bluuebunny/crossref_metadata_2025 huggingface dataset:
Formation of artificial chromosomes in Caenorhabditis elegans and analyses of their segregation in mitosis, DNA sequence composition and holocentromere organization
Authors: Lin Zhongyang , Xie Yichun , Nong Wenyan , Ren Xiaoliang , Li Runsheng , Zhao Zhongying , Hui Jerome Ho Lam , Yuen Karen Wing Yee
Published: July 2021

To investigate how exogenous DNA concatemerizes to form episomal artificial chromosomes (ACs), acquire equal segregation ability and maintain stable holocentromeres, we injected DNA sequences with different features, including sequences that are repetitive or complex, and sequences with different AT-contents, into the gonad of Caenorhabditis elegans to form ACs in embryos, and monitored AC mitotic segregation. We demonstrated that AT-poor sequences (26% AT-content) delayed the acquisition of segregation competency of newly formed ACs. We also co-injected fragmented Saccharomyces cerevisiae genomic DNA, differentially expressed fluorescent markers and ubiquitously expressed selectable marker to construct a less repetitive, more complex AC. We sequenced the whole genome of a strain which propagates this AC through multiple generations, and de novo assembled the AC sequences. We discovered CENP-AHCP-3 domains/peaks are distributed along the AC, as in endogenous chromosomes, suggesting a holocentric architecture. We found that CENP-AHCP-3 binds to the unexpressed marker genes and many fragmented yeast sequences, but is excluded in the yeast extremely high-AT-content centromeric and mitochondrial DNA (> 83% AT-content) on the AC. We identified A-rich motifs in CENP-AHCP-3 domains/peaks on the AC and on endogenous chromosomes, which have some similarity with each other and similarity to some non-germline transcription factor binding sites.
Computational resources to define alleles and altered regulatory motifs at genomically edited candidate response elements
Authors: Ehmsen Kirk T , Knuesel Matthew T , Martinez Delsy , Asahina Masako , Aridomi Haruna , Yamamoto Keith R
Published: July 2021

Unequivocal functional assessment of candidate genomic regulatory regions, such as transcriptional response elements, requires genetic alteration at their native chromosomal loci. Targeted DNA cleavage by Cas9 or other programmable nucleases enables analysis at virtually any genomic region, and diverse alleles generated by editing can be defined by deep sequencing for functional analysis. Interpretation of disrupted response elements, however, presents a special challenge, as these regions typically comprise clustered DNA binding motifs for multiple transcriptional regulatory factors (TFs); DNA sequence differences, natural or engineered, that affect binding by one TF can confer loss or gain of binding sites for other TFs. To address these and other analytical complexities, we created three computational tools that together integrate, in a single experiment, allele definition and TF binding motif evaluation for up to 9216 clones isolated, sequenced and propagated from Cas9-treated cell populations. We demonstrate 1) the capacity to functionally assess edited TF binding sites to query response element function, and 2) the efficacy and utility of these tools, by analyzing cell populations targeted by Cas9 for disruption of example glucocorticoid receptor (GR) binding motifs near FKBP5, a GR-regulated gene in the human adenocarcinoma cell line A549.
Mapping health-related quality of life after kidney transplantation by group comparisons: a systematic review
Authors: Wang Yiman , Hemmelder Marc H , Bos Willem Jan W , Snoep Jaapjan D , de Vries Aiko P J , Dekker Friedo W , Meuleman Yvette
Published: July 2021

Background

Health-related quality of life (HRQOL) is becoming an increasingly important outcome in kidney transplantation (KT). To describe HRQOL in kidney transplant recipients (KTRs), this systematic review summarizes literature that compared HRQOL among KTRs and other relevant populations [i.e. patients receiving dialysis, patients on the waiting list (WL) for KT, patients with chronic kidney disease (CKD) not receiving renal replacement therapy (RRT), the general population (GP) and healthy controls (HCs)] and themselves before KT.

Methods

The literature search was conducted in PubMed, Embase, Web of Science and the Cochrane Library. Eligible studies published between January 2000 and October 2020 were included.

Results

Forty-four studies comprising 6929 KTRs were included in this systematic review. Despite the study heterogeneity, KTRs reported a higher HRQOL after KT compared with pre-transplantation and compared with patients receiving dialysis with or without being on the WL, especially in disease-specific domains (i.e. burden and effects of kidney disease). Additionally, KTRs had similar to marginally higher HRQOL compared with patients with CKD Stages 3–5 not receiving RRT. When compared with HCs or the GP, KTRs reported similar HRQOL in the first 1 or 2 years after KT and lower physical HRQOL and lower to comparable mental HRQOL in studies with longer post-transplant time.

Conclusions

The available evidence suggests that HRQOL improves after KT and can be restored to but not always maintained at pre-CKD HRQOL levels. Future studies investigating intervention targets to improve or maintain post-transplant HRQOL are needed.
Body size is associated with yearling breeding and extra-pair mating in the Island Scrub-Jay
Authors: Desrosiers Michelle A , Langin Kathryn M , Funk W Chris , Sillett T Scott , Morrison Scott A , Ghalambor Cameron K , Angeloni Lisa M
Published: July 2021

Large body size is an important determinant of individual fitness in many animal species, especially in island systems where habitat saturation may result in strong intraspecific competition for mates and breeding territories. Here we show that large body size is associated with benefits to yearling breeding and extra-pair mating in the Island Scrub-Jay (Aphelocoma insularis), endemic to Santa Cruz Island, California. This species is ~20% larger than its mainland congener, consistent with the island syndrome, indicating that body size may be a trait under selection. From 2009 to 2013, we quantified the reproductive success of a marked population of Island Scrub-Jays, tracked which yearlings acquired a breeding territory and bred, and measured the occurrence of extra-pair paternity. Two potential contributors to fitness were positively related to body size. Larger yearling males were more likely to breed, possibly due to greater behavioral dominance during aggressive encounters. Larger males were also less likely to lose paternity to extra-pair males and, anecdotally, extra-pair males were larger than the social male cuckolded. This study provides evidence that larger males may have a fitness advantage over smaller males by breeding earlier and avoiding paternity loss, but estimates of lifetime reproductive success are ultimately needed for Island Scrub-Jays and other long-lived species.
Genome Sequence Resource of Fusarium brachygibbosum Padwick Strain HN-1, a Causal Agent of Maize Stalk Rot Disease
Authors: Haseeb Hafiz Abdul , Hyder Sajjad , Gao Meixu , Guo Wei
Published: July 2021

Fusarium brachygibbosum Padwick, the causal agent of stalk rot disease, is a threat to the maize crop in China. However, genomic information of the pathogen is not available yet. The current study presented the genomic information of F. brachygibbosum, isolated from maize. The genome size is 40.36 Mb and consists of 12,510 genes. The GC content is 47.95%, and there are 913 predicted secretory proteins. The presented genomic data highlighted the virulence features, plant–microbe interaction ability, genes associated with the pathogen’s metabolic processes, and host-binding ability. Presented results would extend our knowledge of the pathogen and help us develop suitable disease management strategies.
Genome Sequence Resource of Xanthomonas citri pv. citri from Formalin-Fixed Citrus Leaves Specimen Showing Canker Lesions Collected in 1982
Authors: Li Wenting , Li Zhenxi , Zhang Ling , Deng Xiaoling , Zheng Zheng
Published: July 2021

Xanthomonas citri pv. citri is the causative agent of citrus canker, one of the most devastating diseases threatening global citrus production. Here, we present the genome sequence of X. citri pv. citri strain GD82 from a formalin-fixed citrus leaf specimen showing canker lesions collected in 1982 in Guangdong Province, China. The GD82 genome consisted of 5,197,217 bp with G+C content of 64.8%, along with four circular plasmids: pXAC33 (32,377 bp), pXAC64 (63,972 bp), pXAC47 (47,810 bp), and pGD82.1 (219,560 bp). This is the oldest X. citri pv. citri genome from historical citrus canker specimens in China, which will enrich the current X. citri pv. citri genome database and facilitate genomic evolution research of X. citri pv. citri.
Efficacy and safety of strong opioids for chronic noncancer pain and chronic low back pain: a systematic review and meta-analyses
Authors: Nury Edris , Schmucker Christine , Nagavci Blin , Motschall Edith , Nitschke Kai , Schulte Erika , Wegwarth Odette , Meerpohl Joerg J.
Published: July 2021

In recent years, long-term prescribing and use of strong opioids for chronic noncancer pain (CNCP) has increased in high-income countries. Yet existing uncertainties, controversies, and differing recommendations make the rationale for prolonged opioid use in CNCP unclear. This systematic review and meta-analyses compared the efficacy, safety, and tolerability of strong opioids with placebo or nonopioid therapy in CNCP, with a special focus on chronic low back pain (CLBP). Systematic literature searches were performed in 4 electronic databases (MEDLINE, Web of Science, Cochrane Library, and CINAHL) in July 2019 and updated by regular alerts until December 2020. We included 16 placebo-controlled randomized controlled trials for CLBP and 5 studies (2 randomized controlled trials and 3 nonrandomized studies) of opioids vs nonopioids for CNCP in the quantitative and qualitative synthesis. Random effects pairwise meta-analyses were performed for efficacy, safety, and tolerability outcomes and subgroup analyses for treatment duration, study design, and opioid experience status. Very low to low certainty findings suggest that 4 to 15 weeks (short or intermediate term) opioid therapy in CLBP (compared with placebo) may cause clinically relevant reductions in pain but also more gastrointestinal and nervous system adverse events, with likely no effect on disability. By contrast, long-term opioid therapy (≥6 months) in CNCP may not be superior to nonopioids in improving pain or disability or pain-related function but seems to be associated with more adverse events, opioid abuse or dependence, and possibly an increase in all-cause mortality. Our findings also underline the importance and need for well-designed trials assessing long-term efficacy and safety of opioids for CNCP and CLBP.
A review of in vitro attempts to develop the axenic culture of Treponema pallidum and genomics-based suggestions to achieve this elusive goal
Authors: Belkacemi Souad , Tidjani Alou Maryam , Khelaifia Saber , Raoult Didier
Published: July 2021

To date, the axenic culture of

Treponema pallidum

remains a challenge in the field of microbiology despite countless attempts. Here, we conducted a comprehensive bibliographic analysis using several databases and search engines, namely Pubmed, Google scholar, Google, Web of Science and Scopus. Numerous unsuccessful empiric studies have been conducted and evaluated using as criteria dark-field microscopic observation of motile spiral shaped cells in the culture and virulence of the culture through rabbit infectivity. All of these studies failed to induce rabbit infectivity, even when deemed positive after microscopic observation leading to the misnomer of avirulent

T. pallidum

. In fact, this criterion was improperly chosen because not all spiral shaped cells are

T. pallidum

. However, these studies led to the formulation of culture media particularly favourable to the growth of several species of Treponema, including Oral Microbiology and Immunology, Zürich medium (OMIZ), Oral Treponeme Enrichment Broth (OTEB) and T-Raoult, thus allowing the increase in the number of cultivable strains of

Treponema

. The predicted metabolic capacities of

T. pallidum

show limited metabolism, also exhibited by other non-cultured and pathogenic

Treponema

species, in contrast to cultured

Treponema

species. The advent of next generation sequencing represents a turning point in this field, as the knowledge inferred from the genome can finally lead to the axenic culture of

T. pallidum

.
Evidence from imaging resilience genetics for a protective mechanism against schizophrenia in the ventral visual pathway
Authors: Hettwer Meike D. , Lancaster Thomas M. , Raspor Eva , Hahn Peter K. , Mota Nina Roth , Singer Wolf , Reif Andreas , Linden David E.J. , Bittner Robert A.
Published: July 2021

Introduction

Illuminating neurobiological mechanisms underlying the protective effect of recently discovered common genetic resilience variants for schizophrenia is crucial for more effective prevention efforts. Current models implicate adaptive neuroplastic changes in the visual system and their pro-cognitive effects as a schizophrenia resilience mechanism. We investigated whether common genetic resilience variants might affect brain structure in similar neural circuits.

Method

Using structural magnetic resonance imaging, we measured the impact of an established schizophrenia polygenic resilience score (PRSResilience) on cortical volume, thickness, and surface area in 101 healthy subjects and in a replication sample of 33,224 healthy subjects (UK Biobank).

Finding

We observed a significant positive whole-brain correlation between PRSResilienceand cortical volume in the right fusiform gyrus (FFG) (r=0.35; p=.0004). Post-hoc analyses in this cluster revealed an impact of PRSResilienceon cortical surface area. The replication sample showed a positive correlation between PRSResilienceand global cortical volume and surface area in the left FFG.

Conclusion

Our findings represent the first evidence of a neurobiological correlate of a genetic resilience factor for schizophrenia. They support the view that schizophrenia resilience emerges from strengthening neural circuits in the ventral visual pathway and an increased capacity for the disambiguation of social and non-social visual information. This may aid psychosocial functioning, ameliorate the detrimental effects of subtle perceptual and cognitive disturbances in at-risk individuals, and facilitate coping with the cognitive and psychosocial consequences of stressors. Our results thus provide a novel link between visual cognition, the vulnerability-stress concept and schizophrenia resilience models.
Patient reported outcome on endourethrotomy combined with Amplatz dilatation for treatment of incompletely obliterated posterior urethral stricture following pelvic trauma: Validation in the era of urethroplasty
Authors: Wishahi Mohamed , Mehena Ahmed
Published: July 2021

Introduction

Direct vision internal urethrotomy (DVIU) is gaining revival among urologists, the procedure having the advantages of being minimally invasive as well as keeping continence and sexual function unaffected. The recurrence rate at 12 months was diminished by combination of DVIU with a Amplatz dilatation at the time of the procedure. Objectives are of present work is to present the outcome of the procedure.

Materials and methods

This is an observational study with a cross-sectional approach. Patients underwent combined endo-urethrotomy and Amplatz dilation for posterior urethral strictures between February 2015 and January2020 were purposively recruited. We performed a retrospective review of the records of 48 patients who completed 12 months follow-up. Patient-reported outcome measures for urethral stricture surgery (USS-PROMs) and sexual function were assessed at 12 months follow-up. A questionnaire was used to assess quality of life, patients in the study filled a questionnaire. Correlation between status before and after treatment were analyzed using simple statistical analysis to evaluate the effect of treatment on quality of life. Clinician-driven outcome were uroflowmetry, retrograde urethrogram, and reporting of complications.

Results

Mean length of stricture segment was 2 cm (range 1-2.5 cm). At 12 months follow up patients reported very satisfactory. Restenosis that was treated with redo was reported in 2%. Mild stenosis that was treated with Amplatz dilatation was in 3%. Patients reported very satisfactory or satisfactory for USS-PROSMs, sexual function in comparison to pre-trauma status.

Conclusions

Endourethrotomy combined with Amplatz dilation is an effective treatment for short segment passable posterior urethral stricture and it has a place in the era of endourethrotomy.
Frontal lobe fALFF measured from resting-state fMRI at baseline predicts acute treatment response in first episode psychosis
Authors: Lencz Todd , Moyett Ashley , Argyelan Miklos , Barber Anita D. , Cholewa John , Birnbaum Michael L. , Gallego Juan A. , John Majnu , Szeszko Philip R. , Robinson Delbert G. , Malhotra Anil K.
Published: July 2021

While antipsychotic medications have been utilized for decades, many patients experiencing psychosis do not demonstrate a satisfactory positive symptom response, even in the first episode of illness. Resting state functional magnetic resonance imaging (rs-fMRI) has increasingly been studied as a potential biomarker of antipsychotic treatment response, but studies to date remain limited in terms of sample size and brain regions examined. The present study examined fractional amplitude of low frequency fluctuations (fALFF) derived from rs-fMRI to search the whole brain, in a hypothesis-free manner, for regions that might predict response to 12 weeks of treatments with standard antipsychotic medications (risperidone or aripiprazole). To our knowledge, the present study represents the largest first episode psychosis treatment sample studied with rs-fMRI to date (N=126). At baseline, patients who would later meet strict criteria for clinical response demonstrated significantly greater baseline fALFF in bilateral orbitofrontal cortex compared to non-responders. In a subset of 62 patients who were scanned a second time at the end of treatment, responders and non-responders demonstrated significant increases in fALFF in differing brain regions. Specifically, responders demonstrated significant increases in fALFF, from baseline to follow-up, in bilateral dorsal prefrontal cortex; prefrontal changes were not observed in non-responders or in healthy individuals (n=45) scanned at two time points. Thus, spontaneous activity in orbitofrontal cortex may serve as a prognostic biomarker of antipsychotic treatment, while spontaneous activity in the dorsal prefrontal cortex may serve as a critical target of effective medication.
Modelling the effect of infection prevention and control measures on rate of Mycobacterium tuberculosis transmission to clinic attendees in primary health clinics in South Africa
Authors: McCreesh Nicky , Karat Aaron S , Baisley Kathy , Diaconu Karin , Bozzani Fiammetta , Govender Indira , Beckwith Peter , Yates Tom A , Deol Arminder K , Houben Rein MGJ , Kielmann Karina , White Richard G , Grant Alison D
Published: July 2021

Background

Elevated rates of tuberculosis in health care workers demonstrate the high rate of Mycobacterium tuberculosis (Mtb) transmission in health facilities in high burden settings. In the context of a project taking a whole systems approach to tuberculosis infection prevention and control (IPC), we aimed to evaluate the potential impact of conventional and novel IPC measures on Mtb transmission to patients and other clinic attendees.

Methods

An individual-based model of patient movements through clinics, ventilation in waiting areas, and Mtb transmission was developed, and parameterised using empirical data from eight clinics in two provinces in South Africa. Seven interventions – co-developed with health professionals and policy-makers - were simulated: 1. queue management systems with outdoor waiting areas, 2. ultraviolet germicidal irradiation systems (UVGI), 3. appointment systems, 4. opening windows and doors, 5. surgical mask wearing by clinic attendees, 6. simple clinic retrofits, and 7. increased coverage of long antiretroviral therapy prescriptions and community medicine collection points through the CCMDD service.

Results

In the model, 1. outdoor waiting areas reduced the transmission to clinic attendees by 83% (interquartile range [IQR] 76-88%), 2. UVGI by 77% (IQR 64-85%), 3. appointment systems by 62% (IQR 45-75%), 4. opening windows and doors by 55% (IQR 25-72%), 5. masks by 47% (IQR 42-50%), 6. clinic retrofits by 45% (IQR 16-64%), and 7. increasing the coverage of CCMDD by 22% (IQR 12-32%).

Conclusions

The majority of the interventions achieved median reductions in the rate of transmission to clinic attendees of at least 45%, meaning that a range of highly effective intervention options are available, that can be tailored to the local context. Measures that are not traditionally considered to be IPC interventions, such as appointment systems, may be as effective as more traditional IPC measures, such as mask wearing.
Association between COVID-19 infection rates by region and implementation of non-pharmaceutical interventions: A cross-sectional study in Japan
Authors: Anan Tomomi , Ishimaru Tomohiro , Hino Ayako , Nagata Tomohisa , Tateishi Seiichiro , Tsuji Mayumi , Ogami Akira , Matsuda Shinya , Fujino Yoshihisa ,   for the CORoNaWork project
Published: July 2021

Background

During a pandemic, non-pharmaceutical interventions (NPIs) play an important role in protecting oneself from infection and preventing the spread of infection to others. There are large regional differences in COVID-19 infection rates in Japan. We hypothesized that the local infection incidence may affect adherence to individual NPIs.

Methods

This cross-sectional study was conducted online among full-time workers in Japan in December 2020. Data from a total of 27,036 participants were analyzed. The questionnaire asked the respondents to identify their habits regarding seven well-known NPIs.

Results

Compared to the region with the lowest infection rate, the odds ratios for the region with the highest infection rate were 1.24 (p<0.001) for wearing a mask in public, 1.08 (p=0.157) for washing hands after using the bathroom, 1.17 (p=0.031) for disinfecting hands with alcohol sanitizers when entering indoors, 1.54 (p<0.001) for gargling when returning home, 1.45 (p<0.001) for ventilating the room, 1.33 (p<0.001) for disinfecting or washing hands after touching frequently touched surfaces, and 1.32 (p<0.001) for carrying alcohol sanitizers when outdoors. Five of the seven NPIs showed statistically significant trends across regional infection levels, the two exceptions being wearing a mask in public and washing hands after using the bathroom. Multivariate adjustment did not change these trends.

Conclusions

This study found that NPIs were more prevalent in regions with higher incidence rates of COVID-19 in Japanese workers. The findings suggest that the implementation of NPIs was influenced not only by personal attributes but also by contextual effects of the local infection level.
Higher polygenic scores for empathy increase posttraumatic stress severity in response to certain traumatic events
Authors: Wendt Frank R , Warrier Varun , Pathak Gita A , Koenen Karestan C , Stein Murray B , Krystal John H , Pietrzak Robert H , Gelernter Joel , Goldfarb Elizabeth V , Baron-Cohen Simon , Polimanti Renato
Published: July 2021

Background

Posttraumatic stress disorder (PTSD) is triggered by environmental stressors. Empathy may predispose an individual to respond to life events differently if high empathizers are emotionally more sensitive to trauma. For the first time, we test this hypothesis at the genetic level.

Methods

We applied polygenic scoring (PGS) to investigate the shared genetics linking empathy (measured using the Empathy Quotient (EQ), a self-report measure of empathy; N=46,861) and PTSD symptom severity (measured using the 6-item PTSD Checklist 6-item (PCL-6)) in the UK Biobank (N=126,219). Follow-up analyses were performed in the context of (1) experiencing any of 16 potential traumas, (2) the total number of traumas endorsed, and (3) the context of trauma. Autism, depression, generalized anxiety, and PCL-17 PGS were included as covariates to verify the specificity of the effect.

Results

EQPGSassociated with PCL-6 (R2=0.012%,P=9.35×10−5). This effect remained significant after accounting for autism, depression, PTSD, and anxiety PGS but was observed only in those who endorsed experiencing at least one traumatic event. EQPGSshowed the strongest effect on PCL-6 (β=2.32, s.e.=0.762,P=0.002) among those who endorsed childhood neglect/abuse (felt hated as a child). In the highest EQPGSdecile, feelinghated as a childwas associated with lower odds of healthy adulthood interpersonal relationships (OR=0.623, 95%CI 0.443-0.885) but this association was not seen in the lowest EQPGSdecile.

Conclusions

A genetic predisposition to higher empathy, which may index greater emotional sensitivity, predisposes an individual to more severe PTSD symptoms, specifically in the presence of early negative life events.
Resting State Functional Connectivity Alterations in Individuals with Autism Spectrum Disorders: A Systematic Review
Authors: Kumar Varun , Garg Rahul
Published: July 2021

Many studies investigate the alterations in resting state functional connectivity in autism. Most of these studies focus on different regions of the brain to find the connectivity differences between autism spectrum disorder and typically developing populations. The present review quantitatively extracts this data from all the seed based studies on autism spectrum disorder and uses it to build, for the first time, an Autism Altered Functional Connectome (AAFC) which summarizes the alterations in functional connectivity consistently reported in the literature. The data extracted from all the studies matching the inclusion criteria are presented at one place in human as well as a machine-readable format for further interpretation and analysis. Systematically reviewing 41 publications on 2818 subjects comprising 1459 typically developing and 1359 subjects with autism spectrum disorder, a total of 932 altered functional connectivity links were employed to construct an AAFC. The AAL atlas mapping of these links resulted in 71 replicated links of which 49 were consistent, and 574 unreplicated links that were reported just once. Out of 49, 38 were replicated across different non overlapping datasets. Majority of the studies analyzed the functional connectivity of the Default Mode Network (DMN) and its regions. Two important DMN regions, namely precuneus and posterior cingulate cortex were reported to exhibit different connectivity profiles with former majorly underconnected and later majorly overconnected consistently reported across multiple studies. After mapping the AAFLs to an atlas of brain networks, poor integration within DMN regions, and poor segregation of DMN regions with extra-DMN regions was observed.
Association of acute kidney injury with the risk of dementia: A meta-analysis protocol
Authors: Hussain Salman , Singh Ambrish , Antony Benny , Klugarová Jitka , Líčeník Radim , Klugar Miloslav
Published: July 2021

Acute kidney injury (AKI) is a complex disorder characterized by an abrupt decline in kidney function over a short period of time. Published epidemiological studies linked AKI with the development of dementia. This meta-analysis aims to understand the pooled risk of dementia in AKI patients compared to non-AKI patients. MEDLINE and Embase databases, and the grey literature in five sources were searched to identify the studies assessing the association of AKI with dementia. The Newcastle-Ottawa scale (NOS) will be used to determine the quality of included studies. The primary outcome of this study will be the risk of dementia among AKI patients compared to non-AKI patients. Subgroup analysis and sensitivity analysis will also be performed. Review Manager version 5.4.1 will be used to perform the meta-analysis.
A Proteogenomic Signature of Age-related Macular Degeneration in Blood
Authors: Emilsson Valur , Gudmundsson Elias F. , Jonmundsson Thorarinn , Twarog Michael , Gudmundsdottir Valborg , Finkel Nancy , Poor Stephen , Liu Xin , Esterberg Robert , Zhang Yiyun , Jose Sandra , Huang Chia-Ling , Liao Sha-Mei , Loureiro Joseph , Zhang Qin , Grosskreutz Cynthia L , Nguyen Andrew A , Huang Qian , Leehy Barrett , Pitts Rebecca , Jonsson Brynjolfur G. , Aspelund Thor , Lamb John R. , Jonasson Fridbert , Launer Lenore J. , Cotch Mary Frances , Jennings Lori L. , Gudnason Vilmundur , Walshe Tony E.
Published: July 2021

Age-related macular degeneration (AMD) is one of the most frequent causes of visual impairment in the elderly population. The overall etiology of AMD is complex and still poorly understood, though age, obesity, smoking, and high-density lipoprotein are known risk factors. In one of the first successful reported genome-wide association studies (GWAS), common genetic variants were strongly associated with AMD, including variants within the complement factor H (CFH) gene. To date, 34 genomic regions have been linked to AMD; however, the genes that mediate the risk remain largely unknown, indicating that novel approaches to identifying causal candidates are needed. Recent advances in proteomic technology have exposed the serum proteome’s depth and complexity. In the Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS), a broad population-based study of the elderly (N = 5764), levels of 4137 human serum proteins and associated networks were integrated with established genetic risk loci for AMD, revealing many predicted as well as novel proteins and pathways, linked to the disease. Serum proteins were also found to reflect AMD severity independent of genetics and predict progression from early to advanced AMD after five years in this population. A two-sample Mendelian randomization study of five proteins associated with AMD found CFHR1, CFHR5, and FUT5 to be causally related to the disease, all of which were directionally consistent with the observational estimates. This study provides a robust and unique framework for elucidating the pathobiology of AMD.
Overlapping Time Scales Obscure Early Warning Signals of the Second COVID-19 Wave
Authors: Dablander Fabian , Heesterbeek Hans , Borsboom Denny , Drake John M.
Published: July 2021

Early warning indicators based on critical slowing down have been suggested as a model-independent and low-cost tool to anticipate the (re)emergence of infectious diseases. We studied whether such indicators could reliably have anticipated the second COVID-19 wave in European countries. Contrary to theoretical predictions, we found that characteristic early warning indicators generallydecreasedrather thanincreasedprior to the second wave. A model explains this unexpected finding as a result of transient dynamics and the multiple time scales of relaxation during a non-stationary epidemic. Particularly, if an epidemic that seems initially contained after a first wave does not fully settle to its new quasi-equilibrium prior to changing circumstances or conditions that force a second wave, then indicators will show a decreasing rather than an increasing trend as a result of the persistent transient trajectory of the first wave. Our simulations show that this lack of time scale separation was to be expected during the second European epidemic wave of COVID-19. Overall, our results emphasize that the theory of critical slowing down applies only when the external forcing of the system across a critical point is slow relative to the internal system dynamics.
Predictive modelling of highly multiplexed tumour tissue images by graph neural networks
Authors: Martin-Gonzalez Paula , Crispin-Ortuzar Mireia , Markowetz Florian
Published: July 2021

The progression and treatment response of cancer largely depends on the complex tissue structure that surrounds cancer cells in a tumour, known as the tumour microenvironment (TME). Recent technical advances have led to the development of highly multiplexed imaging techniques such as Imaging Mass Cytometry (IMC), which capture the complexity of the TME by producing spatial tissue maps of dozens of proteins. Combining these multidimensional cell phenotypes with their spatial organization to predict clinically relevant information is a challenging computational task and so far no method has addressed it directly. Here, we propose and evaluate MULTIPLAI, a novel framework to predict clinical biomarkers from IMC data. The method relies on attention-based graph neural networks (GNNs) that integrate both the phenotypic and spatial dimensions of IMC images. In this proof-of- concept study we used MULTIPLAI to predict oestrogen receptor (ER) status, a key clinical variable for breast cancer patients. We trained different architectures of our framework on 240 samples and benchmarked against graph learning via graph kernels. Propagation Attribute graph kernels achieved a class-balanced accuracy of 66.18% in the development set (N=104) while GNNs achieved a class-balanced accuracy of 90.00% on the same set when using the best combination of graph convolution and pooling layers. We further validated this architecture in internal (N=112) and external test sets from different institutions (N=281 and N=350), demonstrating the generalizability of the method. Our results suggest that MULTIPLAI captures important TME features with clinical importance. This is the first application of GNNs to this type of data and opens up new opportunities for predictive modelling of highly multiplexed images.
Clostridioides difficile SpoVAD and SpoVAE interact and are required for DPA packaging into spores
Authors: Baloh Marko , Sorg Joseph A.
Published: July 2021

Clostridioides difficile spores, like the spores from most endospore-forming organisms, are a metabolically dormant stage of development with a complex structure that conveys considerable resistance to environmental conditions, e.g., dry heat. This resistance is due to the large amount of dipicolinic acid (DPA) that is packaged into the spore core, thereby replacing the majority of water. DPA is synthesized by the mother cell and its packaging into the spore core is regulated by the spoVA operon that has a variable number of genes, depending on the organism. C. difficile encodes 3 spoVA orthologues, spoVAC, spoVAD, and spoVAE. Prior work has shown that C. difficile SpoVAC is a mechanosensing protein responsible for DPA release from the spore core upon the initiation of germination. However, the roles of SpoVAD and SpoVAE remain unclear in C. difficile. In this study we analyzed the roles of SpoVAD and SpoVAE and found that they are essential for DPA packaging into the spore, similar to SpoVAC. Using split luciferase protein interaction assays we found that these proteins interact, and we propose a model where SpoVAC / SpoVAD / SpoVAE proteins interact at or near the inner spore membrane, and each member of the complex is essential for DPA packaging into the spore core.

Importance

C. difficile spore heat resistance provides an avenue for it to survive the disinfection protocols in hospital and community settings. The spore heat resistance is mainly the consequence of the high DPA content within the spore core. By elucidating the mechanism by which DPA is packaged into the spore core, this study may provide insight in how to disrupt the spore heat resistance with the aim of making the current disinfection protocols more efficient at preventing the spread of C. difficile in the environment.
Genome-scale metabolic modelling of lifestyle changes in Rhizobium leguminosarum
Authors: Schulte Carolin C. M. , Ramachandran Vinoy K. , Papachristodoulou Antonis , Poole Philip S.
Published: July 2021

Biological nitrogen fixation in rhizobium-legume symbioses is of major importance for sustainable agricultural practices. To establish a mutualistic relationship with their plant host, rhizobia transition from free-living bacteria in soil to growth down infection threads inside plant roots and finally differentiate into nitrogen-fixing bacteroids. We reconstructed a genome-scale metabolic model for Rhizobium leguminosarum and integrated the model with transcriptome, proteome, metabolome and gene essentiality data to investigate nutrient uptake and metabolic fluxes characteristic of these different lifestyles. Synthesis of leucine, polyphosphate and AICAR is predicted to be important in the rhizosphere, while myo-inositol catabolism is active in undifferentiated nodule bacteria in agreement with experimental evidence. The model indicates that bacteroids utilize xylose and glycolate in addition to dicarboxylates, which could explain previously described gene expression patterns. Histidine is predicted to be actively synthesized in bacteroids, consistent with transcriptome and proteome data for several rhizobial species. These results provide the basis for targeted experimental investigation of metabolic processes specific to the different stages of the rhizobium-legume symbioses.

Importance

Rhizobia are soil bacteria that induce nodule formation on plant roots and differentiate into nitrogen-fixing bacteroids. A detailed understanding of this complex symbiosis is essential for advancing ongoing efforts to engineer novel symbioses with cereal crops for sustainable agriculture. Here, we reconstruct and validate a genome-scale metabolic model for Rhizobium leguminosarum bv. viciae 3841. By integrating the model with various experimental datasets specific to different stages of symbiosis formation, we elucidate the metabolic characteristics of rhizosphere bacteria, undifferentiated bacteria inside root nodules, and nitrogen-fixing bacteroids. Our model predicts metabolic flux patterns for these three distinct lifestyles, thus providing a framework for the interpretation of genome-scale experimental datasets and identifying targets for future experimental studies.
A binary effector module secreted by a type VI secretion system
Authors: Dar Yasmin , Jana Biswanath , Bosis Eran , Salomon Dor
Published: July 2021

Gram-negative bacteria use type VI secretion systems (T6SSs) to deliver toxic effector proteins into neighboring cells. Cargo effectors are secreted by binding non-covalently to the T6SS apparatus. Occasionally, effector secretion is assisted by an adaptor protein, although the adaptor itself is not secreted. Here, we report a new T6SS secretion mechanism, in which an effector and a co-effector are secreted together. Specifically, we identified a novel periplasm-targeting effector that is secreted together with its co-effector, which contains a MIX (marker for type sIX effector) domain previously reported only in polymorphic toxins. The effector and co-effector directly interact, and they are dependent on each other for secretion. We termed this new secretion mechanism “a binary effector module”, and we show that it is widely distributed in marine bacteria.
Deep learning identifies and quantifies recombination hotspot determinants
Authors: Li Yu , Chen Siyuan , Rapakoulia Trisevgeni , Kuwahara Hiroyuki , Yip Kevin Y. , Gao Xin
Published: July 2021

Recombination is one of the essential genetic processes for sexually reproducing organisms, which can happen more frequently in some regions, called recombination hotspots. Although several factors, such as PRDM9 binding motifs, are known to be related to the hotspots, their contributions to the recombination hotspots have not been quantified, and other determinants are yet to be elucidated. Here, we develop a computational method, RHSNet, based on deep learning and signal processing, to identify and quantify the hotspot determinants in a purely data-driven manner, utilizing datasets from various studies, populations, sexes, and species. In addition to being able to identify hotspot regions and the well-known determinants accurately, RHSNet is sensitive to the difference between different PRDM9 alleles and different sexes, and can generalize to PRDM9-lacking species. The cross-sex, cross-population, and cross-species studies suggest that the proposed method has the potential to identify and quantify the evolutionary determinant motifs.

Teaser

RHSNet can accurately identify and quantify recombination hotspot determinants across different studies, sexes, populations, and species.
Quantifying epigenetic modulation of nucleosome breathing by high-throughput AFM imaging
Authors: Konrad Sebastian F. , Vanderlinden Willem , Lipfert Jan
Published: July 2021

Nucleosomes are the basic units of chromatin and critical to the storage and expression of eukaryotic genomes. Chromatin accessibility and gene readout are heavily regulated by epigenetic marks of which post-translational modifications of histones play a key role. However, the mode of action and the structural implications on the single-molecule level of nucleosomes is often still poorly understood. Here, we apply a high-throughput AFM imaging and analysis pipeline to investigate the conformational landscape of the nucleosome variants H3K36me3, H3S10phos and H4K5/8/12/16ac. Our data set of >25,000 nucleosomes reveals nucleosomal unwrapping steps corresponding to 5 bp DNA. We find that H3K36me3 nucleosomes unwrap significantly more than wild type nucleosomes and additionally unwrap stochastically from both sides similar to CENP-A nucleosomes and in contrast to the highly anti-cooperative unwrapping of wild type nucleosomes. Nucleosomes with H3S10phos or H4K5/8/12/16ac modifications show unwrapping populations similar to wild type nucleosomes and also retain the same level of anti-cooperativity. Our findings help putting the mode of action of these modifications into context: While H3K36me3 likely partially acts by directly affecting nucleosome structure on the single-molecule level, H3S10phos and H4K5/8/12/16ac must predominantly act through higher-order processes. Our analysis pipeline is readily applicable to other nucleosome variants and will facilitate future high-resolution studies of the conformational landscape of nucleoprotein complexes.

Statement of Significance

The packing and readout of our genome is tightly regulated by post-translational histone modifications (PTMs). While a vast range of PTMs has been studied with respect to their implications for gene activity and replication, a detailed view of the direct effect of PTMs on conformational changes of nucleosomes is still lacking. Here we investigate the structural implications of several key modifications (H3K36me3, H3S10phos and H4K5/8/12/16ac) by high-throughput AFM imaging. Our findings enable a better understanding of the mode of action of these specific modifications and provide an analysis pipeline for the investigation of other epigenetic modifications.
The sensory code within sense of time
Authors: Reinartz S. , Fassihi A. , Paz L. , Pulecchi F. , Gigante M. , Diamond M.E.
Published: July 2021

Sensory experiences are accompanied by the perception of the passage of time; a cell phone vibration, for instance, is sensed as brief or long. The neuronal mechanisms underlying the perception of elapsed time remain unknown1. Recent work agrees on a role for cortical processing networks2,3, however the causal function of sensory cortex in time perception has not yet been specified. We hypothesize that the mechanisms for time perception are embedded within primary sensory cortex and are thus governed by the basic rules of sensory coding. By recording and optogenetically modulating neuronal activity in rat vibrissal somatosensory cortex, we find that the percept of stimulus duration is dilated and compressed by optogenetic excitation and inhibition, respectively, during stimulus delivery. A second set of rats judged the intensity of tactile stimuli; here, optogenetic excitation amplified the intensity percept, demonstrating sensory cortex to be the common gateway to both time and stimulus feature processing. The coding algorithms for sensory features are well established4–10. Guided by these algorithms, we formulated a 3-stage model beginning with the membrane currents evoked by vibrissal and optogenetic drive and culminating in the representation of perceived time; this model successfully replicated rats’ choices. Our finding that stimulus coding is intrinsic to sense of time disagrees with dedicated pacemaker-accumulator operation models11–13, where sensory input acts only to trigger the onset and offset of the timekeeping process. Time perception is thus as deeply intermeshed within the sensory processing pathway as is the sense of touch itself14,15 and can now be treated through the computational language of sensory coding. The model presented here readily generalizes to humans14,16 and opens up new approaches to understanding the time misperception at the core of numerous neurological conditions17,18.
Interfacial tension driven open droplet microfluidics
Authors: Khor Jian Wei , Lee Ulri N. , Berthier Jean , Berthier Erwin , Theberge Ashleigh B.
Published: July 2021

We developed an open channel droplet microfluidic system that autonomously generates droplets at low Ca (~10-4-10-3) by leveraging competing hydrostatic and capillary pressure. With only our open channel polytetrafluoroethylene (PTFE) device, pipettes, and commercially available carrier fluid, we produce hundreds of microliter droplets; tubing, electronics, or pumps are not required, making droplet technology feasible for research labs without external flow generators. Furthermore, we demonstrated conceptual applications that showcase the process of droplet generation, splitting, transport, incubation, mixing, and sorting in our system. Unlike conventional droplet microfluidics, the open nature of the device enables the use of physical tools such as tweezers and styli to directly access the system; with this, we developed a new method of droplet sorting and transfer that capitalizes on the Cheerios effect, the aggregation of buoyant objects along a liquid interface. Our platform offers enhanced usability, direct access to the droplet contents, easy manufacturability, compact footprint, and high customizability. This design is a first step in exploring the space of power-free open droplet microfluidic systems and provide design rules for similar channel designs.