bluuebunny/crossref_metadata_2025 huggingface dataset:
The Persistence of Blast- Versus Impact-Induced Concussion Symptomology Following Deployment
Authors: Belding Jennifer N. , Khokhar Bilal , Englert Robyn Martin , Fitzmaurice Shannon , Thomsen Cynthia J.
Published: July 2021

Objective:

To examine the persistence of concussion-related symptoms following injury as a function of mechanism of injury (high-level blast [HLB] vs impact) and low-level blast (LLB) exposure among Marines.

Setting:

Upon return from deployment and approximately 6 months later, respectively, Marines completed the Post-Deployment Health Assessment and Post-Deployment Health Re-Assessment in an operational or clinic setting.

Participants:

Data from active duty enlisted Marines who completed both assessments (n = 102 075) and who reported a potentially mild traumatic brain injury (mTBI)-inducing event and completed an mTBI screen (n = 8106) were analyzed.

Design:

This was a retrospective cohort study of Marines deployed between 2008 and 2012. Marines were categorized into groups with relatively high versus low risk for occupational risk of LLB exposure. A mixed model analysis of variance was used to examine the number of symptoms Marines reported experiencing during deployment as a function of probable concussion, HLB exposure, occupational risk, type of symptom, and time of measurement.

Main Measures:

Self-reported deployment exposures including HLB, probable mTBIs, and occupational risk of LLB exposure were identified. Outcomes included the proportion of neurological, musculoskeletal, and immunological symptoms for which Marines reported seeking care during and following deployment were analyzed.

Results:

Probable HLB-induced mTBIs (vs impact-induced) were associated with significantly more neurological symptoms at return from deployment and approximately 6 months later. Although symptom reporting decreased at statistically equivalent rates regardless of mechanism of injury, those with a probable HLB-induced concussion continued to report elevated symptomology post-deployment. Additionally, Marines with probable concussion working in occupations with LLB exposure reported elevated levels of persistent neurological symptoms. Both HLB and LLB exposure were associated with neurological symptoms that persisted following deployment.

Conclusion:

These findings suggest that blast-induced brain injuries may be fundamentally different from impact-induced injuries, and that additional screening and symptomatic treatment for blast-exposed patients may be warranted.
Pre-existing chronic kidney disease and hypertension increased the risk of cardiotoxicity among colorectal cancer patients treated with anticancer drugs
Authors: Ho Chin-Chin , Wen Pin-Chun , Yu Wen-Chung , Hu Yu-Wen , Yang Chen-Chang
Published: July 2021

Background:

This population-based study was to investigate the potential risk factors of cardiotoxicity among colorectal cancer (CRC) patients treated with anticancer drugs.

Methods:

This was a retrospective cohort study using the National Health Insurance Research Database to identify the CRC patients receiving chemotherapy (CT) alone or CT combined with targeted therapies between 2000 and 2013. The patients enrolled were those who had the first diagnosis of CRC established ≥20 years and had no cancer history three years before the incident diagnosis of CRC. The outcomes of cardiotoxicity were defined by the diagnosis of acute myocarditis, cardiomyopathy, heart failure, hypertensive heart disease, and so on.

Results:

A total of 11 819 CRC patients were identified and 3781 were eligible; 556 (14.7%) patients developed cardiotoxicity after receiving anticancer treatment. Patients showed a similar risk of having primary outcome (hazard ratio [HR], 0.7; p = 0.3662) between CT and CT combined with targeted therapy groups, whereas the risk of developing secondary outcome was significantly different between the two groups (HR, 0.7; p = 0.0339). The hazard was found to be increased with age (60–69, HR 2.1, p = 0.0236; 70–79, HR 3.3, p = 0.0003; and ≥80, HR 3.7, p < 0.0001). CRC patients who had a prior history of hypertension exhibited a higher risk than those without hypertension (HR 1.6, p < 0.0001). The hazard of having cardiotoxicity among patients with a prior history of severe chronic kidney disease was 2.4 times than that in those without renal dysfunction, regardless of the stage of cancer (HR 2.4, p < 0.0001).

Conclusion:

CRC patients over 60 years of age run a higher risk of developing cardiotoxicity when treated with anticancer drugs. For CRC patients who have a previous history of hypertension or chronic kidney disease, physicians must be careful in evaluating the risk of anticancer drugs–related cardiotoxicity. Prescribe drugs may prevent cardiotoxicity if necessary.
FDG-Avid Sclerosing Adenosis of the Breast Mimicking Malignancy
Authors: Zhang Jian , Yu Zhongfei , Dong Aisheng , Zhu Yuzhao
Published: July 2021

Sclerosing adenosis is a common benign proliferative disorder of the breast. We describe FDG PET/CT findings in a case of sclerosing adenosis showing focal intense FDG uptake mimicking malignancy. This case indicates that sclerosing adenosis should be included in the differential diagnosis of focal breast FDG accumulation along with malignant and nonmalignant conditions.
The Role of Rigid Suspension and Fixation in Treating Lagophthalmos After Lower Eyelid Reconstruction
Authors: Yang Tianye , Zhang Duo , Rong Li
Published: July 2021

A patient with severe eyelid defects caused by a car accident was admitted to the Plastic Surgery Department of the First Hospital of Jilin University. The lower eyelid was first reconstructed with autogenous palatal mucosa and a temporal musculocutaneous flap, which provided adequate tissue volume. Postoperatively, eyelid closure was good. After long-term follow-up, the reconstructed lower eyelid showed laxity and downward movement. The eyelid could not close completely and lagophthalmos occurred. Then, the lower eyelid was suspended by the fascia lata. The suture at the point of fixation became loose again after the operation. Incomplete eyelid closure recurred. Finally, palmaris longus tendon graft suspension combined with screw fixation was used to obtain a satisfactory therapeutic effect. in summary, rigid suspension and fixation can provide adequate lateral tension to resist lower reconstructed eyelid shifting and lagophthalmos, which is important for the maintenance of lasting effects.
Morphometric Analysis of the Mental Foramen Variation in an Iraqi Population by Using Cone-Beam Computed Tomography
Authors: Hassan Thair Abdel Lateef , Mohammed Heba Basim , Al-Ghurabi Zainab H.
Published: July 2021

The effects of gender, side, and ridge condition on the position of the mental foramen (MF) were investigated in this research. A total of 122 cone-beam computed tomography scans were chosen from healthy patients with age ranging from 18 to 72 years. The following parameters were used to evaluate images: MS-MF (horizontal distance to the mandibular symphysis from the anterior MF limit) and MB-MF (vertical measurement of distance from the inferior boundary of the mandible to the lower border of the MF). The mean distance between the MF and mandibular symphysis was 20.98 ± 1.95. The average measurement between the MF and the mandible's lower boundary was 10.36 ± 1.63. The horizontal distance was slightly different between males and females (21.5 ± 1.59 and 20.6 ± 1.6, respectively). In terms of gender and ridge condition, a significant difference in vertical distance (10.97 ± 1.14 versus 9.9 ± 1.24 and 10.13 ± 1.5 versus 10.55 ± 1.07, respectively) was observed. By contrast, in vertical and horizontal distances, significant differences were noted between edentulous men and women. Meanwhile, a significant difference between dentate male and female patients was found at vertical distances only. In conclusion, in both vertical and horizontal measurements, the location of the MF was higher in males than in females and edentulous more than dentate.
A New Method for Anterior Boundary Demarcation of the Nasopharynx in Three-Dimensional Analysis
Authors: Wang Rongyang , Li Feifei , Chen Shuai , Liu Dongxu , Yang Ruimei
Published: July 2021

Three-dimensional (3D) measurements of the upper airway have been extensively applied and researched, but the division of the airway is carried out in various ways, especially when demarcating the anterior boundary of the nasopharynx. The present study was to propose a new method based on the anatomical definition for the anterior boundary demarcation of the nasopharynx used in three-dimensional analysis. Twenty computed tomography scans (age 9.5 ± 2.5 years, 11 males, and 9 females) of head and neck were randomly selected and transferred to Materialism's interactive medical image control system 19.0 for segmentation of the nasopharynx. Precise localization of the reference points that determining the nasopharyngeal anterior and inferior boundaries was managed by recording their coordinates in the interface of the software. The area of the anterior and the inferior boundaries, and the volume of the nasopharynx were measured and repeated with a 2-week interval for the consistency test. Both the interobserver reliability as well as the intra-observer reliability were very high (intraclass correlation coefficients, 0.985–0.997). Paired t test showed no significant difference between the first and the second examinations. This new simple method proposed for demarcation of the nasopharyngeal anterior boundary was based on the innate anatomical boundary, which was statistically reliable, technically convenient, and clinically reasonable.
The Effect of Immunosuppressant Therapy Adherence on the Comfort of Liver Transplant Recipients
Authors: Saritaş Serdar , Özdemir Ahmet
Published: July 2021

Inadequate immunosuppressive therapy causes rejection, whereas an overdose may lead to infections or malignancy to affect a patient's life and comfort. This study used a descriptive correlational design to determine how compliance with immunosuppressive therapy affected the well-being of liver transplant patients. The study was conducted in the liver transplant unit of a university hospital with 103 patients who underwent liver transplant surgery. The target population included patients who received treatment in liver transplant clinics between July 2016 and August 2017. Mean age of the patients in the study was 44.66 ± 14.86 years and the time after transplant was 15.48 ± 16.90 months on the average. A significant difference was found between mean General Comfort Scale scores according to the variable of adherence status (t = 6.898, p < .05). Simple linear regression analysis showed a positive moderate, significant correlation between the adherence variable and mean General Comfort Scale scores (R = 0.543, p < .001). It was found that the patients who adhered to immunosuppressive therapy experienced higher levels of comfort. Therefore, arrangements to improve patient adherence to therapy, hence comfort, are recommended, as well as periodic evaluations of patient comfort levels.
Prior infection with SARS-CoV-2 boosts and broadens Ad26.COV2.S immunogenicity in a variant dependent manner
Authors: Keeton Roanne , Richardson Simone I. , Moyo-Gwete Thandeka , Hermanus Tandile , Tincho Marius B. , Benede Ntombi , Manamela Nelia P. , Baguma Richard , Makhado Zanele , Ngomti Amkele , Motlou Thopisang , Mennen Mathilda , Chinhoyi Lionel , Skelem Sango , Maboreke Hazel , Doolabh Deelan , Iranzadeh Arash , Otter Ashley D. , Brooks Tim , Noursadeghi Mahdad , Moon James , Grifoni Alba , Weiskopf Daniela , Sette Alessandro , Blackburn Jonathan , Hsiao Nei-Yuan , Williamson Carolyn , Riou Catherine , Goga Ameena , Garrett Nigel , Bekker Linda-Gail , Gray Glenda , Ntusi Ntobeko A. B. , Moore Penny L. , Burgers Wendy A.
Published: July 2021

The Johnson and Johnson Ad26.COV2.S single dose vaccine represents an attractive option for COVID-19 vaccination in resource limited countries. We examined the effect of prior infection with different SARS-CoV-2 variants on Ad26.COV2.S immunogenicity. We compared participants who were SARS-CoV-2 naïve with those either infected with the ancestral D614G virus, or infected in the second wave when Beta predominated. Prior infection significantly boosted spike binding antibodies, antibody-dependent cellular cytotoxicity and neutralizing antibodies against D614G, Beta and Delta, however neutralization cross-reactivity varied by wave. Robust CD4 and CD8 T cell responses were induced after vaccination, regardless of prior infection. T cell recognition of variants was largely preserved, apart from some reduction in CD8 recognition of Delta. Thus, Ad26.COV2.S vaccination following infection may result in enhanced protection against COVID-19. The impact of the infecting variant on neutralization breadth after vaccination has implications for the design of second-generation vaccines based on variants of concern.
Metabolomics and microbiome reveal impacts of rhizosphere metabolites on alfalfa continuous cropping
Authors: Wang Ruiting , Liu Jinxin , Jiang Wanyi , Ji Pingsheng , Li Yonggang
Published: July 2021

Alfalfa long-term continuous cropping (CC) can pose a serious threat to alfalfa production. However, the mechanism of alfalfa CC obstacle is unclear as of today. In this study, we determined physic-chemical property, microbial population structure, and metabolite differences of alfalfa rhizosphere soils with CC for 1, 7, and 14-years based on analysis of metabolomics and microbiomics. Shifts of functional microorganisms in rhizosphere soil were analyzed, key metabolites and their effects on alfalfa seeds, seedlings and root rot pathogens were assessed. Based on anlysis, p-coumaric acid and ferulic acid on alfalfa seed and seedling growth and root rot pathogens were basically consistent with the influence of CC obstacles in the field. With the increase of CC years, the microbial community in soils changed from fungal to bacterial, and beneficial microorganisms decreased with the increase of CC years, which echoed the performance of alfalfa CC obstacles. The autotoxicity of p-coumaric acid was the strongest.This study fully proved that the continuous accumulation of autotoxic substances in alfalfa rhizosphere was the key factor causing alfalfa CC obstacles.
Cash versus Lotteries: COVID-19 Vaccine Incentives Experiment*
Authors: Duch Raymond M. , Barnett Adrian , Filipek Maciej , Roope Laurence , Violato Mara , Clarke Philip
Published: July 2021

Governments are considering financial incentives to increase vaccine uptake to end the COVID-19 pandemic. Incentives being offered include cash-equivalents such as vouchers or being entered into lotteries. Our experiment involved random assignment of 1,628 unvaccinated participants in the United States to one of three 45 second informational videos promoting vaccination with messages about: (a) health benefits of COVID-19 vaccines (control); (b) being entered into lotteries; or (c) receiving cash equivalent vouchers. After seeing the control health information video, 16% of individuals wanted information on where to get vaccinated. This compared with 14% of those assigned to the lottery video (odds ratio of 0.82 relative to control: 95% credible interval 0.57-1.17) and 22% of those assigned to the cash voucher video (odds ratio of 1.53 relative to control: 95% credible interval 1.11-2.11). These results support greater use of cash vouchers to promote COVID-19 vaccine uptake and do not support the use of lottery incentives.
CC- chemokine ligand 25 mediates inflammatory crosstalk between adipose and liver in non-alcoholic fatty liver disease
Authors: Parker Richard , Drake J , Weston CJ , Adams DH
Published: July 2021

Background and Aims

Obesity is closely associated with non-alcoholic fatty liver disease (NAFLD). We investigated expression of the CC-chemokine CCL25 in adipose tissue (AT) and its relation to hepatic inflammation.

Methods

Primary human tissue was used for all experiments. CCL25 concentration in serum was measured with enzyme-linked immunosorbent assay (ELISA). Gene expression of CCL25 was measured with polymerase chain reaction. Protein expression was assessed with ELISA and immunohistochemistry. Leukocyte trafficking was investigated in a dynamic assay to model the hepatic sinusoid. Expression of CCR9 on liver-infiltrating leukocytes analysed with flow cytometry.

Results

Circulating CCL25 was increased in obesity. Gene expression of CCL25 in AT was several-fold higher than in liver, although protein levels of CCL25 were comparable. Soluble CCL25 in flow media increased leukocyte trafficking across hepatic endothelium. Greater numbers of CCR9+ cells were seen in liver tissue from patients with NAFLD, where the greatest difference was in the number of CD14+CD16+ monocytes.

Conclusions

CCL25 and its cognate receptor CCR9 mediate a novel pathway of inflammatory crosstalk between adipose and liver tissue in NAFLD.
Immune responses to a single dose of the AZD1222/Covishield vaccine at 16 weeks in individuals in Sri Lanka
Authors: Jeewandara Chandima , Guruge Dinuka , Pushpakumara Pradeep Darshana , Kamaladasa Achala , Aberathna Inoka Sepali , Tanussiya Shyrar , Banuri Gunasekera B , Wijesinghe Ayesha , Dissanayake Osanda , Kuruppu Heshan , Ranasinghe Thushali , Jayathilaka Deshni , Dayarathna Shashika , Ekanayake Dinithi , Jayamali MPDJ , Gamalath Nayanathara , Mudumkotuwa Anushika , Somathilake Gayasha , Dissanayake Madhushika , Harvie Michael , Nimasha Thashmi , Madusanka Deshan , Jayadas Tibutius , Wijayamuni Ruwan , Schimanski Lisa , Rijal Pramila , Tan Tiong .K. , Townsend Alain , Ogg Graham S. , Malavige Gathsaurie Neelika
Published: July 2021

Introduction

Due to limited access to vaccines, many countries have only administered a single dose of the AZD1222, while the dosage intervals have increased ≥ weeks. We sought to investigate the immunogenicity of a single dose of vaccine at ≥ 16 weeks.

Methods

SARS-CoV-2 specific antibodies in 553 individuals and antibodies to the receptor binding domain (RBD) of the Wuhan virus (WT) and the variants of concern (VOCs), ACE2 receptor blocking antibodies, ex vivo and cultured IFNγ T cell responses and B cell ELISpot responses were investigated in a sub-cohort.

Results

The seropositivity rates in those >70 years of age (93.7%) was not significantly different compared to other age groups (97.7 to 98.2, Pearson Chi-Square = 7.8, p-value = 0.05). The antibody titres (antibody index) significantly declined (p<0.0001) with increase in age. 18/69 (26.1%) of individuals did not have ACE2 receptor blocking antibodies, while responses to the RBD of WT (p=0.03), B.1.1.7 (p=0.04) and B.1.617.2 (p=0.02) were significantly lower in those who were >60 years. Ex vivo IFN γ T cell ELISpot responses were seen in 10/66 (15.1%), while only a few expressed CD107a. However, >85% had a high frequency of cultured IFNγ T cell ELISpot responses and B cell ELISpots.

Conclusion

Virus specific antibodies were maintained at ≥ 16 weeks after receiving a single dose of AZD1222, although levels were lower to VOCs, especially in older individuals. A single dose induced a high frequency of memory T and B cell responses.
Vaccine effectiveness when combining the ChAdOx1 vaccine as the first dose with an mRNA COVID-19 vaccine as the second dose
Authors: Gram Mie Agermose , Nielsen Jens , Schelde Astrid Blicher , Nielsen Katrine Finderup , Moustsen-Helms Ida Rask , Bjørkholt Sørensen Anne Katrine , Valentiner-Branth Palle , Emborg Hanne-Dorthe
Published: July 2021

Background

The recommendations in several countries to stop using the ChAdOx1 vaccine has led to vaccine programs combining different vaccine types, which necessitates new knowledge on vaccine effectiveness (VE). In this study, we aimed to estimate the VE when combining the ChAdOx1 vaccine as the first dose and an mRNA vaccine as the second dose.

Methods

This nationwide population-based cohort study estimated VE against SARS-CoV-2 infection, all-cause and COVID-19 related hospitalization and death after receiving the ChAdOx1 vaccine as the first dose followed by an mRNA vaccine as the second dose. VE estimates were obtained using a Cox regression with calendar time as underlying time and adjusted for sex, age, comorbidity, heritage and hospital admission. Information on all individuals was extracted and linked from high-quality national registries.

Results

A total of 5,542,079 individuals were included in the analyses (97.6% of the total Danish population). A total of 144,360 were vaccinated with the ChAdOx1 vaccine as the first dose and of these 136,551 individuals received an mRNA vaccine as the second dose. A total of 1,691,464 person-years and 83,034 cases of SARS-CoV-2 infection were included. The VE against SARS-CoV-2 infection when combining the ChAdOx1 and an mRNA vaccine was 88% (95% confidence interval (CI): 83; 92) 14 days after the second dose and onwards. There were no COVID-19 related hospitalizations and deaths among the individuals vaccinated with the combination of the ChAdOx1 and an mRNA vaccine during the study period.

Conclusion

In conclusion, this study found a reduction in the risk of SARS-CoV-2 infection when combining the ChAdOx1 and an mRNA vaccine, compared with unvaccinated individuals. This is similar to the VE of two doses of an mRNA vaccine. Longer follow-up time is needed to confirm vaccine induced protection against severe events, such as COVID-19 related hospitalization and death.
Higher serological responses and increased vaccine effectiveness demonstrate the value of extended vaccine schedules in combatting COVID-19 in England
Authors: Amirthalingam Gayatri , Bernal Jamie Lopez , Andrews Nick J , Whitaker Heather , Gower Charlotte , Stowe Julia , Tessier Elise , Subbarao Vani , Ireland Georgina , Baawuah Frances , Linley Ezra , Warrener Lenesha , O’Brien Michelle , Whillock Corinne , Moss Paul , Ladhani Shamez N , Brown Kevin E , Ramsay Mary E
Published: July 2021

Introduction

In January 2021, the UK decided to prioritise the delivery of the first dose of BNT162b2 (Pfizer/BioNTech) and AZD1222 (AstraZeneca) vaccines by extending the interval until the second dose up to 12 weeks.

Methods

Serological responses were compared after BNT162b2 and AZD1222 vaccination with varying intervals in uninfected and previously-infected adults aged 50-89 years. These findings are evaluated against real-world national vaccine effectiveness (VE) estimates against COVID-19 in England.

Results

We recruited 750 participants aged 50-89 years, including 126 (16.8%) with evidence of previous infection; 421 received BNT162b2 and 329 and AZD1222. For both vaccines, over 95% had seroconverted 35-55 days after dose one, and 100% seroconverted 7+ days after dose 2. Following a 65-84 day interval between two doses, geometric mean titres (GMTs) at 14-34 days were 6-fold higher for BNT162b2 (6703; 95%CI, 5887-7633) than AZD1222 (1093; 806-1483), which in turn were higher than those receiving BNT162b2 19-29 days apart (694; 540 - 893). For both vaccines, VE was higher across all age-groups from 14 days after dose two compared to one dose, but the magnitude varied with interval between doses. Higher two-dose VE was observed with >6 week intervals between BNT162b2 doses compared to the authorised 3-week schedule, including ≥80 year-olds.

Conclusion

Our findings support the UK approach of prioritising the first dose of COVID-19 vaccines, with evidence of higher protection following extended schedules. Given global vaccine constraints, these results are relevant to policymakers, especially with highly transmissible variants and rising incidence in many countries.

Funding

Public Health England
ESCRT-I controls lysosomal membrane protein homeostasis and restricts MCOLN1-dependent TFEB/TFE3 signaling
Authors: Wróbel Marta , Szymańska Ewelina , Budick-Harmelin Noga , Kolmus Krzysztof , Goryca Krzysztof , Dąbrowska Michalina , Paziewska Agnieszka , Mikula Michał , Cendrowski Jarosław , Miączyńska Marta
Published: July 2021

Within the endolysosomal pathway in mammalian cells, ESCRT complexes facilitate degradation of proteins residing in endosomal membranes. Recent studies revealed that yeast ESCRT machinery also sorts ubiquitinated proteins from the vacuolar membrane for degradation in the vacuole lumen. However, whether mammalian ESCRTs perform a similar function at lysosomes remained unknown. Here, we show that ESCRT-I restricts the size of lysosomes and promotes degradation of proteins from lysosomal membranes, including MCOLN1, a Ca2+ channel protein. Upon ESCRT-I depletion, the lysosomal accumulation of non-degraded proteins coincided with elevated expression of genes annotated to cholesterol biosynthesis and biogenesis of lysosomes, indicative of response to lysosomal stress. Accordingly, the lack of ESCRT-I promoted abnormal cholesterol accumulation in lysosomes and activated TFEB/TFE3 transcription factors. Finally, we discovered that in contrast to basal TFEB/TFE3 signaling that depended on the availability of exogenous lipids, the stress-induced activation of this pathway was Ca2+-MCOLN1-dependent. Hence, we provide evidence that ESCRT-I is crucial for maintaining lysosomal homeostasis and we elucidate mechanisms distinguishing basal from lysosomal stress-induced TFEB/TFE3 signaling.
The role of trade-offs and feedbacks in shaping integrated plasticity and behavioral correlations
Authors: Dochtermann Ned A.
Published: July 2021

How behaviors vary among individuals and covary with other behaviors has been a major topic of interest over the last two decades. Unfortunately, proposed theoretical and conceptual frameworks explaining the seemingly ubiquitous observation of behavioral (co)variation have rarely successfully generalized. Two observations perhaps explain this failure: First, phenotypic correlations between behaviors are more strongly influenced by correlated and reversible plastic changes in behavior than by “behavioral syndromes”. Second, while trait correlations are frequently assumed to arise via trade-offs, the observed pattern of correlations is not consistent with simple pair-wise trade-offs. A possible resolution to the apparent inconsistency between observed correlations and a role for trade-offs is provided by state-behavior feedbacks. This is critical because the inconsistency between data and theory represents a major failure in our understanding of behavioral evolution. These two primary observations emphasize the importance of an increased research focus on correlated reversible plasticity in behavior—frequently estimated and then disregarded as within-individual covariances.

LAY SUMMARY

Correlations between behaviors are common but observed patterns of these correlations are, at least superficially, inconsistent with expectations of trade-offs. This mismatch is potentially resolved via feedbacks between behaviors and energy availability, suggesting important new research directions.

DATA AND MODEL AVAILABILITY

Model code, as well as the data associated with Figures 2 & 3, are available at github.com/DochtermannLab/FeedbacksModel. Both code and data will be made available at Dryad if accepted.
Site-specific recognition of SARS-CoV-2 nsp1 protein with a tailored titanium dioxide nanoparticle
Authors: Agback P. , Agback T. , Dominguez F. , Frolova E.I. , Seisenbaeva G. , Kessler V.
Published: July 2021

The ongoing world-wide Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) pandemic shows the need for new sensing and therapeutic means against the CoV viruses. The SARS-CoV-2 nsp1 protein is important, both for replication and pathogenesis, making it an attractive target for intervention. In recent years nanoparticles have been shown to interact with peptides, ranging in size from single amino acids up to proteins. These nanoparticles can be tailor-made with specific functions and properties including bioavailability. To the best of our knowledge, in this study we show for the first time that a tailored titanium oxide nanoparticle interacts specifically with a unique site of the full-length SARS-CoV-2 nsp1 protein. This can be developed potentially into a tool for selective control of viral protein functions.
Application of Modular Response Analysis to Medium- to Large-Size Biological Systems
Authors: Mekedem Meriem , Ravel Patrice , Colinge Jacques
Published: July 2021

The development of high-throughput genomic technologies associated with recent genetic perturbation techniques such as short hairpin RNA (shRNA), gene trapping, or gene editing (CRISPR/Cas9) has made it possible to obtain large perturbation data sets. These data sets are invaluable sources of information regarding the function of genes, and they offer unique opportunities to reverse engineer gene regulatory networks in specific cell types. Modular response analysis (MRA) is a well-accepted mathematical modeling method that is precisely aimed at such network inference tasks, but its use has been limited to rather small biological systems so far. In this study, we show that MRA can be employed on large systems with almost 1,000 network components. In particular, we show that MRA performance surpasses general-purpose mutual information-based algorithms. Part of these competitive results was obtained by the application of a novel heuristic that pruned MRA-inferred interactionsa posteriori. We also exploited a block structure in MRA linear algebra to parallelize large system resolutions.

Author Summary

The knowledge of gene and protein regulatory networks in specific cell types, including pathologic cells, is an important endeavor in the post-genomic era. A particular type of data obtained through the systematic perturbation of the actors of such networks enables the reconstruction of the latter and is becoming available at a large scale (networks comprised of almost 1,000 genes). In this work, we benchmark the performance of a classical methodology for such data called modular response analysis, which has been so far applied to networks of modest sizes. We also propose improvements to increase performance and to accelerate computations on large problems.
MAFB surrogates the glucocorticoid receptor ability to induce tolerogenesis in dendritic cells
Authors: Morante-Palacios Octavio , Ciudad Laura , Micheroli Raphael , de la Calle-Fabregat Carlos , Li Tianlu , Barbisan Gisela , Houtman Miranda , Edalat Sam , Frank-Bertoncelj Mojca , Ospelt Caroline , Ballestar Esteban
Published: July 2021

Glucocorticoids (GCs) exert potent anti-inflammatory effects in immune cells through the glucocorticoid receptor (GR). Dendritic cells (DCs), central actors for coordinating immune responses, acquire tolerogenic properties in response to GCs. Tolerogenic DCs (tolDCs) have emerged as a potential treatment for various inflammatory diseases. To date, the underlying cell type-specific regulatory mechanisms orchestrating GC-mediated acquisition of immunosuppressive properties remain poorly understood. In this study, we investigated the transcriptomic and epigenomic remodeling associated with differentiation to DCs in the presence of GCs. Our analysis demonstrates a major role of MAFB in this process, in synergy with GR. GR and MAFB both interact with methylcytosine dioxygenase TET2 and bind to genomic loci that undergo specific demethylation in tolDCs. We also show that the role of MAFB is more extensive, binding to thousands of genomic loci in tolDCs. Finally, MAFB knockdown erases the tolerogenic properties of tolDCs and reverts the specific DNA demethylation and gene upregulation. The preeminent role of MAFB is also demonstrated in vivo for myeloid cells from synovium in rheumatoid arthritis following GC treatment. Our results imply that, once directly activated by GR, MAFB takes over the main roles to orchestrate the epigenomic and transcriptomic remodeling that define the tolerogenic phenotype.
Isolating the Sources of Pipeline-Variability in Group-Level Task-fMRI results
Authors: Bowring Alexander , Nichols Thomas E. , Maumet Camille
Published: July 2021

While the development of tools and techniques has broadened our horizons for comprehending the complexities of the human brain, a growing body of research has highlighted the pitfalls of such methodological plurality. In a recent study, we found that the choice of software package used to run the analysis pipeline can have a considerable impact on the final group-level results of a task-fMRI investigation (Bowring et al., 2019, BMN). Here we revisit our work, seeking to identify the stages of the pipeline where the greatest variation between analysis software is induced. We carry out further analyses on the three datasets evaluated in BMN, employing a common processing strategy across parts of the analysis workflow and then utilizing procedures from three software packages (AFNI, FSL and SPM) across the remaining steps of the pipeline. We use quantitative methods to compare the statistical maps and isolate the main stages of the workflow where the three packages diverge. Across all datasets, we find that variation between the packages’ results is largely attributable to a handful of individual analysis stages, and that these sources of variability were heterogeneous across the datasets (e.g. choice of first-level signal model had the most impact for the ds000001 dataset, while first-level noise model was more influential for ds000109 dataset). We also observe areas of the analysis workflow where changing the software package causes minimal differences in the final results, finding that the group-level results were largely unaffected by which software package is used to model the low-frequency fMRI drifts.
The genetic interaction of REVOLUTA and WRKY53 links plant development, senescence, and immune responses
Authors: Bresson Justine , Doll Jasmin , Vasseur François , Stahl Mark , von Roepenack-Lahaye Edda , Kilian Joachim , Stadelhofer Bettina , Kremer James M. , Kolb Dagmar , Wenkel Stephan , Zentgraf Ulrike
Published: July 2021

In annual plants, tight coordination of successive developmental events is of primary importance to optimize performance under fluctuating environmental conditions. The recent finding of the genetic interaction of WRKY53, a key senescence-related gene with REVOLUTA, a master regulator of early leaf patterning, raises the question of how early and late developmental events are connected. Here, we investigated the developmental and metabolic consequences of an alteration of the REVOLUTA and WRKY53 gene expression, from seedling to fruiting. Our results show that REVOLUTA critically controls late developmental phases and reproduction while inversely WRKY53 determines vegetative growth at early developmental stages. We further show that these regulators of distinct developmental phases frequently, but not continuously, interact throughout ontogeny and demonstrated that their genetic interaction is mediated by the salicylic acid (SA). Moreover, we showed that REVOLUTA and WRKY53 are keys regulatory nodes of development and plant immunity thought their role in SA metabolic pathways, which also highlights the role of REV in pathogen defence. Together, our findings demonstrate how late and early developmental events are tightly intertwined by molecular hubs. These hubs interact with each other throughout ontogeny, and participate to the interplay between plant development and immunity.
Selection and evaluation of qPCR reference genes for expression analysis in the tiny egg parasitoid wasp,Trichogramma dendrolimiMatsumura (Hymenoptera: Trichogrammatidae)
Authors: Huo Liang-xiao , Bai Xue-ping , Che Wu-nan , Ning Su-fang , Lv Lin , Zhang Li-sheng , Zhou Jin-cheng , Dong Hui
Published: July 2021

The egg parasitoidTrichogrammaspp. is an important biological control agent used against multiple species of Lepidopteran pest in forestry and agriculture. Due to the importance ofTrichogrammaspp. in biocontrol programs, its biological characteristics have been studied in detail, and current investigations should focus on the molecular biology of these tiny parasitoids. Real-time quantitative PCR (qPCR) is considered as the standard method for quantifying the gene expression of organisms. Surprisingly, the appropriate reference genes to ensure robust qPCR have not been documented at all for theTrichogrammagenus. This study aimed to identify suitable reference genes for use in qPCR procedure ofTrichogramma dendrolimi. Nine candidate housekeeping genes, namely glyceraldehyde-3-phosphate dehydrogenase (GAPDH), forkhead box O (FOXO), superoxide dismutase (SOD), beta-actin (ACTIN), ribosomal protein L10a (RPL10a), L18 (RPL18), L28 (RPL28), S13 (RPS13), and S15 (RPS15), were tested for their suitability as reference genes for developmental stage (3rd, 4th, 5th, 6th, 7th, 8th, 9th, and 10thday after parasitization), tissue (head, thorax, and abdomen of adults), sex of adults (male and female), and temperature (17 °C, 25 °C, and 32 °C). According to the GeNorm analysis, robust analysis should involve using an appropriate combination of reference genes, namely, at least three genes for different development stages, two genes for different tissues, two genes for different sex, and two genes for different temperature, respectively. According to the RelFinder method and by assessing the integrated values from using the ΔCt method, GeNorm, NormFinder, and BestKeeper, we identified the developmental stage-specific reference genesSOD, GAPDH, andACTIN; tissue-specific reference genesRPL18andRPS15; sex-specific reference genesSODandRPL18; and temperature-specific reference genesRPL18andRPL10. When testing the use of stable vs. unstable reference genes, the substantial differences were observed in the estimation expression of a hypothetical target gene,HSP90, in response to temperature. The present study provides a robust method for the measurement of gene expression inT. dendrolimiand will be helpful for future biological control programs usingTrichogrammawasps.
spatialGE: Quantification and visualization of the tumor microenvironment heterogeneity using spatial transcriptomics
Authors: Ospina Oscar E. , Wilson Christopher M. , Soupir Alex C. , Berglund Anders , Smalley Inna , Tsai Kenneth Y. , Fridley Brooke L.
Published: July 2021

Spatially-resolved transcriptomics promises to increase our understanding of the tumor microenvironment and improve cancer prognosis and therapies. Nonetheless, analytical methods to explore associations between the spatial heterogeneity of the tumor and clinical data are not available. Hence, we have developed spatialGE, a software that provides visualizations and quantification of the tumor microenvironment heterogeneity through gene expression surfaces, spatial heterogeneity statistics (SThet) that can be compared against clinical information, spot-level cell deconvolution, and spatially-informed clustering (STclust), all using a new data object to store data and resulting analyses simultaneously.

Availability and implementation

The R package and tutorial/vignette are available at https://github.com/FridleyLab/spatialGE. A script to reproduce the analyses in this manuscript is available in Supplementary information.

Contact

Fridley.Lab@Moffitt.org or Brooke.Fridley@Moffitt.org

Supplementary information

Available at Bioinformatics online.

Abstract Figure

Graphical abstract

Overview of spatialGE features. A. The STList data object from spatialGE can be creared from several sources, including comma- or tab-separated files containing gene counts and spatial coordinates. The object can also be created directly from Visium outputs, Seurat objects, or GeoMx outputs. B. Users can optionally provide a metadata file, containing information associated with each sample (one row per sample, or per ROI if GeoMx data). C. Methods for quality control of data are provided by spatialGE, including visualizations of counts and genes per spot, as well as filtering of spots or genes within user-determined thresholds. D. A novel method (STclust) performs spatially informed clustering of spots and tissue domain identification. E. spatialGE provides different types of data visualization, including gene expression at each spot (“quilt plots”), as well as adaptation of spatial interpolation (“kriging”) to spatial transcriptomics data (transcriptomic surface). F. spatialGE also leverages spatial statistics (Moran’s I, Geary’s C, Getis-Ord Gi) to quantitatively describe heterogeneity within the tumor microenvironment and to explore associations between spatial heterogeneity and clinical oucomes. G. Gene expression deconvolution can also be applied to each spot to detect immune cell types (xCell) and classification of spots as tumor or stroma (ESTIMATE).
Water Nanoconfined in a Hydrophobic Pore: MD Simulations and Water Models
Authors: Lynch Charlotte I. , Klesse Gianni , Rao Shanlin , Tucker Stephen J. , Sansom Mark S. P.
Published: July 2021

Water molecules within biological ion channels are in a nano-confined environment and therefore exhibit novel behaviours which differ from that of bulk water. Here, we investigate the phenomenon of hydrophobic gating, the process by which a nanopore may spontaneously de-wet to form a ‘vapour lock’ if the pore is sufficiently hydrophobic and/or narrow. Notably, this occurs without steric occlusion of the pore. Using molecular dynamics simulations with both additive and polarisable (AMOEBA) force fields, we investigate this wetting/de-wetting behaviour in the TMEM175 ion channel. We examine how a range of rigid fixed-charge (i.e. additive) and polarisable water models affect wetting/de-wetting in both the wild-type structure and in mutants chosen to cover a range of nanopore radii and pore-lining hydrophobicities. Crucially, we find that the rigid fixed-charge water models lead to similar wetting/de-wetting behaviours, but that the polarisable water model resulted in an increased wettability of the hydrophobic gating region of the pore. This has significant implications for molecular simulations of nano-confined water, as it implies that polarisability may need to be included if we are to gain detailed mechanistic insights into wetting/de-wetting processes. These findings are of importance for the design of functionalised biomimetic nanopores (for e.g. sensing or desalination), as well as for furthering our understanding of the mechanistic processes underlying biological ion channel function.
CRISPR-Cas Controls Cryptic Prophages
Authors: Song Sooyeon , Semenova Ekaterina , Severinov Konstantin , Fernández-García Laura , Benedik Michael J. , Maeda Toshinari , Wood Thomas K.
Published: July 2021

The bacterial archetypal adaptive immune system, CRISPR-Cas, is thought to be repressed in the best-studied bacterium,Escherichia coliK-12. We show here that theE. coliCRISPR-Cas system is active and serves to inhibit its nine defective (i.e., cryptic) prophages. Specifically, compared to the wild-type strain, reducing the amounts of specific interfering RNAs (crRNA) decreases growth by 40%, increases cell death by 700%, and prevents persister cell resuscitation. Similar results were obtained by inactivating CRISPR-Cas by deleting the entire 13 spacer region (CRISPR array); hence, CRISPR-Cas serves to inhibit the remaining deleterious effects of these cryptic prophages, most likely through CRISPR array-derived crRNA binding to cryptic prophage mRNA, rather than through cleavage of cryptic prophage DNA; i.e., self-targeting. Consistently, four of the 13E. colispacers contain complementary regions to the mRNA sequences of seven cryptic prophages, and inactivation of CRISPR-Cas increases the level of mRNA for lysis protein YdfD of cryptic prophage Qin and lysis protein RzoD of cryptic prophage DLP-12. Also, lysis is clearly seen via transmission electron microscopy when the whole CRISPR-Cas array is deleted, and eliminating spacer #12, which encodes crRNA with complementary regions for DLP-12 (includingrzoD), Rac, Qin (includingydfD), and CP4-57 cryptic prophages, also results in growth inhibition and cell lysis. Therefore, we report the novel results that (i) CRISPR-Cas is active inE. coliand (ii) CRISPR-Cas is used to tame cryptic prophages, likely through RNAi; i.e., unlike with active lysogens, active CRISPR-Cas and cryptic prophages may stably co-exist.
miR-17∼92 exerts stage-specific effects in adult V-SVZ neural stem cell lineages
Authors: Favaloro Fabrizio , DeLeo Annina , Delgado Ana C. , Doetsch Fiona
Published: July 2021

In the adult mouse brain, neural stem cells (NSCs) in the ventricular-subventricular zone (V-SVZ) generate neurons and glia throughout life. microRNAs are important regulators of cell states, frequently acting in a stage- or context-dependent manner. Here, miRNA profiling of FACS-purified populations identified miR-17∼92 as highly upregulated in activated NSCs and transit amplifying cells (TACs) in comparison to quiescent NSCs. Conditional deletion of miR-17∼92 in NSCs reduced stem cell proliferation both in vitro and in vivo. In contrast, in TACs, miR-17∼92 deletion caused a selective shift from neurogenic DLX2+ TACs towards oligodendrogenic OLIG2+ TACs, resulting in increased oligodendrogenesis to the corpus callosum. miR-17∼92 deletion also decreased proliferation and maturation of intraventricular oligodendrocyte progenitor cells. Together, these findings reveal stage- and cell-type-specific functions of the miR-17∼92 cluster within adult V-SVZ neural stem cell lineages.
Unravelling the effects of disease-associated mutations in TDP-43 protein via molecular dynamics simulation and machine learning
Authors: Sharma Abhibhav , Dey Pinki
Published: July 2021

Over the last two decades, the pathogenic aggregation of TAR DNA-binding protein 43 (TDP-43) is found to be strongly associated with several fatal neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTD), etc. While the mutations and truncation in TDP-43 protein have been suggested to be responsible for TDP-43 pathogenesis by accelerating the aggregation process, the effects of these mutations on the bio-mechanism of pathologic TDP-43 protein remained poorly understood. Investigating this at the molecular level, we formulized an integrated workflow of molecular dynamic simulation and machine learning models (MD-ML). By performing an extensive structural analysis of three disease-related mutations (i.e. I168A, D169G, and I168A-D169G) in the conserved RNA recognition motifs (RRMs) of TDP-43 and we observed that the I168A-D169G double mutant delineates the highest packing of the protein inner core as compared to the other mutations, which may indicate more stability and higher chances of pathogenesis. Moreover, through our MD-ML workflow, we identified the biological descriptors of TDP-43 which includes the interacting residue pairs and individual protein residues that influence the stability of the protein and could be experimentally evaluated to develop potential therapeutic strategies.