bluuebunny/crossref_metadata_2025 huggingface dataset:
Altered functional connectivity relates to motor performance deficits in bipolar but not unipolar depression
Authors: Marten Lara E. , Singh Aditya , Muellen Anna M. , Noack Sören M. , Kozyrev Vladislav , Schweizer Renate , Goya-Maldonado Roberto
Published: November 2021

Underpinnings of psychomotor deficits in bipolar and unipolar depression remain underexplored. Here, we hypothesize that motor performance deficits in patients may be partially explained by altered functional connectivities between hand primary motor cortex and posterior cingulate cortex with supplementary motor area.

95 participants between 18-65 years of age, including bipolar depressed, unipolar depressed, and sex-, age-, and education-matched healthy controls, participated in this observational study with two separate visits about five weeks apart, during which the patients received psychopharmacological treatment. Motor performance was measured with a finger-tapping-task and related to functional connectivity from individual seeds in hand primary motor cortex and posterior cingulate cortex as well as to the default mode and sensory motor networks from resting state functional MRI data.

79 participants (45.6% females, 21 bipolar depressed, 27 unipolar depressed and 31 healthy controls) were included in the analysis. Using a finger-tapping-task, the groups differed in motor performance (ANOVA factor “group” F(2,76) = 4.122; p = 0.020) and bipolar depressed but not unipolar depressed showed performance deficits compared to controls (post-hoc-test p = 0.023 and p = 0.158 respectively). Behavioral performance correlated with functional coupling of posterior cingulate cortex - supplementary motor area, but not with coupling of primary motor cortex - supplementary motor area at cluster-wise correction level p FWEc < 0.05. Correlation differences were seen in posterior cingulate cortex - supplementary motor area (healthy controls>bipolar depressed, unipolar depressed>bipolar depressed) at second visit and in primary motor cortex - supplementary motor area (bipolar depressed>unipolar depressed) at both visits at cluster-wise correction level p FWEc<0.05. Motor performance did not relate to functional coupling of sensory motor network - anterior (visit 1 p = 0.375, visit 2 p = 0.700) or - posterior (visit 1 p = 0.903, visit 2 p = 0.772) default mode network.

Motor performance deficits were seen exclusively in bipolar depressed and related to reduced posterior cingulate cortex - supplementary motor area functional connectivity at rest. Our results shed new light on a possible disruption in the anticorrelation between these regions, which seems fundamental for the preservation of motor skills. Given that nuisance factors were controlled for in the study, it is unlikely that the main results are biased by lefthanders, medication load, seed volumes, or differences in movements during MRI scanning. If these findings are confirmed, new targeted non-invasive interventions, such as repetitive transcranial magnetic stimulation, may be more effective against psychomotor deficits in bipolar depression, when aimed at modulating the supplementary motor area.
COVID-19 Clinical Characteristics and Outcomes in Children and Adolescents Hospitalized at the University Hospital of the West Indies, Jamaica in 2020-2021
Authors: Berry Crista-Lee Shahine , Melbourne-Chambers Roxanne Helene , Harrison Abigail Natalie , Anzinger Joshua James , Gordon-Johnson Kelly-Ann Maxorinthia , Deyde Varough Mohamed , Claire Christie Celia Dana
Published: November 2021

Background and Objectives

Multisystem inflammatory syndrome of children (MISC) carries a high attributable morbidity. We describe children aged <16 years hospitalised with COVID-19 and/or MISC, April 2020 to June 2021.

Methods

All were tested for SARS-CoV-2, infectious disease consultations performed, modified CDC criteria for MISC applied, charts reviewed and data analyzed.

Results

Among 79 consecutive children with SARS-CoV-2, 41(52%) were hospitalised; with median age 10.5 years; Afro-Caribbean ethnicity 40(98%); males 21(51%); SARS-CoV-2 RT-PCR positivity 26 (63%), IgG/IgM positivity 7(17%), community exposures 8 (20%). MISC-cases 18 (44%) vs. non-MISC 23(56%) had fever (94% vs. 30%; p<0.01), fatigue/lethargy (41% vs. 4%; p=0.004), rhinorrhoea (28% vs. 4%; p=0.035), elevated neutrophils (100% vs. 87%; p=0.024) and ≥4 abnormal inflammatory biomarkers 13 (72%). MISC-cases had ≥2 organ/systems (100% vs. 35%; p<0.01), including gastrointestinal (72% vs. 17%; p<0.01), haematological/coagulopathic (67% vs. 4%; p<0.01); dermatologic (56% vs. 0%; p<0.01), cardiac (17% vs. 0%; p=0.042) with Kawasaki Syndrome (44% vs. 0%; p<0.01) and pleural effusions (17% vs. 0%; p=0.042). MISC-cases were treated with intravenous immune gammaglobulin (14, 78%), aspirin (12, 68%), steroids (9, 50%) and intensive care with non-invasive ventilation (2, 11%). One (6%) with pre-morbid illness died, the remainder recovered.

Conclusion

MISC was treated successfully with intravenous gammaglobulin, steroids and/or aspirin in 94% before cardiopulmonary decompensation, or need for inotropes, vasopressors, or invasive ventilation.
Type II muscle fibre properties are not associated with balance recovery following large perturbations during walking in young and older adults
Authors: McCrum Christopher , Grevendonk Lotte , Schaart Gert , Moonen-Kornips Esther , Jörgensen Johanna. A. , Gemmink Anne , Meijer Kenneth , Hoeks Joris
Published: November 2021

Falls among older adults are often attributed to declining muscle strength with ageing. Associations between muscle strength and balance control have been reported, but the evidence for, and key mechanisms of resistance exercise in fall prevention are unclear. No studies have directly examined the relationship between muscle fibre characteristics and reactive balance control. Here, we address whether or not Type II muscle fibre characteristics associate with reactive balance during walking in young and older adults with varying muscle fibre type composition. We analyse muscle biopsy-derived fibre characteristics and stability during a treadmill-based walking perturbation (trip-like) task of healthy young adults, healthy, normally active older adults, trained older adults and physically impaired older adults. We find no significant associations between Type II muscle fibre properties and reactive balance during walking, indicating that practitioners and researchers should consider more than just the muscle tissue properties when assessing and intervening on fall risk.
Two Liberibacter Effectors Combine to Suppress Critical Innate Immune Defenses and Facilitate Huanglongbing Pathogenesis in Citrus
Authors: Basu Supratim , Huynh Loan , Zhang Shujian , Rabara Roel , Nguyen Hau , Valesquez Jeanette , Hao Guixia , Miles Godfrey , Shi Qingchun , Stover Ed , Gupta Goutam
Published: November 2021

Genome sequence analyses predicted the presence of effectors in the gram-negative Candidatus Liberibacter asiaticus (CLas) even without the presence of a classical type III secretion system. Since CLas is not culturable, it is not possible to perform traditional gene knockout experiments to determine the role of various effectors in Huanglongbing (HLB) pathogenesis. Therefore, we followed an alternative functional genomics approach to examine the role of the CLas effectors in HLB pathogenesis in general and more specifically in suppressing citrus innate immune response. Here, we focused on the CLas effectors, P235 and Effector 3, to perform the following studies. First, proteomic studies by LC-MS/MS were conducted to screen the putative interacting citrus protein partners of P235 and Effector 3 from the healthy and CLas-infected Hamlin extracts and the most probable candidates were identified based upon their high protein scores from LC-MS/MS. Second, a transgenic tobacco split GFP system was designed for in planta detection of the most probable citrus interacting protein partners of P235 and Effector 3. Third, in vitro and in planta studies were performed to show that each of two effectors interacts with and inhibits the functions of multiple citrus proteins belonging to the innate immune pathways. These inhibitory interactions led to a high level of reactive oxygen species (ROS), blocking of bactericidal lipid binding protein (LTP), and induction of premature programmed cell death (PCD), thereby supporting CLas infection and HLB pathogenesis. Finally, an LTP mimic was designed to sequester and block the CLas effector and to rescue the bactericidal activity of LTP.
Comparison of VATS Pleurectomy/Decortication Surgery plus Hyperthermic Intrathoracic Chemotherapy with VATS talc pleurodesis for the treatment of Malignant Pleural Mesothelioma: a randomized pilot study
Authors: Migliore Marcello , Fiore Maria , Tumino Rosario , Filippini Tommaso , Nardini Marco , Spatola Corrado , Castorina Sergio , Vigneri Paolo , Monte Ines , Polosa Riccardo , Ferrante Margherita ,   the University of Catania Study Group on Malignant Pleural Mesothelioma
Published: November 2021

Introduction

No previous study provides compelling evidence to convince surgeons to opt for one procedure over another for the treatment of Malignant Pleural Mesothelioma (MPM). Hyperthermic intrathoracic chemotherapy (HITHOC) adjunct to surgery for MPM has no definite role. The primary objective of this randomized pilot trial was to evaluate the feasibility for future large studies.

Method

The study design was a prospective randomized three-centric pilot trial (ISRCTN12709516). We recruited patients diagnosed with MPM and prospectively assigned them to two groups: Group A Video Assisted Thoracic Surgery (VATS) talc pleurodesis or Group B VATS P/D plus HITHOC. The main outcome measures were description of study feasibility. We collected socio-demographic and clinical patient information. Data of Kaplan-Meier survival analysis and Cox regression analysis are presented.

Results

From November-2011 to July-2017 24 males and 3 females, with a median age of 68-years were enrolled (recruitment rate 5 patients/year). Preoperative stage was I-II, and 18 had epithelioid type. 14 patients were in the Group A. Operative mortality was 0. Follow-up ranged from 6 to 80 months. The median overall survival time started to diverge at 20 months. In Group A, it was 19 months (95% CI:12-25) and in Group B, it was 28 months (95% CI:0-56). Survival rate for the epithelioid type was 15 months (0-34) in groups A. and 45 months (0-107) in the Group B with an HR 0.77 (95% CI:0.28-2.2).

Conclusion

These findings suggest that VATS P/D plus HITHOC may improve survival time in MPM patients undergoing surgical treatment and support the need for a larger multicenter randomized clinical trial.

Strengths and limitations of this study

this pilot study represents an important step forward of the treatment of malignant pleural mesothelioma

The study demonstrates the feasibility for a multicenter randomized trial to compare VATS P/D plus HITHOC with VATS talc pleurodesis in the management of MPM

Although survival for the epitheliod type is 45 months, the inclusion of small number of patients is a limitation.

Although neoadjuvant, adjuvant chemo-radio or immunotherapy have been administered to the patients, we have no specific information about doses for every single patient.

A potential source of bias could be that the house staff of the Centre A has not been formally educated about the study while in the Centre B house staff was informed about the pilot trial.
Insights into spray impingement on mask surface: effect of mask properties on penetration and aerosolization of cough droplets
Authors: Vadlamudi Gautham , Thirumalaikumaran S K , Chakravortty Dipshikha , Saha Abhishek , Basu Saptarshi
Published: November 2021

The emergence of the COVID-19 pandemic has demonstrated the importance of face masks, making them a part of people’s routine during the pandemic which is still continuing. The face masks act as source control, reducing the transmission of infectious respiratory droplets by acting as a physical barrier blocking the droplets during speaking, breathing, coughing, sneezing, etc. The novelty of current study is to generate a spray with the droplet size distribution and velocity scale similar that of an actual cough or a mild sneeze to fundamentally investigate the effects of mask properties on model-cough impingement. The spray replicates the presence of both large-sized and small-sized droplets similar to an actual cough, which makes the observations relevant to real-life situations. The spray is impinged on different mask samples with varying properties like porosity, pore size, fabric thickness, and their combinations in multilayer configuration. The effect of mask properties on the droplet penetration volume is studied as it leads to the release of higher pathogen loading into the surroundings. A two-step penetration criteria based on viscous dissipation and capillary effects have been applied along with a third criteria based on the porosity of the mask sample that is specifically applicable for the spray impingement. The droplets present in the impinging cough can penetrate through the mask, atomizing into the aerosolization range and thus increasing the infection potential. Hence the effect of mask properties on the droplet size distribution as well as the velocity distribution of the penetrated droplets has been investigated using in-vitro experimental manikin model, which will be essential for estimating the range of infection spread. The filtration of virus-emulating nanoparticles as well as the fate of the penetrated respiratory droplets, with a susceptible person in the proximity, has also been investigated.
Predictive utility of mortality by aging measures at different hierarchical levels and the response to modifiable lifestyle factors: Implications for geroprotective programs
Authors: Zhang Jingyun , Cao Xingqi , Chen Chen , He Liu , Ren Ziyang , Xiao Junhua , Han Liyuan , Wu Xifeng , Liu Zuyun
Published: November 2021

Background

Aging, as a multi-dimensional process, can be measured at different hierarchical levels including biological, phenotypic, and functional levels. The aims of this study were to: 1) compare the predictive utility of mortality by three aging measures at three hierarchical levels; 2) develop a composite aging measure that integrated aging measures at different hierarchical levels; and 3) evaluate the response of these aging measures to modifiable lifestyle factors.

Methods

Data from National Health and Nutrition Examination Survey 1999-2002 were used. Three aging measures included telomere length (TL, biological level), Phenotypic Age (PA, phenotypic level), and frailty index (FI, functional level). Mortality information was collected until Dec. 2015. Cox proportional hazards regression and multiple linear regression models were performed.

Results

A total of 3249 participants (20-84 years) were included. Both accelerations (accounting for chronological age) of PA and FI were significantly associated with mortality, with HRs of 1.67 (95% confidence interval [CI] = 1.41-1.98) and 1.59 (95% CI = 1.35-1.87), respectively, while that of TL showed nonsignificant associations. We thus developed a new composite aging measure (named PC1) integrating the accelerations of PA and FI, and demonstrated its better predictive utility relative to each single aging measure. PC1, as well as the accelerations of PA and FI, were responsive to several lifestyle factors.

Conclusion

The findings, for the first time, provide a full picture of the predictive utility of mortality by three aging measures at three hierarchical levels and the response to modifiable lifestyle factors, with important implications for geroprotective programs.
Outcomes of Anti-Spike Monoclonal Antibody Therapy in Pregnant Women with Mild to Moderate COVID-19
Authors: Thilagar Bright P. , Ghosh Aditya K. , Nguyen Jerome , Theiler Regan N. , Wick Myra J. , Hurt Ryan T. , Razonable Raymund R. , Ganesh Ravindra
Published: November 2021

Objective

To evaluate the efficacy and safety of anti-spike monoclonal antibodies (MAb) in the treatment of mild to moderate COVID-19 in high-risk patients who are pregnant.

Methods

The database of patients treated with monoclonal antibodies in the Mayo Clinic Midwest region was reviewed for patients who were pregnant at the time of infusion. Manual chart review was performed to collect demographic details as well as COVID course for both the mother and the infant if delivered. The data are presented using descriptive methods.

Results

We identified fifty-one pregnant patients with mild to moderate COVID-19 who were treated with MAb (4 with bamlanivimab monotherapy, 3 with bamlanivimab-etesevimab combination, and 44 with the casirivimab-imdevimab combination). No adverse effects were reported, and no patient required COVID-19 related hospitalization. Twenty-nine patients delivered healthy babies, there was one case of intrauterine fetal demise secondary to a congenital Ebstein anomaly (not related to MAb treatment), and twenty-one were uncomplicated pregnancies.

Conclusion

MAb infusions were well tolerated in pregnant patients considered at high risk for COVID-19 complications, with no observed adverse effects to mother or fetus. Although preliminary data suggest MAb therapy in pregnancy is safe, further research is recommended to fully assess safety and efficacy in pregnancy.

TEACHING POINTS

Anti-spike monoclonal antibody therapy is well tolerated in high-risk pregnant patients with mild to moderate COVID-19

No adverse effects of anti-spike monoclonal antibody administration were observed in either the mother or fetus.
GnRH pulse generator frequency is modulated by kisspeptin and GABA-glutamate interactions in the posterodorsal medial amygdala in female mice
Authors: Lass G , Li XF , Wall E , de Burgh RA , Ivanova D , McIntyre C , Lin XH , Colledge WH , Lightman SL , O’Byrne KT
Published: November 2021

Kisspeptin neurons in the arcuate nucleus of the hypothalamus generate GnRH pulses, and act as critical initiators of functional gonadotrophin secretion, and reproductive competency. However, kisspeptin in other brain regions, most notably the posterodorsal subnucleus of the medial amygdala (MePD), plays a significant modulatory role over the hypothalamic kisspeptin population; our recent studies using optogenetics have shown that low frequency light stimulation of MePD kisspeptin results in increased LH pulse frequency. Nonetheless, the neurochemical pathways that underpin this regulatory function remain unknown. To study this, we have utilised an optofluid technology, precisely combining optogenetic stimulation with pharmacological receptor antagonism, to investigate the neurotransmission involved in this circuitry. We have shown that functional neurotransmission of both GABAAand glutamate is a requirement for effective modulation of the GnRH pulse generator by amygdala kisspeptin neurons.
Obesity impairs therapeutic efficacy of mesenchymal stem cells by inhibiting cardiolipin-dependent mitophagy and intercellular mitochondrial transfer in mouse models of allergic airway inflammation
Authors: Sagar Shakti , Faizan Md. Imam , Chaudhary Nisha , Gheware Atish , Sharma Khushboo , Azmi Iqbal , Singh Vijay Pal , Kharya Gaurav , Mabalirajan Ulaganathan , Agrawal Anurag , Ahmad Tanveer , Roy Soumya Sinha
Published: November 2021

Mesenchymal stem cell (MSC) transplantation alleviates metabolic defects in diseased recipient cells by intercellular mitochondrial transport (IMT). However, the effect of host metabolic conditions on MSCs in general, and IMT in particular, has largely remained unexplored. This study has identified a molecular pathway that primarily governs the metabolic function and IMT of MSCs. We found underlying mitochondrial dysfunction, impaired mitophagy, and reduced IMT in MSCs derived from high-fat diet (HFD)-induced obese mice (MSC-Ob). Mechanistically, MSC-Ob failed to sequester their damaged mitochondria into LC3-dependent autophagosomes due to decrease in mitochondrial cardiolipin content, which we propose as a putative mitophagy receptor for LC3 in MSCs. Functionally, MSC-Ob exhibited diminished potential to rescue metabolic deficits and cell death in stress-induced epithelial cells. In a small molecule screen, we found pyrroloquinoline quinone (PQQ) as a regulator of mitophagy and IMT. Long-term culture of MSC-Ob with PQQ (MSC-ObPQQ) restored cardiolipin content and sequestration of mitochondria to autophagosomes with concomitant activation of mitophagy. Upon co-culture, MSC-ObPQQrescued cell death in stress-induced epithelial cells by enhancing IMT. The beneficial effect of PQQ was also evident in MSCs derived from human subjects in an in vitro model. In two independent mice models, the transplantation of MSC-ObPQQrestored IMT to airway epithelial cells, improved their mitochondrial metabolism and attenuated features of allergic airway inflammation (AAI). However, unmodulated MSC-Ob failed to do so. In summary, we uncover the molecular mechanism leading to the therapeutic decline of obese-derived MSCs and highlight the importance of pharmacological modulation of these cells for therapeutic intervention.
Improved reference genome annotation of Brassica rapa by PacBio RNA sequencing
Authors: Zhang Zhicheng , Guo Jing , Cai Xu , Li Yufang , Xi Xi , Lin Runmao , Liang Jianli , Wang Xiaowu , Wu Jian
Published: November 2021

The species Brassica rapa includes several important vegetable crops. The draft reference genome of B. rapa ssp. pekinensis was completed in 2011, and it has since been updated twice. The pangenome with structural variations of 18 B. rapa accessions was published in 2021. Although extensive genomic analysis has been conducted on B. rapa, a comprehensive genome annotation including gene structure, alternative splicing events, and non-coding genes is still lacking. Therefore, we used the Pacific Biosciences (PacBio) single-molecular long-read technology to improve gene models and produced the annotated genome version 3.5. In total, we obtained 753,041 full-length non-chimeric (FLNC) reads and collapsed these into 92,810 non-redundant consensus isoforms, capturing 48% of the genes annotated in the B. rapa reference genome annotation v3.1. Based on the isoform data, we identified 830 novel protein-coding genes that were missed in previous genome annotations, defined the UTR regions of 20,340 annotated genes and corrected 886 wrongly-spliced genes. We also identified 28,564 alternative splicing (AS) events and 1,480 long non-coding RNAs (lncRNAs). We produced a relatively complete and high-quality reference transcriptome for B. rapa that can facilitate further functional genomic research.
Ionotropic glutamate receptors in the retina – a bioinformatical meta-analysis
Authors: Pircher Bianca , Pircher Thomas , Feigenspan Andreas
Published: November 2021

Glutamate is an essential neurotransmitter for signal processing in the vertical pathway of the mammalian retina, where it is involved in the distribution of visual information into several parallel channels. The excitatory effects of glutamate are mediated by AMPA-, kainate-, and NMDA-type ionotropic glutamate receptors (iGluRs). The expression patterns of these receptors in the vertebrate retina have been investigated so far with mainly immunocytochemical, in-situ hybridization, and electrophysiological/pharmacological techniques. Here, we have used scRNA sequencing data from chicken, mouse, macaque, and human retina to describe and compare the profile of iGluR expression in major retinal cell types across species. Our results suggest that major retinal cell types each express a unique set of iGluRs with substantial differences between non-mammalian and mammalian retinae. Expression of iGluRs has been investigated in more detail for amacrine and bipolar cell types of the human retina, each showing minor variations of a common pattern. The differential expression of iGluRs is likely to convey unique signal processing properties to individual elements of the retinal circuitry.
Development and characterization of a high fat diet-streptozotocin induced type 2 diabetes model in nude athymic rats
Authors: Sun Xuetao , Nunes Sara S
Published: November 2021

People with diabetes mellitus (DM) are at an increased risk for myocardial infarction (MI) than age matched people without DM. However, assays for pre-clinical therapy are performed in animal models of ischemia that lack the co-morbid conditions present in patients with MI, such as DM. This contributes to the failure to translate pre-clinical trials results to the clinic. Thus, to increase the clinical relevance of xenograft studies in pre-clinical models, it is important to have a DM model in animals that are immunodeficient. Here, we developed a type 2 diabetes mellitus (T2D) model in nude athymic rats using high-fat diet and streptozotocin (HFD-STZ). Nude athymic rats were randomized into a control group (normal chow) or a HFD (45% fat, 20% protein and 35% carbohydrate)-STZ group. STZ (35 mg/kg i.v.) or vehicle was administered 8 weeks after HFD feeding started. Assessments were done longitudinally and at week 9 (endpoint). The HFD-STZ group showed mild hyperglycemia pre STZ administration (7.7 ± 0.3 mM vs 5.8 ± 0.2 mM in control) by week 8. In addition, plasma insulin levels were increased and the HOMA index was 2.5-times higher in the HFD-STZ. The HFD-STZ group showed increased fasting (147%) triglycerides. After STZ-administration, blood glucose levels increased substantially (23.6 ± 1.4 mM vs 5.5 ± 0.3 mM in control). The HFD-STZ treated animals also showed increased left ventricular wall thickness, cardiac hypertrophy and fibrosis, reduced cardiac function compared to normal chow control. In line with the HFD-STZ model in immunocompetent rats, the HFD-STZ treatment of athymic rats recapitulates key features of T2D, including aspects of established clinical diabetic cardiomyopathy and should be suitable for xenograft studies in the context of T2D.
Enemy or ally: a genomic approach to elucidate the lifestyle of Phyllosticta citrichinaensis
Authors: Buijs Valerie A. , Groenewald Johannes Z. , Haridas Sajeet , LaButti Kurt M. , Lipzen Anna , Martin Francis M. , Barry Kerrie , Grigoriev Igor V. , Crous Pedro W. , Seidl Michael F.
Published: November 2021

Members of the fungal genus Phyllosticta can colonize a variety of plant hosts, including several Citrus species such as Citrus sinensis (orange), Citrus limon (lemon), and Citrus maxima (pomelo). Some Phyllosticta species have the capacity to cause disease, such as Citrus Black Spot, while others have only been observed as endophytes. Thus far, genomic differences underlying lifestyle adaptations of Phyllosticta species have not yet been studied. Furthermore, the lifestyle of Phyllosticta citrichinaensis is ambiguous, as it has been described as a weak pathogen but Koch’s postulates may not have been established and the presence of this species was never reported to cause any crop or economic losses. Here, we examined the genomic differences between pathogenic and endophytic Phyllosticta spp. colonizing Citrus and specifically aimed to elucidate the lifestyle of Phyllosticta citrichinaensis. We found several genomic differences between species of different lifestyles, including groups of genes that were only present in pathogens or endophytes. We also observed that species, based on their carbohydrate active enzymes, group independent of their phylogenetic association, and this clustering correlated with trophy prediction. Phyllosticta citrichinaensis shows an intermediate lifestyle, sharing genomic and phenotypic attributes of both pathogens and endophytes. We thus present the first genomic comparison of multiple citrus-colonizing pathogens and endophytes of the genus Phyllosticta, and therefore provide the basis for further comparative studies into the lifestyle adaptations within this genus.
High throughput screening of a new fluorescent G-quadruplex ligand having telomerase inhibitory activity in human A549 cells
Authors: Ghosh Sourav , De Debapriya , Banerjee Victor , Biswas Soumyajit , Ghosh Utpal
Published: November 2021

Genome-wide analysis showed that putative G-quadruplex DNA structures are prevalent in the human genome. The presence of G-quadruplex structure in the telomere and promoter region of certain oncogenes inspired people to use G-quadruplex ligand as anti-cancer agents. G-quadruplex structures, stabilized by ligand at telomere are resolved by telomerase making the cancer cells resistant to G-quadruplex ligand. So, identification of a new G-quadruplex ligand having anti-telomerase activity would be a promising strategy for cancer therapy as about 85% of human cancers are telomerase positive. A set of the drug-like compounds were screened from the ZINC database randomly and 2284 ligands were chosen following Lipinski’s rule of five that were docked with five different G-quadruplex DNA sequences in idock. We screened 43 potential G-quadruplex binders using Z-score as a normalization scoring function. The compound (ZINC ID-05220992) gave the best score (average idock = −10.17 kcal/mol, average normalized idock = −3.42). We performed G4 FID assay, CD analysis to understand its binding with three different G-quadruplex DNA sequences, and checked its anti-telomerase activity in A549 cells using TRAP assay. We observed that this compound had an intrinsic fluorescence, capability to stain live cells with a blue fluorescence, and a specific affinity to only 22AG out of three different G-quadruplex DNA sequences under study. It showed cytotoxicity, good permeability to live cells, and a significant reduction of telomerase activity in human A549 cells at a very low dose. So, this compound has strong potential to be an anti-cancer drug.

Graphical Abstract

Highlights

A set of compounds were screened randomly by a High throughput method and Lipinski’s rule of five from ZINC database to identify potential G4-binders.

The compound (ZINC ID-05220992) was screened after docking with five G-quadruplex DNA

It binds G-quadruplex DNA 22AG as detected by TO displacement and CD spectroscopy.

It inhibits telomerase activity in A549 cells and also cytotoxic to this cell.

It penetrates live A549 cell in culture and stains it with blue fluorescence
Deletion of two genes improves heterologous secretion of fungal lignin-degrading heme peroxidases in S. cerevisiae
Authors: Khlystov Nikita A.
Published: November 2021

Efficient, large-scale heterologous production of enzymes is a crucial component of the biomass valorization industry. Whereas cellulose utilization has been successful in applications such as bioethanol, its counterpart lignin remains significantly underutilized despite being an abundant potential source of aromatic commodity chemicals. Fungal lignin-degrading heme peroxidases are thought to be the major agents responsible for lignin depolymerization in nature, but their large-scale production remains inaccessible due to the genetic intractability of basidiomycete fungi and the challenges in the heterologous production of these enzymes. In this study, we employ a strain engineering approach based on functional genomics to identify mutants of the model yeast Saccharomyces cerevisiae with enhanced heterologous production of lignin-degrading heme peroxidases. We show that our screening method coupling an activity-based readout with fluorescence-assisted cell sorting enables identification of two single null mutants of S. cerevisiae, pmt2 and cyt2, with up to 11-fold improved secretion of a versatile peroxidase from the lignin-degrading fungus Pleurotus eryngii. We demonstrate that the double deletion strain pmt2cyt2 displays positive epistasis, improving and even enabling production of members from all three classes of lignin-degrading fungal peroxidases. We anticipate that these mutant strains will be broadly applicable for improved heterologous production of this biotechnologically important class of enzymes.
Leveraging information in spatial transcriptomics to predict super-resolution gene expression from histology images in tumors
Authors: Pang Minxing , Su Kenong , Li Mingyao
Published: November 2021

Recent developments in spatial transcriptomics (ST) technologies have enabled the profiling of transcriptome-wide gene expression while retaining the location information of measured genes within tissues. Moreover, the corresponding high-resolution hematoxylin and eosin-stained histology images are readily available for the ST tissue sections. Since histology images are easy to obtain, it is desirable to leverage information learned from ST to predict gene expression for tissue sections where only histology images are available. Here we present HisToGene, a deep learning model for gene expression prediction from histology images. To account for the spatial dependency of measured spots, HisToGene adopts Vision Transformer, a state-of-the-art method for image recognition. The well-trained HisToGene model can also predict super-resolution gene expression. Through evaluations on 32 HER2+ breast cancer samples with 9,612 spots and 785 genes, we show that HisToGene accurately predicts gene expression and outperforms ST-Net both in gene expression prediction and clustering tissue regions using the predicted expression. We further show that the predicted super-resolution gene expression also leads to higher clustering accuracy than observed gene expression. Gene expression predicted from HisToGene enables researchers to generate virtual transcriptomics data at scale and can help elucidate the molecular signatures of tissues.
Inference of Rift Valley Fever pathogenesis in Bos taurus using a gene co-expression network
Authors: Gitau John K. , Macharia Rosaline W. , Mwangi Kennedy W. , Ongeso Nehemiah M. , Murungi Edwin
Published: November 2021

Background

Rift Valley Fever (RVF) is a viral disease caused by the Rift Valley Fever virus and spread mainly by the Aedes and Culex mosquito species. The disease primarily infects domestic animals such as sheep, goats, and cattle, resulting in a spectrum of clinical outcomes including morbidity, massive storm abortions, and neonatal fatalities. RVF outbreaks are closely linked to above-average rainfall and flooding, which create an ideal environment for mosquitos to breed, multiply, and transmit the virus to animals. The outcomes of human RVF infection range from self-limiting febrile illness to potentially fatal hemorrhagic diatheses and miscarriage in pregnant women. Collectively, the economic losses due to the zoonotic RVF disease is immense.

Methods

Using the Weighted Gene Co-expression Network Analysis (WGCNA) package, RNA-Seq data generated from five healthy Bos taurus steer calves aged 4-6 months was obtained from the Gene Expression Omnibus (GEO) database (Accession number GSE71417). The data was utilized to construct a gene co-expression network. Enriched modules containing genes potentially involved in RVF infection progression were identified. Moreover, using the Multiple Expectation Maximizations for Motif Elicitation (MEME) suite, consensus regulatory motifs of enriched gene clusters were deciphered and the most abundant putative regulatory motif in each enriched module unveiled by comparative analysis with publicly available motifs using the TOMTOM motif comparison tool. The potential roles of the identified regulatory motifs were inferred by literature mining.

Results

The constructed gene co-expression network revealed thirty-three (33) modules, nine of which were enriched for Gene Ontology terms linked to RVF pathogenesis. Functional enrichment in two (red and turquoise) of the nine modules was significant. ASH1-like histone lysine methyltransferase and Astrotactin were the hub genes for the red and turquoise modules respectively. ASH1-like histone lysine methyltransferase gene is involved in chromatin epigenetic modification while Astrotactin is a vertebrate-specific gene that plays an important role in neurodevelopment. Additionally, consensus regulatory motifs located on the 3' end of genes in each enriched module was identified.

Conclusions

In this study, we have developed a gene co-expression network that has aided in the unveiling of functionally related genes, intramodular hub genes, and immunity genes potentially involved in RVF pathogenesis. The discovery of functional genes with putative critical roles in the establishment of RVF infection establishment will contribute to the understanding of the molecular mechanism of RVF pathogenesis. Importantly, the putative regulatory motifs identified are plausible targets for RVF drug and vaccine development.
The bacterial hitchhiker’s guide to COI: Universal primer-based COI capture probes fail to exclude bacterial DNA, but 16S capture leaves metazoa behind
Authors: Hintikka Sanni , Carlsson Jeanette E.L. , Carlsson Jens
Published: November 2021

Environmental DNA (eDNA) metabarcoding from water samples has, in recent years, shown great promise for biodiversity monitoring. However, universal primers targeting the cytochrome oxidase I (COI) marker gene popular in metazoan studies have displayed high levels of nontarget amplification. To date, enrichment methods bypassing amplification have not been able to match the detection levels of conventional metabarcoding. This study evaluated the use of universal metabarcoding primers as capture probes to either isolate target DNA or to remove nontarget DNA, prior to amplification, by using biotinylated versions of universal metazoan and bacterial barcoding primers, namely metazoan COI (mlCOIintF) and bacterial 16S (515F). Additionally, each step of the protocol was assessed by amplifying for both metazoan COI (mlCOIintF/jgHCO2198) and bacterial 16S (515F/806R) to investigate the effect on the metazoan and bacterial communities. Bacterial read abundance increased significantly in response to the captures (COI library), while the quality of the captured DNA was also improved. The metazoan-based probe captured bacterial DNA in a range that was also amplifiable with the 16S primers, demonstrating the ability of universal capture probes to isolate larger fragments of DNA from eDNA. Although the use of the tested COI probe cannot be recommended for metazoan enrichment, based on the experimental results, the concept of capturing longer fragments could be applied to metazoan metabarcoding. By using a truly conserved site without a high-level taxonomic resolution as a target for capture, it may be possible to isolate DNA fragments large enough to span over a nearby barcoding region (e.g., COI), which can then be processed through a conventional metabarcoding-by-amplification protocol.
Convergent evolution of mevalonate pathway in Inonotus obliquus and Betula pendula
Authors: Safronov Omid , Bal Guleycan Lutfullahoglu , Sipari Nina , Wilkens Maya , Safdari Pezhman , Smolander Olli-Pekka , Lihavainen Jenna , Silvan Niko , Rajaraman Sitaram , Laine Pia K. , Paulin Lars G , Auvinen Petri , Sarjala Tytti , Overmyer Kirk , Kangasjärvi Jaakko , Battersby Brendan , Richter Uwe , Salojärvi Jarkko
Published: November 2021

Inonotus obliquus, Chaga mushroom, is a fungal species from Hymenochaetaceae family (Basidiomycota) which has been widely used for traditional medicine in Europe and Asia. Here, chaga genome was sequenced using Pacbio sequencing into a 50.7Mbp assembly consisting of 301 primary contigs with an N50 value of 375 kbp. Genome evolution analyses revealed a lineage-specific whole genome duplication event and an expansion of Cytochrome P450 superfamily. Fungal biosynthetic clusters were enriched for tandemly duplicated genes, suggesting that biosynthetic pathway evolution has proceeded through small-scale duplications. Metabolomic fingerprinting confirmed a highly complex terpene biosynthesis chemistry when compared against related fungal species lacking the genome duplication event.
The membrane-actin linker ezrin acts as a sliding anchor
Authors: Korkmazhan Elgin , Dunn Alexander R.
Published: November 2021

Protein linkages to filamentous (F)-actin provide the cell membrane with mechanical resiliency and give rise to intricate membrane architectures. However, the actin cytoskeleton is highly dynamic, and undergoes rapid changes in shape during cell motility and other processes. The molecular mechanisms that underlie the mechanically robust yet fluid connection between the membrane and actin cytoskeleton remain poorly understood. Here, we used a single-molecule optical trap assay to examine how the prototypical membrane-actin linker ezrin acts to anchor F-actin to the cell membrane. Remarkably, we find that ezrin forms a complex that slides along F-actin over micron distances while resisting mechanical detachment. The ubiquity of ezrin and analogous proteins suggests that sliding anchors such as ezrin may constitute an important but overlooked element in the construction of the actin cytoskeleton.
Intravenous haloperidol and cocaine alter the distribution of T CD4+ and B lymphocytes and NKT cells in rats
Authors: Jankowski Maciej M. , Ignatowska-Jankowska Bogna M. , Glac Wojciech , Wiergowski Marek , Kaźmierska-Grębowska Paulina , Świergiel Artur H.
Published: November 2021

Modulation of dopamine transmission evokes strong behavioral effects that can be achieved by psychoactive drugs such as haloperidol or cocaine. Cocaine non-specifically increases dopamine transmission by blocking dopamine active transporter (DAT) and evokes behavioral arousal, while haloperidol is a non-specific dopamine D2 receptor antagonist with sedative effects. Interestingly, dopamine has been found to affect immune cells in addition to its action in the central nervous system. Here we address the possible interactions between haloperidol and cocaine and their effects on both immune cells and behavior in freely moving rats. We use an intravenous model of haloperidol and binge cocaine administration to evaluate the drugs’ impact on the distribution of lymphocyte subsets in both the peripheral blood and the spleen. We assess the drugs’ behavioral effects by measuring locomotor activity. Cocaine evoked a pronounced locomotor response and stereotypic behaviors, both of which were completely blocked after pretreatment with haloperidol. The results suggest that blood lymphopenia which was induced by haloperidol and cocaine (except for NKT cells), is independent of dopaminergic activity and most likely results from the massive secretion of corticosterone. Haloperidol pretreatment prevented the cocaine-induced decrease in NKT cell numbers. On the other hand, the increased systemic dopaminergic activity after cocaine administration is a significant factor in retaining T CD4+ and B lymphocytes in the spleen.

Abstract Figure
propeller: testing for differences in cell type proportions in single cell data
Authors: Phipson Belinda , Sim Choon Boon , Porrello Enzo R. , Hewitt Alex W , Powell Joseph , Oshlack Alicia
Published: November 2021

Motivation

Single cell RNA Sequencing (scRNA-seq) has rapidly gained popularity over the last few years for profiling the transcriptomes of thousands to millions of single cells. This technology is now being used to analyse experiments with complex designs including biological replication. One question that can be asked from single cell experiments, which has been difficult to directly address with bulk RNA-seq data, is whether the cell type proportions are different between two or more experimental conditions. As well as gene expression changes, the relative depletion or enrichment of a particular cell type can be the functional consequence of disease or treatment. However, cell type proportions estimates from scRNA-seq data are variable and statistical methods that can correctly account for different sources of variability are needed to confidently identify statistically significant shifts in cell type composition between experimental conditions.

Results

We have developed propeller, a robust and flexible method that leverages biological replication to find statistically significant differences in cell type proportions between groups. Using simulated cell type proportions data we show that propeller performs well under a variety of scenarios. We applied propeller to test for significant changes in proportions of cell types related to human heart development, ageing and COVID-19 disease severity.

Availability and implementation

The propeller method is publicly available in the open source speckle R package (https://github.com/phipsonlab/speckle). All the analysis code for the paper is available at https://github.com/phipsonlab/propeller-paper-analysis/, and the associated analysis website is available at https://phipsonlab.github.io/propeller-paper-analysis/.

Contact

Alicia Oshlack: Alicia.Oshlack@petermac.org

Belinda Phipson: phipson.b@wehi.edu.au

Supplementary information

Yes.
High-throughput phenotyping reveals a link between transpiration efficiency and transpiration restriction under high evaporative demand and new loci controlling water use-related traits in African rice,Oryza glaberrimaSteud
Authors: Affortit Pablo , Effa-Effa Branly , Ndoye Mame Sokhatil , Moukouanga Daniel , Luchaire Nathalie , Cabrera-Bosquet Llorenç , Perálvarez Maricarmen , Pilloni Raphaël , Welcker Claude , Champion Antony , Gantet Pascal , Diedhiou Abdala Gamby , Manneh Baboucarr , Aroca Ricardo , Vadez Vincent , Laplaze Laurent , Cubry Philippe , Grondin Alexandre
Published: November 2021

Because water availability is the most important environmental factor limiting crop production, improving water use efficiency, the amount of carbon fixed per water used, is a major target for crop improvement. In rice, the genetic bases of transpiration efficiency, the derivation of water use efficiency at the whole-plant scale, and its putative component trait transpiration restriction under high evaporative demand, remain unknown. These traits were measured in a panel of 147 African riceOryza glaberrimagenotypes, known as potential sources of tolerance genes to biotic and abiotic stresses. Our results reveal that higher transpiration efficiency is associated with transpiration restriction in African rice. Detailed measurements in a subset of highly differentiated genotypes confirmed these associations and suggested that the root to shoot ratio played an important role in transpiration restriction. Genome wide association studies identified marker-trait associations for transpiration response to evaporative demand, transpiration efficiency and its residuals, that links to genes involved in water transport and cell wall patterning. Our data suggest that root shoot partitioning is an important component of transpiration restriction that has a positive effect on transpiration efficiency in African rice. Both traits are heritable and define targets for breeding rice with improved water use strategies.
Restricted X chromosome introgression and support for Haldane’s rule in hybridizing damselflies
Authors: Swaegers Janne , Sánchez-Guillén Rosa Ana , Chauhan Pallavi , Wellenreuther Maren , Hansson Bengt
Published: November 2021

Contemporary hybrid zones act as natural laboratories for the investigation of species boundaries and allow to shed light on the little understood roles of sex chromosomes in species divergence. Sex chromosomes are considered to function as a hotspot of genetic divergence between species; indicated by less genomic introgression compared to autosomes during hybridisation. Moreover, they are thought to contribute to Haldane’s rule which states that hybrids of the heterogametic sex are more likely to be inviable or sterile. To test these hypotheses, we used contemporary hybrid zones of Ischnura elegans, a damselfly species that has been expanding its range into the northern and western regions of Spain, leading to chronic hybridization with its sister species Ischnura graellsii. We analysed genome-wide SNPs in the Spanish I. elegans and I. graellsii hybrid zone and found (i) that the X chromosome shows less genomic introgression compared to autosomes and (ii) that males are underrepresented among admixed individuals as predicted by Haldane’s rule. This is the first study in Odonata that suggests a role of the X chromosome in reproductive isolation.

Moreover, our data adds to the few studies on species with X0 sex determination system and contradicts the hypothesis that the absence of a Y chromosome causes exceptions to Haldane’s rule.