Some useful markers for the diagnosis of PCNSL have been reported. However, all have limited sensitivity and specificity. Each examinations are also restricted by patient, institution and time. The combination of the useful examinations will improve the diagnostic accuracy of PCNSL.
CS-01 Rapid Recurrence and Anaplastic Transformation of a Pilocytic Astrocytoma in an Elderly Patient
Authors: Tanaka Toshihide , Teshigawara Akihiko , Tochigi Satoru , Hasegawa Yuzuru , Takei Jun , Akasaki Yasuharu , Murayama Yuichi , Yokoo Hideaki
Published: November 2020

BACKGROUND: Rapid recurrence of a pilocytic astrocytoma with anaplastic transformation is extremely rare. The case of an elderly patient with a cerebellar pilocytic astrocytoma with anaplastic transformation during short-term follow-up is reported. CASE DESCRIPTION: An 83-year-old woman presented initially with dizziness and a gait deviation to the right. Magnetic resonance imaging (MRI) demonstrated a homogeneously enhanced mass in the right cerebellar hemisphere, and the tumor was subtotally removed by right suboccipital craniotomy. Histological examination showed that the tumor cells contained eosinophilic cytoplasm and spindle-shaped processes with Rosenthal fibers and eosinophilic granular bodies, diagnosed as a typical pilocytic astrocytoma (PA). The MIB-1 index was less than 1%. The patient did not receive postoperative adjuvant radiation and chemotherapy. Two months after surgery, MRI showed growth of the residual tumor adjacent to the fourth ventricle, causing obstructive hydrocephalus. She underwent surgery again, and the tumor was totally removed. Histological findings showed mitotic cells and increased cellularity compared with the primary tumor, which was compatible with anaplastic transformation of PA with a MIB-1 index of 50%. Postoperatively, she was observed with best supportive care without postoperative adjuvant therapy. Nine months after the second operation, she died due to tonsillar herniation and obstructive hydrocephalus caused by a recurrent tumor. An autopsy was performed. CONCLUSION: It is extremely rare, as in the present case, that a cerebellar PA in an elderly patient recurs rapidly with anaplastic transformation, despite deferred postoperative adjuvant therapy including radiation and chemotherapy A novel molecular-targeted therapy is needed for anaplastic PA showing aggressive biological behavior.
COT-04 Circulating biomarker for glioblastoma and primary central nervous system lymphoma -Next Generation Sequencing of small noncoding RNA-
Authors: Onishi Shumpei , Yamasaki Fumiyuki , Takano Motoki , Yonezawa Ushio , Sugiyama Kazuhiko , Tahara Hidetoshi
Published: November 2020

Objective: Glioblastoma (GBM) and Primary Central Nervous System Lymphoma (PCNSL) are common intracranial malignant tumors. They sometimes present similar radiological findings and diagnoses could be difficult without surgical biopsy. For improving the current management, development of non-invasive biomarkers are desired. In this study, we explored the differently expressed circulating small noncoding RNA (sncRNA) in serum for specific diagnostic tool of GBM and PCNSL. Material & Methods: Serum samples were obtained from three groups: 1) GBM patients (N=26), 2) PCNSL patients (N=14) 3) healthy control (N=114). The total small RNAs were extracted from serum. The whole expression profiles of serum sncRNAs were measured using Next-Generation Sequencing System. We analyzed serum levels of sncRNAs (15–55 nt) in each serum samples. The difference of sncRNAs expression profile among three groups were compared. Data analysis was performed by logistic regression analysis followed by leave-one-out cross-validation (LOOCV). The accuracy of diagnostic models of sncRNAs combination were evaluated by receiver operating characteristic (ROC) analysis. Results: We created the combination models using three sncRNA in each models based on the logistic regression analysis. The model 1 (based on sncRNA-X1, X2 and X3) enabled to differentiate GBM patients form healthy control with a sensitivity of 92.3% and a specificity of 99.2% (AUC: 0.993). The model 2 (based on sncRNA-Y1, Y2 and Y3) enabled to differentiate PCNSL patients form healthy control with a sensitivity of 100% and a specificity of 93.9% (AUC: 0.984). The model 3 (based on sncRNA-Z1, Z2 and Z3) enabled to differentiate GBM patients form PCNSL patients with a sensitivity of 92.3% and a specificity of 78.6% (AUC: 0.920). Conclusion: We found three diagnostic models of serum sncRNAs as non-invasive biomarkers potentially useful for detection of GBM and PCNSL from healthy control, and for differentiation GBM from PCNSL.
COT-05 Experience of fertility preservation in 3 male cases and 1 female case with high-grade glioma
Authors: Nakayama Noriyuki , Yamada Tetsuya , Yano Hirohito , Kato Yuki , Iwama Toru
Published: November 2020

High-grade glioma (HGG) has a low survival rate, and fertility preservation (FP) has rarely been discussed in the field of Japanese neurosurgery. We report on 4 reproductive patients, including 2 male patients who became biological fathers. Case 1 was a 23-year-old man with anaplastic oligodendroglioma (AO) of the right frontal lobe. Temozolomide maintenance therapy (TMZ-MT) was completed 42 courses after the initial surgery for economic reasons. 21 months later, a local recurrent lesion appeared, so TMZ-MT was restarted after removal this lesion. When he married at 32 years old, the couple wished a desire for childbearing. The TMZ-MT was stopped at 47 courses from the resumption and they aimed for spontaneous pregnancy. At 5 months after discontinuation of TMZ-MT, Gd-enhanced lesions increased again, so we changed the course to in vitro fertilization and resumed TMZ-MT. The couple had a biological baby at his 33 years and 10 months old. Case 2 was a 33-year-old married man with AO of the right parietal lobe. After partial removal, the FP information was explained and cryopreservation of sperm was performed. As of 23 months after the first operation, he became a biological father by in vitro fertilization. Case 3 was a 31-year-old married man with diffuse midline glioma (H3K27M mutant) in the cervical spinal cord. After partial removal, we provided FP information in the same manner, but the couple did not chose cryopreservation of sperm due to his mRS 5. Case 4 was a 24-year-old female with anaplastic astrocytoma of the brain stem. FP information was provided after stereotactic biopsy, but she chose to start radiochemotherapy without cryopreservation of eggs. Patients of reproductive age with HGG, especially oligodendroglial tumors who have a higher survival rate than astrocytic tumors, should be positively informed about FP before treatment begins.
Identifying the Best Questions for Rapid Screening of Secondhand Smoke Exposure Among Children
Authors: Ksinan Albert J , Sheng Yaou , Do Elizabeth K , Schechter Julia C , Zhang Junfeng (Jim) , Maguire Rachel L , Hoyo Cathrine , Murphy Susan K , Kollins Scott H , Rubin Bruce , Fuemmeler Bernard F
Published: November 2020

Introduction

Many children suffer from secondhand smoke exposure (SHSe), which leads to a variety of negative health consequences. However, there is no consensus on how clinicians can best query parents for possible SHSe among children. We employed a data-driven approach to create an efficient screening tool for clinicians to quickly and correctly identify children at risk for SHSe.

Methods

Survey data from mothers and biospecimens from children were ascertained from the Neurodevelopment and Improving Children’s Health following Environmental Tobacco Smoke Exposure (NICHES) study. Included were mothers and their children whose saliva were assayed for cotinine (n = 351 pairs, mean child age = 5.6 years). Elastic net regression predicting SHSe, as indicated from cotinine concentration, was conducted on available smoking-related questions and cross-validated with 2015–2016 National Health and Nutrition Examination Survey (NHANES) data to select the most predictive items of SHSe among children (n = 1670, mean child age = 8.4 years).

Results

Answering positively to at least one of the two final items (“During the past 30 days, did you smoke cigarettes at all?” and “Has anyone, including yourself, smoked tobacco in your home in the past 7 days?”) showed area under the curve = .82, and good specificity (.88) and sensitivity (.74). These results were validated with similar items in the nationally representative NHANES sample, area under the curve = .82, specificity = .78, and sensitivity = .77.

Conclusions

Our data-driven approach identified and validated two items that may be useful as a screening tool for a speedy and accurate assessment of SHSe among children.

Implications

The current study used a rigorous data-driven approach to identify questions that could reliably predict SHSe among children. Using saliva cotinine concentration levels as a gold standard for determining SHSe, our analysis employing elastic net regression identified two questions that served as good classifier for distinguishing children who might be at risk for SHSe. The two items that we validated in the current study can be readily used by clinicians, such as pediatricians, as part of screening procedures to quickly identify whether children might be at risk for SHSe.
Effect of environmental enrichment devices on behavior of individually housed beef heifers
Authors: Bruno Kelsey , DeSocio Elizabeth , White Jason , Wilson Blake K
Published: November 2020

In research settings, certain experimental designs may require cattle to be housed individually. Individual housing of cattle may make the animals more susceptible to boredom and result the development of undesirable behaviors. The objective of this trial was to investigate the effects of different environmental enrichment devices (EED) on the behavior and feed intake of heifers. Twenty mixed-breed single-sourced heifers were used in a completely random design. Heifers were housed individually (3.05 m × 3.66 m) with the ability to have physical contact with adjacent heifers. Heifers were randomly assigned to one of the four EED treatments, including a jolly ball (JLY), a broom head (SRCH), a 182 cm 5-knot rope (RP), or a Pas-a-Fier roller (RLR). Behavior was recorded using 8 h long daily instantaneous scan sampling in 30 min intervals over three periods: 7 d prior to EED addition (PR), 7 d with EED (EDP), and 7 d after removing EED (PST). Standing, laying, eating, drinking, and exploratory behaviors were evaluated. Exploratory behaviors included: interaction with water trough, feed bunk, water pipe, pen gate, pen wall, EED, grooming, or allogrooming. Rumination behavior was also recorded during each observation time. Time standing and standing bouts were greatest for RP (P < 0.05), while JLY and RLR spent the most time lying down (P < 0.05). All heifers spent the majority of observation times lying down, followed by solely standing (P < 0.05). Heifers on the RP treatment interacted the most with their EED, followed by SRCH (P < 0.001). Rumination increased during EDP compared to PR (P < 0.001). These results suggest that a RP suspended from the ceiling in the pen may be used most frequently by individually housed beef heifers.
High Prevalence of Molecular Markers of Plasmodium falciparum Resistance to Sulphadoxine–Pyrimethamine in Parts of Ghana: A Threat to ITPTp-SP?
Authors: Afutu Leslie L , Boampong Johnson N , Quashie Neils B
Published: November 2020

Malaria in pregnancy is a huge public health problem as it is the cause of maternal anaemia, still birth, premature delivery, low birth weight among others. To tackle this problem, WHO recommended the administration, during pregnancy, of intermittent preventive treatment with sulphadoxine–pyrimethamine (IPTp-SP). The introduction of this policy is likely to create SP drug pressure which may lead to the emergence of parasite strains resistant to the drug. This study investigated the prevalence of the molecular markers of SP resistance as pointers to potential failure of IPTp-SP among pregnant women attending antenatal clinic, women at the point of baby delivery and out patients department (OPD) attendees. The study was conducted in health facilities located in parts of Ghana. Prevalence of mutations in dhfr and dhps genes of Plasmodium falciparum was determined using the method described by Duraisingh et al. The outcome of the study indicated the presence of high prevalence of strains of P.falciparum with the resistant alleles of the dhfr or dhps genes in the three categories of participants. There was a high prevalence of triple mutations (IRN) in the dhfr gene of P.falciparum isolates: 71.4% in peripheral blood of antenatal attendees; 74.1% in placenta cord blood of delivering mothers and 71.1% in OPD attendees. Quintuple mutations were only found in 2 (0.5%) isolates from OPD attendees. This observation might have occurred due to the increased use of SP for IPTp among others. There is the need for an interventional measure in order to protect pregnant women and their unborn children.

 

Lay summary

When pregnant women get infected with the malaria parasites they are exposed to all manner of dangers including pre-term delivery, still birth, maternal anaemia and low birth weight. Taking sulphadoxine–pyrimethamine (SP) at predetermined periods during pregnancy, referred to as ‘intermittent preventive treatment with SP’ (IPTp-SP)’ helps to curtail these problems. However, the frequent taking of these drugs is likely to create SP drug pressure which may lead to the emergence of parasite strains that are not readily killed by the drugs. In order to ascertain this phenomenon and advice stakeholders, this study determined the prevalence of certain ‘materials’ certified as markers of parasite resistance to SP. Alarmingly, more than 5% of all the category of women recruited to participate in this study were found to harbour the parasites that causes malaria. The outcome, also suggest the existence of high levels of strains of the malaria parasite, carrying the materials that make them to become resistant to SP. Policy makers must pay attention to these observations and institute measures to avoid escalation of the situation.
When Obsessive-Compulsive Disorder Mimics Schizophrenia
Authors: Duarte-Mangas Mariana , Bravo Lucilia , Matos-Pires Ana
Published: November 2020

Obsessive-compulsive disorder (OCD) encompasses a broad range of symptoms and is normally considered a heterogeneous disorder. Sometimes, OCD seems to be psychotic in nature, being complex in the differentiation between OCD and schizophrenia. This report describes a female adult patient who was diagnosed in her adolescence with schizophrenia due to her complains of “hearing voices “criticizing her. In response to team request for a second evaluation, she was admitted to the acute inpatient service. After a careful reassessment, the core symptom was recognized as obsession, and her diagnosis was revised to OCD; this allowed for a more direct treatment and management, with cognitive-behavior therapy and high doses of selective serotonin reuptake inhibitors, achieving a sustained clinical improvement over 2 years of follow-up. Currently, she is more functional, participates in social activities, and totally recognizes the egodystonic and intrusive thoughts. This case demonstrates the importance of eliciting psychopathology in greater detail for specific diagnosis and treatment decisions, especially in a complex clinical presentation.
Seasonal patterns of dengue incidence in Thailand across the urban-rural gradient
Authors: Bi Qifang , Cummings Derek AT , Reich Nicholas G. , Keegan Lindsay T. , Kaminsky Joshua , Salje Henrik , Clapham Hannah , Doung-ngern Pawinee , Iamsirithaworn Sopon , Lessler Justin
Published: November 2020

In Southeast Asia, endemic dengue follows strong spatio-temporal patterns with major epidemics occurring every 2-5 years. However, important spatio-temporal variation in seasonal dengue epidemics remains poorly understood. Using 13 years (2003-2015) of dengue surveillance data from 926 districts in Thailand and wavelet analysis, we show that rural epidemics lead urban epidemics within a dengue season, both nationally and within health regions. However, local dengue fade-outs are more likely in rural areas than in urban areas during the off season, suggesting rural areas are not the source of viral dispersion. Simple dynamic models show that stronger seasonal forcing in rural areas could explain the inconsistency between earlier rural epidemics and dengue “over wintering” in urban areas. These results add important nuance to earlier work showing the importance of urban areas in driving multi-annual patterns of dengue incidence in Thailand. Feedback between geographically linked locations with markedly different ecology is key to explaining full disease dynamics across urban-rural gradient.
Pharmacogenomics implementation training improve self-efficacy and competency to drive adoption in clinical practice
Authors: Adesta Fadhli , Mahendra Caroline , Junusmin Kathleen Irena , Selva Rajah Arya Melissa , Goh Sharon , Sani Levana , Chan Alexandre , Irwanto Astrid
Published: November 2020

Background

Administration of pharmacogenomics (PGx) testing in clinical practice has been suboptimal, presumably due to lack of PGx education. Here, we aim to evaluate the standpoint of PGx testing among a diverse group of healthcare professionals (HCPs) through conducting surveys before and after training.

Materials & Methods

Training modules were designed to cover 3 key learning objectives and deployed in 5 sections. A pre- and post-training survey questionnaire was used to evaluate participants self-assessments on employing PGx in clinical practice.

Results & Conclusion

Out of all enrollments, 102 survey responses were collected. Overall, respondents agree on the benefits of PGx testing, but have inadequate self-efficacy and competency in utilizing PGx data. Our results show that training significantly improve these, and even leading to greater anticipation of PGx adoption.
HealthCall: Smartphone Enhancement of Brief Interventions to Reduce Heavy Drinking In HIV Care
Authors: Hasin Deborah , Aharonovich Efrat , Zingman Barry , Stohl Malka , Walsh Claire , Elliott Jennifer C. , Fink David , Knox Justin , Durant Sean , Menchaca Raquel , Sharma Anjali
Published: November 2020

Background

Heavy drinking among people living with HIV (PLWH) worsens their health outcomes and disrupts their continuum of care. Brief interventions to reduce heavy drinking in primary care are effective, but in heavy-drinking PLWH, more extensive intervention may be needed. Lengthy interventions are not feasible in most HIV primary care settings, and patients seldom follow referrals to outside treatment. Utilizing visual and video features of smartphone technology, we developed the “HealthCall” app to provide continued engagement after brief intervention, in order to reduce drinking and improve other aspects of HIV care while making minimal demands on providers.

Methods

Alcohol-dependent patients at a large urban HIV clinic were randomized to one of three groups: (1) Motivational Interviewing (MI) plus HealthCall (n=39), (2) NIAAA Clinician’s Guide (CG) plus HealthCall (n=38), or (3) CG-only (n=37). Baseline drinking-reduction interventions were ∼25 minutes, with brief (10-15 min) check-in sessions at 30 and 60 days. HealthCall involved daily use of the smartphone for 3-5 min/day, covering drinking and other aspects of the prior 24 hours. Outcomes assessed at 30 and 60 days, and 3, 6 and 12 months, included drinks per drinking day, drinks per day, and days drank, using the Timeline Followback. Analysis were conducted using generalized linear mixed models with pre-planned contrasts.

Results

Study retention was excellent (85%-94% across timepoints) and unrelated to treatment arm or patient characteristics. During treatment, patients in MI+HealthCall drank less than others (p=0.07-0.003). However, at 6 and 12 months, drinking was lowest among patients who had been in CG+HealthCall (p=0.04-0.06).

Conclusion

During treatment, patients in MI+HealthCall drank less than patients in the CG conditions. However, at 6 and 12 months, drinking was lower among patients in CG+HealthCall. Given the importance of drinking reduction and the low costs and time required for HealthCall, pairing HealthCall with brief interventions within HIV clinics merits widespread consideration.
The interaction of p38 with its upstream kinase MKK6
Authors: Kumar Ganesan Senthil , Page Rebecca , Peti Wolfgang
Published: November 2020

Mitogen-activated protein kinase (MAPK; p38, ERK and JNK) cascades are evolutionarily conserved signaling pathways that regulate the cellular response to a variety of extracellular stimuli, such as growth factors and interleukins. The MAPK p38 is activated by its specific upstream MAPK kinases, MKK6 and MKK3. However, a comprehensive molecular understanding of how these cognate upstream kinases bind and activate p38 is still missing. Here, we combine NMR spectroscopy and isothermal titration calorimetry to define the binding interface between full-length MKK6 and p38. We show that p38 engages MKK6 not only via its hydrophobic docking groove, but also helix αF, a secondary structural element that plays a key role in organizing the kinase core. We also show that, unlike MAPK phosphatases, the p38 conserved docking (CD) site is much less affected by MKK6 binding. Finally, we demonstrate that these interactions with p38 are conserved independent of the MKK6 activation state. Together, our results reveal differences between specificity markers of p38 regulation by upstream kinases, which do not effectively engage the CD site, and downstream phosphatases, which require the CD site for productive binding.
Global Trends in eHealth Research: Analysis and Visualization of Author and Indexer-Supplied Keywords
Authors: Nwagwu Williams Ezinwa , Onyancha Omwoye Bosire
Published: November 2020

This article examined the growth and development of ehealth research based on the headcount and analysis of the characteristics of keywords used by authors and indexers to represent their research content during 1945-2019 as indexed in the Elsevier’s Scopus database. The results show that although the term ehealth originated in the late 1990s, but it has become an envelope term for much older terms such as telemedicine, and its variants which originated much earlier. The keywords were spread in 27 Scopus Subject Areas, with medicine (44.04%), engineering (12.84%) and computer science (11.47%) leading while by Scopus All Science Journal Classification, Health Sciences accounted for 55.83% of the keywords and physical sciences followed with 30.62%. The rest two classifications namely social sciences and life sciences made only single digit contributions. Although the primary essence of ehealth was how to meet health needs, the work of engineers who either initially deployed telephone to meet their health needs or, and, computer scientists, who addressed the need to design technologies for medical services is very significant. It is concluded that ehealth is a multidisciplinary area that is attractive to researchers from all disciplines because of its sensitive focus on health, and therefore requires pooling and integrating of resources and expertise, methods and approaches.
Convergent morphology and divergent phenology: unravelling the coexistence of mimeticMorphobutterfly species
Authors: Le Roy Camille , Roux Camille , Authier Elisabeth , Bastide Héloïse , Debat Vincent , Llaurens Violaine
Published: November 2020

The emergence and persistence of closely-related species in sympatry is puzzling because the potential gene flow and the common local selective pressures may lead to either merging or competitive exclusion. Some species ofMorphobutterflies occurring in sympatry display highly similar wing colour patterns. Associated with erratic flight abilities, their bright colouration may limit predator success and discourage future attacks. The evolution of similar colouration in sympatric species is thus likely under local selection by predators (i.e. escape mimicry). Such phenotypic similarity may promote interspecific territoriality and/or reproductive interference, questioning how closely-related co-mimetic species become sexually isolated and coexist in sympatry. We performed a series of field experiments using flyingMorphodummies placed in a natural habitat where wild males commonly patrol. Analysing the interactions of wildMorphowith different dummies, we show that similarity in wing colour pattern leads to interspecific territoriality and courtship among sympatric species. Using genomic data, we then showed that sympatricMorphospecies are surprisingly strictly isolated despite their close relatedness and the observed heterospecific interactions. Finally, using a mark-recapture experiment, we discovered a strong temporal segregation in patrolling activity of males from two co-mimetic sister species. Such divergence in phenology may favour sympatry between closely-related species, despite behavioural interferences induced by the local convergence in colour pattern. Altogether, our findings show that temporal segregation may facilitate the co-existence of closely-related species sharing the same ecological niche, suggesting that phenological shifts may represent an overlooked factor of sympatric speciation. Our study therefore highlights how the evolution of multiple traits may favour species diversification in sympatry by partitioning niche in different dimensions.
Automated Morphometric Analysis Reveals Plasticity Induced by Chronic Antidepressant Treatment in Hippocampal Astrocytes
Authors: Sethi Parul , Virmani Garima , Thumu Surya Chandra Rao , Ramanan Narendrakumar , Marathe Swananda
Published: November 2020

Nervous system development and plasticity involves changes in cellular morphology, making morphological analysis a valuable exercise in the study of nervous system development, function and disease. Morphological analysis is a time-consuming exercise requiring meticulous manual tracing of cellular contours and extensions. We have developed a software tool, called SMorph, to rapidly analyse the morphology of cells of the nervous system. SMorph performs completely automated Sholl analysis. It extracts 23 morphometric features based on cell images and Sholl analysis parameters, followed by Principal Component Analysis. SMorph is tested on neurons, astrocytes and microglia and reveals subtle changes in cell morphology. Using SMorph, we found that chronic 21-day treatment with antidepressant desipramine results in a significant structural remodeling in hippocampal astrocytes. Given the proposed involvement of astroglial structural changes and atrophy in major depression in humans, our results reveal a novel kind of structural plasticity induced by chronic antidepressant administration.
A Novel Cell Therapy for COVID-19 and Potential Future Pandemics: Virus Induced Lymphocytes (VIL)
Authors: Sivapalan Rohan , Liu Jinyan , Chakraborty Krishnendu , Arthofer Elisa , Choudhry Modassir , Barie Philip S , Barouch Dan H , Henley Tom
Published: November 2020

Thea prioriT cell repertoire and immune response against SARS-CoV-2 viral antigens may explain the varying clinical course and prognosis of patients having a mild COVID-19 infection as opposed to those developing more fulminant multisystem organ failure and associated mortality. Using a novel SARS-Cov-2-specific artificial antigen presenting cell (aAPC), coupled with a rapid expansion protocol (REP) as practiced in tumor infiltrating lymphocytes (TIL) therapy, we generate an immune catalytic quantity of Virus Induced Lymphocytes (VIL). Using T cell receptor (TCR)-specific aAPCs carrying co-stimulatory molecules and major histocompatibility complex (MHC) class-I immunodominant SARS-CoV-2 peptide-pentamer complexes, we expand virus-specific VIL derived from peripheral blood mononuclear cells (PBMC) of convalescent COVID-19 patients up to 1,000-fold. This is achieved in a clinically relevant 7-day vein-to-vein time-course as a potential adoptive cell therapy (ACT) for COVID-19. We also evaluate this approach for other viral pathogens using Cytomegalovirus (CMV)-specific VIL from donors as a control. Rapidly expanded VIL are enriched in virus antigen-specificity and show an activated, polyfunctional cytokine profile and T effector memory phenotype which may contribute to a robust immune response. Virus-specific T cells can also be delivered allogeneically via MHC-typing and patient human leukocyte antigen (HLA)-matching to provide pragmatic treatment in a large-scale therapeutic setting. These data suggest that VIL may represent a novel therapeutic option that warrants further clinical investigation in the armamentarium against COVID-19 and other possible future pandemics.
Plot diversity differentially affects the chemical composition of leaves, roots and root exudates in four subtropical tree species
Authors: Weinhold Alexander , Döll Stefanie , Liu Min , Schedl Andreas , Xu Xingliang , Neumann Steffen , van Dam Nicole M.
Published: November 2020

Plants produce thousands of compounds, collectively called the metabolome, which mediate interactions with other organisms. The metabolome of an individual plant may change according to the number and nature of these interactions. We tested the hypothesis that tree diversity level affects the metabolome of four subtropical tree species in a biodiversity ecosystem-functioning experiment, BEF-China. We postulated that the chemical diversity of leaves, roots and root exudates increases with tree diversity. We expected the strength of this diversity effect to differ among leaf, root and root exudates samples. Considering their role in plant competition, we expected to find the strongest effects in root exudates.

In an ecometabolomics approach, roots, root exudates and leaves of four tree species(Cinnamomum camphora, Cyclobalanopsis glauca, Daphniphyllum oldhamii, Schima superba)were sampled from selected plots in BEF-China. Samples were extracted and analysed using Liquid Chromatography-Time of Flight-Mass Spectrometry. The exudate metabolomes were normalized over their non-purgeable organic carbon level. Multivariate analyses were applied to identify the effect of both neighbouring (local) trees and plot diversity on tree metabolomes. The species and sample specific metabolites were assigned to major compound classes using the ClassyFire tool, whereas m/z features related to diversity effects were annotated manually.

Individual tree species showed distinct leaf, root and root exudate metabolomes. The main compound class in leaves were the flavonoids, whereas carboxylic acids, prenol lipids and specific alkaloids were most prominent in root exudates and roots. Overall plot diversity had a stronger effect on metabolome profiles than the diversity of local, directly neighbouring trees. Leaf metabolomes responded more often to tree diversity level than exudates, whereas root metabolomes varied the least. We found not overall correlation between metabolite richness or diversity and tree diversity.

Synthesis: Classification of metabolites supported initial ecological interpretation of differences among species and organs. Particularly the metabolomes of leaves and root exudates respond to differences in tree diversity. These responses were neither linear nor uniform and individual metabolites showed different dynamics. More controlled interaction experiments are needed to dissect the causes and consequences of the observed shifts in plant metabolomes.
A Non-Genetic, Cell Cycle Dependent Mechanism of Platinum Resistance in Lung Adenocarcinoma
Authors: Gonzalez-Rajal Alvaro , Marzec Kamila A , McCloy Rachael , Nobis Max , Chin Venessa , Hastings Jordan F. , Lai Kaitao , Kennerson Marina , Hughes William E , Vaghjiani Vijesh , Timpson Paul , Cain Jason E. , Neil Watkins D. , Croucher David R. , Burgess Andrew
Published: November 2020

We previously used a pulse-based in vitro assay to unveil targetable signalling pathways associated with innate cisplatin resistance in lung adenocarcinoma (Hastings et al., 2020). Here we advanced this model system and identified a non- genetic mechanism of resistance that drives recovery and regrowth in a subset of cells. Using RNAseq and a suite of biosensors to track single cell fates both in vitro and in vivo, we identified that early S phase cells have a greater ability to maintain proliferative capacity, which correlated with reduced DNA damage over multiple generations. In contrast, cells in G1, late S or those treated with PARP/RAD51 inhibitors, maintained higher levels of DNA damage and underwent prolonged S/G2 phase arrest and senescence. Combined with our previous work, these data indicate that there is a non-genetic mechanism of resistance in lung adenocarcinoma that is dependent on the cell cycle stage at the time of cisplatin exposure.
Heritability of DNA methylation in threespine stickleback (Gasterosteus aculeatus)
Authors: Hu Juntao , Wuitchik Sara J. S. , Barry Tegan N. , Rogers Sean M. , Jamniczky Heather A. , Barrett Rowan D. H.
Published: November 2020

Epigenetic mechanisms underlying phenotypic change are hypothesized to contribute to population persistence and adaptation in the face of environmental change. To date, few studies have explored the heritability of intergenerationally stable methylation levels in natural populations, and little is known about the relative contribution ofcis- andtrans-regulatorychanges to methylation variation. Here, we explore the heritability of DNA methylation, and conduct methylation quantitative trait loci (meQTL) analysis to investigate the genetic architecture underlying methylation variation between marine and freshwater ecotypes of threespine stickleback(Gasterosteus aculeatus).We quantitatively measured genome-wide DNA methylation in fin tissue using reduced representation bisulfite sequencing of F1 and F2 crosses, and their marine and freshwater source populations. We identified cytosines (CpG sites) that exhibited stable methylation levels across generations. We found that genetic variance explained an average of 24 to 35% of the methylation variance, with a number of CpG sites possibly autonomous from genetic control. Finally, we detected bothcis- andtrans-meQTLs, with onlytrans-meQTLs overlapping with previously identified genomic regions of high differentiation between marine and freshwater ecotypes, as well as identified the genetic architecture underlying two key CpG sites that were differentially methylated between ecotypes. These findings demonstrate a potential role for DNA methylation in facilitating adaptation to divergent environments and improve our understanding of the heritable basis of population epigenomic variation.
Nonlinear Stability Analysis for Artificial Kidney Multi-compartmental Models
Authors: Abohtyra Rammah
Published: November 2020

This paper addresses a new global stability analysis for a specific class of nonlinear multi-compartment models with non-positive flows and whose balances are described by equilibrium sets. We apply the stability analysis to our physiological-based model of extracellular fluid used during dialysis therapy in end-stage kidney disease patients. To gain an in-depth understanding of the risk associated with fluid removal by the artificial kidney during the short time (3-5hrs) of the dialysis therapy, we use the stability results to analyze the solution’s behavior of our model under standard ultrafiltration and patient-specific ultrafiltration profiles. Therefore, the standard ultrafiltration profiles do not guarantee optimal outcomes, and we highly recommend incorporating physiological insights into the ultrafiltration profiles to improve outcomes.
An initial ‘snapshot’ of sensory information biases the likelihood and speed of subsequent changes of mind
Authors: Turner William , Feuerriegel Daniel , Hester Robert , Bode Stefan
Published: November 2020

We often need to rapidly change our mind about perceptual decisions in order to account for new information and correct mistakes. One fundamental, unresolved question is whether information processed prior to a decision being made (‘pre-decisional information’) has any influence on the likelihood and speed with which that decision is reversed. We investigated this using a luminance discrimination task in which participants indicated which of two flickering greyscale squares was brightest. Following an initial decision, the stimuli briefly remained on screen, and participants could change their response. Using psychophysical reverse correlation, we examined how moment-to-moment fluctuations in stimulus luminance affected participants’ decisions. This revealed that the strength of even the very earliest (pre-decisional) evidence was associated with the likelihood and speed of later changes of mind. To account for this effect, we propose an extended diffusion model in which an initial ‘snapshot’ of sensory information biases ongoing evidence accumulation.

Author Summary

To avoid harm in an ever-changing world we need to be able to rapidly change our minds about our decisions. For example, imagine being unable to overrule a decision to run across a street when you realise a speeding car is approaching. In this study, we examined the information processing dynamics which underlie perceptual judgements and changes of mind. By reverse correlating participants decisions with the moment-to-moment sensory evidence they received, we show that the very earliest information, processed prior to an initial decision being made, can have a lasting influence over the speed and likelihood of subsequent changes of mind. To account for this, we develop a model of perceptual decisions in which initial sensory evidence exerts a lasting bias over later evidence processing. When fit to participants’ behavioural responses alone, this model predicted their observed information usage patterns. This suggests that an initial ‘snapshot’ of sensory information may influence the ongoing dynamics of the perceptual decision process, thus influencing the speed and likelihood of decision reversals.
Possible biased virulence attenuation in the Senegal strain of Ehrlichia ruminantium by ntrX gene conversion from an inverted segmental duplication
Authors: Gordon Jonathan L. , Oliva Chavez Adela S. , Martinez Dominique , Vachiery Nathalie , Meyer Damien F.
Published: November 2020

Ehrlichia ruminantium is a tick-borne intracellular pathogen of ruminants that causes heartwater, a disease present in Sub-saharan Africa, islands in the Indian Ocean and the Caribbean, inducing significant economic losses. At present, three avirulent strains of E. ruminantium (Gardel, Welgevonden and Senegal isolates) have been produced by a process of serial passaging in mammalian cells in vitro, but unfortunately their use as vaccines do not offer a large range of protection against other strains, possibly due to the genetic diversity present within the species (Cangi et al. 2016). So far no genetic basis for virulence attenuation has been identified in any E. ruminantium strain that could offer targets to facilitate vaccine production. Virulence attenuated Senegal strains have been produced twice independently, and require many fewer passages to attenuate than the other strains. We compared the genomes of a virulent and attenuated Senegal strain and identified a likely attenuator gene, ntrX, a global transcription regulator and member of a two-component system that is linked to environmental sensing. This gene has an inverted partial duplicate close to the parental gene that shows evidence of gene conversion in different E. ruminantium strains. The pseudogenisation of the gene in the avirulent Senegal strain occurred by gene conversion from the duplicate to the parent, transferring a 4bp deletion which is unique to the Senegal strain partial duplicate amongst the wild isolates. We confirmed that the ntrX gene is not expressed in the avirulent Senegal strain by RT-PCR. The inverted duplicate structure combined with the 4bp deletion in the Senegal strain can explain both the attenuation and the faster speed of attenuation in the Senegal strain relative to other strains of E. ruminantium. Our results identify nrtX as a promising target for the generation of attenuated strains of E. ruminantium by random or directed mutagenesis that could be used for vaccine production.
CA2 inhibition reduces the precision of hippocampal assembly reactivation
Authors: He Hongshen , Boehringer Roman , Huang Arthur J.Y. , Overton Eric T.N. , Polygalov Denis , Okanoya Kazuo , McHugh Thomas J.
Published: November 2020

The structured reactivation of hippocampal neuronal ensembles during fast synchronous oscillatory events termed sharp-wave ripples (SWRs) has been suggested to play a crucial role in the storage and use of memory. Activity in both the CA2 and CA3 subregions can proceed this population activity in CA1 and chronic inhibition of either region alters SWR oscillations. However, the precise contribution of CA2 to the oscillation, as well as to the reactivation of CA1 neurons within it, remains unclear. Here we employ chemogenetics to transiently silence CA2 pyramidal cells in mice and observe that while SWRs still occur, the reactivation of CA1 pyramidal cell ensembles within the events lose both temporal and informational precision. These observations suggest that CA2 activity contributes to the fidelity of experience-dependent hippocampal replay.
Tackling the phylogenetic conundrum of Hydroidolina (Cnidaria: Medusozoa: Hydrozoa) by assessing competing tree topologies with targeted high-throughput sequencing
Authors: Bentlage Bastian , Collins Allen G.
Published: November 2020

Higher-level relationships of the Hydrozoan subclass Hydroidolina, which encompasses the vast majority of medusozoan cnidarian species diversity, have been elusive to confidently infer. The most widely adopted phylogenetic framework for Hydriodolina based on ribosomal RNA data received low support for several higher level relationships. To address this issue, we developed a set of RNA baits to target more than a hundred loci from the genomes of a broad taxonomic sample of Hydroidolina for high-throughput sequencing. Using these data, we inferred the relationships of Hydroidolina using maximum likelihood and Bayesian approaches. Both inference methods yielded well-supported phylogenetic hypotheses that largely agree with each other. Using maximum likelihood and Baysian hypothesis testing frameworks, we found that several alternate topological hypotheses proposed previously may be rejected in light of the genomic data generated for this study. Both the maximum likelihood and Bayesian topologies inferred herein consistently score well across testing frameworks, suggesting that their consensus represents the most likely phylogenetic hypothesis of Hydroidolina. This phylogenetic framework places Aplanulata as sister lineage to the remainder of Hydroidolina. This is a strong deviation from previous phylogenetic analyses that placed Capitata or Siphonophorae as sister group to the remainder of Hydroidolina. Considering that Aplanulata represents a lineage comprised of species that for the most part possess a life cycle involving a solitary polyp and free-swimming medusa stage, the phylogenetic hypotheses presented herein have potentially large implications for clarifying the evolution of life cycles, coloniality, and the division of labor in Hydrozoa as taxon sampling for phylogenetic analyses becomes more complete.
3D super-resolution fluorescence microscopy maps the variable molecular architecture of the Nuclear Pore Complex
Authors: Sabinina Vilma Jimenez , Hossain M. Julius , Hériché Jean-Karim , Hoess Philipp , Nijmeijer Bianca , Mosalaganti Shyamal , Kueblbeck Moritz , Callegari Andrea , Szymborska Anna , Beck Martin , Ries Jonas , Ellenberg Jan
Published: November 2020

Nuclear pore complexes (NPCs) are large macromolecular machines that mediate the traffic between the nucleus and the cytoplasm. In vertebrates, each NPC consists of ~1000 proteins, termed nucleoporins, and has a mass of over 100 MDa. While a pseudo-atomic static model of the central scaffold of the NPC has recently been assembled by integrating data from isolated proteins and complexes, many structural components still remain elusive due to the enormous size and flexibility of the NPC. Here, we explored the power of 3D super-resolution microscopy combined with computational classification and averaging to explore the 3D structure of the NPC in single human cells. We show that this approach can build the first integrated 3D structural map containing both central as well as peripheral NPC subunits with molecular specificity and nanoscale resolution. Our unbiased classification of over ten thousand individual NPCs indicates that the nuclear ring and the nuclear basket can adopt different conformations. Our approach opens up the exciting possibility to relate different structural states of the NPC to function in situ.
Profiling Germline Adaptive Immune Receptor Repertoire with gAIRR Suite
Authors: Lin Mao-Jan , Lin Yu-Chun , Chen Nae-Chyun , Luo Allen Chilun , Lai Sheng-Kai , Hsu Chia-Lang , Hsu Jacob Shujui , Chen Chien-Yu , Yang Wei-Shiung , Chen Pei-Lung
Published: November 2020

Genetic profiling of germline adaptive immune receptor repertoire (AIRR), including T cell receptor (TR) and immunoglobulin (IG), is imaginably relevant to numerous immune-related conditions, but currently insurmountable due to high genetic complexity. Our gAIRR Suite comprises three modules. gAIRR-seq, a probe capture-based targeted sequencing pipeline, profiles AIRR from individual DNA samples. gAIRR-call and gAIRR-annotate call alleles from gAIRR-seq reads and annotate whole-genome assemblies respectively. We gAIRR-seqed TRV and TRJ of seven Genome in a Bottle (GIAB) DNA samples with 100% accuracy, and discovered novel alleles. We also gAIRR-seqed and gAIRR-called a subject from both the peripheral blood mononuclear cells (PBMC) and oral mucosal cells. The calling results from these two cell types have a high concordance (99% for all known AIRR alleles). We gAIRR-annotated 36 genomes to cumulatively unearth 325 novel TRV alleles and 29 novel TRJ alleles. We could further profile the flanking sequences, including the recombination signal sequence (RSS). We validated two structural variants for HG002. We uncovered substantial conflicts of AIRR genes in references GRCh37 and GRCh38. The gAIRR Suite can potentially benefit future genetic study and clinical applications of various immune-related phenotypes.