bluuebunny/crossref_metadata_2025 huggingface dataset:
The physio-affective phenome of major depression is strongly associated with biomarkers of astroglial and neuronal projection toxicity which in turn are associated with peripheral inflammation, insulin resistance and lowered calcium
Authors: Al-Hakeim Hussein Kadhem , Al-Naqeeb Tabarek Hadi , Almulla Abbas F. , Maes Michael
Published: July 2022

Background

Major depressive disorder (MDD) is characterized by elevated activity of peripheral neuro-immune and neuro-oxidative pathways, which may cause neuro-affective toxicity by disrupting neuronal circuits in the brain. No study has explored peripheral indicators of neuroaxis damage in MDD in relation to serum inflammatory and insulin resistance (IR) biomarkers, calcium, and the physio-affective phenome consisting of depressive, anxious, chronic fatigue, and physiosomatic symptoms.

Methods

Serum levels of phosphorylated tau protein 217 (P-tau217), platelet-derived growth factor receptor beta (PDGFR), neurofilament light chain (NF-L), glial fibrillary acidic protein (GFAP), C-reactive protein (CRP), calcium and the HOMA2-insulin resistance (IR) index were measured in 94 MDD patients and 47 controls.

Results

61.1% of the variance in the physio-affective phenome (conceptualized as a factor extracted from depression, anxiety, fatigue and physiosomatic symptoms) is explained by the regression on GFAP, NF-L, P-tau2017, PDGFRβ and HOMA2-IR (all positively associated), and decreased calcium. In addition, CRP and HOMA2-IR predicted 28.9% of the variance in the neuroaxis index. We observed significant indirect effects of CRP and calcium on the physio-affective phenome which were partly mediated by the four neuroaxis biomarkers. Annotation and enrichment analysis revealed that the enlarged GFAP, P-tau217, PDGFR, and NF-L network was enriched in glial cell and neuronal projections, the cytoskeleton and axonal transport, including a mitochondrion.

Conclusions

Peripheral inflammation and IR may damage the astroglial and neuronal projections thereby interfering with mitochondrial transport. This toxicity, combined with inflammation, IR and lowered calcium, may, at least in part, induce the phenome of MDD.
Proteome dynamics of COVID-19 severity learnt by a graph convolutional network of multi-scale topology
Authors: Gauthier Samy , Tran-Dinh Alexy , Morilla Ian
Published: July 2022

Many efforts have been recently done to characterise the molecular mechanisms of COVID-19 disease. These efforts resulted in a full structural identification of ACE2 as principal receptor of the Sars-CoV-2 spike protein in the cell. However, there are still important open questions related to other proteins involved in the progression of the disease. To this end, we have modelled the plasma proteome of 384 COVID patients. The model calibrated proteins measures at three time tags and make also use of the detailed clinical evaluation outcome of each patient after their hospital stay at day 28. Our analysis is able to discriminate severity of the disease by means of a metric based on available WHO scores of disease progression. Then, we identify by topological vectorisation those proteins shifting the most in their expression depending on that severity classification. Finally, the extracted topological invariants respect the protein expression at different times were used as base of a graph convolutional network. This model enabled the dynamical learning of the molecular interactions produced between the identified proteins.
Chiral Derivatization-enabled Discrimination and Visualization of Proteinogenic Amino Acids by Ion Mobility Mass Spectrometry
Authors: Xie Chengyi , Chen Yanyan , Wang Xiaoxiao , Song Yuanyuan , Shen Yuting , Diao Xin , Zhu Lin , Wang Jianing , Cai Zongwei
Published: July 2022

The importance of chiral amino acids (AAs) in living organisms has been widely recognized since the discovery of endogenous D-AAs as potential biomarkers in several metabolic disorders. Chiral analysis by ion mobility spectrometry-mass spectrometry (IMS-MS) has the advantages of high speed and sensitivity but is still in its infancy. Here, a Nα-(2,4-dinitro-5-fluorophenyl)-L-alaninamide (FDAA) derivatization is combined with trapped ion mobility spectrometry-mass spectrometry (TIMS-MS) for chiral AA analysis. For the first time, we demonstrate the simultaneous separation of 19 pairs of chiral proteinogenic AAs in a single fixed condition TIMS-MS run. The utility of this approach presents for mouse brain extracts by direct-infusion TIMS-MS. The robust separation ability in complex biological sample was proven in MALDI TIMS mass spectrometry imaging (MSI) as well by directly depositing 19 pairs of AAs on a tissue slide following on-tissue derivatization. In addition, endogenous chiral amino acids were also detected and distinguished. The developed methods show compelling application prospects in biomarker discovery and biological research.

Entry for the Table of Contents

The combination of chiral derivatization and trapped ion mobility-mass spectrometry provides the first insights into the separation of 19 pairs of chiral proteinogenic D/L-amino acids in a single run and further visualization of chiral amino acids under complex biological matrix.
Large-scale expansions of Friedreich’s ataxia GAA•TTC repeats in human cells are prevented by LNA-DNA oligonucleotides and PNA oligomers
Authors: Rastokina Anastasia , Mozafari Negin , Cebrián Jorge , Smith C.I Edvard , Mirkin Sergei M. , Zain Rula
Published: July 2022

The human disease Friedreich’s ataxia (FRDA) is caused by expansions of GAA•TTC repeats in the first intron intron of the frataxin (FXN) gene, and both intergenerational and somatic expansions are crucial for disease development. We and others have shown earlier that expanded GAA•TTC repeats can form an intramolecular triplex structure (H-DNA). Here we studied the effects of locked nucleic acid (LNA)-DNA mixmer oligonucleotides and peptide nucleic acid (PNA) oligomers on the expansion of GAA•TTC repeats in cultured human cells. Our experimental system employes a mammalian/yeast shuttle plasmid containing a selectable cassette to detect repeat expansions. Using our in-house in vitro triplex-specific DNA cleavage assay, we first confirmed H-DNA formation by the (GAA)100•(TTC)100 repeat in the selectable cassette and demonstrated that the designed LNA-DNA oligonucleotides as well as PNA oligomers are able to disrupt this structure. We then found that both LNA-DNA mixmers and PNA oligomers prevent repeat expansions in human cells. In the accompanying paper, we show that expansions of GAA•TTC repeats in this experimental system occur during replication fork stalling, regression and restart at the repetitive run. We hypothesize, therefore, that triplex DNA formation by the GAA•TTC repeats is a key to their instability, while LNA-DNA oligonucleotides and PNA oligomers counteract repeat expansions by disrupting the triplex at the fork or preventing triplex formation upon fork reversal.
Evofosfamide and Gemcitabine Act Synergistically in Pancreatic Cancer Xenografts by Dual Action on Tumor Vasculature and Inhibition of Homologous Recombination DNA Repair
Authors: Otowa Yasunori , Kishimoto Shun , Saida Yu , Yamashita Kota , Yamamoto Kazutoshi , Chandramouli Gadisetti VR , Devasahayam Nallathamby , Mitchell James B. , Krishna Murali C. , Brender Jeffery R.
Published: July 2022

Aims

Pancreatic ductal adenocarcinomas (PDACs) form hypovascular and hypoxic tumors which are difficult to treat with current chemotherapy regimens. Gemcitabine (GEM) is often used as a first line treatment for PDACs, but has issues with chemoresistance and penetration in the interior of the tumor. Evofosfamide, a hypoxia activated prodrug, has been shown to be effective in combination with GEM, although the mechanism of each drug on the other has not been established. We used two mouse xenografts from two cell lines (MIA Paca-2 and SU 86.86) with different tumor microenvironmental characteristics to probe the action of each drug on the other.

Results

GEM treatment enhanced survival times in mice with SU.86.86 xenografts (HR =0.35, 95% CI=0.13 to 0.90 p=0.03) but had no effect on MIA Paca-2 mice (HR =0.91, 95% CI=0.37 to 2.25, p=0.84). Conversely, evofosfamide had no effect on SU86.86 mice and did not improve survival times to a statistically significant degree (HR=0.57, 95% CI=0.23 to 1.42, p=0.22). In MIA Paca-2 tumors, which were initially poorly perfused, electron paramagnetic resonance (EPR) imaging showed that oxygenation worsened when treated with GEM, providing a direct mechanism for the activation of evofosfamide by GEM and the effectiveness of evofosfamide and GEM combinations. Sublethal amounts of either treatment enhanced the toxicity of other treatment in vitro in Su86.86 but not in MIAPaca-2. Repair of double stranded DNA lesions was enhanced in the combination treatment in Su86.86 but not MIA Paca-2.

Innovations

A possible mechanism for the synergy between evofosfamide and GEM has been proposed.

Conclusion

The synergy between GEM and evofosfamide appears to stem from the dual action of GEM’s effect on tumor vasculature and the GEM inhibition of the homologous recombination DNA repair process. The relative importance of each pathway is dependent on the tumor microenvironment and merits further study.
ELISA–on-Chip: High throughput antibody profiling using antigen microarrays
Authors: Levy Shlomia , Abd Alhadi Marwa , Azulay Asaf , Kahana Amit , Bujanover Nir , Gazit Roi , McGargill Maureen A. , Friedman Lilach M. , Hertz Tomer
Published: July 2022

Vaccination and natural infection both elicit potent humoral responses that provide protection from subsequent infections. The immune-history of an individual following such exposures is in part encoded by antibodies. While there are multiple immunoassays for measuring antibody responses, the majority of these methods measure responses to a single antigen. A commonly used method for measuring antibody responses is the enzyme-linked immunosorbent assay (ELISA) assay - a semi-quantitative assay that is simple to perform in research and clinical settings. Here we present the ELISA-on-Chip assay - a novel antigen microarray based assay for rapid high-throughput antibody profiling. The assay can be used for profiling IgG, IgA and IgM responses to multiple antigens simultaneously, requiring minimal amounts of sample and antigens. Using three different types of influenza antigen microarrays, we demonstrated the specificity and sensitivity of our novel assay and compared it to the traditional ELISA assay, using samples from mice, chickens and humans. We also showed that our assay can be readily used with dried blood spots, which can be collected from wild birds, as well as from newborns and children. The ELISA-on-Chip assay can be readily used to profile hundreds of samples against dozens of antigens in a single day, and therefore offers an attractive alternative to the traditional ELISA assay.
Cardiac Post-acute Sequelae symptoms of SARS-CoV-2 in Community-Dwelling Adults: Cross-sectional Study
Authors: Ogungbe Oluwabunmi , Gilotra Nisha A. , Davidson Patricia M. , Farley Jason E. , Dennison Himmelfarb Cheryl R. , Post Wendy S. , Commodore-Mensah Yvonne
Published: July 2022

Objective

To examine risk factors for cardiac-related PASC in community-dwelling adults after acute coronavirus disease 2019 (COVID-19) infection.

Methods

We performed a cross-sectional analysis among adults who tested positive for COVID-19. Outcomes were self-reported cardiac-related PASC. We conducted stepwise multivariable logistic regression to assess association between the risk factors (existing cardiovascular disease, pre-existing conditions, days since positive test, COVID hospitalization, age, sex, education, income) and cardiac-related PASC.

Results

Among a sample of 442 adults, mean(±SD) age was 45.4 (16.2) years, 71% female, 13% Black; 46% reported pre-existing conditions; 23% had cardiovascular (CV) risk factors; and 4% had cardiovascular diseases (CVD). The prevalence of persistent cardiac-related symptoms and newly diagnosed cardiac conditions was 43% and 27%, respectively. The odds for cardiac-related PASC were 2.01 (95%CI: 1.27-3.17) higher in persons with underlying CV risk factors/CVD than in those without. The odds for cardiac-related PASC were higher among persons with underlying pre-existing conditions (adjusted odds ratio aOR: 2.00, 95% CI:1.28-3.10) and among those who were hospitalized (aOR: 3.03, 95%CI:1.58-5.83).

Conclusions

More than a third of persons with COVID-19 reported cardiac-related PASC symptoms. Risk factors for cardiac-related PASC symptoms include underlying CV risk factors/CVD, pre-existing conditions, increasing age, and COVID-19 hospitalization. COVID-19 may play an important role in worsening the prognosis of existing CV risk factors and increasing risk of complications.

Key Messages

What is already known on this topic

Infection with SARS-CoV-2 virus may lead to persistent cardiac symptoms indicative of cardiac injury. COVID-19 may play an important role in worsening the prognosis of existing CVD and pre-existing conditions.

What this study adds

Little is known about characterization of cardiac-related Post-Acute Sequelae of SARS-CoV-2 Infection (PASC) and recovery in community-dwelling adults. Hence, this study provides further evidence on the burden of possible cardiac-related PASC symptoms and diagnosed cardiac conditions. The findings also suggest that underlying CVD, pre-existing conditions, older age, and COVID-19 hospitalization, may be risk factors for persistent cardiac-related PASC symptoms.

How this study might affect research, practice or policy

These results underscore urgent needs for coordinated efforts directed at resource allocation and optimization of primary care for persons with cardiac PASC and for prevention of resulting CV events and complications
Drivers of COVID-19 policy stringency in 175 countries and territories: COVID-19 cases and deaths, gross domestic products per capita, and health expenditures
Authors: Jalloh Mohamed F. , Zeebari Zangin , Nur Sophia A. , Prybylski Dimitri , Nur Aasli A. , Hakim Avi J. , Winters Maike , Steinhardt Laura C. , Gatei Wangeci , Omer Saad B. , Brewer Noel T. , Nordenstedt Helena
Published: July 2022

Objective

To understand the associations of COVID-19 cases and deaths with policy stringency globally and regionally.

Methods

We modeled the marginal effects of new COVID-19 cases and deaths on policy stringency (scored 0–100) in 175 countries and territories, adjusting for gross domestic product (GDP) per capita and health expenditure (% of GDP). Time periods examined were March–August 2020, September 2020– February 2021, and March–August 2021.

Results

Policy response to new cases and deaths was faster and more stringent early in the COVID-19 pandemic (March–August 2020) compared to subsequent periods. New deaths were more strongly associated with stringent policies than new cases. In an average week, 1 new death per 100,000 people was associated with a stringency increase of 2.1 units in March–August 2020, 1.3 units in September 2020–February 2021, and 0.7 units in March–August 2021. New deaths in Africa and the Western Pacific were associated with more stringency than in other regions. Higher health expenditure was associated with less stringent policies. GDP per capita did not have consistent patterns of associations with stringency.

Conclusions

Our findings demonstrate the need for enhanced mortality surveillance to ensure policy alignment during health emergencies. Countries that invest less of their GDP in health are inclined to enact stringent policies during health emergencies than countries with more significant health expenditure.
IFNγ insufficiency during mouse intravaginal Chlamydia trachomatis infection exacerbates alternative activation in macrophages with compromised CD40 functions
Authors: Challagundla Naveen , Shah Dhruvi , Dalai Sarat K , Agrawal-Rajput Reena
Published: July 2022

Chlamydia trachomatis (C.tr), an obligate intracellular pathogen, causes asymptomatic genital infections in women and is also a leading cause of preventable blindness. Limited mouse model of chronic C.tr infection are available to study the host immune response. We have developed in vivo mice models of acute and chronic infections for C. trachomatis to explore the significance of macrophage-directed response in mediating immune activation/suppression. During chronic and repeated infections, IFNγ secretion from T cells is abated while TGFβ and IL-10 secretion is enhanced. An increase in exhaustion (PD1, CTLA4) and anergic (Klrg3, Tim3) T cell markers is also observed during chronic infection. It was observed that alternatively-activated macrophages with low CD40 expression promote Th2 and Treg differentiation and lead to sustained C. trachomatis genital infection. Macrophages infected with C. trachomatis or treated with supernatant of infected epithelial cells drive them to alternately-activated phenotype. C. trachomatis infection prevents increase in CD40 expression. Low IFNγ, as observed in chronic infection leads to incomplete clearance of bacteria and poor immune activation. C. trachomatis decapacitates IFNγ responsiveness in macrophages via hampering IFNγRI and IFNγRII expression which can be correlated with poor expression of MHC-II, CD40, iNOS and NO release even following IFNγ supplementation. Alternatively-activated macrophages during C. trachomatis infection express low CD40 rendering immunosuppressive, Th2 and Treg differentiation which could not be reverted even after IFNγ supplementation. The alternative macrophages also harbour high bacterial load and are poor responders to IFNγ, thus promoting immunosupression. Thus, C. trachomatis modulate the innate immune cells attenuating the anti-chlamydial functions of T cells in a manner that involves decreased CD40 expression on macrophages.
Manipulation of neuronal activity in the entorhinal-hippocampal circuit affects intraneuronal amyloid-β levels
Authors: Bjorkli Christiana , Ebbesen Nora C , Julian Joshua B. , Witter Menno P , Sandvig Axel , Sandvig Ioanna
Published: July 2022

One of the neuropathological hallmarks of Alzheimer’s disease (AD) is the accumulation of amyloid-β (Aβ) plaques, which is preceded by intraneuronal build-up of toxic, aggregated Aβ during disease progression. Aβ plaques are first deposited in the neocortex before appearing in the medial temporal lobe, and tau pathology with subsequent neurodegeneration in the latter anatomical region causes early memory impairments in patients. Current research suggests that early intraneuronal Aβ build-up may begin in superficial layers of lateral entorhinal cortex (LEC). To examine whether manipulation of neuronal activity of LEC layer II neurons affected intraneuronal Aβ levels in LEC and in downstream perforant path terminals in the hippocampus (HPC), we used a chemogenetic approach to selectively and chronically silence superficial LEC neurons in young and aged 3xTg AD mice and monitored its effect on intraneuronal Aβ levels in LEC and HPC. Chronic chemogenetic silencing of LEC neurons led to reduced early intraneuronal Aβ in LEC and in projection terminals in the HPC, compared with controls. Early intraneuronal Aβ levels in the downstream HPC correlated with activity levels in superficial layers of LEC, with the subiculum being the earliest subregion involved, and our findings give evidence to early AD neuropathology originating in select neuronal populations.
Parameter inference for enzyme and temperature constrained genome-scale models
Authors: Pettersen Jakob Peder , Almaas Eivind
Published: July 2022

The metabolism of all living organisms is dependent on temperature, and therefore, having a good method to predict temperature effects at a system level is of importance. A recently developed Bayesian computational framework for enzyme and temperature constrained genome-scale models (etcGEM) predicts the temperature dependence of an organism’s metabolic network from thermodynamic properties of the metabolic enzymes, markedly expanding the scope and applicability of constraint-based metabolic modelling.

Here, we show that the Bayesian calculation method for inferring parameters for an etcGEM is unstable and unable to estimate the posterior distribution. The Bayesian calculation method assumes that the posterior distribution is unimodal, and thus fails due to the multimodality of the problem. To remedy this problem, we developed an evolutionary algorithm which is able to obtain a diversity of solutions in this multimodal parameter space.

We quantified the phenotypic consequences on six metabolic network signature reactions of the different parameter solutions resulting from use of the evolutionary algorithm. While two of these reactions showed little phenotypic variation between the solutions, the remainder displayed huge variation in flux-carrying capacity. This result indicates that the model is underdetermined given current experimental data and that more data is required to narrow down the model predictions. Finally, we made improvements to the software to reduce the running time of the parameter set evaluations by a factor of 8.5, allowing for obtaining results faster and with less computational resources.
HDAC6 inhibition partially alleviates mitochondrial trafficking defects and restores motor function in human motor neuron and zebrafish models of Charcot-Marie-Tooth Disease Type 2A
Authors: Butler Larissa , Adamson Kathryn I. , Johnson Stuart L. , Jestice Lydia H. , Price Christopher J. , Stavish Dylan , Pooranachandran Niedharsan , Malicki Jarema J. , Tsakiridis Anestis , Grierson Andrew J. , Barbaric Ivana
Published: July 2022

Charcot Marie Tooth Disease (CMT) is a group of inherited progressive conditions affecting distal motor and sensory neurons, leading to muscle weakness, pain and loss of sensation in limbs. There are currently no treatments for this debilitating disease. To investigate disease mechanisms and facilitate treatment discovery, here we developed an in vitro model for CMT type 2A by introducing the patient-specific MFN2R94Q mutation into human embryonic stem cells (hESCs). Isogenic mutant and wild-type hESCs differentiated to spinal motor neurons with similar efficiency and gave rise to functional motor neurons in vitro. However, MFN2R94Q/+ spinal motor neurons displayed impaired mitochondrial trafficking, resulting in reduced numbers of mitochondria in distal parts of axons. Importantly, we showed that mitochondrial trafficking defects can be alleviated by treatment with an HDAC6 inhibitor. Chemical and genetic inhibition of HDAC6 also significantly rescued the motor phenotype in a zebrafish CMT2A model. Taken together, our study reveals a mutation-specific insight into CMT2A disease mechanism and confirms HDAC6 as a promising target for further therapeutic development.
Performances of bioinformatics tools for the analysis of sequencing data of Mycobacterium tuberculosis complex strains
Authors: Quagliaro Pauline , Dziri Samira , Magdoud El Alaoui Fatma , Saint Louis Patrick , de Pontual Loïc , Marin Julie , Carbonnelle Etienne , Billard-Pomares Typhaine
Published: July 2022

Whole genome sequencing of Mycobacterium tuberculosis complex (MTBC) strains is a new and rapidly growing tool to obtain results regarding resistance, virulence factors and phylogeny of the strains. Bioinformatics tools presented as user-friendly and easy to use are available online. The objective of this work was to evaluate the performances of two bioinformatics tools, easily accessible on the internet, for the analysis of sequencing data of MTBC strains.

Two hundred and twenty-seven MTBC strains isolated at the laboratory of the Avicenne Hospital between 2015 and 2021 were sequenced using Illumina®(USA) MiSeq technology. An analysis of the sequencing data was performed using the two tools Mykrobe and PhyResSE. Sequencing quality, resistance or susceptibility status and phylogeny were investigated for each strain. Genotypic resistance results were compared to the results obtained by phenotypic drug susceptibility testing performed in the hospital’s routine laboratory.

Using the PhyResSE tool we found an average coverage of 98% against the reference strain H37Rv and an average depth of 119X. No information on sequencing quality was obtained with the Mykrobe tool. The concordance of each tool with the phenotypic method for determining susceptibility to first-line anti-tuberculosis drugs was 95%. Mykrobe and PhyResSE tools identified resistance to second-line anti-tuberculosis drugs in 5.3% and 5.7% of cases respectively. The sensitivity and specificity of each tool compared to the phenotypic method was respectively 70% and 98% for Mykrobe and 76% and 97% for PhyResSE. Finally, the two tools showed 99.5% agreement in lineage determination.

The Mykrobe and PhyResSE bioinformatics tools were easy to use, fast and efficient. The Mykrobe tool had the advantage of being offline and its interface was more user-friendly. The use of these platforms depends on their accessibility and updating. However, their use is accessible to people not trained in bioinformatics and would allow a complementary approach to phenotypic methods for the study of MTBC strains.
Metformin Alleviates Arthrofibrosis via Fibroblast Metabolic Reprogramming
Authors: Zhu Zhenglin , Gao Shengqiang , Zhu Hui , Chen Yi , Wu Dandong , Chen Zhiyu , Zou Jing , Wu Xiangdong , Hu Ning , Chen Di , Huang Wei , Chen Hong
Published: July 2022

Background

Emerging studies have suggested an essential role of fibroblast metabolic reprogramming in the pathogenesis of arthrofibrosis. The metabolic modulator metformin appears to be a therapeutic candidate for fibrotic disorders. However, whether metformin could alleviate arthrofibrosis has not been defined. In this study we have determined if treatment with metformin has the beneficial effect on arthrofibrosis and its underlying mechanism.

Methods

Articular capsule samples were collected from patients with/without arthrofibrosis to perform gene and protein expression analysis. Arthrofibrosis animal model was established to examine the anti-fibrotic effect of metformin. Cell culture experiments were conducted to determine the mechanism by which metformin inhibits fibroblast activation.

Results

We found that glycolysis was upregulated in human fibrotic articular capsules. In an arthrofibrosis animal model, intra-articular injection of metformin mitigated inflammatory reactions, downregulated expression of both fibrotic and glycolytic markers, improved range of motion of the joint, and reduced capsular fibrosis and thickening. At the cellular level, metformin inhibited the activation of fibroblasts and mitigated the abundant influx of glucose into activated fibroblasts. Interestingly, metformin prompted a metabolic shift from oxidative phosphorylation to aerobic glycolysis in activated fibroblasts, resulting in the anti-fibrotic effect of metformin.

Conclusion

Metformin decreased glycolysis, causing a metabolic shift toward aerobic glycolysis in activated fibroblasts and has beneficial effect on the treatment of arthrofibrosis.

The translational potential of this article

The finding of this study demonstrated the therapeutic effect of metformin on arthrofibrosis and defined novel targets for the treatment of articular fibrotic disorders.
Predicting causal citations without full text
Authors: Hoppe Travis A. , Arabi Salsabil , Hutchins B. Ian
Published: July 2022

Insights from biomedical citation networks can be used to identify promising avenues for accelerating research and its downstream bench-to-bedside translation. Citation analysis generally assumes that each citation documents causal knowledge transfer that informed the conception, design, or execution of the main experiments. Citations may exist for other reasons. In this paper we identify a subset of citations that are unlikely to represent causal knowledge flow. Using a large, comprehensive feature set of open access data, we train a predictive model to identify such citations. The model relies only on the title, abstract, and reference set and not the full-text or future citations patterns, making it suitable for publications as soon as they are released, or those behind a paywall (the vast majority). We find that the model identifies, with high prediction scores, citations that were likely added during the peer review process, and conversely identifies with low prediction scores citations that are known to represent causal knowledge transfer. Using the model, we find that federally funded biomedical research publications represent 30% of the estimated causal knowledge transfer from basic studies to clinical research, even though these comprise only 10% of the literature, a three-fold overrepresentation in this important type of knowledge transfer. This finding underscores the importance of federal funding as a policy lever to improve human health.

Significance statement

Citation networks document knowledge flow across the literature, and insights from these networks are increasingly used to form science policy decisions. However, many citations are known to be not causally related to the inception, design, and execution of the citing study. This adds noise to the insights derived from these networks. Here, we show that it is possible to train a machine learning model to identify such citations, and that the model learns to identify known causal citations as well. We use this model to show that government funding drives a disproportionate amount of causal knowledge transfer from basic to clinical research. This result highlights a straightforward policy lever for accelerating improvements to human health: federal funding.
Duration of immune protection of SARS-CoV-2 natural infection against reinfection in Qatar
Authors: Chemaitelly Hiam , Nagelkerke Nico , Ayoub Houssein H. , Coyle Peter , Tang Patrick , Yassine Hadi M. , Al-Khatib Hebah A. , Smatti Maria K. , Hasan Mohammad R. , Al-Kanaani Zaina , Al-Kuwari Einas , Jeremijenko Andrew , Kaleeckal Anvar Hassan , Latif Ali Nizar , Shaik Riyazuddin Mohammad , Abdul-Rahim Hanan F. , Nasrallah Gheyath K. , Al-Kuwari Mohamed Ghaith , Butt Adeel A. , Al-Romaihi Hamad Eid , Al-Thani Mohamed H. , Al-Khal Abdullatif , Bertollini Roberto , Abu-Raddad Laith J.
Published: July 2022

BACKGROUND

The future of the SARS-CoV-2 pandemic hinges on virus evolution and duration of immune protection of natural infection against reinfection. We investigated duration of protection afforded by natural infection, the effect of viral immune evasion on duration of protection, and protection against severe reinfection, in Qatar, between February 28, 2020 and June 5, 2022.

METHODS

Three national, matched, retrospective cohort studies were conducted to compare incidence of SARS-CoV-2 infection and COVID-19 severity among unvaccinated persons with a documented SARS-CoV-2 primary infection, to incidence among those infection-naïve and unvaccinated. Associations were estimated using Cox proportional-hazard regression models.

RESULTS

Effectiveness of pre-Omicron primary infection against pre-Omicron reinfection was 85.5% (95% CI: 84.8-86.2%). Effectiveness peaked at 90.5% (95% CI: 88.4-92.3%) in the 7th month after the primary infection, but waned to ∼70% by the 16th month. Extrapolating this waning trend using a Gompertz curve suggested an effectiveness of 50% in the 22nd month and <10% by the 32nd month. Effectiveness of pre-Omicron primary infection against Omicron reinfection was 38.1% (95% CI: 36.3-39.8%) and declined with time since primary infection. A Gompertz curve suggested an effectiveness of <10% by the 15th month. Effectiveness of primary infection against severe, critical, or fatal COVID-19 reinfection was 97.3% (95% CI: 94.9- 98.6%), irrespective of the variant of primary infection or reinfection, and with no evidence for waning. Similar results were found in sub-group analyses for those ≥50 years of age.

CONCLUSIONS

Protection of natural infection against reinfection wanes and may diminish within a few years. Viral immune evasion accelerates this waning. Protection against severe reinfection remains very strong, with no evidence for waning, irrespective of variant, for over 14 months after primary infection.
Polygenic architecture of rare coding variation across 400,000 exomes
Authors: Weiner Daniel J. , Nadig Ajay , Jagadeesh Karthik A. , Dey Kushal K. , Neale Benjamin M. , Robinson Elise B. , Karczewski Konrad J. , O’Connor Luke J.
Published: July 2022

Both common and rare genetic variants influence complex traits and common diseases. Genome-wide association studies have discovered thousands of common-variant associations, and more recently, large-scale exome sequencing studies have identified rare-variant associations in hundreds of genes1–3. However, rare-variant genetic architecture is not well characterized, and the relationship between common- and rare-variant architecture is unclear4. Here, we quantify the heritability explained by gene-wise burden of rare coding variants and compare the genetic architecture of common and rare variation across 22 common traits and diseases in 400,000 UK Biobank exomes5. Rare coding variants (AF = 1e-6 - 1e-3) explain 1.3% (SE = 0.03%) of phenotypic variance on average – much less than common variants – and most burden heritability is explained by ultra-rare loss-of-function variants (AF = 1e-6 - 1e-5). Common and rare variants implicate the same cell types, with similar enrichments, and they have pleiotropic effects on the same pairs of traits, with similar genetic correlations. They partially colocalize at individual genes and loci, but not to the same extent: burden heritability is strongly concentrated in a limited number of significant genes (median: 6 genes explaining 19% of h2), while common-variant heritability is much more polygenic. Burden heritability is also more strongly concentrated in constrained genes (median enrichment: 4.5x vs. 2.1x for common variants), indicating that negative selection affects common- and rare-variant architecture differently. Finally, we find that burden heritability for schizophrenia and bipolar disorder6,7 is approximately 2%. Our results show that there are a tractable number of large-effect genes to discover by studying rare variants, that common and rare associations are mechanistically convergent, and that rare coding variants will contribute only modestly to missing heritability and population risk stratification.
Fibromyalgia patients with high levels of anti-satellite glia cell IgG antibodies present with more severe symptoms
Authors: Krock Emerson , Morado-Urbina Carlos E. , Menezes Joana , Hunt Matthew A. , Sandström Angelica , Kadetoff Diana , Tour Jeanette , Verma Vivek , Kultima Kim , Haglund Lisbet , Meloto Carolina B. , Diatchenko Luda , Kosek Eva , Svensson Camilla I.
Published: July 2022

Objective

Transferring fibromyalgia patient IgG to mice induces pain-like behaviour and fibromyalgia IgG binds mouse and human satellite glia cells (SGCs). These findings suggest that autoantibodies could be part of fibromyalgia pathology. However, it is unknown how frequently fibromyalgia patients have anti-SGC antibodies and how anti-SGC antibodies associate with disease severity.

Methods

We quantified serum or plasma anti-SGC IgG levels in two fibromyalgia cohorts from Sweden and Canada using an indirect immunofluorescence murine cell culture assay. Fibromyalgia serum IgG binding to human SGCs in human dorsal root ganglia tissue sections was assessed by immunofluorescence (n=14/group).

Results

In the cell culture assay anti-SGC IgG levels were increased in both fibromyalgia cohorts compared to controls. Elevated anti-SGC IgG was associated with higher levels of self-reported pain in both cohorts, and higher fibromyalgia impact questionnaire scores and increased pressure sensitivity in the Swedish cohort. Anti-SGC IgG levels were not associated with fibromyalgia duration. Swedish FM patients were clustered into FM-severe and FM-mild groups and the FM-severe group had elevated anti-SGC IgG compared to the FM-mild and controls. Anti-SGC IgG levels detected in culture were positively correlated with increased binding to human SGCs. Moreover, the FM-severe group had elevated IgG binding to human SGCs compared to the FM-mild and control groups.

Conclusions

A subset of fibromyalgia patients have elevated levels of anti-SGC antibodies, and the antibodies are associated with more severe fibromyalgia severity. Screening fibromyalgia patients for anti-SGC antibodies could provide a path to personalized treatment options that target autoantibodies and autoantibody production.
An Early Miocene skeleton ofBrachydiceratheriumLavocat, 1951 (Mammalia, Perissodactyla) from the Baikal area, Russia, and a revised phylogeny of Eurasian teleoceratines
Authors: Sizov Alexander , Klementiev Alexey , Antoine Pierre-Olivier
Published: July 2022

Hippo-like rhinocerotids, or teleoceratines, were a conspicuous component of Holarctic Miocene mammalian faunas, but their phylogenetic relationships remain poorly known. Excavations in lower Miocene deposits of the Olkhon Island (Tagay locality, Eastern Siberia; 16–18 Ma) have opened a unique window on the poorly-known early history of the Lake Baikal ecosystems, notably by unearthing a skeleton of the teleoceratineBrachydiceratherium shanwangense(Wang, 1965). The remains provide new insights into the skull and postcranial morphology of this elusive species. The new material is compared with other Eurasian teleoceratines and the relationships within Teleoceratina are investigated through a phylogenetic analysis.DiaceratheriumDietrich, 1931 (earliest Miocene, Western Europe) is found to be monotypic and is retrieved as the earliest teleoceratine offshoot. Other genera have more than one species and are also found to be monophyletic, withProsantorhinusHeissig, 1974 (early Miocene, Eurasia) +TeleocerasHatcher, 1894 (Miocene, North America) forming the sister clade ofBrachypotheriumRoger, 1904 (Miocene, Old World) +BrachydiceratheriumLavocat, 1951.Brachydiceratheriumincludes eight species spanning the late Oligocene to Late Miocene in Europe and Asia. All teleoceratine genera exceptDiaceratheriumspan considerable geographical and stratigraphical ranges, likely related to their ultra-generalist ecological preferences.
Restoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunction
Authors: Yeh Yu-Te , Sona Chandan , Yan Xin , Pathak Adrija , McDermott Mark I. , Xie Zhigang , Liu Liangwen , Arunagiri Anoop , Wang Yuting , Cazenave-Gassiot Amaury , Ghosh Adhideb , von Meyenn Ferdinand , Kumarasamy Sivarajan , Najjar Sonia M. , Jia Shiqi , Wenk Markus R. , Traynor-Kaplan Alexis , Arvan Peter , Barg Sebastian , Bankaitis Vytas A. , Poy Matthew N.
Published: July 2022

Defects in insulin processing and granule maturation are linked to pancreatic beta-cell failure during type 2 diabetes (T2D). Phosphatidylinositol transfer protein alpha (PITPNA) stimulates activity of phosphatidylinositol (PtdIns) 4-OH kinase to produce sufficient PtdIns-4-phosphate (PtdIns-4-P) in the trans-Golgi network to promote insulin granule maturation. PITPNA in beta-cells of T2D human subjects is markedly reduced suggesting its depletion accompanies beta-cell dysfunction. Conditional deletion of Pitpna in the beta-cells of Ins-Cre;Pitpnaflox/flox mice leads to hyperglycemia resulting from decreased glucose-stimulated insulin secretion (GSIS) and reduced pancreatic beta-cell mass. Furthermore, PITPNA silencing in human islets confirmed its role in PtdIns-4-P synthesis and led to impaired insulin granule maturation and docking, GSIS, and proinsulin processing with evidence of ER stress. Restoration of PITPNA in islets of T2D human subjects reversed these beta-cell defects and identify PITPNA as a critical target linked to beta-cell failure in T2D.
NAD+repletion with niacin counteracts cancer cachexia
Authors: Beltrà Marc , Pöllänen Noora , Fornelli Claudia , Tonttila Kialiina , Hsu Myriam Y. , Zampieri Sandra , Moletta Lucia , Porporato Paolo E. , Kivelä Riikka , Sandri Marco , Hulmi Juha J. , Sartori Roberta , Pirinen Eija , Penna Fabio
Published: July 2022

Cachexia is a debilitating wasting syndrome and highly prevalent comorbidity in cancer patients. It manifests especially with energy and mitochondrial metabolism aberrations that promote tissue wasting. We recently identified nicotinamide adenine dinucleotide (NAD+) loss to associate with muscle mitochondrial dysfunction in cancer hosts. In this study we confirmed that depletion of NAD+and downregulation ofNrk2, an NAD+biosynthetic enzyme, are common features of different mouse models and cachectic cancer patients. Testing NAD+repletion therapy in cachectic mice revealed that NAD+precursor, vitamin B3 niacin, efficiently corrected tissue NAD+levels, improved mitochondrial metabolism and ameliorated cancer- and chemotherapy-induced cachexia. To examine NAD+metabolism in a clinical setting, we showed that the low expression ofNRK2in cancer patients correlated with metabolic abnormalities underscoring the significance of NAD+in the pathophysiology of human cancer cachexia. Overall, our results propose a novel therapy target, NAD+metabolism, for cachectic cancer patients.
A Dimer between Monomers and Hexamers – Oligomeric Variations in Glucosamine 6-Phosphate Deaminase Family
Authors: Srinivasachari Sathya , Tiwari Vikas R. , Kharbanda Tripti R. , Sowdamini Ramanathan , Subramanian Ramaswamy
Published: July 2022

In bacteria that live in hosts whose terminal sugar is a sialic acid, Glucosamine 6-phosphate deaminase (NagB) catalyzes the last step in the conversion of sialic acid into Fructose-6-phosphate, which enters the glycolytic pathway. The enzyme exists as a hexamer in Gram-negative bacteria and is shown to be allosterically regulated. In Gram-positive bacteria, it exists as a monomer and lacks allosteric regulation. Our identification of a dimeric Gram-negative bacterial NagB motivated us to characterize the structural basis of the various oligomeric forms. We characterized the crystal structures of NagB from two Gram-negative pathogens, Haemophilus influenzae (Hi) and Pasturella multocida (Pm). The Hi-NagB is active as a hexamer, while Pm-NagB is active as a dimer. We confirm that this is not a crystallographic artifact by cryo-electron microscopy. Both Hi-NagB and Pm-NagB contain the C-terminal helix, and the residues in the interface involved in oligomerization are conserved. The hexamer is described as a dimer of trimers. In the Pm-NagB dimer, the dimeric interface is conserved. This would suggest that the three possible oligomeric forms of NagB are a monomer, a dimer, and a trimer of dimers. Computational modeling and MD simulations indicate that the residues at the trimeric interface have less stabilizing energy of oligomer formation than those in the dimer interface. We propose that Pm-NagB is the evolutionary link between the monomer and the hexamer forms.
An interpretable machine learning algorithm to predict disordered protein phase separation based on biophysical interactions
Authors: Cai Hao , Vernon Robert M. , Forman-Kay Julie D.
Published: July 2022

Protein phase separation is increasingly understood to be an important mechanism of biological organization and biomaterial formation. Intrinsically disordered protein regions (IDRs) are often significant drivers of protein phase separation. A number of protein phase separation prediction algorithms are available, with many specific for particular classes of proteins and others providing results that are not amenable to interpretation of contributing biophysical interactions. Here we describe LLPhyScore, a new predictor of IDR-driven phase separation, based on a broad set of physical interactions or features. LLPhyScore uses sequence-based statistics from the RCSB PDB database of folded structures for these interactions, and is trained on a manually curated set of phase separation driver proteins with different negative training sets including the PDB and human proteome. Competitive training for a variety of physical chemical interactions shows the greatest importance of solvent contacts, disorder, hydrogen bonds, pi-pi contacts, and kinked-beta structure, with electrostatics, cation-pi, and absence of helical secondary structure also contributing. LLPhyScore has strong phase separation prediction recall statistics and enables a quantitative breakdown of the contribution from each physical feature to a sequence’s phase separation propensity. The tool should be a valuable resource for guiding experiment and providing hypotheses for protein function in normal and pathological states, as well as for understanding how specificity emerges in defining individual biomolecular condensates.

Graphical Abstract
Improving Bacterial Genome Assembly Using a Test of Strand Orientation
Authors: Greenberg Grant , Shomorony Ilan
Published: July 2022

The complexity of genome assembly is due in large part to the presence of repeats. In particular, large reverse-complemented repeats can lead to incorrect inversions of large segments of the genome. To detect and correct such inversions in finished bacterial genomes, we propose a statistical test based on tetranucleotide frequency (TNF), which determines whether two segments from the same genome are of the same or opposite orientation. In most cases, the test neatly partitions the genome into two segments of roughly equal length with seemingly opposite orientations. This corresponds to the segments between the DNA replication origin and terminus, which were previously known to have distinct nucleotide compositions. We show that, in several cases where this balanced partition is not observed, the test identifies a potential inverted misassembly, which is validated by the presence of a reverse-complemented repeat at the boundaries of the inversion. After inverting the sequence between the repeat, the balance of the misassembled genome is restored. Our method identifies 31 potential misassemblies in the NCBI database, several of which are further supported by a reassembly of the read data.