bluuebunny/crossref_metadata_2025 huggingface dataset:
The Impact of Compliance During Exclusive Enteral Nutrition on Faecal Calprotectin in Children With Crohn Disease
Authors: Mckirdy Shona , Russell Richard K. , Svolos Vaios , Gkikas Konstantinos , Logan Michael , Hansen Richard , Gerasimidis Konstantinos
Published: February 2022

It remains unclear whether suboptimal response to exclusive enteral nutrition (EEN) in some children with Crohn disease (CD) is explained by poor compliance. The present study measured faecal gluten immunogenic peptides (GIP), a biomarker of gluten intake, in 45 children (3– 17 years) with CD, and explored associations with faecal calprotectin (FC) levels at 33 and 54 days of EEN. FC decreased in patients with undetectable GIP at both 33 and 54 days of EEN (mean decrease, 33 days: −743 mg/kg, 54 days: –1043 mg/kg, P < 0.001) but not in patients who had detectable levels. At EEN completion, patients with undetectable GIP had a lower FC by 717 mg/kg compared with patients with a positive GIP result (P = 0.042) and demonstrated a greater decline from baseline FC (–69% vs +5%, P = 0.011). Poorer response to EEN is explained in part by diminished compliance. Faecal GIP might be useful as proxy biomarker of EEN compliance.
Acute and Posttraumatic Stress in Family Members of Children With a Prolonged Stay in a PICU: Secondary Analysis of a Randomized Trial
Authors: Erçin-Swearinger Hazal , Lindhorst Taryn , Curtis J. Randall , Starks Helene , Doorenbos Ardith Z.
Published: February 2022

OBJECTIVES:

To identify the prevalence of screening criteria for acute and posttraumatic stress disorders (PTSDs) and stress symptoms among family members of children in the PICU for more than 8 days and examine risk factors for stress symptoms.

DESIGN:

Secondary analysis of data from a randomized trial of a palliative care intervention conducted between 2010 and 2014.

SETTING:

An urban pediatric hospital in Seattle, WA.

SUBJECTS:

The sample included 377 family members of 220 children.

INTERVENTIONS:

Family Communication Study.

MEASUREMENTS AND MAIN RESULTS:

Outcomes were symptom scores and diagnostic screening criteria for acute stress disorder (ASD) and PTSD. Predictors included demographic- and admission-related characteristics and hypothesized risk factors for developing stress-related mental health disorders. The mean score for acute stress symptoms during the ICU stay was 40.3 (sd = 13.8) and 59 family members in total met diagnostic screening criteria for ASD during hospitalization (15.6%). At 3-month follow-up, the mean score for posttraumatic stress symptoms was 30.8 (sd = 12.9) and 52 family members met diagnostic criteria for PTSD (13.8%). Factors associated with meeting ASD screening criteria were unplanned admission and poorer family relationships. Factors associated with PTSD symptoms and diagnosis were longer length of stay, meeting ASD criteria during admission, child’s death, and less perceived social support.

CONCLUSIONS:

Meeting screening criteria for PTSD was associated with demographic, length of stay, and family relationships among family members of seriously ill children. PTSD outcomes were higher among family members whose child died. This study helps identify risk factors that can be used to target needed psychosocial screening, monitoring and support during and following a prolonged PICU admission, as well as family-centered interventions and supportive bereavement intervention for the family members of a deceased child.
Review and Evaluation of mHealth Apps in Solid Organ Transplantation: Past, Present, and Future
Authors: Fleming James N. , Pollock McLean D. , Taber David J. , McGillicuddy John W. , Diamantidis Clarissa J. , Docherty Sharron L. , Chambers Eileen T.
Published: February 2022

Background.

With the rapid and widespread expansion of smartphone availability and usage, mobile health (mHealth) has become a viable multipurpose treatment medium for the US healthcare system.

Methods.

The purpose of this review is to identify posttransplant mHealth applications that support patient self-management or a patient–provider relationship and aim to improve clinical outcomes. The interventions were then analyzed and evaluated to identify current gaps and future needs of mHealth apps in solid organ transplantation.

Results.

The authors found a nearly universal dichotomy between perceived utility and sustained use, with most studies demonstrating significant attrition during the course of the intervention. In addition, interoperability continues to be a challenge.

Conclusions.

The authors present potential methods for mitigating the identified barriers and gaps in mHealth apps for solid organ transplant recipients.
Overview of tau PET molecular imaging
Authors: Cassinelli Petersen Gabriel , Roytman Michelle , Chiang Gloria C. , Li Yi , Gordon Marc L. , Franceschi Ana M.
Published: February 2022

Purpose of review

This article reviews tau PET imaging with an emphasis on first-generation and second-generation tau radiotracers and their application in neurodegenerative disorders, including Alzheimer's disease and non-Alzheimer's disease tauopathies.

Recent findings

Tau is a critical protein, abundant in neurons within the central nervous system, which plays an important role in maintaining microtubules by binding to tubulin in axons. In its abnormal hyperphosphorylated form, accumulation of tau has been linked to a variety of neurodegenerative disorders, collectively referred to as tauopathies, which include Alzheimer's disease and non-Alzheimer's disease tauopathies [e.g., corticobasal degeneration (CBD), argyrophilic grain disease, progressive supranuclear palsy (PSP), and Pick's disease]. A number of first-generation and second-generation tau PET radiotracers have been developed, including the first FDA-approved agent [18F]-flortaucipir, which allow for in-vivo molecular imaging of underlying histopathology antemortem, ultimately guiding disease staging and development of disease-modifying therapeutics.

Tau PET is an emerging imaging modality in the diagnosis and staging of tauopathies.
The effect of the degree and location of danger in traffic hazard perception: an ERP study
Authors: Li Haoze , Chang Ruosong , Sui Xue
Published: February 2022

Objectives

The aim of this study is to explore the influence of the degree and location of the danger of traffic hazards on the neural reaction process.

Methods

26 automobile drivers were asked to look at the pictures and press buttons on the pictures unrelated to traffic. Electroencephalography responses to traffic-related images were recorded and analyzed.

Results

It was found that danger in the central visual region induced a larger amplitude of the N100 component than in the peripheral visual region and the trend of different hazard levels was consistent. The danger in the central visual area also induced a larger amplitude of the P200 component than in the peripheral vision area. In addition, when the danger appeared in the central visual area (0°), the P200 amplitude induced by the low-hazard situation was smaller than that of the high-hazard situation. When the danger appeared in the peripheral visual area (7°), the P200 amplitude induced by the low-hazard situation was larger than that of the high-hazard situation. Finally, the presence of danger evoked a larger amplitude of the P300 component in the peripheral visual area than in the central visual area and the P300 amplitude was larger in the low-hazard situation than in the high-hazard situation.

Conclusions

The results suggest that hazards are more easily processed in the central visual area during the early stage of automatic perception. In the later hazard evaluation stage, the hazard in the central visual area and the high-hazard situation were more easily processed.
Genome-wide association studies-supported rs12966547 variant of the long noncoding RNA LOC105372125 is significantly associated with susceptibility to schizophrenia and bipolar disorder in Han Chinese women
Authors: Zhao Zhi , Zhu Lulu , Wu Xulong , Chen Qiang , Xu Bingyi , Yang Jialei , Guo Xiaojing , Su Li
Published: February 2022

Objective

Genome-wide association studies have found that rs12966547 polymorphism was associated with susceptibility to schizophrenia in European populations. Recent studies showed that a genetic overlap may exist in schizophrenia and bipolar disorder. Here, we analyzed the associations between LOC105372125 rs12966547 polymorphism and schizophrenia and bipolar disorder in the Han Chinese population.

Methods

Our study recruited 548 schizophrenia patients, 512 bipolar disorder patients, and 598 healthy controls. Genotyping of rs12966547 were performed using the Sequenom MassARRAY platform.

Results

A significant association between rs12966547 polymorphism and susceptibility to bipolar disorder was observed after adjusting for sex and age (additive model: P

adj
= 0.040, recessive model: P

adj
= 0.044). However, no significant association was found between rs12966547 polymorphism and schizophrenia risk (all P > 0.05). In the analysis of gender, rs12966547 polymorphism was significantly associated with bipolar disorder (additive model: P

adj
= 0.027) and schizophrenia (dominant model: P

adj
= 0.039) in women. However, no significant association was found between rs12966547 polymorphism and the risk of bipolar disorder or schizophrenia in men (all P
adj > 0.05).

Conclusions

Polymorphism of rs12966547 on the long noncoding RNA LOC10537215 are a shared genetic variant of schizophrenia and bipolar disorder in Han Chinese women.
Neobacillus kokaensis sp. nov., isolated from soil
Authors: Yuki Kensuke , Matsubara Hirotaka , Yamaguchi Shotaro
Published: February 2022

A Gram-stain-variable, motile, aerobic, spore-forming, rod-shaped bacterium, designated as strain LOB 377T, was isolated from soil sampled in Koka County (now Konan City), in Shiga Prefecture, Japan. To determine its taxonomic position, the bacterium was evaluated by a polyphasic approach based on genomic, phenotypic and chemotaxonomic tests. From phylogenetic analysis based on 16S rRNA gene sequences, strain LOB 377T (LC570960) was revealed to have the highest similarity to the type strain of

Neobacillus mesonae

FJAT-13985T (9.1 %). The average nucleotide identity and digital DNA–DNA hybridization values between both strains based on whole genome sequences were 84.1 and 42.8 %, respectively, which were below the recommended thresholds. The strain grew at 15–45 °C (optimum, 25–37 °C), at pH 5.5–9.5 (optimum, pH 6.5–8.5) and with 1.0–2.0 % (w/v) NaCl. Cell-wall peptidoglycan of the strain contained meso-diaminopimelic acid. The major menaquinone was menaquinone-7. Predominant fatty acids were iso-C15 : 0, anteiso-C15 : 0, iso-C14 : 0 and C16 : 1 ω11c. The polar lipids were phosphatidylglycerol, unidentified phospholipid and unidentified aminophospholipid. The DNA G+C content was 40.5 mol%. According to the genomic, phenotypic and chemotaxonomic results, strain LOB 377T represents a novel species in the genus

Neobacillus

, for which the name Neobacillus kokaensis sp. nov. is proposed. The type strain is LOB 377T (=ATCC 31382T=NBRC 114637T=DSM 113418T).
Companilactobacillus salsicarnum Zheng et al. 2020 is a later heterotypic synonym of Companilactobacillus mishanensis (Wei and Gu 2019) Zheng et al. 2020
Authors: Jiang Cheng-Shan , Gu Chun Tao
Published: February 2022

Lactobacillus mishanensis

was isolated from Chinese traditional pickle, and validly published in October 2019.

Lactobacillus salsicarnum

was isolated from salami products in Germany, and effectively described in November 2019. In the reclassification of the genus

Lactobacillus

by Zheng et al. in April 2020,

L. mishanensis

was transferred to

Companilactobacillus

as

Companilactobacillus mishanensis

comb. nov., and

Companilactobacillus salsicarnum

was proposed as a novel species. In the present study, the relationship between

C. mishanensis

and

C. salsicarnum

was evaluated. The type strains of

C. mishanensis

and

C. salsicarnum

shared 100 % 16S rRNA gene sequence similarity, 100 % pheS sequence similarity, 99.9 % rpoA sequence similarity, a 99.9 % average nucleotide identity value and a 99.5 % digital DNA–DNA hybridization value, indicating that they represent the same species. On the basis of the results presented here, we propose

C. salsicarnum

[Zheng et al. 2020] as a later heterotypic synonym of

C. mishanensis

(Wei and Gu 2019) [Zheng et al. 2020].
Transcriptional background effects on a tumor driver gene in a transgenic medaka melanoma model
Authors: Abdulsahib Shahad , Boswell William , Boswell Mikki , Savage Markita , Schartl Manfred , Lu Yuan
Published: February 2022

The Xiphophorus melanoma receptor kinase gene, xmrk, is a bona fide oncogene driving melanocyte tumorigenesis of Xiphophorus fish. When ectopically expressed in medaka, it not only induces development of several pigment cell tumor types in different strains of medaka, but also induces different tumor types within the same animal, suggesting its oncogenic activity has a transcriptomic background effect. Although the central pathways that xmrk utilizes to lead to melanomagenesis are well documented, genes and genetic pathways that modulate the oncogenic effect, and alter the course of disease have not been studied so far. To understand how the genetic networks between different histocytes of xmrk-driven tumors are composed, we isolated two types of tumors, melanoma and xanthoerythrophoroma, from the same xmrk transgenic medaka individuals, established the transcriptional profiles of both xmrk-driven tumors, and compared (1) genes that are co-expressed with xmrk in both tumor types, and (2) differentially expressed genes and their associated molecular functions, between the two tumor types. Transcriptomic comparisons between the two tumor types show melanoma and xanthoerythrophoroma are characterized by transcriptional features representing varied functions, indicating distinct molecular interactions between the driving oncogene and the cell type-specific transcriptomes. Melanoma tumors exhibited gene signatures that are relevant to proliferation and invasion while xanthoerythrophoroma tumors are characterized by expression profiles related metabolism and DNA repair. We conclude the transcriptomic backgrounds, exemplified by cell-type specific genes that are downstream of xmrk effected signaling pathways, contribute the potential to change the course of tumor development and may affect overall tumor outcomes.
Influenza vaccination and single cell multiomics reveal sex dimorphic immune imprints of prior mild COVID-19
Authors: Sparks Rachel , Lau William W. , Liu Can , Han Kyu Lee , Vrindten Kiera L. , Sun Guangping , Cox Milann , Andrews Sarah F. , Bansal Neha , Failla Laura E. , Manischewitz Jody , Grubbs Gabrielle , King Lisa R. , Koroleva Galina , Leimenstoll Stephanie , Snow LaQuita ,   OP11 Clinical Staff, Chen Jinguo , Tang Juanjie , Mukherjee Amrita , Sellers Brian A. , Apps Richard , McDermott Adrian B. , Martins Andrew J. , Bloch Evan M. , Golding Hana , Khurana Surender , Tsang John S.
Published: February 2022

Viral infections can have profound and durable functional impacts on the immune system. There is an urgent need to characterize the long-term immune effects of SARS-CoV-2 infection given the persistence of symptoms in some individuals and the continued threat of novel variants. Here we use systems immunology, including longitudinal multimodal single cell analysis (surface proteins, transcriptome, and V(D)J sequences) from 33 previously healthy individuals after recovery from mild, non-hospitalized COVID-19 and 40 age- and sex-matched healthy controls with no history of COVID-19 to comparatively assess the post-infection immune status (mean: 151 days after diagnosis) and subsequent innate and adaptive responses to seasonal influenza vaccination. Identification of both sex-specific and -independent temporally stable changes, including signatures of T-cell activation and repression of innate defense/immune receptor genes (e.g., Toll-like receptors) in monocytes, suggest that mild COVID-19 can establish new post-recovery immunological set-points. COVID-19-recovered males had higher innate, influenza-specific plasmablast, and antibody responses after vaccination compared to healthy males and COVID-19-recovered females, partly attributable to elevated pre-vaccination frequencies of a GPR56 expressing CD8+ T-cell subset in male recoverees that are “poised” to produce higher levels of IFNγ upon inflammatory stimulation. Intriguingly, by day 1 post-vaccination in COVID-19-recovered subjects, the expression of the repressed genes in monocytes increased and moved towards the pre-vaccination baseline of healthy controls, suggesting that the acute inflammation induced by vaccination could partly reset the immune states established by mild COVID-19. Our study reveals sex-dimorphic immune imprints andin vivofunctional impacts of mild COVID-19 in humans, suggesting that prior COVID-19, and possibly respiratory viral infections in general, could change future responses to vaccination and in turn, vaccines could help reset the immune system after COVID-19, both in an antigen-agnostic manner.
COVID-19 vaccine incentive scheduling using an optimally controlled reinforcement learning model
Authors: Stuckey K. , Newton P.K.
Published: February 2022

We model Covid-19 vaccine uptake as a reinforcement learning dynamic between two populations: the vaccine adopters, and the vaccine hesitant. Using data available from the Center for Disease Control (CDC), we calculate a payoff matrix governing the dynamic interaction between these two groups and show they are playing a Hawk-Dove evolutionary game with an internal evolutionarily stable Nash equilibrium (the asymptotic percentage of vaccinated in the population). We then ask whether vaccine adoption can be improved by implementing dynamic incentive schedules that reward/punish the vaccine hesitant, and if so, what schedules are optimal and how effective are they likely to be? When is the optimal time to start an incentive program, and how large should the incentives be? By using a tailored replicator dynamic reinforcement learning model together with optimal control theory, we show that well designed and timed incentive programs can improve vaccine uptake by shifting the Nash equilibrium upward in large populations, but only so much, and incentive sizes above a certain threshold show diminishing returns.
Development of Parkinson’s disease and its relationship with incidentally-discovered white matter disease and covert brain infarction in a real world cohort
Authors: Kent David M. , Leung Lester Y. , Puttock Eric J. , Wang Andy Y. , Luetmer Patrick H. , Kallmes David F. , Nelson Jason , Fu Sunyang , Zheng Chengyi , Liu Hongfang , Noyce Alastair J. , Chen Wansu
Published: February 2022

Importance

While a link between cerebrovascular disease and cerebrovascular risk factors and subsequent development of Parkinson’s disease has been suggested, the association between covert cerebrovascular disease and subsequent Parkinson’s disease has not been rigorously examined.

Objective

To examine the relationship between covert cerebrovascular disease, comprised of covert brain infarction and white matter disease, discovered incidentally in routine care and subsequent Parkinson’s disease.

Design

Enrollment in this observational cohort study occurred between 2009 and 2019.

Setting

Kaiser Permanente Southern California health system.

Participants

Patients were ≥50 years old and received neuroimaging for a non-stroke indication.

Exposure

Incidental covert brain infarction and white matter disease identified by natural language processing of neuroimaging reports. Natural language processing also classified white matter disease severity.

Main Outcomes

Parkinson’s disease.

Results

230,062 patients were included with a total of 980,772 person-years of follow-up and a median follow-up time of 3.72 years. 1,941 cases of Parkinson’s disease were identified, with a median time-to-event of 2.35 (IQR 0.90 to 4.58) years. Covert cerebrovascular disease was identified in 70,592 (30.68%) patients, 10,622 (4.62%) with covert brain infarction and 65,814 (28.61%) with white matter disease. After adjustment for known risk factors, white matter disease was found to be associated with Parkinson’s disease, with an adjusted hazard ratio of 1.67 (1.44, 1.93) for patients <70 years and 1.33 (1.18, 1.50) for those ≥70 years. Greater severity of white matter disease was associated with an increased incidence of Parkinson’s disease per 1000 person-years, from 1.52 (1.43, 1.61) in patients without white matter disease to 4.90 (3.86, 6.13) in those with severe white matter disease. Findings were robust when more specific definitions of Parkinson’s disease were used. Covert brain infarction was not associated with Parkinson’s disease (adjusted hazard ratio=1.05 [0.88, 1.24]).

Conclusions and Relevance

White matter disease was associated with subsequent Parkinson’s disease, an association strengthened with younger age and increased white matter disease severity. Covert brain infarction did not appear to be associated with subsequent Parkinson’s disease.
Activation and inhibition of the C-terminal kinase domain of p90 ribosomal S6 kinases
Authors: Fruergaard Marlene Uglebjerg , Fælled Nielsen Christine Juul , Kjeldsen Cecilia Rosada , Iversen Lars , Andersen Jacob Lauwring , Nissen Poul
Published: February 2022

The p90 ribosomal S6 kinases (RSKs) contain two distinct catalytic kinase domains, the N-terminal and C-terminal kinase domains (NTKD and CTKD, respectively). The activation of CTKD is regulated by phosphorylation by extracellular signal-regulated kinase (ERK1/2) and an autoinhibitory αL helix. Through a mutational seriesin vitroof the RSK CTKDs, we found a complex mechanism lifting autoinhibition that led us to design constitutively active RSK CTKDs. These are based on a phosphomimetic mutation and a C-terminal truncation (e.g. RSK2 T577E D694*) where a high activity in absence of ERK phosphorylation is obtained. Using these constructs, we characterize IC50values of ATP-competitive inhibitors and provide a setup for determining specificity constants (kinact/Ki) of covalent CTKD inhibitors.
Mesoamerican Nephropathy in Central Panama
Authors: Courville Karen , Bustamante Norman , Hurtado Bárbara , Pecchio Maydelin , Rodríguez Clarissa , Núñez-Samudio Virginia , Landires Iván
Published: February 2022

Background

In the last three decades, there has been an increase in the frequency of patients diagnosed with chronic kidney disease of nontraditional causes (CKDnt) in the Mesoamerican region. A region with an increased frequency of patients with chronic kidney disease (CKD) has been identified in central Panama. The present study aims to characterize the clinical presentation of patients with CKDnt in an understudied population of the central region of Panama and compare them with patients with traditional CKD (CKDt).

Methods

A retrospective descriptive study was conducted in a nephrology reference hospital in the central provinces of Herrera and Los Santos, comparing a group of 15 patients with CKDnt to 91 patients with CKDt. Sociodemographic variables, personal history, laboratory parameters, and of renal ultrasound were compared.

Results

CKDnt is more common among relatively younger male patients who engage in strenuous work activities at high temperatures. CKDnt is not associated with type 2 diabetes mellitus or chronic hypertension, as it is the case in patients with CKDt. Renal atrophy and hyperuricemia are significant clinical markers of CKDnt.

Conclusion

To our knowledge, this is the first study in Panama and one of the few in Central America and the world to address the clinical presentation of patients with CKDnt compared to patients with CKDt. Because CKDnt remains asymptomatic for a long time, early detection is important, and efforts should be directed at halting disease progression at an early stage. Current evidence can also inform policies addressing occupational and environmental risk factors associated with CKDnt.
At Least Three Doses of Leading Vaccines Essential for Neutralisation of SARS-CoV-2 Omicron Variant
Authors: Singanallur Nagendrakumar B , van Vuren Petrus Jansen , McAuley Alexander J , Bruce Matthew P , Kuiper Michael J , Gwini Stella M , Riddell Shane , Goldie Sarah , Drew Trevor W , Blasdell Kim R , Tachedjian Mary , Mangalaganesh Shruthi , Chahal Simran , Caly Leon , Druce Julian D , Juno Jennifer A , Kent Stephen J , Wheatley Adam K , Vasan Seshadri S
Published: February 2022

Plasma samples taken at different time points from donors who received either AstraZeneca (Vaxzevria) or Pfizer (Comirnaty) or Moderna (Spikevax) coronavirus disease-19 (COVID-19) vaccine were assessed in virus neutralization assays against Delta and Omicron variants of concern and a reference isolate (VIC31). With the Pfizer vaccine there was 6-8-fold reduction in 50% neutralizing antibody titres (NT50) against Delta and VIC31 at 6 months compared to 2 weeks after the second dose; followed by 25-fold increase at 2 weeks after the third dose. Neutralisation of Omicron was only consistently observed 2 weeks after the third dose, with most samples having titres below the limit of detection at earlier timepoints. Moderna results were similar to Pfizer at 2 weeks after the second dose, while the titres for AstraZeneca samples derived from older donors were 7-fold lower against VIC31 and below the limit of detection against Delta and Omicron. Age and gender were not found to significantly impact our results. These findings indicate that vaccine matching may be needed, and that at least a third dose of these vaccines is necessary to generate sufficient neutralising antibodies against emerging variants of concern, especially Omicron, amidst the challenges of ensuring vaccine equity worldwide.
Pneumococcal within-host diversity during colonisation, transmission and treatment
Authors: Tonkin-Hill Gerry , Ling Clare , Chaguza Chrispin , Salter Susannah J , Hinfonthong Pattaraporn , Nikolaou Elissavet , Tate Natalie , Pastusiak Andrzej , Turner Claudia , Chewapreecha Claire , Frost Simon DW , Corander Jukka , Croucher Nicholas J , Turner Paul , Bentley Stephen D
Published: February 2022

Characterising the genetic diversity of pathogens within the host promises to greatly improve surveillance and reconstruction of transmission chains. For bacteria, it also informs our understanding of inter-strain competition, and how this shapes the distribution of resistant and sensitive bacteria. Here we study the genetic diversity of Streptococcus pneumoniae within individual infants and their mothers by deep sequencing whole pneumococcal populations from longitudinal nasopharyngeal samples. We demonstrate deep sequencing has unsurpassed sensitivity for detecting multiple colonisation, doubling the rate at which highly invasive serotype 1 bacteria were detected in carriage compared to gold-standard methods. The greater resolution identified an elevated rate of transmission from mothers to their children in the first year of the child’s life. Comprehensive treatment data demonstrated infants were at an elevated risk of both the acquisition, and persistent colonisation, of a multidrug resistant bacterium following antimicrobial treatment. Some alleles were enriched after antimicrobial treatment, suggesting they aided persistence, but generally purifying selection dominated within-host evolution. Rates of co-colonisation imply that in the absence of treatment, susceptible lineages outcompeted resistant lineages within the host. These results demonstrate the many benefits of deep sequencing for the genomic surveillance of bacterial pathogens.
Cobalamin riboswitches are broadly sensitive to corrinoid cofactors to enable an efficient gene regulatory strategy
Authors: Kennedy Kristopher J. , Widner Florian J. , Sokolovskaya Olga M. , Innocent Lina V. , Procknow Rebecca R. , Mok Kenny C. , Taga Michiko E.
Published: February 2022

In bacteria, many essential metabolic processes are controlled by riboswitches, gene regulatory RNAs that directly bind and detect metabolites. Highly specific effector binding enables riboswitches to respond to a single biologically relevant metabolite. Cobalamin riboswitches are a potential exception because over a dozen chemically similar but functionally distinct cobalamin variants (corrinoid cofactors) exist in nature. Here, we measured cobalamin riboswitch activity in vivo using a Bacillus subtilis fluorescent reporter system and found that among 38 tested riboswitches, a subset responded to corrinoids promiscuously, while others were semi-selective. Analyses of chimeric riboswitches and structural models indicate that, unlike other riboswitch classes, cobalamin riboswitches indirectly differentiate among corrinoids by sensing differences in their structural conformation. This regulatory strategy aligns riboswitch-corrinoid specificity with cellular corrinoid requirements in a B. subtilis model. Thus, bacteria can employ broadly sensitive riboswitches to cope with the chemical diversity of essential metabolites.
Hormone levels increase in response to video playback in the Siamese fighting fish
Authors: Alex Deepa , Cardoso Sara D. , Ramos Andreia , Gonçalves David
Published: February 2022

The mechanisms of action of hormones regulating aggression in fish remain poorly understood. One possibly confounding variable is the lack of standardization in the type of stimuli used to elicit aggression. The presentation of controlled stimuli in videos, a.k.a. video playback, can provide better control of the fight components. However, this technique has produced conflicting results in animal behaviour studies and needs to be carefully validated. Here, the response of male Betta splendens to a matched for size conspecific fighting behind a one-way mirror presented live or through video playback was compared. Despite their non-interactive nature, both stimuli elicited a strong aggressive response by focal fish, which started with stereotypical threat displays and progressed to overt attacks. Overall, the frequency and duration of aggressive behaviours and swimming activity were similar towards live and video stimuli. Post-fight plasma levels of the androgen 11-ketotestosterone were elevated as compared to controls, regardless of the type of stimuli. Cortisol also increased in response to the video images, as previously described for interactive live fights in this species. The study shows for the first time in a fish a robust endocrine response to video stimuli and supports the use of this technique for researching aggressive behaviour in B. splendens.
The impact of malaria-protective red blood cell polymorphisms on parasite biomass in children with severe Plasmodium falciparum malaria
Authors: Uyoga S , Watson JA , Wanjiku P , Rop JC , Makale J , Macharia AW , Kariuki SN , Nyutu GM , Shebe M , Mosobo M , Mturi N , Rockett KA , Woodrow CJ , Dondorp AM , Maitland K , White NJ , Williams TN
Published: February 2022

Severe falciparum malaria is a major cause of preventable child mortality in sub-Saharan Africa. The sequestration of parasitized erythrocytes in the microvasculature of vital organs is a central pathophysiological feature. The plasma concentration of the parasite protein P. falciparum Histidine-Rich Protein 2 (PfHRP2) has diagnostic and prognostic value in severe malaria. In the current study we investigate the potential use of plasma PfHRP2 and the sequestration index (the ratio of plasma PfHRP2 to circulating parasites) as quantitative traits in the conduct of case-only genetic association studies of severe malaria. We demonstrate the utility of this approach using data from over 2,000 Kenyan children with severe malaria, genotyped for 14 major candidate genes that were found to be associated with protection against severe malaria in previous studies. We show that PfHRP2 is a more informative quantitative trait than peripheral parasite density, and that polymorphisms in four major red cell genes (the βS sickle mutation in HBB, the blood group mutation O in ABO, the α-thalassaemia mutation in HBA, and the Dantu blood group mutation in GYP) are associated with substantially lower concentrations of plasma PfHRP2 at admission. Further, the effect sizes we observed were considerably larger than those relating to peripheral parasite density. An unexpected outlier was the rs1541255 A>G polymorphism in ATP2B4 for which we saw higher plasma PfHRP2 concentrations, lower parasite densities and a higher sequestration index. We provide testable hypotheses for how this might be explained in the context of this specific protective allele.
Do we parse the background into separate streams in the cocktail party?
Authors: Szalárdy Orsolya , Tóth Brigitta , Farkas Dávid , Orosz Gábor , Winkler István
Published: February 2022

Abstract

In the cocktail party situation, people with normal hearing usually follow a single speaker among multiple concurrent ones. However, there is no agreement in the literature as to whether the background is segregated into multiple streams/speakers. The current study varied the number of concurrent speech streams and investigated target detection and memory for the contents of a target stream as well as the processing of distractors. A male-spoken target stream was either presented alone (single-speech), together with one male-spoken (one-distractor), or a male- and a female-spoken distractor (two-distractor). Behavioral measures of target detection and content tracking performance as well as target- and distractor detection related ERPs were assessed. We found that the detection sensitivity and the target N2b amplitude decreased whereas the P3b amplitude increased from the single-speech to the concurrent speech streams conditions. Importantly, the behavioral distractor effect differed between the conditions with one- vs. two-distractor (distraction by the female speaker was lower than that of the male speaker in either condition) and the target N2b elicited in the presence of two distractors was significantly smaller than that elicited in the presence of one distractor. Further, the voltage in the N2b time window significantly differed between the one- and two-distractor conditions for the same (M2) speaker. These results show that speech processing was different in the presence of one vs. two distractors, and thus, the current data suggest that the two background speech streams were segregated from each other.
Gradients of orientation, composition and hydration of proteins for efficient light collection by the cornea of the horseshoe crab
Authors: Spaeker Oliver , Taylor Gavin , Wilts Bodo , Slabý Tomáš , Abdel-Rahman Mohamed Ashraf Khalil , Scoppola Ernesto , Schmitt Clemens NZ , Sztucki Michael , Liu Jiliang , Bertinetti Luca , Wagermaier Wolfgang , Scholtz Gerhard , Fratzl Peter , Politi Yael
Published: February 2022

The lateral eyes of the horseshoe crab, Limulus polyphemus, are the largest compound eyes within recent Arthropoda. While this visual system has been extensively described before, the precise mechanism allowing vision has remained controversial. Correlating quantitative refractive index (RI) mapping and detailed structural analysis, we demonstrate how gradients of RI in the cornea result from the hierarchical organization of chitin-protein fibers, heterogeneity in protein composition and bromine doping, as well as spatial variation in water content. Combining the realistic cornea structure and measured RI gradients with full-wave optical modelling and ray-tracing approaches, we show that the light collection mechanism depends on both refraction-based graded index (GRIN) optics and total internal reflection. The optical properties of the cornea are governed by different mechanisms at different hierarchical levels, demonstrating the remarkable versatility of arthropod cuticle.

One-sentence summary

Structural hierarchy and protein hydration determine the optical performance of the cornea of L. polyphemus.
Monomeric α-Synuclein activates the Plasma Membrane Calcium Pump
Authors: Kowalski Antoni , Betzer Cristine , Larsen Sigrid Thirup , Gregersen Emil , Newcombe Estella Anne , Bermejo Montaña Caballero , Langkilde Annette Eva , Kragelund Birthe Brandt , Jensen Poul Henning , Nissen Poul
Published: February 2022

Alpha-synuclein (aSN) is a membrane-associated and intrinsically disordered protein, well-known for pathological aggregation in neurodegeneration. The physiological function of aSN however is disputed. Pull-down experiments have pointed to plasma membrane Ca2+-ATPase (PMCA) as a potential interaction partner. From proximity ligation assays we find that aSN and PMCA colocalize at neuronal synapses, and that calcium expulsion is activated by aSN and PMCA. From PMCA activity studies we show that soluble, monomeric aSN activates PMCA at par with CaM, yet independent of the autoinhibitory domain of PMCA, but highly dependent on acidic phospholipids and membrane-anchoring of aSN. On PMCA, the key site is mapped to the acidic lipid-binding site, located within a disordered PMCA-specific loop region connecting the cytosolic A domain and transmembrane segment 3. Our studies point towards a novel physiological role of monomeric aSN as a stimulator of calcium clearance in neurons through activation of PMCA.
Retinoic acid-induced protein 14 controls dendritic spine dynamics associated with depressive-like behaviors
Authors: Kim Soo Jeong , Woo Youngsik , Kim Hyun Jin , Goo Bon Seong , Nhung Troung Thi My , Lee Seol-Ae , Suh Bo Kyoung , Mun Dong Jin , Kim Joung-Hun , Park Sang Ki
Published: February 2022

Dendritic spines are the central postsynaptic machinery that determines synaptic function. The F-actin within dendritic spines regulates their dynamic formation and elimination. Rai14 is an F-actin-regulating protein with a membrane-shaping function. Here, we identified the roles of Rai14 for the regulation of dendritic spine dynamics associated with stress-induced depressive-like behaviors. Rai14-deficient neurons failed to maintain a proper dendritic spine density in the Rai14+/- mouse brain, resulting in impaired functional synaptic activity. Rai14 was protected from degradation by complex formation with Tara, and accumulated in the dendritic spine neck, thereby enhancing spine maintenance. Concurrently, Rai14 deficiency in mice altered gene expression profile relevant to depressive conditions and increased depressive-like behaviors. Moreover, Rai14 expression was reduced in the prefrontal cortex of the mouse stress model, which was blocked by antidepressant treatment. Thus, we propose that Rai14-dependent regulation of dendritic spines may underlie the plastic changes of neuronal connections relevant to depressive-like behaviors.
A Facile Method to Produce N-Terminally Truncated α-Synuclein
Authors: Thrush Rebecca J. , Vadukul Devkee M. , Aprile Francesco A.
Published: February 2022

α-Synuclein is a key protein of the nervous system, which regulates the release and recycling of neurotransmitters in the synapses. It is also involved in several neurodegenerative conditions, including Parkinson’s disease and Multiple System Atrophy, where it forms toxic aggregates. The N-terminus of α-synuclein is of particular interest as it has been linked to both the physiological and pathological functions of the protein and undergoes post-translational modification. One such modification, N-terminal truncation, affects the aggregation propensity of the protein in vitro and is also found in aggregates from patients’ brains. To date, our understanding of the role of this modification has been limited by the many challenges of introducing biologically relevant N-terminal truncations with no overhanging starting methionine. Here, we present a method to produce N-terminally truncated variants of α-synuclein that do not carry extra terminal residues. We show that our method can generate highly pure protein to facilitate the study of this modification and its role in physiology and disease. Thanks to this method, we have determined that the first six residues of α-synuclein play an important role in the formation of the amyloids.
c-Src-dependent phosphorylation of Mfn2 regulates endoplasmic reticulum-mitochondria tethering
Authors: Zhang Peng , Ford Kara , Sung Jae Hwi , Suzuki Yuta , Landherr Maria , Moeller Jacob , Chaput Isabel , Polina Iuliia , Kelly Madeline , Nieto Bridget , Tachibana Toshiaki , Kusakari Yoichiro , Cypress Michael W. , Drenkova Kamelia , Adaniya Stephanie M. , Mishra Jyotsna , Mende Ulrike , Jhun Bong Sook , O-Uchi Jin
Published: February 2022

Contact sites between the mitochondria and endoplasmic reticulum (ER) regulate the exchange of lipids, Ca2+, and reactive oxygen species (ROS) across the two organelles. Mitofusin 2 (Mfn2) has been identified as one of the major components tethering these two organelles together. Several post-translational modifications (PTMs) of Mfn2 have been shown to modulate canonical (i.e., mitochondrial fusion) and non-canonical Mfn2 functions, such as mitophagy and activation of ER stress signaling. However, there is little information about whether any PTMs can regulate mitochondrial and ER tethering. Basal tyrosine phosphorylation of Mfn2 was detected by mass spectroscopy, but it is unknown whether Mfn2 is a substrate of mitochondria-localized tyrosine kinases. Here, we show that mitochondria-localized c-Src can phosphorylate the C-terminal tail of Mfn2, which decreases the distance between the mitochondria and ER and facilitates Ca2+transfer from the ER to mitochondria, followed by changes in ROS generation and mitochondrial bioenergetics. Our findings suggest that tyrosine phosphorylation of Mfn2 may uniquely work to fine-tune ER-mitochondrial Ca2+transport under physiological and pathological conditions.
Network profiling of hepatocellular carcinoma targets for evidence based pharmacological approach to improve clinical efficacy
Authors: Manchukonda Bhavya , Kumar Arun HS
Published: February 2022

Introduction

Hepatocellular carcinoma (HCC) is the most prevalent malignancy of the liver with limited clinical efficacy of currently used drugs such as sorafenib. Hence in this study we assessed the network proteins of HCC targets to identify the target/s which can achieve optimal clinical efficacy.

Materials and Methods

The reported HCC targets and their network proteins were identified in the string database. The interactions of the network proteins based on the number of hydrogen bonds formed were evaluated using the chimera software and used to merit the network protein interactions. The merit of network protein interactions in clinical efficacy was assessed based on the expression pattern of the network proteins and corelating their targeting by sorafenib.

Results

22 potential HCC targets were identified along with their 152 unique network proteins. The following HCC targets; PDGFRB, IFNA2, VEGFR2, PD1, C-MET, RAR and IGF1R were observed to be among the top networks with the most number of hydrogen bond interactions between them. Among these, C-MET, RAR and IGF1R were significantly expressed in hepatocytes, making them relevant HCC targets. PD-1 and PD-L1, which are immune checkpoint regulators and hence used as part of immune therapy, were observed to form higher numbers of hydrogen bonds with HCC network proteins.

Conclusion

Our analysis suggest that selectively targeting IGF1R, C-MET and RAR in hepatocytes together with immunotherapy will result in optimal clinical efficacy in the management of HCC.
Granulocyte Colony Stimulating Factor causes cerebellar deficits and anxiety in a mouse model of CSF-1 receptor-related leukoencephalopathy
Authors: Biundo Fabrizio , Chitu Violeta , Tindi Jaafar , Burghardt Nesha S. , Shlager Gabriel G. L. , Ketchum Harmony C. , DeTure Michael A. , Dickson Dennis W. , Wszolek Zbignew K. , Khodakhah Kamran , Stanley E. Richard
Published: February 2022

Colony stimulating factor (CSF) receptor-1 (CSF-1R)-related leukoencephalopathy (CRL) is an adult-onset, demyelinating neurodegenerative disease caused by autosomal dominant mutations in CSF1R, modeled by the Csf1r+/- mouse. The expression of Csf2, encoding granulocyte- macrophage CSF (GM-CSF) and of Csf3, encoding granulocyte CSF (G-CSF), are elevated in both mouse and human CRL brains. While monoallelic targeting of Csf2 has been shown to attenuate many behavioral and histological deficits of mouse CRL, including cognitive dysfunction and demyelination, the contribution of Csf3 has not been explored. In this manuscript, we investigate the behavioral, electrophysiological and histopathological phenotypes of CRL mice following monoallelic targeting of Csf3. We show that Csf3 heterozygosity normalized the Csf3 levels in Csf1r+/- mouse brains and ameliorated anxiety-like behavior, motor coordination and social interaction deficits, but not their cognitive impairment. Consistent with this, Csf3 heterozygosity attenuated microglial activation in the cerebellum and in the ventral but not in the dorsal hippocampus. Csf3 heterozygosity also failed to prevent demyelination. Csf1r+/- mice exhibited altered synaptic activity in the deep cerebellar nuclei (DCN) associated with increased deposition of the complement factor C1q on glutamatergic synapses and with increased engulfment of glutamatergic synapses by DCN microglia. These phenotypes were significantly ameliorated by monoallelic deletion of Csf3. Our findings indicate that G-CSF and GM-CSF play non-overlapping roles in mouse CRL development and suggest that G-CSF could be an additional therapeutic target in CRL.
On the Mental Status of Stargazer Mice
Authors: Schirmer Catharina , Abboud Mark A , Lee Samuel C , Bass John S , Mazumder Arindam G , Kamen Jessica L , Krishnan Vaishnav
Published: February 2022

In many childhood-onset genetic epilepsies, seizures are accompanied by neurobehavioral impairments and motor disability. In the Stargazer mutant mouse, genetic disruptions of Cacng2 result in absence-like spike-wave seizures, cerebellar gait ataxia and vestibular dysfunction. Here, we combine videotracking and instrumented home-cage monitoring to resolve the neurobehavioral facets of the murine Stargazer syndrome. We find that despite their gait ataxia, stargazer mutants display horizontal hyperactivity and variable rates of repetitive circling behavior. While feeding rhythms, circadian or ultradian oscillations in activity are unchanged, mutants exhibit fragmented sleep bouts, atypical licking dynamics and lowered sucrose preference. Mutants also display an attenuated response to visual and auditory home-cage perturbations, together with profound reductions in voluntary wheel-running. Our results reveal that the seizures and ataxia of Stargazer mutants occur in the context of a more pervasive behavioral syndrome with elements of encephalopathy, repetitive behavior and anhedonia. These findings expand our understanding of the function of Cacng2/CACNG2, variants in which have been identified in patients with bipolar disorder and schizophrenia.