bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of COVID-19 lockdowns on fertility in the Democratic Republic of the Congo
Authors: Feng Shuo , Kyomba Gabriel , Mayaka Serge Manitu , Grépin Karen Ann 
Published: December 2022

AbstractMost countries implemented public health measures, including lockdowns, during the COVID-19 pandemic. It has been speculated that the pandemic will affect fertility, but the direction, magnitude, and mechanisms of these effects are not well understood. Using data from the national health management information system and an augmented synthetic control methodology, we examined the impact of a lockdown of Kinshasa in April 2020 on the subsequent fertility of women, which we proxy by the number of births in health facilities months after the policy was implemented. Seven months after the lockdown, we see a large increase in births in Kinshasa, as compared to control areas, which at its peak represents an additional 5000 monthly births, or a 45% increase relative to baseline. We also observe increases in complimentary maternal health services but not in other health services. Increased births were observed among women both older and younger than 20. Lockdown policies have likely affected fertility and future pandemic preparedness plans should anticipate the effects find strategies to mitigate any negative unintended effects.
Pre-Diagnostic Circulating RNAs Networks Identify Testicular Germ Cell Tumour Susceptibility Genes
Authors: Burton Joshua , Rounge Trine B. , Haugen Trine B. , Wojewodzic Marcin W. 
Published: December 2022

AbstractTesticular germ cell tumour (TGCT) is a malignancy with known inherited risk factors, affecting young men. We have previously identified several hundred circulating RNAs that were differentially expressed in pre-diagnostic serum samples from TGCT cases when compared to healthy controls. In this study we performed network preservation analyses of pre-diagnostic serum mRNA and miRNA. Hub genes, enriched functional pathways, and regulatory feature prediction were identified for all TGCT, seminoma, and non-seminoma cases separately, compared to controls. We identifiedUBCA1, RCC1, FMR1, OSA3,andUBE2Was hub genes associated with TGCT. The genesOSA3andUBE2Whave previously been associated with testicular dysgenesis syndrome (TDS) disorders. Previously described TGCT susceptibility genesTEX14,NARS2,andG3BP2were identified as hub genes in both seminoma and non-seminoma networks. Furthermore, network module analysis showed prediction of transcription factors for oestrogen-related receptors. The overlap between network hub genes and TGCT susceptibility genes indicates a role in the progression from germ cell neoplasia in situ (GCNIS) to TGCT that should be further investigated.
Immunogenicity and reactogenicity of mRNA COVID-19 vaccine booster administered by intradermal or intramuscular route in Thai Older adults
Authors: Assantachai Prasert , Niyomnaitham Suvimol , Chatthanawaree Wichai , Intalapaporn Somboon , Muangpaisan Weerasak , Phannarus Harisd , Saichompoo Rangsimatiti Binda , Sura-amonrattana Unchana , Wongprompitak Patimaporn , Toh Zheng Quan , Licciardi Paul V , Srisutthisamphan Kanjana , Chokephaibulkit Kulkanya 
Published: December 2022

AbstractIntroductionIntradermal (ID) vaccination may alleviate COVID-19 vaccine shortages and vaccine hesitancy due to systemic reactogenicity among older adults.ObjectivesTo compare the immunogenicity and reactogenicity of fractional ID and standard intramuscular (IM) booster vaccination of mRNA-1273 and BNT162b2 vaccines in older adults.MethodsParticipants aged ≥65 years who previously vaccinated with 2-dose ChAdOx1 were randomized to receive one of the four booster vaccinations: 0.1mL ID mRNA-1273, 0.5mL IM mRNA-1273, 0.1mL ID BNT162b2 and 0.3mL IM BNT162b2. Immunogenicity as measured by anti-receptor binding domain (anti-RBD) IgG against Wuhan, neutralising antibody (NAb) against Wuhan and Omicron BA.1, BA.2 and BA.4/5, and IFNγ-producing cells. Local and systemic adverse effects (AEs) were self-reported via an electronic diary card.ResultsOf the 210 participants enrolled, 70.5% were female and median age was 77.5 years (interquartile range (IQR): 71.0-84.0). Following the booster dose, both ID vaccination induced 37% lower levels of anti-RBD IgG than IM vaccination of the same vaccine. NAb against ancestral and Omicron BA.1 strains was highest following IM mRNA-1273 (1,718 and 617), followed by ID mRNA-1273 (1,212 and 318), IM BNT162b2 (713 and 230), and ID BNT162b2 (587 and 148), respectively. Spike-specific IFNγ responses were similar or higher in the ID groups when compared with their respective IM groups. Vaccine delivery through ID route tended to have lower systemic AEs, although more local AEs reported in ID mRNA-1273 group.ConclusionsFractional ID vaccination induced immunogenicity and reactogenicity comparable to IM and may be an alternative option for older people.Key pointsFractional dose intradermal mRNA COVID-19 booster vaccination induces robust immunogenicity in adults aged ≥65 years.For each vaccine, intradermal route induced lower humoral but similar or higher cellular immune responses than IM route.Intradermal mRNA-1273 vaccination induced similar immunogenicity to intramuscular BNT162b2 vaccination.Immune responses were marginally lower among participants aged ≥80 years than among participants aged 65-79 years.Systemic reaction was lower following intradermal mRNA COVID-19 vaccination compared with intramuscular vaccination.
Identification of novel PGRP3 protein -protein interactions using yeast two hybrid system
Authors: Lin Li-jung , Lee Clarence , Ranganathan Srivathsan , Kreth Jens , Merritt Justin , Prakasam Sivaraman 
Published: December 2022

AbstractBackgroundPeptidoglycan recognition protein-3 (PGRP3) is a pattern recognition receptor that binds peptidoglycan to elicit an immune response. How PGRP3 mediates these immunomodulatory effects remains unknown. Identifying the proteins that interact with PGRP3 will help begin to address this important knowledge gap. Therefore, in this study our objective was to identify and validate novel PGRP3-protein interactions.MethodsPGRP3-protein interactions were identified using a yeast two-hybrid system. PGRP3 cloned into a pGBKT7 DNA-BD vector and transformed into a Y2HGold yeast strain served as the bait. A normalized universal human cDNA library cloned in a pGADT7 AD vector and pre-transformed into an Y187 yeast strain served as the prey. Y2HGold and Y187 yeast strains were mated and diploids were plated on selective media. True positive clones were sent in for DNA sequencing and corresponding proteins were identified through NCBI Blast. Two proteins were selected for validation. His-tagged PGRP3 expressing 293T cells were then co-transfected with expression vectors containing the identified proteins tagged with c-Myc. Lysates from co-transfected cells were subjected to anti-His and anti-Myc co-immunoprecipitation and analyzed with western blots.ResultsFour unique proteins— MBNL3, RBP5, ATXN2, and GPATCH8—were identified from our yeast two-hybrid screen. Co-transfection and co-immunoprecipitation assays successfully confirmed MBNL3 and RBP5 as positive interactors with PGRP3.ConclusionsBased on the known functions of MBNL3, RBP5, ATXN2, and GPATCH8, we hypothesize that PGRP3 may be involved in RNA processing, endocytic trafficking, and PPARγ pathways related to innate immunity.
High-Throughput Discovery and Characterization of Viral Transcriptional Effectors in Human Cells
Authors: Ludwig Connor H. , Thurm Abby R. , Morgens David W. , Yang Kevin J. , Tycko Josh , Bassik Michael C. , Glaunsinger Britt A. , Bintu Lacramioara 
Published: December 2022

SummaryViruses encode transcriptional regulatory proteins critical for controlling viral and host gene expression. Given their multifunctional nature and high sequence divergence, it is unclear which viral proteins can affect transcription and which specific sequences contribute to this function. Using a high-throughput assay, we measured the transcriptional regulatory potential of over 60,000 protein tiles across ∼1,500 proteins from 11 coronaviruses and all nine human herpesviruses. We discovered hundreds of new transcriptional effector domains, including a conserved repression domain in all coronavirus Spike homologs, dual activation-repression domains in VIRFs, and an activation domain in six herpesvirus homologs of the single-stranded DNA-binding protein that we show is important for viral replication and late gene expression in KSHV. For the effector domains we identified, we investigated their mechanisms via high-throughput sequence and chemical perturbations, pinpointing sequence motifs essential for function. This work massively expands viral protein annotations, serving as a springboard for studying their biological and health implications and providing new candidates for compact gene regulation tools.
Resting-state functional connectivity in children cooled for neonatal encephalopathy
Authors: Spencer Arthur P C , Goodfellow Marc , Chakkarapani Ela , Brooks Jonathan C W 
Published: December 2022

AbstractTherapeutic hypothermia improves outcomes following neonatal hypoxic-ischaemic encephalopathy (HIE), reducing cases of death and severe disability such as cerebral palsy compared to normothermia management. However, when cooled children reach early school-age they have cognitive and motor impairments which are associated with underlying alterations to brain structure and white matter connectivity. It is unknown whether these differences in structural connectivity are associated with differences in functional connectivity between cooled children and healthy controls. Resting-state fMRI has been used to characterise static and dynamic functional connectivity in children, both with typical development and those with neurodevelopmental disorders. Previous studies of resting-state brain networks in children with HIE have focussed on the neonatal period. In this study, we used resting-state fMRI to investigate static and dynamic functional connectivity in children aged 6-8 years who were cooled for neonatal HIE without cerebral palsy (n = 22, median age [IQR] 7.08 [6.85-7.52] years), and healthy controls matched for age, sex and socioeconomic status (n = 20, median age [IQR] 6.75 [6.48-7.25] years). Using group independent component analysis, we identified 31 intrinsic functional connectivity networks consistent with those previously reported in children and adults. We found no case-control differences in the spatial maps of these intrinsic connectivity networks. We constructed subject-specific static functional connectivity networks by measuring pairwise Pearson correlations between component time courses, and found no case-control differences in functional connectivity after FDR correction. To study the time-varying organisation of resting-state networks, we used sliding-window correlations and deep clustering to investigate dynamic functional connectivity characteristics. We found k = 4 repetitively occurring functional connectivity states, which exhibited no case-control differences in dwell time, fractional occupancy, or state functional connectivity matrices. In this small cohort, the spatiotemporal characteristics of resting-state brain networks in cooled children without severe disability were too subtle to be differentiated from healthy controls at early school-age, despite underlying differences in brain structure and white matter connectivity, possibly reflecting a level of recovery of healthy resting-state brain function. To our knowledge, this is the first study to investigate resting-state functional connectivity in children with HIE beyond the neonatal period, and the first to investigate dynamic functional connectivity in any children with HIE.
A realist interview study of a participatory public mental health project “#KindnessByPost”
Authors: Scott Hannah Rachel , Warran Katey , Fraser Kathleen , Chipp Beverley , McGinnes Gail , Towers Mike , Lloyd-Evans Brynmor , Rains Luke Sheridan 
Published: December 2022

AbstractBackground#KindnessByPost (KbP) is a participatory public health initiative in which people anonymously send and receive cards containing messages of goodwill with others also taking part in the programme. Quantitative evaluations of KbP consistently find evidence of improvements to people’s mental wellbeing and feelings of loneliness after participation and three months later. Our aim in the present study is to develop a programme theory of KbP, which describes for whom the KbP intervention improves mental wellbeing, other reported impacts, in which contexts it has these effects, and the mechanisms by which it worksMethodsWe use a realist interviewing methodology to develop the programme theory. We conducted a focus group with the KbP executive team, and 20 one-to-one interviews with KbP participants. During analysis, a co-production working group iteratively developed a Theory of Change model comprising context-mechanism-outcome statements [CMOs] to map out the mechanisms present in KbP.ResultsWe developed 145 CMO statements, which we condensed and categorized into 32 overarching CMOs across nine thematic topics: access to scheme; pathways to involvement; resources; culture; giving post; receiving post; content of received post; community; long term impact. These CMOs set out pathways through which KbP benefited participants, including from doing something kind for someone else, of receiving post and appreciating the effort that went into it, and from the creative process of creating post and writing the messages inside them. Effects were sustained in part through people keeping the cards and through the social media communities that emerged around KbP.DiscussionBoth giving and receiving post and the sense of community benefited participants and improved their mood and feelings of connectedness with others. Connection with a stranger, rather than friends and family, was also an important feature of the initiative for participants. Our wide range of CMO pathways by which KbP produced positive outcomes may mean that the intervention is applicable or adaptable across many communities and settings. Taken together with evidence from the quantitative evaluations, KbP is potentially an effective, low-cost, and highly scalable public health intervention for reducing loneliness and improving wellbeing.
Transgenic Mouse Models Establish a Protective Role of Type 1 IFN Response in SARS-CoV-2 infection-related Immunopathology
Authors: Chauhan Nishant Ranjan , Kundu Soumya , Bal Ramyasingh , Chattopadhyay Diya , Mehto Subhash , Sahu Rinku , Yadav Rina , Krishna Sivaram , Jena Kautilya Kumar , Satapathy Sameekshya , Murmu Krushna C , Singh Bharati , Das Saroj Kumar , Jena Sarita , Harshan Krishnan H , Syed Gulam Hussain , Prasad Punit , Chauhan Santosh 
Published: December 2022

AbstractType 1 interferon (IFN-I) response is the first line of host defense against invading viruses. In the absence of definite mouse models, the role of IFN-I in SARS-CoV-2 infections remained to be perplexing. Here, we developed two mouse models, one with constitutively high IFN-I response (hACE2;Irgm1−/−) and the other with dampened IFN-I response (hACE2;Ifnar1−/−) to comprehend the role of IFN-I response during SARS-CoV-2 invasion. We found that hACE2;Irgm1−/−mice were resistant to lethal SARS-CoV-2 infection with substantially reduced cytokine storm and immunopathology. In striking contrast, a severe SARS-CoV-2 infection along with immune cells infiltration, inflammatory response, and enhanced pathology was observed in the lungs of hACE2;Ifnar1−/−mice. Additionally, hACE2;Ifnar1−/−mice were highly susceptible to SARS-CoV-2 neuroinvasion in the brain accompanied by immune cell infiltration, microglia/astrocytes activation, cytokine response, and demyelination of neurons. The hACE2;Irgm1−/−Ifnar1−/−double knockout mice or hACE2;Irgm1−/−mice treated with STING or RIPK2 pharmacological inhibitors displayed loss of the protective phenotypes observed in hACE2;Irgm1−/−mice suggesting that heightened IFN-I response accounts for the observed immunity. Taken together, we explicitly demonstrate that IFN-I protects from lethal SARS-CoV-2 infection, andIrgm1(IRGM) could be an excellent therapeutic target.GRAPHICAL ABSTRACT
A monkeypox mRNA-lipid nanoparticle vaccine targeting virus binding, entry, and transmission drives protection against lethal orthopoxviral challenge
Authors: Freyn Alec W. , Atyeo Caroline , Earl Patricia L. , Americo Jeffrey L. , Chuang Gwo-Yu , Natarajan Harini , Frey Tiffany , Gall Jason , Moliva Juan I , Hunegnaw Ruth , Arunkumar Guha Asthagiri , Ogega Clinton , Nasir Arshan , Bennett Hamilton , Johnson Joshua , Durney Michael A. , Stewart-Jones Guillaume , Hooper Jay W , Colpitts Tonya , Alter Galit , Sullivan Nancy J. , Carfi Andrea , Moss Bernard 
Published: December 2022

AbstractMonkeypox virus (MPXV) caused a global outbreak in 2022, fueled by behaviorally-altered and enhanced human-to-human transmission. While smallpox vaccines were rapidly deployed to curb spread and disease among those at highest risk, breakthrough disease was noted after complete immunization. Given the imminent threat of additional zoonotic events as well as the virus’ evolving ability to drive human-to-human transmission, there is an urgent need for the development of a MPXV-specific vaccine that is able to also confer broad protection against evolving strains and related orthopoxviruses. Here, we demonstrate that an mRNA-lipid nanoparticle vaccine encoding a set of four highly conserved MPXV surface proteins involved in virus attachment, entry and transmission can induce MPXV-specific immunity and heterologous protection against a lethal vaccinia virus (VACV) challenge. Compared to Modified Vaccinia Virus Ankara (MVA), which forms the basis for the current MPXV vaccine, mRNA-vaccination generated superior neutralizing and cellular spread-inhibitory activities against MPXV and VACV as well as greater Fc-effector Th1-biased humoral immunity to the four MPXV antigens and the four VACV homologs. Single MPXV antigen mRNA vaccines provided partial protection against VACV challenge, while combinations of two, three or four MPXV antigen expressing mRNAs protected against disease-related weight loss and death. Remarkably, the cross-protection by multivalent MPXV mRNAs was superior to the homologous protection by MVA, associated with a combination of neutralizing and non-neutralizing antibody functions. These data reveal robust protection against VACV using an mRNA-based vaccine targeting four highly conserved viral surface antigens, linked to the induction of highly functional antibodies able to rapidly control viral infection.
STING-dependent cytosolic DNA sensing pathway drives the progression to leukemia in TET2-mutated HSPCs
Authors: Xie Jiaying , Sheng Mengyao , Rong Shaoqin , Wang Chao , Wu Wanling , Huang Jingru , Sun Yue , Chen Pingyue , Wu Yushuang , Wang Yuanxian , Wang Lan , Zhou Bo O. , Huang Xinxin , Walsh Colum P. , Bohlander Stefan K. , Huang Jian , Wang Xiaoqin , Gao Hai , Zhou Dan , Shi Yuheng , Xu Guo-Liang 
Published: December 2022

AbstractSomatic loss-of-function mutations of the dioxygenase Ten-eleven translocation-2 (TET2) occur frequently in individuals with clonal hematopoiesis (CH) and acute myeloid leukemia (AML). These common hematopoietic disorders can be recapitulated in mouse models. However, the underlying mechanisms by which the deficiency in TET2 promotes these disorders remain largely unknown. Here we show that the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway is activated to mediate the effect of TET2 deficiency in leukemogenesis in mouse models. DNA damage arising inTet2-deficient hematopoietic stem/progenitor cells (HSPCs) leads to activation of the cGAS-STING pathway which in turn induces the development of CH and myeloid transformation. Notably, both pharmacological inhibition and genetic deletion of STING suppressesTet2mutation-induced aberrant myelopoiesis. In patient-derived xenograft (PDX) models, STING inhibition specifically attenuates the proliferation of leukemia cells from TET2-mutated individuals. These observations suggest that the hematopoietic transformation associated with TET2 mutations is powered through sterile inflammation dependent on the activated cGAS-STING pathway, and that STING may represent a potential target for intervention of relevant hematopoietic malignancies.Key pointsTet2deficiency leads to DNA damage which in turn activates the cGAS-STING pathway to induce an inflammatory responseBlocking STING in TET2-mutated hematopoietic stem/progenitor cells suppresses clonal hematopoiesis in mice and leukemogenesis in patient-derived xenograft models
Changes in cancer prevention and management and patient needs during the COVID-19 pandemic: An umbrella review of systematic reviews
Authors: Muka Taulant , Li Joshua J X , Farahani Sahar J. , Ioannidis John P.A. 
Published: December 2022

ABSTRACTIntroductionThe COVID-19 pandemic led to relocation and reconstruction of health care resources and systems, and to a decrease in healthcare utilization, and this may have affected the treatment, diagnosis, prognosis, and psychosocial well-being of cancer patients.ObjectiveTo summarize and quantify the evidence on the impact of the COVID-19 pandemic on the full spectrum of cancer care.MethodsWe performed an umbrella review to summarize and quantify the findings from systematic reviews on impact of the COVID-19 pandemic on cancer treatment modification, delays, and cancellations; delays or cancellations in screening and diagnosis; psychosocial well-being, financial distress, and use of telemedicine as well as on other aspects of cancer care. PubMed was searched for relevant systematic reviews with or without meta-analysis published before November 29th, 2022. Abstract, full text screening and data extraction were performed by two independent reviewers. AMSTAR-2 was used for critical appraisal of included systematic reviews.Results45 systematic reviews evaluating different aspects of cancer care were included in our analysis. Most reviews were based on observational studies judged to be at medium and high risk of bias. Only 2 of the included reviews had high or moderate scores based on AMSTAR-2. Findings suggest treatment modifications in cancer care during the pandemic versus the pre-pandemic period were based on low level of evidence. Different degrees of delays and cancellations in cancer treatment, screening and diagnosis were observed, with low-and-middle income countries and countries that implemented lockdowns being disproportionally affected. A shift from in-person appointments to telemedicine use was observed, but utility of telemedicine, challenges in implementation and cost-effectiveness in different areas of cancer care were little explored. Evidence was consistent in suggesting psychosocial well-being (e.g., depression, anxiety, and social activities) of cancer patients deteriorated, and cancer patients experienced financial distress, albeit results were in general not compared to pre-pandemic levels. Impact of cancer care disruption during the pandemic on cancer prognosis was little explored.ConclusionSubstantial but heterogenous impact of COVID-19 pandemic on cancer care has been observed. Evidence gaps exist on this topic, with mid- and long-term impact on cancer care being most uncertain.