bluuebunny/crossref_metadata_2025 huggingface dataset:
Baseline Serum C-Reactive Protein Level Predicts Mortality in Cryptococcal Meningitis
Authors: Chesdachai Supavit , Engen Nicole W , Rhein Joshua , Tugume Lillian , Kiiza Kandole Tadeo , Abassi Mahsa , Ssebambulidde Kenneth , Kasibante John , Williams Darlisha A , Skipper Caleb P , Hullsiek Kathy H , Musubire Abdu K , Rajasingham Radha , Meya David B , Boulware David R
Published: October 2020

Background

C-reactive protein (CRP) is an acute phase protein produced by the liver in response to systemic inflammation. CRP is a helpful surrogate biomarker used for following the progression and resolution of infection. We aimed to determine the association of baseline CRP level and the temporal change in CRP over time with cryptococcal meningitis outcome.

Methods

We reviewed 168 prospectively enrolled HIV-infected Ugandans with confirmed first-episode cryptococcal meningitis. Baseline plasma CRP collected within 5 days of meningitis diagnosis was categorized into quartiles. We compared baseline CRP with 18-week survival using time-to-event analysis.

Results

Of 168 participants, the baseline first quartile of serum CRP was <29.0 mg/L, second quartile 29.0–49.5 mg/L, third quartile 49.6–83.6 mg/L, and fourth quartile >83.6 mg/L. Baseline CD4 count, HIV viral load, and cerebrospinal fluid results did not differ by CRP quartile. Participants with CRP >49.5 mg/L more likely presented with Glasgow Coma Scale (GCS) <15 (P = .03). The 18-week mortality rate was 55% (46/84) in the highest 2 quartile CRP groups (>49.5 mg/L), 41% (17/42) in the mid-range CRP group (29.0–49.5 mg/L), and 14% (6/42) in the low-CRP group (<29.0 mg/L; P < .001). After adjustment for possible confounding factors including GCS <15, CRP remained significantly associated with mortality (adjusted hazard ratio, 1.084 per 10 mg/L; 95% CI, 1.031–1.139; P = .0016).

Conclusions

Higher baseline CRP is associated with increased mortality in HIV-infected individuals with first-episode cryptococcal meningitis. CRP could be a surrogate marker for undiagnosed coinfections or may reflect immune dysregulation, leading to worse outcomes in persons with advanced AIDS and concomitant cryptococcal meningitis.
Unemployment Insurance and Job Search Behavior
Authors: Marinescu Ioana , Skandalis Daphné
Published: October 2020

How does unemployment insurance (UI) affect unemployed workers’ search behavior? Search models predict that until benefit exhaustion, UI depresses job search effort and increases reservation wages. Over an unemployment spell, search effort should increase up to benefit exhaustion and stay high thereafter. Meanwhile, reservation wages should decrease up to benefit exhaustion and stay low thereafter. To test these predictions, we link administrative registers to data on job search behavior from a major online job search platform in France. We follow over 400,000 workers, as long as they remain unemployed. We analyze the changes in search behavior around benefits exhaustion and take two steps to isolate the individual response to unemployment benefits. First, our longitudinal data allows us to correct for changes in sample composition over the spell. Second, we exploit data on workers eligible for 12–24 months of UI as well as workers ineligible for UI, to control for behavior changes over the unemployment spell that are independent of UI. Our results confirm the predictions of search models. We find that search effort (the number of job applications) increases by at least 50% during the year preceding benefits exhaustion and remains high thereafter. The target monthly wage decreases by at least 2.4% during the year preceding benefits exhaustion and remains low thereafter. In addition, we provide evidence for duration dependence: workers decrease the wage they target by 1.5% over each year of unemployment, irrespective of their UI status.
CGE analysis of R&D investment policy considering trade-offs between economic growth and stability
Authors: Hwang Won-Sik , Yeo Yeongjun , Oh Inha , Hong Chanyoung , Jung Sungmoon , Yang Heewon , Lee Jeong-Dong
Published: October 2020

This study analysed economic growth and industrial structure under different conditions on research and development (R&D) investment. To simulate counterfactual scenarios, we built a recursive dynamic computable general equilibrium model named as Technology and Economy Modelling for Innovation Policy assessment (TEMIP) that focuses on private and public R&D investments and their net effects from a macroeconomic perspective. The simulation shows gross domestic product increases rapidly in South Korea when a given amount of expenditure is spent on public R&D activities rather than private R&D. Moreover, our simulation results imply that resource allocation for R&D investments should be elaborated through considering whether the ultimate policy goal is oriented towards economic growth or stability.
Distinct Transcriptomic Reprogramming in the Wheat Stripe Rust Fungus During the Initial Infection of Wheat and Barberry
Authors: Zhao Jing , Duan Wanlu , Xu Yiwen , Zhang Ce , Wang Long , Wang Jierong , Tian Song , Pei Guoliang , Zhan Gangming , Zhuang Hua , Zhao Jie , Kang Zhensheng
Published: October 2020

Puccinia striiformis f. sp. tritici is the causal agent of wheat stripe rust that causes severe yield losses all over the world. As a macrocyclic heteroecious rust fungus, it is able to infect two unrelated host plants, wheat and barberry. Its urediniospores infect wheat and cause disease epidemic, while its basidiospores parasitize barberry to fulfill the sexual reproduction. This complex life cycle poses interesting questions on the different mechanisms of pathogenesis underlying the infection of the two different hosts. In the present study, transcriptomes of P. striiformis f. sp. tritici during the initial infection of wheat and barberry leaves were qualitatively and quantitatively compared. As a result, 142 wheat-specifically expressed genes (WEGs) were identified, which was far less than the 2,677 barberry-specifically expressed genes (BEGs). A larger proportion of evolutionarily conserved genes were observed in BEGs than that in WEGs, implying a longer history of the interaction between P. striiformis f. sp. tritici and barberry. Additionally, P. striiformis f. sp. tritici differentially expressed genes (DEGs) between wheat at 1 and 2 days postinoculation (dpi) and barberry at 3 and 4 dpi were identified by quantitative analysis. Gene Ontology analysis of these DEGs and expression patterns of P. striiformis f. sp. tritici pathogenic genes, including those encoding candidate secreted effectors, cell wall–degrading enzymes, and nutrient transporters, demonstrated that urediniospores and basidiospores exploited distinct strategies to overcome host defense systems. These results represent the first analysis of the P. striiformis f. sp. tritici transcriptome in barberry and contribute to a better understanding of the evolutionary processes and strategies of different types of rust spores during the infection process on different hosts.

[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Chickpea Seed Rot and Damping-Off Caused by Metalaxyl-Resistant Pythium ultimum and Its Management with Ethaboxam
Authors: Wang Moying , Van Vleet Stephen , McGee Rebecca , Paulitz Timothy , Porter Lyndon , Schroeder Kurtis , Vandemark George , Chen Weidong
Published: October 2020

Metalaxyl and its isomer mefenoxam have been the primary fungicides used as seed treatments in managing Pythium seed rot and damping-off of chickpea (Cicer arietinum). However, outbreaks of seed rot and damping-off of metalaxyl-treated chickpea seeds were found in the dryland agriculture regions of southeastern Washington and northern Idaho. Pythium spp. isolated from rotten seeds and associated soils showed high levels of resistance to metalaxyl. Large proportions (31 to 91%) of Pythium isolates resistant to metalaxyl were detected in areas where severe chickpea damping-off occurred and were observed in commercial chickpea fields over several years. All metalaxyl-resistant (MR) isolates were identified as Pythium ultimum var. ultimum. The metalaxyl resistance trait measured by EC50 values was stable over 10 generations in the absence of metalaxyl, and no observable fitness costs were associated with metalaxyl resistance. Under controlled conditions, metalaxyl treatments failed to protect chickpea seeds from seed rot and damping-off after inoculation with MR Pythium isolates. In culture, ethaboxam inhibited mycelial growth of both MR and metalaxyl-sensitive isolates. Greenhouse and field tests showed that ethaboxam is effective in managing MR Pythium. Ethaboxam in combination with metalaxyl is commonly applied as seed treatments in commercial chickpea production.
Serum Oxytocin Level Among Male Patients With Opioid Dependence and Its Relation to Craving
Authors: Mobasher Maha W. , Eid Heba F. , Soliman Aliaa M. , El-Hanafi Hadeel M. , El-Makawi Shirin M.
Published: October 2020

Introduction:

Oxytocin (OT), a known hormone and neurotransmitter, has been lately known to be involved in the drug addiction cycle especially during developing tolerance, in relation to craving and during withdrawal.

Objectives:

The aim was to assess serum OT level in patients with active opiate dependency in comparison with abstinent patients and healthy controls, and its relation with craving among patients and abstinent patients.

Materials and Methods:

A consecutive sample of 30 opiate-dependent patients who fully meet the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for opiate dependence, in addition to 30 patients fulfilling DSM-5 criteria of opiate dependence with at least 6 months of abstinence were assessed regarding serum OT levels, craving levels using immunoassay kit and brief substance craving scale, respectively. They were compared with each other and with a sample of 30 healthy controls matching both groups.

Results:

There was a statistically significant difference between the patient and the control groups in serum OT levels (P<0.05) but not between the other 2 groups, that is, patient versus abstinent and abstinent versus controls. Craving levels showed a statistically significant difference between the patient and the abstinent groups (P<0.001). A negative correlation was found between OT level and craving in the abstinent group (P<0.05).

Conclusions:

The interaction between serum OT levels and craving should be considered when dealing with opiate-dependent patients as they affect and are affected by opiate dependence. Further studies regarding how to implement this during patients treatment should be considered.
Complete Decompression of a Forearm Neonatal Compartment Syndrome Using a Volar Approach: A Surgical Technique
Authors: El Beaino Marc , Connors Katherine M. , Koehler Steven M.
Published: October 2020

Fasciotomy of the forearm is a well-described technique for the treatment of compartment syndrome in adults; however, it has not been discussed with sufficient details in the setting of neonatal compartment syndrome. When performing a fasciotomy, it is imperative to decompress all compartments within the forearm to limit the ischemic damage and prevent the progression of the disease. Although it is common to utilize both volar and dorsal incisions to release these compartments, we describe a method that potentially allows for total decompression through a single volar incision with minimal to no morbidity. This novel technique provides sufficient soft-tissue exposure while improving upon the cosmesis that results from a traditional approach.
Tinospora cordifolia and arabinogalactan exert chemopreventive action during benzo(a)pyrene-induced pulmonary carcinogenesis: studies on ultrastructural, molecular, and biochemical alterations [RETRACTED]
Authors: Dou Yawei , Tu Fangling , Wu Yan , Wang Xiaodong , Lu Guannan , Zhao Long
Published: October 2020

The aim of the present study was to unveil the chemopreventive potentials of aqueous Tinospora cordifolia stem extract and its active component viz. Arabinogalactan against Benzo(a)pyrene-induced pulmonary carcinogenesis. Animals were divided into six groups: (I) Control, (II) aqueous Tinospora cordifolia (200 mg/kg b.wt, p.o.), (III) arabinogalactan (7.5 mg/kg b.wt, p.o.), (IV) benzo(a)pyrene (50 mg/kg b.wt, i.p.) at second and fourth week of study, (V) benzo(a)pyrene + aqueous Tinospora cordifolia, and (VI) benzo(a)pyrene + arabinogalactan. The benzo(a)pyrene treatment resulted in severe alterations in the cellular arrangement and morphology of the alveolar tissue in benzo(a)pyrene group. However, benzo(a)pyrene + aqueous Tinospora cordifolia and benzo(a)pyrene + arabinogalactan groups revealed classical features of apoptosis including chromatin condensation and formation of apoptotic bodies. Furthermore, Fourier transform Infrared spectroscopy analysis showed disturbed phospholipid saturation and protein secondary structures in benzo(a)pyrene treated animals. Depletion in relative glycogen and enhancement in total nucleic acid content was observed in benzo(a)pyrene treated animals, and the same was found to be restored upon arabinogalactan and aqueous Tinospora cordifolia supplementation. Benzo(a)pyrene insult also upregulated the phase I carcinogen metabolizing enzymes and differentially modulated the phase II metabolizing enzymes during pulmonary carcinogenesis. Also, depleted (reduced glutathione) and increased lipid peroxidation levels were observed in benzo(a)pyrene treated animals, which was found to be normalized upon aqueous Tinospora cordifolia and arabinogalactan administration. Clastogenic damage inflicted by benzo(a)pyrene was also reversed in benzo(a)pyrene + aqueous Tinospora cordifolia and benzo(a)pyrene + arabinogalactan group. Thus, the present study infers that aqueous Tinospora cordifolia and arabinogalactan showed promising anticancer activity against lung tumorigenesis in terms of ultrastructural, biochemical, and biomolecular aspects.
Inflammation reduces osteoblast cytotoxicity induced by diclofenac
Authors: Aguirre José , Bonvini John M. , Rupnik Barbara , Camponovo Claudio , Saporito Andrea , Borgeat Alain
Published: October 2020

BACKGROUND

Diclofenac and other NSAIDs are routinely used in the postoperative period. Their effect on fracture healing remains unclear and controversial.

OBJECTIVE

The primary outcome was to assess the potential cytotoxicity of clinically relevant concentrations of diclofenac on human osteoblasts.

DESIGN

Laboratory in vitro study.

SETTING

Institute of Physiology, Zurich, Center for Integrative Human Physiology, University of Zurich.

MATERIALS

Monolayers of human osteoblasts.

INTERVENTION(S)

Exposure of human osteoblast monolayers to several concentrations of diclofenac, for different periods of time, with and without an artificially induced inflammatory process.

MAIN OUTCOME MEASURES

Cell count, cell viability, cell proliferation and apoptosis.

RESULTS

A concentration-mediated, time and exposure dependent cytotoxic effect of diclofenac-mediated apoptosis was observed. Stimulated inflammatory conditions seemed to reduce toxic effects.

CONCLUSION

Cytotoxic effects of diclofenac are exposure, time and concentration dependent. Simulating aspects of inflammatory conditions seems to increase resistance to diclofenac cytotoxicity, especially in the presence of higher concentration and longer exposure time.
FOCUSED (Femtosecond Optimized Continuous Uncorrected Sight with EDOF and Diffractive Multifocal IOLs) - A Review
Authors: Barnett Brad P.
Published: October 2020

Purpose of review

The aim of this article is to review techniques to maximize all-distance uncorrected visual acuity and minimize photic phenomena after the implantation of multifocal and extended-depth of focus (EDOF) intraocular lenses (IOLs). This review examines the role of femtosecond laser-assisted cataract surgery (FLACS) in postoperative minimization of astigmatism and optimization of outcomes with multifocal and EDOF lenses.

Recent findings

By incorporating intraoperative and preoperative imaging, femtosecond platforms such as those that utilize iris or conjunctival vessel registration, can enable a precision of corneal incisions and toric IOL markings that enable the lowest possible postoperative levels of astigmatism. Current studies suggest that with increasing IOL complexity, that is, trifocal versus bifocal, image degradation with even low levels of postoperative astigmatism are increased. To this end, current data support the utility of femtosecond laser arcuate incisions to enable the achievement of 0.5 D or less postoperative astigmatism for best outcomes with multifocal lenses.

The synergistic combination of multifocal/EDOF IOLs with FLACS is an extremely promising route in achieving postoperative spectacle independence for patients. The marriage of the precision of FLACS with the increasing complexity of multifocal/EDOF IOLs will fuel nomogram adjustment and systematic improvements, such as the Wörtz–Gupta formula. Such strategies provide an unprecedented precision to cataract surgery that makes FOCUSED (Femtosecond Optimized Continuous Uncorrected Sight with EDOF and Diffractive Multifocal IOLs) a reality.
Countertransference in Forensic Inpatient Settings: An Empirical Examination of Therapist Responses to Patients With Psychotic Disorders
Authors: De Page Louis , Boulanger Marie , De Villers Bénédicte , Di Virgilio Patrizio , Pham Thierry , Saloppé Xavier , Thiry Benjamin
Published: October 2020

Objective

Countertransference in forensic inpatient settings has received little empirical attention despite frequent emotional reactions in staff members, such as anger, disgust, or fear. In this exploratory study, we investigated countertransference in two forensic medium-secure units for patients with psychotic disorders.

Method

We measured countertransference using the Therapist Response Questionnaire and measured staff personality using the Ten-Item Personality Inventory. Our design allowed all staff members to participate anonymously.

Results

One hundred thirty-four Therapist Response Questionnaire forms, along with data on patient and staff characteristics, were collected. Staff characteristics such as profession, experience, and personality were associated with different countertransference reactions. Psychologists and psychiatrists tended to report more countertransference feelings than nursing staff. Patient and staff variables (such as patient having committed violent offenses or a diagnosis of personality disorder and staff experience or gender) were associated with more negative countertransference feelings and subscale scores as well as less positive countertransference feelings such as parental, protective, and satisfying countertransference feelings. Some patient and staff variables (such as patient cooperativeness, staff personality trait agreeableness) had the inverse effect on countertransference feelings.

Conclusion

We discussed several conceptual problems inherent to measuring countertransference (in forensic inpatient settings) and the clinical implications of our findings.
Subjective and Objective Evaluation of the Effect of Blink Type on Tear-film Breakup Time and Its Estimation
Authors: Szczesna-Iskander Dorota H. , Llorens Quintana Clara
Published: October 2020

SIGNIFICANCE

While evaluating the tear-film breakup time, a careful set of precise instructions should be given to the subjects regarding the blink type because it substantially impacts the assessment of tear-film surface quality.

PURPOSE

The purpose of this study was to determine to what extent the type of blink affects the tear-film breakup time and its assessment using two types of videokeratoscopes and the fluorescein test.

METHODS

Thirty-three volunteers were assessed considering two different types of blinks: natural (short) and forced (unnaturally prolonged). Objective noninvasive breakup time estimation was performed using Oculus Keratograph 5M and Medmont E300, both equipped with tear-film analysis modules, followed by the fluorescein test. In addition, while overviewing videokeratoscopy recordings, noninvasive breakup time was assessed subjectively by one experienced observer marking the first noticeable distortion in the Placido-disk pattern. Statistical analyses included two-way ANOVA and paired-samplettest. The agreement between blinking and measuring modalities was assessed using Bland-Altman plots.

RESULTS

Forced blink significantly shortened the tear-film breakup time in all measuring modalities (two-way ANOVA,P= .003). The mean difference between breakup time after natural and forced blink was 3.2 (P= .002), 2.4 (P= .005), and 2.1 seconds (P= .002), for Keratograph 5M, E300, and fluorescein test, respectively. The group median of differences between objective and subjective noninvasive breakup time was less than 1 second with both videokeratoscopes. The objective noninvasive breakup time measured with Keratograph 5M was significantly longer than those with E300 and fluorescein test (bothP< .001). No statistically significant difference was found between E300 objective assessment and fluorescein test (P= .19).

CONCLUSIONS

Forced blinks affect the assessment of tear-film stability. Hence, attention should be given in instructing the subjects before tear-film breakup time evaluation irrespectively to the method of measurement.
Spelling as Part of the Writing Process in Intermediate-Grade Students
Authors: Koutsoftas Anthony D. , Srivastava Pradyumn , Harris Sarah B.
Published: October 2020

Spelling is an important skill that requires knowledge of phonology, morphology, and orthography, as well as strong visual memory. In this study, we introduce a spelling coding rubric that accounts for different knowledge types needed for spelling and can be used to describe error patterns for both encoding and decoding as part of the writing process. Eighty participants wrote a first draft and final copy of a narrative generated with extended time over 3 days. Spelling error patterns from these samples were coded using the spelling coding rubric, which was informed by prior research. Approximately 2% of words were misspelled, and the frequency of error types across error codes was similar on first drafts and final copies and required that all 15 error codes be applied to writing samples. Interrater agreement for coding errors was acceptable. The spelling coding rubric described the spelling error patterns in the writing samples while accounting for spelling knowledge in a usable way for educators. Clinical implications and future directions of this research are discussed.
Evidence-Based Class Literacy Instruction for Children With Speech and Language Difficulties
Authors: Gillon Gail , McNeill Brigid , Denston Amanda , Scott Amy , Macfarlane Angus
Published: October 2020

This study investigated the response to class-wide phonological awareness and oral language teaching for 40 children who entered school with speech and language difficulties. A stepped wedge research design was adopted to compare the immediate impact of the 10-week teacher-led instruction. The progress of the children with speech and language difficulties was monitored over the first school year and compared with 110 children with language difficulties alone and 95 children with typical development. Children with speech and language needs showed a strong intervention response in phoneme awareness and vocabulary learning but needed more support to transfer skills to word decoding and spelling. Implementing the approach earlier in the school year resulted in stronger literacy performance at the year-end for all three groups. The importance of positive speech–language pathologist and teacher collaborations to support a systematic approach to evidence-based foundational literacy teaching is discussed.
Chronic Electroconvulsive Therapy May Induce Calvarial Hyperemia and Marrow Replacement
Authors: Khattab Mohamed H. , Sherry Alexander D. , Aulino Joseph M. , Becker Jonathan E. , Petrie William M. , Cmelak Anthony J.
Published: October 2020

Electroconvulsive therapy (ECT) is a treatment option for a number of psychiatric disorders, including refractory major depression and obsessive compulsive disorder. There are no known structural sequelae of ECT. Here we present a patient with severe refractory obsessive compulsive disorder and major depression treated over 2 years with ECT every 2 weeks. Planning magnetic resonance imaging intended for a potential procedural intervention for her psychiatric disease incidentally demonstrated a new area of increased enhancement and loss of marrow signal within the right frontal bone. Imaging findings were suggestive of underlying bone marrow or bone changes, although there was no evidence of bone destruction on bone-windowed computed tomography (CT) and there was no uptake on nuclear bone scan. The CT chest/abdomen/pelvis were also reassuring that this did not represent metastatic disease, and findings were unchanged on repeat magnetic resonance imaging 4 months later. Thus, this area corresponded to the site directly underlying the unilateral ECT electrode placement, suggestive of never-before described ECT-induced hyperemia. We report for the first time that frequent, chronic ECT may induce asymptomatic skull bone marrow hyperemia with radiologic findings. This appears to be a direct consequence of electrical current leading to chronic inflammatory and edematous marrow replacement. Electroconvulsive therapy should be added to the neuroradiological differential diagnosis of calvarial enhancement and loss of marrow signal. Psychiatrists should counsel patients on the possibility of this rare radiological finding, which may be confused for other processes.
In silico analysis of the chemotactic system of Agrobacterium tumefaciens
Authors: Xu Nan , Wang Mingqi , Yang Xiaojing , Xu Yujuan , Guo Minliang
Published: October 2020

Agrobacterium tumefaciens

is an efficient tool for creating transgenic host plants. The first step in the genetic transformation process involves

A. tumefaciens

chemotaxis, which is crucial to the survival of

A. tumefaciens

in changeable, harsh and even contaminated soil environments. However, a systematic study of its chemotactic signalling pathway is still lacking. In this study, the distribution and classification of chemotactic genes in the model

A. tumefaciens

C58 and 21 other strains were annotated. Local blast was used for comparative genomics, and hmmer was used for predicting protein domains. Chemotactic phenotypes for knockout mutants of ternary signalling complexes in

A. tumefaciens

C58 were evaluated using a swim agar plate. A major cluster, in which chemotaxis genes were consistently organized as MCP (methyl-accepting chemotaxis protein), CheS, CheY1, CheA, CheR, CheB, CheY2 and CheD, was found in

A. tumefaciens

, but two coupling CheW proteins were located outside the ‘che’ cluster. In the ternary signalling complexes, the absence of MCP atu0514 significantly impaired

A. tumefaciens

chemotaxis, and the absence of CheA (atu0517) or the deletion of both CheWs abolished chemotaxis. A total of 465 MCPs were found in the 22 strains, and the cytoplasmic domains of these MCPs were composed of 38 heptad repeats. A high homology was observed between the chemotactic systems of the 22

A. tumefaciens

strains with individual differences in the gene and receptor protein distributions, possibly related to their ecological niches. This preliminary study demonstrates the chemotactic system of

A. tumefaciens

, and provides some reference for

A. tumefaciens

sensing and chemotaxis to exogenous signals.
Markov Chain Abstractions of Electrochemical Reaction-Diffusion in Synaptic Transmission for Neuromorphic Computing
Authors: Wagner Margot , Bartol Thomas M. , Sejnowski Terrence J. , Cauwenberghs Gert
Published: October 2020

Progress in computational neuroscience towards understanding brain function is challenged both by the complexity of molecular-scale electrochemical interactions at the level of individual neurons and synapses and the dimensionality of network dynamics across the brain covering a vast range of spatial and temporal scales. Our work abstracts an existing highly detailed, biophysically realistic 3D reaction-diffusion model of a chemical synapse to a compact internal state space representation that maps onto parallel neuromorphic hardware for efficient emulation at a very large scale and offers near-equivalence in input-output dynamics while preserving biologically interpretable tunable parameters.
Structural basis for effector transmembrane domain recognition by type VI secretion system chaperones
Authors: Ahmad Shehryar , Tsang Kara K. , Sachar Kartik , Quentin Dennis , Tashin Tahmid M. , Bullen Nathan P. , Raunser Stefan , McArthur Andrew G. , Prehna Gerd , Whitney John C.
Published: October 2020

Type VI secretion systems facilitate the delivery of antibacterial effector proteins between neighbouring Gram-negative bacteria. A subset of these effectors harbor N-terminal transmembrane domains (TMDs) implicated in effector translocation across the target cell membrane. However, the abundance and distribution of these TMD-containing effectors has remained unknown. Here we report the discovery of prePAAR, a conserved motif found in over 6,000 putative TMD-containing effectors. Based on their differing sizes and number of TMDs these effectors fall into two distinct classes that are unified by their requirement for a member of the Eag family of T6SS chaperones for export. Co-crystal structures of class I and class II effector TMD-chaperone complexes fromSalmonellaTyphimurium andPseudomonas aeruginosa, respectively, reveals that Eag chaperones mimic transmembrane helical packing to stabilize effector TMDs. In addition to participating in the chaperone-TMD interface, we find that prePAAR functions to facilitate proper folding of the downstream PAAR domain, which is required for effector interaction with the T6SS spike. Taken together, our findings define the mechanism of chaperone-assisted secretion of a widespread family of T6SS membrane protein effectors.
Intolerance to uncertainty modulates neural synchrony between political partisans
Authors: van Baar Jeroen M. , Halpern David J. , FeldmanHall Oriel
Published: October 2020

Political partisans see the world through an ideologically biased lens. What drives political polarization? It has been posited that polarization arises because holding extreme political views satisfies a need for certain and stable beliefs about the world. We examined the relationship between uncertainty tolerance and political polarization using brain-to-brain synchrony analysis, which measured committed liberals’ and conservatives’ subjective interpretation of a continuous political narrative. Participants (N=44) watched a political debate while undergoing fMRI. Shared ideology between participants increased neural synchrony in many brain areas including key regions of the valuation and theory-of-mind networks (e.g. temporoparietal junction). The degree of neural synchrony was modulated by uncertainty aversion: Uncertainty-intolerant individuals experienced greater brain-to-brain synchrony with politically like-minded peers and lower synchrony with political opponents. This effect was observed for liberals and conservatives alike. Moreover, increasing neural synchrony between committed partisans predicted subsequent polarized attitude formation about the debate after the scanning session. These results suggest that uncertainty attitudes gate the shared neural processing of political narratives, thereby fueling polarized attitude formation about hot-button issues.
The scales and signatures of climate adaptation by theArabidopsistranscriptome
Authors: Colicchio Jack M. , Akman Melis , Blackman Benjamin K.
Published: October 2020

Clines in allele frequency and trait variation can be highly informative for understanding how populations have historically adapted to climate variation across landscapes. However, as a consequence of the many complexities inherent to this process, these climate-associated differentiation patterns can be confounded, misleading, or obscured. Molecular phenotypes like gene expression levels are a potentially valuable means for resolving these complexities. Their intermediate position between genomes and organismal traits and their interrelatedness structured by gene regulatory networks can help parse how different climatic factors contribute to unique components of range-wide or region-specific diversity patterns. Here, we demonstrate these explanatory values of gene expression variation through integrative analyses of transcriptomic data from 665Arabidopsis thalianaaccessions. Differentiation of co-expressed genes is often associated with source site climate. Although some patterns hold range-wide, many other gene expression clines are specific to particular ancestry groups, reflecting how broad-scale and local combinations of selective agents differentially resolve functional interrelationships between plant defense, drought tolerance, and life history traits. We also extend these analyses to parse how different factors explain climate-associated variation in flowering time and its plasticity. Expression of key regulatorsFLCandSOC1strongly predicts time to flower, consistent with previous work, but our results also highlight novel relationships that indicate as yet unexplored climate-related connections between defense signaling and flowering. Finally, we show that integrative models combining genotype and gene expression information predict variation in flowering time under ecologically realistic conditions more accurately than models based on either source alone.

Significance Statement

Populations often adapt to local conditions along climate gradients, and associations between climate parameters and traits or alleles often indicate a history of adaptive differentiation. However, such signals can be obscured or misleading due to the complex genetics underlying trait variation or other historical processes, frustrating our capacity to reveal how populations adapt to diverse climates. As a molecular intermediate between genetic polymorphisms and their impact on organismal traits, gene expression variation is a useful readout for addressing several of these difficulties. Here, we leverage transcriptomic data from hundreds ofArabidopsis thalianaaccessions to reveal continental and region-specific patterns of climate-associated differentiation as well as investigate how gene expression adaptation at both scales shapes flowering time variation along climate gradients.
A “Cell-Nucleus Segmentation” Script for Non-Invasive Nuclear Dry Mass Measurement
Authors: Kong Edward M. , Hu Chenfei , Kim Byoung Soo , Popescu Gabriel
Published: October 2020

The nucleus is the largest organelle in cells carrying genetic materials that support genetic replication and transcription. It is likely that such genetic activities can influence the nucleardry mass, but there is a lack of analytical tools enabling us to monitor dynamic changes in this quantity. To this end, this study demonstrates an image analysis script that allows us to quantify these changes in the nuclear dry mass. The script runs the cell-nuclei segmentation using Matlab. By using the fluorescent image as a template for the boundaries of cell nuclei and quantitative phase images for retrieving the dry mass density, the script recognizes nuclei of all cells in an image at a time and quantifies the nuclear dry mass. Using the “the cell-nucleus segmentation” script, this study reveals an interesting correlation between the nuclear dry mass and the filopodia protrusion of cervical epithelial cells. As the filopodia density and protrusion length increase, the nuclear dry mass increases. On the other hand, whenever the nuclear dry mass decreases, cells filopodia retract significantly. Taken together, the imaging script developed here will be useful to quantifying dynamic nuclear activities of a broad array of cells non-invasively.
DTI reveals whole-brain microstructural changes in the P301L mouse model of tauopathy
Authors: Massalimova Aidana , Ni Ruiqing , Nitsch Roger M. , Reisert Marco , von Elverfeldt Dominik , Klohs Jan
Published: October 2020

Introduction

Increased expression of hyperphosphorylated tau and the formation of neurofibrillary tangles are associated with neuronal loss and white matter damage. Using high resolutionex vivodiffusion tensor imaging (DTI), we investigated microstructural changes in the white and grey matter in the P301L mouse model of human tauopathy at 8.5 months-of-age. For unbiased computational analysis, we implemented a pipeline for voxel-based analysis (VBA) and atlas-based analysis (ABA) of DTI mouse brain data.

Methods

Hemizygous and homozygous transgenic P301L mice and non-transgenic littermates were used. DTI data were acquired for generation of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD) maps. VBA on the entire brain were performed using SPM8 and SPM Mouse toolbox. Initially, all DTI maps were co-registered with Allen mouse brain atlas to bring them to one common coordinate space. In VBA, co-registered DTI maps were normalized and smoothed in order to perform two-sample t-tests to compare hemizygotes with non-transgenic littermates, homozygotes with non-transgenic littermates, hemizygotes with homozygotes on each DTI parameter map. In ABA, the average values for selected regions-of-interests were computed with co-registered DTI maps and labels in Allen mouse brain atlas. After, the same two-sample t-tests were executed on the estimated average values.

Results

We made reconstructed DTI data and VBA and ABA pipeline publicly available. With VBA, we found microstructural changes in the white matter in hemizygous P301L mice compared to non-transgenic littermates. In contrast, more pronounced and brain-wide spread changes were observed in VBA when comparing homozygous P301L mice with non-transgenic littermates. Statistical comparison of DTI metrics in selected brain regions by ABA corroborated findings from VBA. FA was found to be decreased in most brain regions, while MD, RD and AD were increased compared to hemizygotes and non-transgenic littermates.

Discussion/Conclusion

High resolutionex vivoDTI demonstrated brain-wide microstructural changes in the P301L mouse model of human tauopathy. The comparison between hemizygous and homozygous P301L mice revealed a gene-dose dependent effect on DTI metrics. The publicly available computational data analysis pipeline can provide a platform for future mechanistic and longitudinal studies.
Mechanism of SARS-CoV-2 polymerase inhibition by remdesivir
Authors: Kokic Goran , Hillen Hauke S. , Tegunov Dimitry , Dienemann Christian , Seitz Florian , Schmitzova Jana , Farnung Lucas , Siewert Aaron , Höbartner Claudia , Cramer Patrick
Published: October 2020

Remdesivir is the only FDA-approved drug for the treatment of COVID-19 patients1–4. The active form of remdesivir acts as a nucleoside analogue and inhibits the RNA-dependent RNA polymerase (RdRp) of coronaviruses including SARS-CoV-25–7. Remdesivir is incorporated by the RdRp into the growing RNA product and allows for addition of three more nucleotides before RNA synthesis stalls6,8. Here we use synthetic RNA chemistry, biochemistry and cryo-electron microscopy to establish the molecular mechanism of remdesivir-induced RdRp stalling. We show that addition of the fourth nucleotide following remdesivir incorporation into the RNA product is impaired by a barrier to further RNA translocation. This translocation barrier causes retention of the RNA 3’-nucleotide in the substrate-binding site of the RdRp and interferes with entry of the next nucleoside triphosphate, thereby stalling RdRp. In the structure of the remdesivir-stalled state, the 3’-nucleotide of the RNA product is matched with the template base, and this may prevent proofreading by the viral 3’-exonuclease that recognizes mismatches9,10. These mechanistic insights should facilitate the quest for improved antivirals that target coronavirus replication.
Integrative transcriptomic analysis of tissue-specific metabolic crosstalk after myocardial infarction
Authors: Arif Muhammad , Klevstig Martina , Benfeitas Rui , Doran Stephen , Turkez Hasan , Uhlén Mathias , Clausen Maryam , Wikström Johannes , Etal Damla , Zhang Cheng , Levin Malin , Mardinoglu Adil , Boren Jan
Published: October 2020

Abstract/Summary

Myocardial infarction (MI) promotes a range of systemic effects, many of which are unknown. Here, we investigated the alterations associated with MI progression in heart and other metabolically active tissues (liver, skeletal muscle, and adipose) in a mouse model of MI (induced by ligating the left ascending coronary artery) and sham-operated mice. We performed a genome-wide transcriptomic analysis on tissue samples obtained 6- and 24-hours post MI or sham operation. By generating tissue-specific biological networks, we observed: (1) dysregulation in multiple biological processes (including immune system, mitochondrial dysfunction, fatty-acid beta-oxidation, and RNA and protein processing) across multiple tissues post MI; and (2) tissue-specific dysregulation in biological processes in liver and heart post MI. Finally, we validated our findings in two independent MI cohorts. Overall, our integrative analysis highlighted both common and specific biological responses to MI across a range of metabolically active tissues.
DNAJB12 and Hsp70 Facilitate the Conformation Specific Degradation of Arrested N1303K-CFTR Intermediates by ER Associated-Autophagy
Authors: He Lihua , Kennedy Andrew S. , Houck Scott , Aleksandrov Andrei , Quinney Nancy L. , Cholon Deborah M. , Gentzsch Martina , Randell Scott H. , Ren Hong Yu , Cyr Douglas M.
Published: October 2020

The transmembrane Hsp40 DNAJB12 and cytosolic Hsp70 cooperate on the ER’s cytoplasmic face to facilitate the triage of nascent polytopic membrane proteins for folding versus degradation. N1303K is the second most common mutation in the ion channel CFTR, but unlike F508del-CFTR, biogenic and functional defects in N1303K-CFTR are resistant to correction bolding modulators. N1303K is reported to arrest CFTR folding at a late stage after partial assembly of its N-terminal domains. N1303K-CFTR intermediates are clients of JB12-Hsp70 complexes, maintained in a detergent soluble-state, and have a relatively long 3-hour half-life. ERAD-resistant pools of N1303K-CFTR are concentrated in ER-tubules that associate with autophagy initiation sites containing WIPI1, FlP200, and LC3. Destabilization of N1303K-CFTR or depletion of JB12 prevents entry of N1303K-CFTR into the membranes of ER-connected phagophores and autolysosomes. Whereas, the stabilization of intermediates with the modulator VX-809 promotes the association of N1303K-CFTR with autophagy initiation machinery. N1303K-CFTR is excluded from the ER-exits site, and its passage from the ER to autolysosomes does not require ER-phagy receptors. DNAJB12 operates in biosynthetically active ER-microdomains to triage in a conformation-specific manner membrane protein intermediates for secretion versus degradation via ERAD or selective-ER associated autophagy.
Effects of pro-depressant and immunomodulatory drugs on biases in decision-making in the rat judgement bias task
Authors: Hales CA , Bartlett JM , Arban R , Hengerer B , Robinson ESJ
Published: October 2020

Studies in human and non-human species suggest that decision-making behaviour can be biased by affective state, also termed an affective bias. To study these behaviours in non-human species, judgement bias tasks have been developed. Animals are trained to associate specific cues (tones) with a positive or negative/less positive outcome. Animals are then presented with intermediate ambiguous cues and affective biases quantified by observing whether animals make more optimistic or more pessimistic choices. Here we use a high versus low reward judgement bias task and test whether pharmacologically distinct compounds, which induce negative biases in learning and memory, have similar effects on decision-making: tetrabenazine (0.0-1.0mg/kg), retinoic acid (0.0-10.0mg/kg) and rimonabant (0.0-10.0mg/kg). We also tested immunomodulatory compounds: interferon-α (0-100units/kg), lipopolysaccharide (0.0-10.0μg/kg) and corticosterone (0.0-10.0mg/kg). We observed no specific effects in the judgement bias task with any acute treatment except corticosterone which induced a negative bias. We have previously observed a similar lack of effect with acute but not chronic psychosocial stress and so next tested decision-making behaviour following chronic interferon-alpha. Animals developed a negative bias which was sustained even after treatment was ended. These data suggest that decision-making behaviour in the task is sensitive to chronic but not acute effects of most pro-depressant drugs or immunomodulators, but exogenous administration of acute corticosterone induces pessimistic behaviour. This work supports our hypothesis that biases in decision-making develop over a different temporal scale to those seen with learning and memory which may be relevant in the development and perpetuation of mood disorders.

Graphical abstract and text

Decision-making bias in rats, measured using a judgement bias task, is not altered by acute treatments with pro-depressant or immunomodulatory drugs, but becomes more negative following chronic treatment. The time course of change in decision-making bias reflects the subjective reporting of changes in depression symptoms in humans treated with these drugs.
Modelling disease transmission from touchscreen user interfaces
Authors: Di Battista Andrew , Nicolaides Christos , Georgiou Orestis
Published: October 2020

The extensive use of touchscreens for all manner of human-computer interactions has made them plausible instruments of touch-mediated disease transmission. To that end, we employ stochastic simulations to model human-fomite interaction with a distinct focus on touchscreen interfaces. The timings and frequency of interactions from within a closed population of infectious and susceptible individuals was modelled using a basic queuing network. Apseudoreproductive number (R) was used to compare outcomes under various parameter conditions. We also expanded the simulation to a specific real-world scenario; namely airport self check-in and baggage drop. Results revealed that the required rate of cleaning/disinfecting of screens to effectively mitigateRcan be inordinately high. This suggests that revised or alternative methods should be considered.
Long-term stability of neuronal ensembles in mouse visual cortex
Authors: Pérez-Ortega Jesús , Alejandre-García Tzitzitlini , Yuste Rafael
Published: October 2020

Coactive neuronal ensembles are found in spontaneous and evoked cortical activity and are thought to participate in the internal representation of memories, perceptions, and mental states. In mouse visual cortex, ensembles can be optogenetically imprinted and are causally related to visual percepts, but it is still unknown how stable they are over time. Using two-photon volumetric microscopy, we performed calcium imaging over several weeks of the same neuronal populations in layer 2/3 of visual cortex of awake mice, tracking over time the activity of the same neurons in response to visual stimuli and under spontaneous activity. Only a small number of neurons remained active across days. Analyzing them, we found both stable ensembles, lasting up to 46 days, and transient ones, observed during only one imaging session. The majority of ensembles in visually-evoked activity were stable, whereas in spontaneous activity similar numbers of stable and transient ensembles were found. Among stable ensembles, more than 60 % of neurons still belonged to the same ensemble even after several weeks. These core ensemble cells had stronger functional connectivity than neurons that stopped belonging to the ensemble. Our results demonstrate that spontaneous and evoked neuronal ensembles can last weeks, providing a neuronal mechanism for the long-lasting representation of perceptual states or memories.