bluuebunny/crossref_metadata_2025 huggingface dataset:
SUPREME: A cancer subtype prediction methodology integrating multiomics data using Graph Convolutional Neural Network
Authors: Kesimoglu Ziynet Nesibe , Bozdag Serdar
Published: August 2022

To pave the road towards precision medicine in cancer, patients with highly similar biology ought to be grouped into the same cancer subtypes. Utilizing high-dimensional multiomics datasets, several integrative computational approaches have been developed to uncover cancer subtypes. Recently, Graph Neural Networks (GNNs) was discovered to learn node embeddings while utilizing node features and node associations at the same time on graph-structured data. Although there are some commonly used architectures such as Graph Convolutional Network (GCN) for cancer subtype prediction, the existing prediction tools have some limitations in leveraging those architectures with multiomics integration on multiple networks. Addressing them, we developed SUPREME (asubtypepredictionmethodology) by comprehensively analyzing multiomics data and associations between patients with graph convolutions on multiple patient similarity networks. Unlike the existing tools, SUPREME generates patient embeddings from patient similarity networks, on which it utilizes all the multiomics features. In addition, SUPREME integrates all the possible combinations of embeddings with the raw multiomics features to capture the complementary signals. Extensive evaluation of all combinations makes SUPREME interpretable in terms of utilized networks and features. On three different datasets from The Cancer Genome Atlas (TCGA), Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), and both combined, our method significantly outperformed other integrative cancer (sub)type prediction tools and baseline methods, with overall consistent results. SUPREME-inferred subtypes had significant survival differences, mostly having more significance than ground truth (PAM50) labels, and outperformed nine cancer subtype differentiating tools and baseline methods. These results suggest that with proper utilization of multiple datatypes and patient associations, SUPREME could demystify the undiscovered characteristics in cancer subtypes that cause significant survival differences and could improve the ground truth label, which depends mainly on a single datatype. Source code for our tool is publicly available athttps://github.com/bozdaglab/SUPREME.
A single-molecule method for measuring fluorophore labeling yields for the study of membrane protein oligomerization in membranes
Authors: Ernst Melanie , Ozturk Tugba N. , Robertson Janice L.
Published: August 2022

Membrane proteins are often structured as higher-order oligomers. Yet, the role of these specific assemblies is not always apparent, raising the question of whether differential oligomerization states can be linked to modulation of function. To better understand this hypothetical regulatory mechanism, there is an ongoing effort to quantify equilibrium reactions of membrane proteins in membranes. Single-molecule photobleaching analysis is particularly useful for this as it provides a binary readout of fluorophores attached to protein subunits at dilute conditions. The subunit capture method adds consideration of the Poisson probability of protein partitioning into liposomes from large equilibrium membranes. If the liposome size distribution is known, then the capture statistics can be modeled with accuracy to quantify oligomerization as a function of membrane density to obtain binding isotherms, as was demonstrated for the dimeric chloride/proton antiporter CLC-ec1. However, any quantification of stoichiometry also critically requires knowing the probability that a subunit is fluorescently labeled. Since labeling uncertainty is often unavoidable, we tested an alternate approach to estimate labeling yields using the photobleaching probability of an intrinsic dimeric control, the disulfide cross-linked R230C/L249C CLC-ec1. By iterative fitting of the experimental dimeric photobleaching probability distribution to a dimer model while varying labeling parameters, we predict the labeling yields measured by direct absorbance measurements of the purified protein before reconstitution. Finally, the average predicted labeling yield over multiple samples is used to estimate the dissociation constant of CLC-ec1 dimerization reactions, eliminating the need to quantify fluorophore labeling a priori. This approach can be generalized to study dimerization reactions where an irreversible dimeric control can be prepared. Thus, our study maps out a new method for quantifying fluorophore occupancy in samples that cannot be purified directly and improves quantification of membrane protein stoichiometry in membranes.
Subfunctionalization and constrained size of the immunoglobulinlociinAmbystoma mexicanum
Authors: Martinez-Barnetche J , Godoy-Lozano EE , Saint Remy-Hernández S , Pacheco-Olvera DL , Téllez-Sosa J , Valdovinos-Torres H , Pastelin-Palacios R , Mena-González H , Zambrano-Gonzalez L , López-Macías C
Published: August 2022

Background

The axolotl,Ambystoma mexicanumis a unique biological model for complete tissue regeneration. Is a neotenic endangered species and is highly susceptible to environmental stress, including infectious disease. In contrast to other amphibians, the axolotl is particularly vulnerable to certain viral infections. Like other salamanders, the axolotl genome is one of the largest (32 Gb) and the impact of genome size on Iglociarchitecture is unknown. To better understand the immune response in axolotl, we aimed to characterize the immunoglobulinlociofA. mexicanumand compare it with other model tetrapods.

Methods

The most recently published genome sequence ofA. mexicanum(V6) was used for alignment-based annotation and manual curation using previously described axolotl Ig sequences or reference sequences from other tetrapods. Gene models were further curated usingA. mexicanumspleen RNA-seq data. Human reference genomes,Xenopus tropicalis, andDanio rerio(zebrafish) were used for comparison.

Results

CanonicalA. mexicanumHeavy chain (IGH), lambda (IGL), sigma (IGS) and Surrogate light chain (SLC)lociwere identified. No kappalocuswas found. More than half of the IGHV genes and the IGHF gene are pseudogenes, there are no clan I IGHV genes and CDRH3 diversity is restricted. Although the IGHlocussize is proportional to genome size, we found local size restriction in the IGHM gene and in the V gene intergenic distances. In addition, there were V genes with abnormally large V-intron sizes, which correlated with loss of gene functionality.

Conclusion

TheA. mexicanumimmunoglobulinlocishare the same general genome architecture as most studied tetrapods. Consistent with its large genome, Iglociare larger; however, local size restrictions indicate evolutionary constraints likely to be imposed by high transcriptional demand of certain Ig genes, as well as the V(D)J recombination over very long genomic distance ranges. TheA. mexicanumhas undergone an extensive process of pseudogenization which partially explains a reduced potential repertoire diversity that may contribute to its impaired antibody response.
Canonical Wnt signaling regulates soft palate development through mediating ciliary homeostasis
Authors: Janečková Eva , Feng Jifan , Guo Tingwei , Han Xia , Pareek Siddhika , Ghobadi Aileen , Ho Thach-Vu , Araujo-Villalba Angelita , Alvarez Jasmine , Chai Yang
Published: August 2022

Craniofacial morphogenesis requires complex interactions among tissues, signaling pathways, secreted factors, and organelles. The details of these interactions remain elusive. In this study, we analyzed the molecular mechanisms and homeostatic cellular activities governing soft palate development to improve regenerative strategies for cleft palate patients. We have identified canonical Wnt signaling as a key signaling pathway primarily active in cranial neural crest (CNC)-derived mesenchymal cells surrounding soft palatal myogenic cells. Using Osr2-Cre;β-cateninfl/fl mice, we further discovered that Wnt signaling is indispensable for mesenchymal cell proliferation and subsequently myogenesis through mediating ciliogenesis. Specifically, we identified that Wnt signaling directly regulates expression of the ciliary gene Ttll3 through β-catenin/Tcf7l2 complex. Impaired ciliary disassembly leads to differentiation defects of mesenchymal cells and indirectly disrupts myogenesis through decreased expression of Dlk1, a mesenchymal cell-derived pro-myogenesis factor. Moreover, we found that restoring ciliary homeostasis rescues mesenchymal cell proliferation in Osr2-Cre;β-cateninfl/fl samples. This study highlights the role of Wnt signaling in palatogenesis through controlling ciliary homeostasis, which establishes a new mechanism for Wnt-regulated craniofacial morphogenesis.
An unbiased characterization of the HLA-E and CD94/NKG2x peptide repertoire reveals peptide ligands that skew NK cell activation
Authors: Huisman Brooke D. , Guan Ning , Rückert Timo , Garner Lee , Singh Nishant K. , McMichael Andrew J. , Gillespie Geraldine M. , Romagnani Chiara , Birnbaum Michael E.
Published: August 2022

HLA-E is a non-classical class I MHC protein involved in innate and adaptive immune recognition. While recent studies have shown HLA-E can present diverse peptides to NK cells and T cells, the HLA-E and NK receptor peptide repertoire has remained poorly defined, with only a limited number of peptide ligands identified. Here we screen a yeast-displayed peptide library in the context of HLA-E to identify 500 high-confidence unique peptides that bind both HLA-E and CD94/NKG2A or CD94/NKG2C. Utilizing the sequences identified via yeast display selections, we train prediction algorithms and identify human and cytomegalovirus (CMV) proteome-derived, HLA-E-presented peptides capable of binding and signaling through both CD94/NKG2A and CD94/NKG2C. In addition, we identify peptides which selectively activate NKG2C+ NK cells. Taken together, characterization of the HLA-E-binding peptide repertoire and identification of NK activity-modulating peptides present opportunities for studies of NK cell regulation in health and disease, in addition to vaccine and therapeutic design.
Optogenetic control of RelA reveals effect of transcription factor dynamics on downstream gene expression
Authors: Osimiri Lindsey C. , Bonny Alain R. , Takagishi Seesha R. , Luecke Stefanie , Riehs Nina , Hoffmann Alexander , El-Samad Hana
Published: August 2022

Many transcription factors (TFs) translocate to the nucleus with varied dynamic patterns in response to different inputs. A notable example of such behavior is RelA, a subunit of NF-κB, which translocates to the nucleus with either pulsed or sustained dynamics, depending on the stimulus. Our understanding of how these dynamics are interpreted by downstream genes has remained incomplete, partly because ubiquitously used environmental inputs activate other transcriptional regulators in addition to RelA. Here, we use an optogenetic tool, CLASP (controllable light-activated shuttling and plasma membrane sequestration), to control RelA spatiotemporal dynamics in mouse fibroblasts and quantify their effect on downstream genes using RNA-seq. Using RelA-CLASP, we show for the first time that nuclear translocation of RelA, without post-translational modifications or activation of other transcriptional regulators, is sufficient to activate downstream genes. Furthermore, we find that TNFα, a common endogenous input, regulates many genes independently of RelA, and that this gene regulation is different from that induced by RelA-CLASP. Genes responsive to RelA-CLASP show a wide range of dynamics in response to a constant RelA input. We use a simple promoter model to recapitulate these diverse dynamic responses, as well as data collected in response to a pulsed RelA-CLASP input, and extract features of many RelA-responsive promoters. We also pinpoint many genes for which more complex models, involving feedback or multi-step promoters, may be needed to explain their response to constant and pulsed TF inputs. This study introduces a new robust tool for studying mammalian transcriptional regulation and demonstrates the power of optogenetic tools in dissecting the quantitative features of important cellular pathways.
Spatiotemporal variation in risk ofShigellainfection in childhood: a global risk mapping and prediction model using individual participant data
Authors: Badr Hamada S. , Colston Josh M. , Nguyen Nhat-Lan H. , Chen Yen Ting , Ali Syed Asad , Rayamajhi Ajit , Satter Syed M. , Van Trang Nguyen , Eibach Daniel , Krumkamp Ralf , May Jürgen , Adegnika Ayola Akim , Prince Manouana Gédéon , Kremsner Peter Gottfried , Chilengi Roma , Hatyoka Luiza , Debes Amanda K. , Ateudjieu Jerome , Faruque Abu S. G. , Hossain M. Jahangir , Kanungo Suman , Kotloff Karen L. , Mandomando Inácio , Nisar M. Imran , Omore Richard , Sow Samba O. , Zaidi Anita K. M. , Lambrecht Nathalie , Adu Bright , Page Nicola , Platts-Mills James A. , Freitas Cesar Mavacala , Pelkonen Tuula , Ashorn Per , Maleta Kenneth , Ahmed Tahmeed , Bessong Pascal , Bhutta Zulfiqar A. , Mason Carl , Mduma Estomih , Olortegui Maribel P. , Yori Pablo Peñataro , Lima Aldo A. M. , Kang Gagandeep , Humphrey Jean , Ntozini Robert , Prendergast Andrew J. , Okada Kazuhisa , Wongboot Warawan , Langeland Nina , Moyo Sabrina J. , Gaensbauer James , Melgar Mario , Freeman Matthew , Chard Anna N. , Thongpaseuth Vonethalom , Houpt Eric , Zaitchik Benjamin F. , Kosek Margaret N.
Published: August 2022

Background

Diarrheal disease remains a leading cause of childhood illness and mortality andShigellais a major etiological contributor for which a vaccine may soon be available. This study aimed to model the spatiotemporal variation in pediatricShigellainfection and map its predicted prevalence across low- and middle-income countries (LMICs).

Methods

Independent participant data onShigellapositivity in stool samples collected from children aged ≤59 months were sourced from multiple LMIC-based studies. Covariates included household- and subject-level factors ascertained by study investigators and environmental and hydrometeorological variables extracted from various data products at georeferenced child locations. Multivariate models were fitted, and prevalence predictions obtained by syndrome and age stratum.

Findings

20 studies from 23 countries contributed 66,563 sample results. Age, symptom status, and study design contributed most to model performance followed by temperature, wind speed, relative humidity, and soil moisture.Shigellaprobability exceeded 20% when both precipitation and soil moisture were above average and had a 43% peak in uncomplicated diarrhea cases at 33°C temperatures, above which it decreased. Improved sanitation and open defecation decreasedShigellaodds by 19% and 18% respectively compared to unimproved sanitation.

Interpretation

The distribution ofShigellais more sensitive to climatological factors like temperature than previously recognized. Conditions in much of sub-Saharan Africa are particularly propitious forShigellatransmission, though hotspots also occur in South and Central America, the Ganges–Brahmaputra Delta, and New Guinea. These findings can inform prioritization of populations for future vaccine trials and campaigns.

Funding

NASA 16-GEO16-0047; NIH-NIAID 1R03AI151564-01; BMGF OPP1066146.
Forecasting COVID-19 activity in Australia to support pandemic response: May to October 2020
Authors: Moss Robert , Price David J. , Golding Nick , Dawson Peter , McVernon Jodie , Hyndman Rob J. , Shearer Freya M. , McCaw James M.
Published: August 2022

As of January 2021, Australia had effectively controlled local transmission of COVID-19 despite a steady influx of imported cases and several local, but contained, outbreaks in 2020. Throughout 2020, state and territory public health responses were informed by weekly situational reports that included an ensemble forecast for each jurisdiction. We present here an analysis of one forecasting model included in this ensemble across the variety of scenarios experienced by each jurisdiction from May to October 2020. We examine how successfully the forecasts characterised future case incidence, subject to variations in data timeliness and completeness, showcase how we adapted these forecasts to support decisions of public health priority in rapidly-evolving situations, evaluate the impact of key model features on forecast skill, and demonstrate how to assess forecast skill in real-time before the ground truth is known. Conditioning the model on the most recent, but incomplete, data improved the forecast skill, emphasising the importance of developing strong quantitative models of surveillance system characteristics, such as ascertainment delay distributions. Forecast skill was highest when there were at least 10 reported cases per day, the circumstances in which authorities were most in need of forecasts to aid in planning and response.
The Impact of Fasting the Holy Month of Ramadan on Colorectal Cancer Patients and Two Tumor Biomarkers: A Tertiary-Care Hospital Experience
Authors: Alshammari Kanaan , Alhaidal Haifa , Alharbi Reem , Alrubaiaan Alanood , Alyousif Ghadah , Alkaiyat Mohammad , Abdel-Razaq Wesam
Published: August 2022

Background

Fasting during the holy month of Ramadan is a religious ritual practiced by the majority of Muslims around the globe. This daytime fasting is short-term or intermittent fasting, which may be associated with valuable health benefits, particularly in cancer patients.

Methods

A prospective cohort study of pre-and post-evaluation of 37 colorectal cancer (CRC) patients was conducted in the oncology outpatient clinics to assess the impact of fasting during Ramadan on the tolerability of chemotherapy side effects and to assess changes in the levels of carcinoembryonic antigen (CEA) and lactate dehydrogenase (LDH) tumor biomarkers.

Result

The vast majority of CRC patients (89.2%) had fasted at least part of the month of Ramadan. Most (73%) reported “Serenity” after fasting during Ramadan with improved tolerability of chemotherapy side effects. The results did not reveal any significant difference in the measured laboratory variables between pre-fasting values and by the end of the 30 days of Ramadan. Although statistically insignificant, the levels of CEA and LDH were reduced in 46.9% and 55.6% of CRC patients, respectively. The mean level of CEA in the fasting group was substantially reduced by more than 40%, attributed to the highly significant decline of CEA levels in three patients only (p=0.0283).

Conclusion

The current study confirms the safety and tolerability of intermittent fasting in CRC patients actively receiving chemotherapy, which is consistent with several reports. Nonetheless, the results did not reveal a significant decrease in CEA and LDH tumor biomarkers.
Assessing Predictors of Mortality Among Children admitted with Sepsis at a Referral Tertiary Health Center, Northwestern Nigeria
Authors: Hassan-Hanga Fatimah , Ibrahim Baffa Sule , Kabir Halima , Hafsat Ibrahim U , Abdulsalam Kabiru , Ahmed Zainab Datti , Kabara Halima Salisu , Gaya Sule Abdullahi , Haliru Dalha Gwarzo , Sadiq Nasiru Magaji , Inuwa Salisu , Mohammad Mohammad Aminu
Published: August 2022

Background

Sepsis is a life-threatening infection that can lead to organ failure and death. We aim to assess predictors of mortality among children admitted with Septicemia at a referral health facility in Northwestern Nigeria.

Methods

We conducted a prospective cross-sectional study of children aged 0-14 years admitted to various units of the pediatrics department of the health facilities. Children were recruited between September 2018 and November 2019. All recruited children were followed up on clinical progress until either discharge, abscondment, or death. We assessed the children clinically daily and collected whole-blood samples for laboratory tests. We conducted a univariate and multivariable analysis using STATA-16 to assess identified predictive factors with our outcome variable.

Results

A total of 326 children were recruited, median age: 2-years. About 54.0% of the children were boys, and 53.1% were within 1-5 years age-group. Predominant organisms cultured from the blood of the children wereSalmonella typhi(5.7%),Klebsiella pneumoniae(2.3%), andStaphylococcus aureus(2.0%). A total of 35 deaths were recorded with a case fatality rate (CFR) of 10.7%. CFR is highest in children <1years (13.6%).

Child’s vaccination status, mother’s education level as well as blood lactate levels, GCS, qSOFA score and positive blood culture were significantly associated with child’s mortality. Factors associated with increase mortality include; children with incomplete vaccination history [OR=1.72, 95%CI: 2.74–15.53] versus those with full vaccination; children whose mothers had no formal education [OR=14.39, 95%CI: 3.24–63.99] when compared to those children whose mothers have tertiary level of education. Furthermore, children with whole blood lactate level between 4-8mmol/l [OR=3.23, 95%CI: 1.15–9.07], or greater than 8mmol/l [OR=10.54, 95%CI: 3.68–30.14] versus children with whole blood lactate level less than 4mmol/l; children with qSOFA score of 3 [OR=15.62, 95%CI: 3.31–73.60] versus children with qSOFA score of 1; and children who had a positive blood culture [OR=6.90, 95%CI: 3.04–15.64].

Conclusion

We found a high prevalence of severe sepsis at pediatrics department of AKTH. Serum lactate levels, GCS, and qSOFA scores were predictive of mortality. Routine measurement and monitoring of these parameters will improve case management and reduce sepsis related mortality in the hospital.
Determining population-level allocation strategies for COVID-19 treatments in the United States using a quantitative framework, a case study using nirmatrelvir/ritonavir
Authors: Savinkina Alexandra , Gonsalves Gregg , Ross Joseph S. , Paltiel A. David
Published: August 2022

Background

New COVID-19 medications force decision makers to weigh limited evidence of efficacy and cost in determining which patient populations to target for treatment. A case in point is nirmatrelvir/ritonavir, a drug that has been recommended for elderly, high-risk individuals, regardless of vaccination status, even though clinical trials have only evaluated it in unvaccinated patients. A simple optimization framework might inform a more reasoned approach to the tradeoffs implicit in the treatment allocation decision.

Methods

We used a mathematical model to analyze the cost-effectiveness of four nirmatrelvir/ritonavir allocation strategies, stratified by vaccination status and risk for severe disease. We considered treatment effectiveness at preventing hospitalization ranging from 21% to 89%. Sensitivity analyses were performed on major parameters of interest. A web-based tool was developed to permit decision-makers to tailor the analysis to their settings and priorities.

Results

Providing nirmatrelvir/ritonavir to unvaccinated patients at high-risk for severe disease was cost-saving when effectiveness against hospitalization exceeded 33% and cost-effective under all other data scenarios we considered. The cost-effectiveness of other allocation strategies, including those for vaccinated adults and those at lower-risk for severe disease, depended on willingness-to-pay thresholds, treatment cost and effectiveness, and the likelihood of severe disease.

Conclusions

Priority for nirmatrelvir/ritonavir treatment should be given to unvaccinated persons at high-risk of severe disease from COVID-19. Further priority may be assigned by weighing treatment effectiveness, disease severity, drug cost, and willingness to pay for deaths averted.
Multi-ancestry genome-wide meta-analysis in Parkinson’s disease
Authors: Kim Jonggeol Jeffrey , Vitale Dan , Véliz Otani Diego , Lian Michelle , Heilbron Karl ,   the 23andMe Research Team, Iwaki Hirotaka , Lake Julie , Solsberg Caroline Warly , Leonard Hampton , Makarious Mary B. , Tan Eng-King , Singleton Andrew B. , Bandres-Ciga Sara , Noyce Alastair J , Blauwendraat Cornelis , Nalls Mike A. , Foo Jia Nee , Mata Ignacio
Published: August 2022

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, all studies have been performed in just one population at the time. Here we performed the first large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases, and 2,458,063 controls including individuals of European, East Asian, Latin American, and African ancestry. In a single joint meta-analysis, we identified 78 independent genome-wide significant loci including 12 potentially novel loci (MTF2, RP11-360P21.2, ADD1, SYBU, IRS2, USP8:RP11-562A8.5, PIGL, FASN, MYLK2, AJ006998.2, Y_RNA, PPP6R2) and finemapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 23 genes near these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations.
Patterns and Drivers of Internal Migration and Its Association with Access to Reproductive and Maternity Care Among Women in Pakistan: Evidence from a Recent National Survey
Authors: Dadras Omid , Nakayama Takeo
Published: August 2022

Background

During the last decades, migratory behavior has had a key role in population growth and redistribution in Pakistan. Migration has far-reaching socioeconomic implications for individuals and society at large that could influence the health integrity of Pakistani women. This study aimed to describe the migration patterns and drivers as well as its association with adequate access to reproductive and maternal care among married Pakistani women aged 15-49.

Methods

The data from the 2017-18 Pakistan Demographic Health Survey (PDHS) was used to extract the information on the explanatory (sociodemographic and migration backgrounds) and outcome variables (unmet needs for family planning, adequate antenatal care, and delivery at health facilities). Bivariate and multivariate logistic regression analyses were employed to examine the relationship between these explanatory and outcome variables before and after adjustment for sociodemographic inequalities.

Results

In unadjusted models, the odds of having adequate ANC and delivery at health facilities were approximately 2 to 4 times higher in those living (urban non-migrant), moving to (urban to urban, rural to urban), or leaving the urban areas (rural to urban) as compared to rural non-migrants; likewise, the odds of the unmet needs for family planning was about 20-50% lower in the same migration streams compared to rural non-migrant. However, after adjustment for sociodemographic inequalities, most of these associations attenuated and only the association of urban to urban migration with unmet needs for family planning and the association of urban non-migrant with delivery at health facilities remained significant.

Conclusion

Although the findings suggest that Internal migration flows, particularly those to urban areas (urban to urban and rural to urban), could be associated with better access to reproductive and maternity care among married Pakistani women aged 15-49 years; adjustment for sociodemographic inequalities, particularly education and wealth, nullified this association to a great extent. This has important implications for current policies and interventions in Pakistan and calls for policy reform and women’s rights advocacy to enhance the literacy level of young Pakistani girls through well-tailored interventions, maintaining them at school.
Sensorimotor control of object manipulation following middle cerebral artery (MCA) stroke
Authors: Fercho Kelene A. , Scholl Jamie L. , Bikash KC , Bosch Taylor J. , Baugh Lee A.
Published: August 2022

Current bedside diagnostics used for the assessment of the loss of hand function post-stroke examine limited aspects of motor performance. Further, they are not sensitive to subtle changes that can cause deficits in everyday object manipulation tasks. Efficiently lifting an object is a complex neurological event which entails a prediction of required forces based on intrinsic features of the object (sensorimotor integration), short-term updates in the forces required to lift objects that are poorly predicted (sensorimotor memory), as well as the ability to modulate distal fingertip forces. Unfortunately, this complexity is not represented by the existing assessment tools used in clinics for both diagnostic and rehabilitative purposes. The presented research examined these three critical components of skilled object manipulation—production of finely graded muscular forces, sensorimotor integration, and sensorimotor memory—in a heterogeneous population of 60 chronic, unilateral middle cerebral artery stroke participants. Performance was compared to age-matched control participants in each of the three tasks. To examine control of distal fingertip forces, a force-matching task was utilized. To examine sensorimotor integration, participants were presented with familiar objects –large wood or brass blocks—following lifting trials of small and medium sized blocks from the same size-weight families. To accurately predict the weight of the larger blocks, sensorimotor integration of object size and apparent material is required during the first lifts of the large blocks. To examine sensorimotor memory, participants were required to lift a series of size-weight blocks of different colors. One color signified an inverse size-weight relationship that required the modification of short-term sensorimotor memory to efficiently lift. Most post-stroke participants performed below control levels in at least one of the tasks. Importantly, post-stroke participants presented with several different combinations of deficits in each of the tasks performed. The presented research demonstrates MCA stroke patients may have deficits in one or more components required for the successful manipulation of hand-held objects. Further, this information may be used in future studies to aid efforts that target rehabilitation regimens to a stroke survivor’s specific pattern of deficits.
Differential Impacts of Perceived Social Support on Alcohol and Cannabis Use in Young Adults: Lessons from the COVID-19 Pandemic
Authors: Blumberg Michelle J. , Lo Lindsay A. , Harrison Geoffrey W. , Dodwell Alison , Irwin Samantha H. , Olmstead Mary C.
Published: August 2022

Coronavirus (COVID-19) lockdowns provided a unique opportunity to examine how changes in the social environment impact mental health and wellbeing. We addressed this issue by assessing how perceived social support across COVID-19 restrictions alters alcohol and cannabis use in emerging adults, a population vulnerable to adverse outcomes of substance use. Four hundred sixty-three young adults in Canada and the United States completed online questionnaires for three retrospective time points: Pre-Covid, Lockdown and Eased Restrictions. Sociodemographic factors, perceived social support, and substance use were assessed. Overall, alcohol use decreased while cannabis use increased during Lockdown. Interestingly, social support negatively predicted alcohol use and positively predicted cannabis use during Lockdown. These findings suggest a difference in motives underlying alcohol and cannabis use in emerging adults. Importantly, these changes were not sustained when restrictions eased, suggesting that emerging adults exhibit resiliency to the impacts of COVID-19 restrictions on substance use.
COVID-19 rebound after Paxlovid treatment during Omicron BA.5 vs BA.2.12.1 subvariant predominance period
Authors: Wang Lindsey , Volkow Nora D. , Davis Pamela B. , Berger Nathan A. , Kaelber David C. , Xu Rong
Published: August 2022

Paxlovid was authorized by FDA to treat mild-to-moderate COVID-19. In May 2022, the Centers for Disease Control and Prevention (CDC) issued a Health Alert Network Health Advisory on potential COVID-19 rebound after Paxlovid treatment. Since June 2022, Omicron BA.5 has become the dominant subvariant in the US, which is more resistant to neutralizing antibodies than the previous subvariant BA.2.12.1. Questions remain as to how COVID-19 rebound after Paxlovid treatment differs between the BA.5 and BA.2.12.1 subvariants. This is a retrospective cohort study of 15,913 patients who contracted COVID-19 between 5/8/2022-7/18/2022 and were prescribed Paxlovid within 5 days of their COVID-19 infection. The study population was divided into 2 cohorts: (1) BA.5 cohort (n=5,161) – contracted COVID-19 during 6/19/22-7/18/22 when BA.5 was the predominant subvariant2. (2) BA.2.12.1 cohort (n=10,752) – contracted COVID-19 during 5/8/22-6/18/22 when the BA.2.12.1 was the predominant subvariant. The risks of both COVID-19 rebound infections and symptoms 2-8 days after Paxlovid treatment were higher in the BA.5 cohort than in the propensity-score matched BA.2.12.1 cohort: rebound infections (Hazard Ratio or HR: 1.32, 95% CI: 1.06-1.66), rebound symptoms (HR: 1.32, 95% CI: 1.04-1.68). As SARS-CoV-2 evolves with successive subvariants more evasive to antibodies, continuous vigilant monitoring is necessary for COVID-19 rebounds after Paxlovid treatment and longer time duration of Paxlovid treatment warrants evaluation.
10β-Hydroxyestra-1,4-diene-3,17-dione Does Not Bind to the Nuclear Estrogen Receptor α
Authors: Prokai-Tatrai Katalin , Prokai Laszlo
Published: August 2022

The lack of nuclear estrogen receptor (ERα and ERβ) bindings of 10β-hydroxyestra-1,4-diene-3,17-dione (HEDD) and structurally related steroidal para-quinols have been shown by an extensive series of multidisciplinary investigational evidence including specific receptor binding studies. In support of the latter, the absence of estrogen-derived para-quinols’ in vivo uterotrophic effects has also been well documented. Via in silico docking, a recent publication by Canário et al. (2022) reported a robust binding of HEDD (Figure 1B) to ERα. The authors claimed a strong binding of HEDD — as strong as that of its natural ligand, 17β-estradiol (E2), the main human estrogen. However, an examination of the virtual binding pocket revealed that at least one residue near the critical ligand-binding site of their reported HEDD–ERα complex was labelled as “unknown” indicating thereby alteration of the receptor’s published structure (Tannenbaum et al, 1998; Bafna et al., 2020) to fit the ligand. Based on these arguments, the contradictory result by Canário et al. (2022) on HEDD’s binding to ERα should be dismissed.
Distinct eosinophil subsets are modulated by agonists of the commensal-metabolite and vitamin B3 receptor GPR109A during allergic-type inflammation
Authors: Azzoni Rossana , Filbey Kara J. , Daw Rufus H. , Krauss Maria Z. , Hepworth Matthew R. , Konkel Joanne E. , Hessel Edith M. , Kannan Yashaswini , Grainger John R.
Published: August 2022

Eosinophils are key contributors to allergic pathology, however, increasingly eosinophils are described to have important roles in organ health and immunoregulation. Factors that impact these diverse functions of eosinophils are not understood. Here we show in allergic-type lung inflammation, metabolically distinct populations of eosinophils can be identified based on expression of Siglec-F (Siglec-Fhi and Siglec-Fint). Notably, the lung Siglec-Fhi population was responsive to the commensal microbiome, expressing the short-chain fatty acid receptor GPR109A. Animals deficient in GPR109A displayed augmented eosinophilia during allergy. Moreover, transferred GPR109A-deficient eosinophils released more eosinophil peroxidase than controls. Treatment with butyrate or vitamin B3, both GPR109A ligands, reduced Siglec-Fhi eosinophil frequency and activation, which was associated with apoptosis of Siglec-Fhi eosinophils. These findings identify GPR109A as an unappreciated regulator of glycolytic Siglec-Fhi eosinophils, raising the possibility of depleting pathological eosinophil populations in disease states while sparing those with homeostatic functions.
In silicoevidence for the utility of parsimonious root phenotypes for improved vegetative growth and carbon sequestration under drought
Authors: Schäfer Ernst D. , Ajmera Ishan , Farcot Etienne , Owen Markus R. , Band Leah R. , Lynch Jonathan P.
Published: August 2022

Drought is a primary constraint to crop yields and climate change is expected to increase the frequency and severity of drought stress in the future. It has been hypothesized that crops can be made more resistant to drought and better able to sequester atmospheric carbon in the soil by selecting appropriate root phenotypes. We introduceOpenSimRoot_v2, an upgraded version of the functional-structural plant/soil modelOpenSimRoot, and use it to test the utility of a maize root phenotype with fewer and steeper axial roots, reduced lateral root branching density, and more aerenchyma formation (i.e. the ‘Steep, Cheap, and Deep’ (SCD) ideotype) and different combinations of underlying SCD root phene states under rainfed and drought conditions in three distinct maize growing pedoclimatic environments in the USA, Nigeria, and Mexico. In all environments where plants are subjected to drought stress the SCD ideotype as well as several intermediate phenotypes lead to greater shoot biomass after 42 days. As an additional advantage, the amount of carbon deposited below 50 cm in the soil is twice as great for the SCD phenotype as for the reference phenotype in 5 out of 6 simulated environments. We conclude that crop growth and deep soil carbon deposition can be improved by breeding maize plants with fewer axial roots, reduced lateral root branching density, and more aerenchyma formation.
Heterodimerization-dependent secretion of BMPs in Drosophila
Authors: Bauer Milena , Aguilar Gustavo , Wharton Kristi A. , Matsuda Shinya , Affolter Markus
Published: August 2022

Combinatorial signaling is key to instruct context-dependent cell behaviors. During embryonic development, adult homeostasis and disease, Bone Morphogenetic Proteins (BMPs) act as dimers to instruct specific cellular responses. BMP ligands can form both homo- or heterodimers; however, obtaining direct evidence of the endogenous localization and function of each form has proven challenging. Here, we make use of precise genome editing and direct protein manipulation via protein binders to dissect the existence and functional relevance of BMP homo- and heterodimers in the Drosophila wing imaginal disc. This approach revealed in situ the existence of Dpp (BMP2/4)/Gbb (BMP5/6/7/8) heterodimers. We found that Gbb, despite being produced by all the cells of the wing imaginal disc, is only secreted by the cells in which Dpp is expressed. Dpp and Gbb form a gradient of heterodimers whereas neither Dpp nor Gbb homodimers are evident under endogenous physiological conditions. We find that the formation of heterodimers is critical for obtaining optimal signaling and long-range BMP distribution in the developing wing. These results indicate that Dpp/Gbb heterodimers are the active signal required for epithelial patterning and growth.
The medial entorhinal cortex is necessary for the stimulus control over hippocampal place fields by distal, but not proximal, landmarks
Authors: Allison Elizabeth A.M.A. , Moore Joe W. , Arkell Daisy , Dudchenko Paul A. , Wood Emma R.
Published: August 2022

A fundamental property of place cells in the hippocampus is the anchoring of their firing fields to salient landmarks within the environment. However, it is unclear how such information reaches the hippocampus. In the current experiment, we tested the hypothesis that the stimulus control exerted by distal visual landmarks requires input from the medial entorhinal cortex (MEC). Place cells were recorded from mice with ibotenic acid lesions of the MEC (n = 7) and from sham-lesioned mice (n = 6) following 90° rotations of either distal landmarks or proximal cues in a cue controlled environment. We found that lesions of the MEC impaired the anchoring of place fields to distal landmarks, but not proximal cues. We also observed that, relative to sham-lesioned mice, place cells in animals with MEC lesions exhibited significantly reduced spatial information and increased sparsity. These results support the view that distal landmark information reaches the hippocampus via the MEC, but that proximal cue information can do so via an alternative neural pathway.
LambdaPP: Fast and accessible protein-specific phenotype predictions
Authors: Olenyi Tobias , Marquet Céline , Heinzinger Michael , Kröger Benjamin , Nikolova Tiha , Bernhofer Michael , Sändig Philip , Schütze Konstantin , Littmann Maria , Mirdita Milot , Steinegger Martin , Dallago Christian , Rost Burkhard
Published: August 2022

The availability of accurate and fast Artificial Intelligence (AI) solutions predicting aspects of proteins are revolutionizing experimental and computational molecular biology. The webserverLambdaPPaspires to supersede PredictProtein, the first internet server making AI protein predictions available in 1992. Given a protein sequence as input,LambdaPPprovides easily accessible visualizations of protein 3D structure, along with predictions at the protein level (GeneOntology, subcellular location), and the residue level (binding to metal ions, small molecules, and nucleotides; conservation; intrinsic disorder; secondary structure; alpha-helical and beta-barrel transmembrane segments; signal-peptides; variant effect) in seconds. The structure prediction provided byLambdaPP- leveragingColabFold and computed in minutes- is based onMMseqs2multiple sequence alignments. All other feature prediction methods are based on the pLMProtT5. Queried by a protein sequence,LambdaPPcomputes protein and residue predictions almost instantly for various phenotypes, including 3D structure and aspects of protein function.

Accessibility Statement

LambdaPP is freely available for everyone to use underembed.predictprotein.org, the interactive results for the case study can be found underhttps://embed.predictprotein.org/o/Q9NZC2. The frontend of LambdaPP can be found on GitHub (github.com/sacdallago/embed.predictprotein.org), and can be freely used and distributed under the academic free use license (AFL-2). For high-throughput applications, all methods can be executed locally via the bio-embeddings (bioembeddings.com) python package, or docker image atghcr.io/bioembeddings/bio_embeddings, which also includes the backend of LambdaPP.

Impact Statement

We introduce LambdaPP, a webserver integrating fast and accurate sequence-only protein feature predictions based on embeddings from protein Language Models (pLMs) available in seconds along with high-quality protein structure predictions. The intuitive interface invites experts and novices to benefit from the latest machine learning tools. LambdaPP’s unique combination of predicted features may help in formulating hypotheses for experiments and as input to bioinformatics pipelines.
Shifts from non-obligate generalists to obligate specialists in simulations of mutualistic network assembly
Authors: Metz Timo , Blüthgen Nico , Drossel Barbara
Published: August 2022

Understanding ecosystem recovery after perturbation is crucial for ecosystem conservation. Mutualisms contribute key functions for plants such as pollination and seed dispersal. We modelled the assembly of mutualistic networks based on trait matching between plants and their animal partners that have different degrees of specialization on plant traits. Additionally, we addressed the role of non-obligate animal mutualists, including facultative mutualists or non-resident species that have their main resources outside the target site. Our computer simulations show that non-obligate animals facilitate network assembly during the early stages, furthering colonization by an increase in niche space and reduced competition. While non-obligate and generalist animals provide most of the fitness benefits to plants in the early stages of the assembly, obligate and specialist animals dominate at the end of the assembly. Our results thus demonstrate the combined occurrence of shifts from diet, trait, and habitat generalists to more specialised animals.
Activation of Cerebellar Lobule VI PCTH+–Med Pathway Selectively blocks METH-induced Conditioned Place Preference in mice
Authors: Ge Feifei , Wang Zilin , Wang Guanxiong , Chen Liying , Yang Ping , Wen Jun , Pan Weichao , Yu Wen , Cai Qinglong , Fan Yu , Chang Jiasong , Guan Xiaowei
Published: August 2022

The cerebellum is implicated in drug addiction. However, the cerebellar neuronal circuitry underlying addiction, especially classic pathway of Purkinje cells (PCs) to deep cerebellar nuclei (DCN), are largely unknown. Here, tracing experiments showed robust projections from the cerebellar lobule VI tyrosine hydroxylase (TH)-positive PCs (PCTH+) to CaMKII-positive glutamatergic neurons in medial cerebellar nucleus (MedCaMKII), forming PCTH+–MedCaMKII pathway. Then, mice were subjected to methylamphetamine (METH)-induced conditioned place preference (CPP), showing that METH exposure excited MedCaMKII and inhibited PCTH+. Silencing MedCaMKII by tettox suppressed the formation and expression of METH-induced CPP, but produced serious motor coordination deficits. Chemogenetic activation of lobule VI PCTH+–Med pathway during METH CPP training blocked the formation and expression of METH-induced CPP without affecting motor coordination, locomotor activity and sucrose reinforcements in mice. Our findings revealed a novel cerebellar lobule VI PCTH+–MedCaMKII pathway and pointed out is critical role in encoding METH-preferred behaviors.
A histone deacetylase complex establishes a transgenerationally inherited maternal epigenetic state controlling progeny seed dormancy
Authors: Chen Xiaochao , Macgregor Dana R. , Stefanato Francesca L. , Zhang Naichao , Barros-Galvão Thiago , Penfield Steven
Published: August 2022

Mother plants play an important role in the control of dormancy and dispersal characters of their progeny. In Arabidopsis seed dormancy is imposed by the embryo-surrounding tissues of the endosperm and seed coat. Here we show that the VERNALIZATION5/VIN3-LIKE 3 (VEL3) gene maintains maternal control over progeny seed dormancy by establishing an epigenetic state early in endosperm development that primes the depth of primary seed dormancy later established during seed maturation. VEL3 relocates MSI1 to the nucleolus and associates with other components of the histone deacetylase complex (HDAC), and is required for gene repression via PRC2 and HDAC at pericentromeric regions established in the central cell. Interestingly, the epigenetic state established by the maternal VEL3 is retained trans-generationally in mature seeds, and controls seed dormancy through the repression of programmed cell death-associated gene ORE1. Our data demonstrates a novel mechanism by which maternal control of progeny seed physiology persists post-shedding, maintaining parental control of seed behaviour.