bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparing the genetic and environmental architecture of blood count, blood biochemistry and urine biochemistry biological ages with machine learning
Authors: Le Goallec Alan , Diai Samuel , Vincent Théo , Patel Chirag J.
Published: July 2021

While a large number of biological age predictors have been built from blood samples, a blood count-based biological age predictor is lacking, and the genetic and environmental factors associated with blood-measured accelerated aging remain elusive. In the following, we leveraged 31 blood count biomarkers measured from 489,079 blood samples, 28 blood biochemistry biomarkers measured from 245,147 blood samples, and four urine biochemistry biomarkers measured from 158,381 samples to build three distinct biological age predictors by training machine learning models to predict age. Blood biochemistry significantly outperformed blood count and urine biochemistry in terms of age prediction (RMSE: 5.92+-0.02 vs. 7.60+-0.02 years and 7.72+-0.04 years). We performed genome wide association studies [GWASs], and found accelerated blood biochemistry, blood count and urine biochemistry aging to be respectively 26.2+-0.3%, 18.1+-0.2% and 10.5±0.5% GWAS-heritable. We identified 1,081 single nucleotide polymorphisms [SNPs] associated with accelerated blood biochemistry aging, 2,636 SNPs associated with accelerated blood cells aging and 24 SNPs associated with accelerated urine biochemistry aging. Similarly, we identified biomarkers, clinical phenotypes, diseases, environmental and socioeconomic factors associated with accelerated blood biochemistry, blood cells and urine biochemistry aging.
A functional TGFB1 polymorphism in the donor associates with long-term graft survival after kidney transplantation
Authors: Poppelaars Felix , da Costa Mariana Gaya , Faria Bernardo , Eskandari Siawosh K. , Damman Jeffrey , Seelen Marc A.
Published: July 2021

Introduction

Improvement of long-term outcomes in kidney transplantation remains one of the most pressing challenges, yet drug development is stagnating. Human genetics offers an opportunity for much-needed target validation in transplantation. Conflicting data exist about the effect of transforming growth factor-beta 1 (TGF-β1) on kidney transplant survival since TGF-β1 has pro-fibrotic and protective effects. We investigated the impact of a recently discovered functional TGBF1 polymorphism on kidney graft survival.

Methods

We performed an observational cohort study analyzing recipient and donor DNA in 1,271 kidney transplant-pairs from the University Medical Center Groningen in The Netherlands and associated a low-producing TGBF1 polymorphism (rs1800472-C>T) with 5, 10, and 15-year death-censored kidney graft survival.

Results

Donor genotype frequencies of rs1800472 in TGBF1 differed significantly between patients with and without graft loss (P=0.014). Additionally, the low-producing TGBF1 polymorphism in the donor was associated with an increased risk of graft loss following kidney transplantation (HR 2.12 for the T-allele; 95%-CI 1.18–3.79; P=0.012). The incidence of graft loss within 15 years of follow-up was 16.4% in the CC-genotype group and 31.6% in the CT-genotype group. After adjustment for transplant-related covariates, the association between the TGBF1 polymorphism in the donor and graft loss remained significant. In contrast, there was no association between the TGBF1 polymorphism in the recipient and graft loss.

Conclusion

Kidney allografts possessing a low-producing TGBF1 polymorphism have a higher risk of late graft loss. Our study adds to a growing body of evidence that TGF-β1 is beneficial, rather than harmful, for kidney transplant survival.
Vaccination and COVID-19 dynamics in hemodialysis patients: a population-based study in France
Authors: Karoui Khalil El , Hourmant Maryvonne , Ayav Carole , Glowacki François , Couchoud Cécile , Lapidus Nathanaël
Published: July 2021

Importance

Maintenance hemodialysis (MHD) patients have a high mortality risk after COVID-19 and an altered humoral response to vaccines, but vaccine clinical efficacy remains unknown in this population.

Objective

To estimate the association between vaccination and COVID-19 hospitalization rate in MHD patients

Design

Using Bayesian multivariable spatiotemporal models, we estimated the expected number of SARS-CoV-2 severe infections (infections with hospital admission) in MHD patients from simultaneous cases in the general population.

Setting

French population-based retrospective analysis in MHD and non-dialysis patients.

Participants

Models were fitted from 3620 hospitalizations of MHD patients and 457,160 hospitalizations in the general population.

Exposure

Severe SARS-CoV-2 infections in the general population and vaccine exposure.

Main Outcome and Measure

Weekly incidence of severe infections in MHD patients.

Results

During the first epidemic wave, incidence of severe infections in MHD patients was approximately proportional to incidence in the general population. However, our model overestimated incidence during the second wave, suggesting an effect of prevention measures during the 2nd wave. A second model (based on data up to the end of the 2nd wave) estimated that the risk in MHD patients decreased between waves 1 and 2, with incidence rate ratio (IRR) = 0.70 (95% CI: 0.64, 0.76). Moreover, while this model correctly estimated the reported MHD cases up to the end of the 2nd wave, predictions overestimated the expected number of cases from the beginning of the vaccination campaign. Using vaccination coverages as additional predictors permitted to correctly fit the weekly reported number of cases, with IRR in MHD patients of 0.41 (95% CI: 0.28, 0.58) for vaccine exposure in MHD patients and 0.50 (95% CI: 0.40, 0.61) per 10% increase in vaccination coverage in the same-age general population.

Conclusions and Relevance

Our findings suggest that both individual and herd immunity due to vaccination may yield a protective effect against severe forms of COVID-19 in MHD patients.

Question

Whether vaccination against SARS-CoV-2 limits hospitalization rates in hemodialysis patients is still unknown.

Findings

By modeling the dynamics of 3620 hospital admissions for SARS-CoV-2 infections among hemodialysis patients, as a proportion of 457,160 cases reported in the French general population from March 2020 to April 2021, we identified vaccination coverage in both hemodialysis patients and the general population as independently associated with protection of hemodialysis patients against severe infection.

Meaning

Vaccination against SARS-CoV-2 is associated with reduced hospitalization rate in hemodialysis patients.
A Design Thinking Approach to Enhance Interprofessional Education Between Technology and Medicine for Innovative Elder Pain Care
Authors: Gomutbutra Patama , Choosri Noppon , Lerttrakarnnon Peerasak
Published: July 2021

Background

Design thinking (DT) describes three stages in the design thinking cycle: 1) inspiration, which embodies the initial problem or opportunity; 2) ideation, which encompasses the development and refinement of ideas; and 3) implementation, which involves the introduction and application of the derived solution.

Method

The prospective educational program evaluation July 2020 – December 2020. A 150 min interactive workshop regarding developing innovative elder pain care. Medical students will be grouping into four medical students: 1 technological student. Then they will be assigned to match with a technology student. The interprofessional education design thinking activity consists of three parts; a brief introduction, the brainstorming process to identified pain points by persona and user journey to generate the idea, and the prototype presentation.

Results

Forty sixth-year medical students and twelve technological students participated. 58% of medical students and 95% of technological students perceived DT as very helpful for their careers. However, only 30% of medical students and 60% of technological students were inspired to develop actual prototypes after the course. Nearly all of the students responded they comfortable with this interdisciplinary project-based style. Still, the time of the workshop is too limited, and among those responding with no interest pursue the project gave a reason that they lack time after rotating to other courses.

Conclusion

Most medical students and technological students perceived DT as beneficial for their career and displayed satisfy in this co-project style. However, finding matched schedule of two disciplines made long-term interpersonal education challenging.
Applying Topical Anesthetic on Pediatric Lacerations in the Emergency Department: A Quality Improvement Project
Authors: Faris Nagham , Mesto Mohamad , Mrad Sandra , Kebbi Ola El , Asi Noor , Sawaya Rasha D.
Published: July 2021

Background

Caring for pediatric lacerations in the Emergency Department (ED) is typically painful because of irrigation and suturing. To improve this painful experience, we aimed to increase the use of a topical anesthetic, Eutectic Mixture of Local Anesthetics (EMLA) on eligible pediatric lacerations with an attainable, sustainable, and measurable goal of 60%.

Local Problem

The baseline rate of applying topical anesthetic to eligible lacerations was 23% in our ED. We aimed to increase the use of topical anesthetics on eligible pediatric lacerations to a measurable goal of 60% within 3 months of implementing our intervention.

Methods

We conducted a prospective, single center, interrupted time series, ED quality improvement project from November 2019 to July 2020. A multidisciplinary team of physicians and nurses performed a cause-and-effect analysis identifying two key drivers: early placement of EMLA and physician buy-in on which we built our Plan, Do, Study, and Act (PDSA) cycles. We collected data on number of eligible patients receiving EMLA, as well as patient and physician feedback via phone calls within 2 days post encounter. Balancing measures included ED length of stay (LOS), patient and physician satisfaction with EMLA, and side effects of EMLA.

Results

We needed 3 PDSA cycles to reach our goal of 60% in 3 months, which was also maintained for 5 months. PDSA cycles used educational interventions, direct provider feedback about non-compliance and patient satisfaction results obtained via phone calls. Balancing measures were minimally impacted: 75% good patient satisfaction, No adverse events but an increase in LOS of patients who received EMLA compared to those who did not (1.79 ± 0.66 VS 1.41 ± 0.83 hours, p<0.001). The main reasons for dissatisfaction for physicians were the increased LOS and the preference for procedural sedation or intranasal medications.

Conclusion

With a few simple interventions, our aim of applying EMLA to 60% of eligible pediatric lacerations was attained and maintained.
Prevalence of SARS-CoV-2 Antibodies from a one-year National Serosurveillance of Kenyan Blood Transfusion Donors
Authors: Uyoga Sophie , Adetifa Ifedayo M.O. , Otiende Mark , Gitonga John N. , Mugo Daisy , Nyagwange James , Karanja Henry K. , Tuju James , Makale Johnstone , Aman Rashid , Mwangangi Mercy , Amoth Patrick , Kasera Kadondi , Ng’ang’a Wangari , Kilonzo Nduku , Chege Evelynn , Yegon Christine , Odhiambo Elizabeth , Rotich Thomas , Orgut Irene , Kihara Sammy , Bottomley Christian , Kagucia Eunice W. , Gallagher Katherine E. , Etyang Anthony , Voller Shirine , Lambe Teresa , Wright Daniel , Barasa Edwine , Tsofa Benjamin , Mwangangi Joseph , Bejon Philip , Ochola-Oyier Lynette I. , Warimwe George M. , Agweyu Ambrose , Scott J. Anthony G.
Published: July 2021

In tropical Africa, SARS-CoV-2 epidemiology is poorly described because of lack of access to testing and weak surveillance systems. Since April 2020, we followed SARS-CoV-2 seroprevalence in plasma samples across the Kenya National Blood Transfusion Service. We developed an IgG ELISA against full length spike protein. Validated in locally-observed, PCR-positive COVID-19 cases and in pre-pandemic sera, sensitivity was 92.7% and specificity was 99.0%. Using sera from 9,922 donors, we estimated national seroprevalence of SARS-CoV-2 antibodies at 4.3% in April-June 2020 and 9.1% in August-September 2020. Kenya’s second COVID-19 wave peaked in November 2020. Here we estimate national seroprevalence in early 2021.

Between January 3 and March 15, 2021, we collected 3,062 samples from donors aged 16-64 years. Among 3,018 samples that met our study criteria, 1,333 were seropositive (crude seroprevalence 44.2%, 95% CI 42.4-46.0%). After Bayesian test-performance adjustment and population weighting to represent the national population distribution, the national estimate of seroprevalence was 48.5% (95% CI 45.2-52.1%). Seroprevalence varied little by age or sex but was higher in Nairobi (61.8%), the capital city, and lower in two rural regions.

Almost half of Kenya’s adult donors had evidence of past SARS-CoV-2 infection by March 2021. Although high, the estimate is corroborated by other population-specific estimates in country. Between March and June, 2% of the population were vaccinated against COVID-19 and the country experienced a third epidemic wave. Natural infection is outpacing vaccine delivery substantially in Africa, and this reality needs to be considered as objectives of the vaccine programme are set.
Critical timing for triggering public health interventions to prevent COVID-19 resurgence: a mathematical modelling study
Authors: Zou Zhuoru , Fairley Christopher K , Shen Mingwang , Scott Nick , Xu Xianglong , Li Zengbing , Li Rui , Zhuang Guihua , Zhang Lei
Published: July 2021

To prevent the catastrophic health and economic consequences from COVID-19 epidemics, some nations have aimed for no community transmission outside of quarantine. To achieve this, governments have had to respond rapidly to outbreaks with public health interventions. But the exact characteristics of an outbreak that trigger these measures differ and are poorly defined. We used existing data from epidemics in Australia to establish a practical model to assist stakeholders in making decisions about the optimal timing and extent of interventions. We found that the number of reported cases on the day that interventions commenced strongly predicted the size of the outbreaks. We quantified how effective interventions were at containing outbreaks in relation to the number of cases at the time the interventions commenced. We also found that containing epidemics from novel variants that had higher transmissibility would require more stringent interventions that commenced earlier. In contrast, increasing vaccination coverage would enable more relaxed interventions. Our model highlights the importance of early and decisive action in the early phase of an outbreak if governments aimed for zero community transmission, although new variants and vaccination coverage may change this.
Initial SARS-CoV-2 vaccination response can predict booster response for BNT162b2 but not for AZD1222
Authors: Perkmann Thomas , Perkmann-Nagele Nicole , Mucher Patrick , Radakovics Astrid , Repl Manuela , Koller Thomas , Jordakieva Galateja , Wagner Oswald F , Binder Christoph J , Haslacher Helmuth
Published: July 2021

Objectives

Our objective was to determine whether SARS-CoV-2 antibody levels after the first dose can predict the final antibody response and whether this is dependent on the vaccine type.

Methods

69 BNT162b2 (Pfizer/BioNTech) and 55 AZD1222 (AstraZeneca) vaccinees without previous infection or immunosuppressive medication were included. Anti-body levels were quantified 3 weeks after dose 1, in case of AZD1222 directly before boostering (11 weeks after dose 1) and 3 weeks after dose 2, with the Roche SARS-CoV-2 S total antibody assay.

Results

Pre-booster (BNT162b2: 80.6 [25.5-167.0] BAU/mL, AZD1222: 56.4 [36.4-104.8] BAU/mL, not significant) and post-booster levels (BNT162b2: 2,092.0 [1,216.3-4,431.8] BAU/mL, AZD1222: 957.0 [684.5-1,684.8] BAU/mL, p<0.0001) correlated well in BNT162b2 (ρ=0.53) but not in AZD1222 recipients. Moreover, antibody levels after the first dose of BNT162b2 correlated inversely with age (ρ=-0.33, P=0.013), whereas a positive correlation with age was observed after the second dose in AZD1222 recipients (ρ=0.26, P=0.030).

Conclusions

In conclusion, our data suggest that antibody levels quantified by the Roche Elecsys SARS-CoV-2 S assay before the booster shot could infer post-booster responses to BNT162b2, but not to AZ1222. In addition, we found a vaccine-dependent effect on antibody responses, suggesting a possible link between vaccine response and vector immunity.
A general model for the demographic signatures of the transition from pandemic emergence to endemicity
Authors: Li Ruiyun , Metcalf C. Jessica E. , Stenseth Nils Chr. , Bjørnstad Ottar N.
Published: July 2021

Anticipating the medium- and long-term trajectory of pathogen emergence has acquired new urgency given the ongoing COVID-19 pandemic. For many human pathogens the burden of disease depends on age and prior exposure. Understanding the intersection between human population demography and transmission dynamics is therefore critical. Here, we develop a realistic age-structured (RAS) mathematical model that integrates demography, social mixing and immunity to establish the suite of possible scenarios of future age-incidence and burden of mortality. With respect to COVID-19, we identify a plausible transition in the age-structure of risks once the disease reaches seasonal endemism, whether assuming long-lasting or brief protective immunity, and across a range of assumptions of relative severity of primary versus subsequent reinfections. We train the model using diverse real-world demographies and age-structured social mixing patterns to bound expectations for changing age-incidence and disease burden. The mathematical framework is flexible and can help tailoring mitigation strategies countries worldwide with varying demographies and social mixing patterns.

One Sentence Summary

A shift of COVID-19 risks to younger age-classes in future endemic circulation.
On the effectiveness of COVID-19 restrictions and lockdowns: Pan metron ariston
Authors: Spiliopoulos Leonidas
Published: July 2021

I examine the dynamics of confirmed case (and death) growth rates conditional on different levels of severity in implemented NPIs, the mobility of citizens and other non restrictive policies. To account for the endogeneity of many of these variables, and the possibility of correlated latent (unobservable) country characteristics, I estimate a four structural model of the evolution of case growth rates, death growth rates, average changes in mobility and the determination of the severity of NPIs. There are strongly decreasing returns to the stringency of NPIs, especially for extreme lockdowns, as no significant improvement in the main outcome measures is found beyond NPIs corresponding to a Stringency Index range of 51–60 for cases and 41–50 for deaths. A non-restrictive policy of extensive and open testing has half of the impact on pandemic dynamics as the optimal NPIs, with none of the associated social and economic costs resulting from the latter. Decreases in mobility were found to increase, rather than decrease case growth rates, consistent with arguments that within-household transmission–resulting from spending more time at residences due to mobility restrictions–may outweigh the benefits of reduced community transmission. Vaccinations led to a fall in case and death growth rates, however the effect size must be re-evaluated when more data becomes available. Governments conditioned policy choice on recent pandemic dynamics, and were found to de-escalate the associated stringency of implemented NPIs more cautiously than in their escalation, i.e., policy mixes exhibited significant hysteresis. Finally, at least 90% of the maximum effectiveness of NPIs can be achieved by policies with an average Stringency index of 31–40, without restricting internal movement or imposing stay at home measures, and only recommending (not enforcing) closures on workplaces and schools, accompanied by public informational campaigns. Consequently, the positive effects on case and death growth rates of voluntary behavioral changes in response to beliefs about the severity of the pandemic, generally trumped those arising from mandatory behavioral restrictions. The exception being more stringent mandatory restrictions on gatherings and international movement, which were found to be effective. The findings suggest that further work should be directed at re-evaluating the effectiveness of NPIs, particularly towards empirically determining the optimal policy mix and associated stringency of individual NPIs.
Impact of Fkbp5 × Early Life Adversity × Sex in Humanized Mice on Multidimensional Stress Responses and Circadian Rhythmicity
Authors: Nold Verena , Portenhauser Michelle , Del Prete Dolores , Blasius Andrea , Harris Isabella , Koros Eliza , Peleh Tatiana , Hengerer Bastian , Kolassa Iris-Tatjana , Slezak Michal , Allers Kelly Ann
Published: July 2021

The cumulative load of genetic predisposition, early life adversity (ELA) and lifestyle shapes the prevalence of psychiatric disorders. Single nucleotide polymorphisms (SNPs) in the human FKBP5 gene were shown to modulate disease risk. To enable investigation of disease-related SNPs in behaviorally relevant context, we generated humanized mouse lines carrying either the risk (AT) or the resiliency (CG) allele of the rs1360780 locus and exposed litters of these mice to maternal separation. Behavioral and physiological aspects of their adult stress responsiveness displayed interactions of genotype, early life condition and sex. In humanized females carrying the CG-but not the AT-allele, ELA led to altered HPA-axis functioning, exploratory behavior and sociability. These changes correlated with differential expression of genes in the hypothalamus, where synaptic transmission, metabolism, and circadian entrainment pathways were deregulated. Our data suggest an integrative role of FKBP5 in shaping the sex-specific outcome of ELA in adulthood.
Spatial heterogeneity in forest carbon storage affects priorities for reforestation
Authors: Chaplin-Kramer Rebecca , Johnson Justin Andrew , Sharp Richard P. , Chatterton Julia , Weil Charlotte , Baccini Alessandro , Sim Sarah
Published: July 2021

Reforestation is an important strategy for nature-based climate solutions and identifying carbon storage potential of different locations is critical to its success. Applying average carbon values from forest inventories ignores the spatial heterogeneity in forest carbon and the effects of forest edges on carbon storage degradation. Here we show how spatially-explicit, predictive carbon modeling, that leverages satellite, social and biogeophysical datasets, can be used to identify more efficient restoration opportunities for climate mitigation than area-based carbon stock averages. Accounting for regeneration of forest edges, in addition to reforestation, boosts estimates of potential carbon gains by more than 20%. The total potential carbon gain that could be achieved through reforestation at the level indicated by the Bonn Challenge (350Mha) is 51 Gt CO2-eq, but the “missing carbon” in our current forests accounts for 64.6 Gt CO2-eq globally; the greatest potential carbon gains are found in areas of high fragmentation.
Genome-Wide Disease Screening in Early Human Embryos with Primary Template-Directed Amplification
Authors: Xia Yuntao , Gonzales-Pena Veronica , Klein David J , Luquette Joe J , Puzon Liezl , Siddiqui Noor , Reddy Vikrant , Park Peter , Behr Barry R , Gawad Charles
Published: July 2021

Current preimplantation genetic testing (PGT) enables the selection of embryos based on fetal aneuploidy or the presence a small number of preselected disease-associated variants. Here we present a new approach that takes advantage of the improved genome coverage and uniformity of primary template-directed amplification (PTA) to call most early embryo genetic variants accurately and reproducibly from a preimplantation biopsy. With this approach, we identified clonal and mosaic chromosomal aneuploidy, de novo mitochondrial variants, and variants predicted to cause mendelian and non-mendelian diseases. In addition, we utilized the genome-wide information to compute polygenic risk scores for common diseases. Although numerous computational, interpretive, and ethical challenges remain, this approach establishes the technical feasibility of screening for and preventing numerous debilitating inherited diseases.
m6A demethylase ALKBH5 promotes tumor cell proliferation by destabilizing IGF2BPs target genes and worsens the prognosis of patients with non-small cell lung cancer
Authors: Tsuchiya Kazuo , Yoshimura Katsuhiro , Iwashita Yuji , Inoue Yusuke , Ohta Tsutomu , Watanabe Hirofumi , Yamada Hidetaka , Kawase Akikazu , Tanahashi Masayuki , Ogawa Hiroshi , Funai Kazuhito , Shinmura Kazuya , Suda Takafumi , Sugimura Haruhiko
Published: July 2021

The modification of N6-methyladenosine (m6A) in RNA and its eraser ALKBH5, an m6A demethylase, play important roles across various steps of human carcinogenesis. However, the involvement of ALKBH5 in non-small cell lung cancer (NSCLC) development remains to be completely elucidated. The current study revealed that the expression of ALKBH5 were increased in NSCLC and increased expression of ALKBH5 worsened the prognosis of patients with NSCLC. In vitro study revealed that ALKBH5 knockdown suppressed cell proliferation ability of PC9 and A549 cells as well as promoted G1 arrest and increased the number of apoptotic cells. Furthermore, ALKBH5 overexpression increased the cell proliferation ability of the immortalized cell lines. Microarray analysis and western blotting revealed that the expression of CDKN1A or TIMP3 were increased by ALKBH5 knockdown. These alterations were offset by a double knockdown of both ALKBH5 and one of the IGF2BPs. The decline of mRNAs was, at least partly, owing to the destabilization of these mRNAs by one of the IGF2BPs. In conclusions, the ALKBH5–IGF2BPs axis promotes cell proliferation and tumorigenicity, which in turn causes the unfavorable prognosis of NSCLC.
Re-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic and targetable tissue states
Authors: Al-Dalahmah Osama , Argenziano Michael G. , Kannan Adithya , Mahajan Aayushi , Furnari Julia , Paryani Fahad , Boyett Deborah , Save Akshay , Humala Nelson , Khan Fatima , Li Juncheng , Lu Hong , Sun Yu , Tuddenham John F. , Goldberg Alexander R. , Dovas Athanassios , Banu Matei A. , Sudhakar Tejaswi , Bush Erin , Lassman Andrew B. , McKhann Guy M. , Gill Brian J. A. , Youngerman Brett , Sisti Michael B. , Bruce Jeffrey N. , Sims Peter A. , Menon Vilas , Canoll Peter
Published: July 2021

Glioblastoma (GBM) is an aggressive diffusely infiltrating neoplasm that spreads beyond surgical resection margins, where it intermingles with non-neoplastic brain cells. This complex microenvironment harboring infiltrating glioma and non-neoplastic brain cells is the origin of tumor recurrence. Thus, understanding the cellular and molecular features of the glioma microenvironment is therapeutically and prognostically important. We used single-nucleus RNA sequencing (snRNAseq) to determine the cellular composition and transcriptional states in primary and recurrent glioma and identified three compositional ‘tissue-states’ defined by the observed patterns of cohabitation between neoplastic and non-neoplastic brain cells. These comprise states enriched in A) neurons and non-neoplastic glia, B) reactive astrocytes and inflammatory cells, and C) proliferating tumor cells. The tissue states also showed distinct associations with the different transcriptional states of GBM cells. Spatial transcriptomics revealed that the cell-types/transcriptional-states associated with each tissue state colocalize in space. Tissue states are clinically significant because they correlate with radiographic, histopathologic, and prognostic features. Importantly, we found that our compositionally-defined tissue states are enriched in distinct metabolic pathways. One such pathway is fatty acid biosynthesis, which was enriched in tissue state B – a state enriched in recurrent glioblastoma and associated with shorter overall survival- and composed of astrocyte-like/mesenchymal glioma cells, reactive astrocytes, and monocyte-like myeloid cells. We showed that treating acute slices of GBM with a fatty acid synthesis inhibitor is sufficient to deplete the transcriptional signature of tissue state B. Our findings define a novel compositional approach to analyze glioma-infiltrated tissue which allows us to discover prognostic and targetable features, paving the way to new mechanistic and therapeutic discoveries.
Chronic CNS Pathology is Associated with Abnormal Collagen Deposition and Fibrotic-like Changes
Authors: Macapagal Daphne Palacios , Cann Jennifer , Cresswell Georgia , Zerrouki Kamelia , Dacosta Karma , Wang Jingya , Connor Jane , Davidson Todd S.
Published: July 2021

Multiple sclerosis is a chronic debilitating disease of the CNS. The relapsing remitting form of the disease is driven by CNS directed inflammation. However, in the progressive forms of the disease, inflammation has abated and the underlying pathology is less well understood. In this paper, we show that chronic lesions in progressive MS are associated with fibrotic changes, a type of pathology that has previously not thought to occur in the CNS. In an animal model of chronic MS, late stage disease contains no inflammatory infiltrates and is instead characterized by collagen deposition that is histologically similar to fibrosis. In human MS samples, chronic, but not acute lesions, are devoid of inflammatory infiltrates and instead contain significant collagen deposition. Furthermore, we demonstrate that both mouse and human astrocytes are the cellular source of collagen. These results suggest that anti-fibrotic therapy may be beneficial in the treatment of progressive MS.
Comparative transcriptomics of tropical woody plants supports fast and furious strategy along the leaf economics spectrum in lianas
Authors: Sezen U. Uzay , Worthy Samantha J. , Umaña Maria N. , Davies Stuart J. , McMahon Sean M. , Swenson Nathan G.
Published: July 2021

Lianas, climbing woody plants, influence the structure and function of tropical forests. Climbing traits have evolved multiple times, including ancestral groups such as gymnosperms and pteridophytes, but the genetic basis of the liana strategy is largely unknown. Here, we use a comparative transcriptomic approach for 47 tropical plant species, including ten lianas of diverse taxonomic origins, to identify genes that are consistently expressed or downregulated only in lianas. Our comparative analysis of full-length transcripts enabled the identification of a core interactomic network common to lianas. Sets of transcripts identified from our analysis reveal features related to functional traits pertinent to leaf economics spectrum in lianas, include upregulation of genes controlling epidermal cuticular properties, cell wall remodeling, carbon concentrating mechanism, cell cycle progression, DNA repair and a large suit of downregulated transcription factors and enzymes involved in ABA-mediated stress response as well as lignin and suberin synthesis. All together, these genes are known to be significant in shaping plant morphologies through responses such as gravitropism, phyllotaxy and shade avoidance.
Area-based conservation planning in Japan: protected area network effectiveness to the post-2020 Global Biodiversity Framework
Authors: Shiono Takayuki , Kubota Yasuhiro , Kusumoto Buntarou
Published: July 2021

To reframe the imperfect review processes of nation-scale actions on area-based conservation through protected area (PA) networks, we first created novel infrastructure to visualize nation-level biodiversity information in Japan. We then assessed the performance of the existing PA network relative to land exploitation pressure and evaluated conservation effectiveness of PA expansion for the post-2020 Global Biodiversity Framework. The Zonation algorithm was used to spatially prioritize conservation areas to minimize biodiversity loss and the extinction risk for 8,500 Japanese vascular plant and vertebrate species under constraints of the existing PA network and land use. The spatial pattern of the identified priority areas, which were considered candidate areas for expansion of the current PA network, was influenced by land-use types according to the mask layers of non-PAs, and low-, middle-, and high-ranked PAs. The current PA network reduced the aggregate extinction risk of multiple species by 36.6%. Indeed, the percentage of built-up areas in the existing PAs was in general smaller than that in the areas surrounding PAs. Notably, high-ranked PAs fully restrained built-up pressure (0.037% per 10 years), whereas low-ranked PAs in the national park and wild-life protection areas did not (1.845% per 10 years). Conservation effects were predicted to substantially improve by expansion of high-ranked (legally strict) PAs into remote non-PAs without population/socio-economic activities, or expansion of medium-ranked PAs into agriculture forestry satoyama and urban areas. A 30% land conservation target was predicted to decrease extinction risk by 74.1% when PA expansion was implemented across remote areas, satoyama, and urban areas; moreover, PA connectivity almost doubled compared with the existing PA network. In contrast, a conventional scenario showed that placing national parks in state-owned and non-populated areas would reduce extinction risk by only 4.0%. The conservation prioritization analyses demonstrated an effectiveness of using a comprehensive conservation approach that reconciles land-sparing protection and land-sharing conservation in other effective area-based conservation measures (OECM) in satoyama and urban green spaces. Our results revealed that complementary inclusion of various PAs interventions related to their governance and land-use planning plays a critical role in effectively preventing biodiversity loss and makes it more feasible to achieve ambitious conservation targets.
Linking individual differences in cognitive control and perception: Meta-perception in older and younger adults
Authors: Klever Lena , Mamassian Pascal , Billino Jutta
Published: July 2021

Visual perception is not only shaped by sensitivity, but also by confidence, i.e. the ability to estimate the accuracy of a visual decision. There is robust evidence that younger observers have access to a reliable measure of their own uncertainty when making visual decisions. This metacognitive ability might be challenged during aging due to increasing sensory noise and decreasing cognitive control resources. We investigated age effects on visual confidence using a confidence forced-choice paradigm. We determined discrimination thresholds for trials in which perceptual judgements were indicated as confident and for those in which they were declined as confident. Younger adults (19-38 years) showed significantly lower discrimination thresholds than older adults (60-78 years). In both age groups, perceptual performance was linked to confidence judgements, but overall results suggest reduced confidence efficiency in older adults. However, we observed substantial variability of confidence effects across all particpants. This variability was closely linked to individual differences in cognitive control capacities, i.e. executive function. Our findings provide evidence for age-related differences in meta-perceptual efficiency that present a specific challenge to perceptual performance in old age. We propose that these age effects are primarily mediated by cognitive control resources, supporting their crucial role for metacognitive efficiency.
SARS-CoV-2 promotes microglial synapse elimination in human brain organoids
Authors: Samudyata  , Oliveira Ana Osório , Malwade Susmita , de Sousa Nuno Rufino , Goparaju Sravan K , Lekander Jessica Gracias , Orhan Funda , Steponaviciute Laura , Schalling Martin , Sheridan Steven D , Perlis Roy H. , Rothfuchs Antonio , Sellgren Carl M.
Published: July 2021

Neuropsychiatric manifestations are common in both the acute and post-acute phase of SARS-CoV-2 infection, but the mechanisms of these effects are unknown. In a newly established brain organoid model with innately developing microglia, we demonstrate that SARS-CoV-2 infection causes an extensive cell death and loss of post-synaptic termini. Despite limited neurotropism and a decelerating viral replication, we observe a threefold increase in microglial engulfment of postsynaptic termini after SARS-CoV-2 exposure. We define the microglial responses to SARS-CoV-2 infection by single cell transcriptomic profiling and observe an upregulation of interferon-responsive genes as well as genes promoting migration and synaptic stripping. To a large extent, SARS-CoV-2 exposed microglia display a transcriptomic profile previously observed in neurodegenerative disorders characterized by early a synapse loss and an increased incident risk after a Covid-19 infection. Our results reveal that brain organoids infected with SARS-CoV-2 display disruption in circuit integrity via microglia-mediated synapse elimination and identifies a potential novel mechanism contributing to cognitive impairments in patients recovering from Covid-19.
Complete depletion ofArabidopsislinker histones impairs the correlations among chromatin compartmentalization, DNA methylation and gene expression
Authors: Sun Zhenfei , Li Min , Wang Yunlong , Zhang Hui , Zhang Yu , Ma Min , Wang Pan , Fang Yaping , Li Guoliang , Fang Yuda
Published: July 2021

In eukaryotic cells, linker histone H1 anchors in and out ends of nucleosome DNA to promote chromatin to fold into the 30 nm fiber. However, if H1 plays a role in coordinating the three-dimensional (3D) chromatin architecture, DNA methylation, and transcriptional regulation is not clear. We engineered H1 knockout mutants inArabidopsis thalianawhich shows pleiotropic phenotypes. Using High-throughput Chromosome Conformation Capture (Hi-C), we found that H1 complete depletion dampens inter- and intra-chromosomal interactions, as well as intra- and inter-chromosomal arm interactions. MNase accessibility assays followed by sequencing (MNase-seq) showed that the nucleosome density decreases in centromeric regions and increases in chromosome arms. In contrast, DNA methylation level in CHG and CHH contexts increases in centromeric regions and decreases in chromosome arms as revealed by whole genome bisulfite sequencing (WGBS) inh1mutant. Importantly, the functional link between DNA methylation and gene transcription is defected, and the extensive switches between chromatin compartment A and B are uncoupled from genome-wide DNA methylation and most of gene transcriptions upon H1 depletion. These results suggested that linker histone H1 works as linkers among chromatin compartmentalization, DNA methylation and transcription.
Crystallographic studies of piperazine derivatives of 3-methyl-5-spirofluorenehydantoin in search of structural features of P-gp inhibitors
Authors: Żesławska Ewa , Szymańska Ewa , Nitek Wojciech , Handzlik Jadwiga
Published: July 2021

5-Spirofluorenehydantoin derivatives show efflux modulating, cytotoxic and antiproliferative effects in sensitive and resistant mouse T-lymphoma cells. In order to extend the knowledge available about the pharmacophoric features responsible for the glycoprotein P (P-gp) inhibitory properties of arylpiperazine derivatives of 3-methyl-5-spirofluorenehydantoin, we have performed crystal structure analyses for 1-[3-(3′-methyl-2′,4′-dioxospiro[fluorene-9,5′-imidazolidin]-1′-yl)propyl]-4-phenylpiperazine-1,4-diium dichloride monohydrate, C29H32N4O2
2+·2Cl−·H2O (1), 3′-methyl-1′-{3-[4-(4-nitrophenyl)piperazin-1-yl]propyl}spiro[fluorene-9,5′-imidazolidine]-2′,4′-dione, C29H29N5O4·H2O (2), 3′-methyl-1′-{5-[4-(4-nitrophenyl)piperazin-1-yl]pentyl}spiro[fluorene-9,5′-imidazolidine]-2′,4′-dione, C31H33N5O4 (3), and 1-benzyl-4-[5-(3′-methyl-2′,4′-dioxospiro[fluorene-9,5′-imidazolidin]-1′-yl)pentyl]piperazine-1,4-diium dichloride 0.613-hydrate, C32H38N4O2
2+·2Cl−·0.613H2O (4). Structure 3 is anhydrous but the other three structures crystallize with water present. The investigated compounds crystallize in the monoclinic crystal system, with the space group P21/n for 1 and 3, and P21/c for 2 and 4. The cations of salts 1 and 4 are doubly protonated, with the protons located on the N atoms of the piperazine rings. The packing of 1 and 4 in the crystals is dominated by intermolecular N—H...Cl and O—H...Cl hydrogen bonds. In the crystal structure of 2, the intermolecular interactions are dominated by O—H...O and O—H...N hydrogen bonds, while in 3, which is lacking in classic hydrogen-bond donors, it is C—H...O contacts that dominate. Additionally, we have performed induced-fit docking studies for the investigated compounds docked to the P-gp human homology model.
Talent management practices: perception of registered nurses in Malawian public hospitals
Authors: Dzimbiri George Lewis , Molefakgotla Alex Molefi
Published: July 2021

Purpose

The purpose of this study is to investigate nurses’ perception towards the current application of talent management practices in Malawian public hospitals. It further explores whether significant differences exist between the registered nurses’ perceptions of the current application of talent management practices based on their demographic factors.

Design/methodology/approach

The study employed a quantitative research approach, using a cross-sectional survey strategy. An adapted version of Human Capital Index (HCI) questionnaire with 45-items was administered amongst 947 registered nurses in four public hospitals. Eventually, 580 responses, representing 61.2 per cent were found to be acceptable for analysis. Stata version-16 software programme was used to analyse the data.

Findings

Findings of the study demonstrated that talent management practices are currently poorly applied amongst the nurses. Substantial gaps existed between the current applications versus the importance of talent management practices. Significant differences exist between the nurses perceptions of talent management practices based on their marital status.

Research limitations/implications

The study only focused on a single perspective (registered nurses) and a single area (Malawian public hospitals) – an issue that disregarded different views (e.g. doctors, hospital administrators, hospital directors and other hospital staff). Furthermore, the results of this study cannot be generalised to other public and private hospitals settings because the data were collected from central hospitals only.

Practical implications

Practically, this study highlights the problematic areas of talent management practices hence the need for effective talent management for nurses.

Social implications

The study has huge social implications in that the results will inform best practices for public hospitals thereby improving welfare of the patients and society at large.

Originality/value

The study contributes to new knowledge on nurses’ perception towards the application of talent management practices within the Malawian health sector and presents a valid and reliable measure to assess their perception.
Omnichannel promotions and their effect on customer satisfaction
Authors: Blom Angelica , Lange Fredrik , Hess Ronald L.
Published: July 2021

Purpose

This paper aims to investigate whether customer satisfaction varies when presented with different types of omnichannel promotions (shopping goal-congruent vs shopping goal-incongruent and monetary vs non-monetary promotions) and if the effect on satisfaction is mediated by service excellence. In addition, this paper examines whether consumers respond differently to these promotions when shopping for utilitarian or hedonic products or when they have an inherent utilitarian or hedonic shopping motivation.

Design/methodology/approach

Two online shopping scenario experiments are conducted. Study 1 (n = 1,034) differentiates effects of omnichannel promotions between hedonic and utilitarian product categories. Study 2 (n = 345) contrasts hedonic and utilitarian shopping motivation in the same product category.

Findings

The findings in this paper demonstrate positive effects from both presenting a shopping goal congruent and a monetary promotion in an omnichannel setting on customer satisfaction. The positive effects are explained by service excellence and are demonstrated to be attenuated in the hedonic product category and for consumers with a hedonic shopping motivation.

Research limitations/implications

The effect of omnichannel promotions was demonstrated using a scenario-based experimental approach, future research should use field experiments.

Practical implications

The findings in this paper demonstrate practical implications for a retailer who wishes to optimize its omnichannel promotion strategy across channels and touchpoints.

Originality/value

To date there is little directions for retailers on how to optimize their omnichannel promotion strategy. This paper contributes to research and practice by demonstrating that shopping goal-congruent promotions (vs in-congruent) and monetary promotions (vs non-monetary) increase customer satisfaction more in an omnichannel context. The effects are enhanced for utilitarian (vs hedonic) products/shopping motivation.
Budgetary restrictions and ethical behaviours in a hospital context – evidence from general surgeons
Authors: Silva Cristina Piedade , Sousa Rita Martins de
Published: July 2021

Purpose

The purpose of this paper is to study how budgetary constraints can have ethical implications on patient treatment options.

Design/methodology/approach

By applying a qualitative methodological approach (interviews) and participant observation, this paper studies the behaviour of surgeons in scenarios of financial restriction.

Findings

The empirical findings show that despite the conflict between the economy and the leges artis, surgeons maintain the ethical and deontological principles of their profession with fair rules of orientation.

Practical implications

The importance of this study can be realised by its continuity. One of the authors is already implicated on a wider research to investigate the influence of the economic scarcity of resources on general surgeons’ ethical behaviours.

Social implications

This paper is a contribution to understanding the rules that restrain the activities of surgeons. Politicians sometimes do not have a full understanding of the pressures that the medical profession faces in their day-to-day activities. Currently, with the addition of problems relate to COVID-19, politicians and populations seem to better understand the importance of the Serviço Nacional de Saúde (SNS), This paper hopes that this understanding will be not only a conjectural moment.

Originality/value

In conjunction with the economic recession that began in the first decade of this century, health institutions have long faced budgetary constraints that condition their material and human resources and correspondingly shape the scope of health professional activities. Until now, it has not been studied the impact of economic crises on the ethical behaviour of Portuguese surgeons. Therefore, this research is a first step and a useful contribution to understanding the rules that can restrain (or not) the ethical conduct of these health professionals.