bluuebunny/crossref_metadata_2025_split huggingface dataset:
Uncovering neglected subtypes and zoonotic transmission of Hepatitis E virus (HEV) in Brazil
Authors: dos Santos Debora Regina Lopes , Durães-Carvalho Ricardo , Gardinali Noemi Rovaris , Machado Lais Ceschini , de Paula Vanessa Salete , da Luz Wallau Gabriel , de Oliveira Jaqueline Mendes , Pena Lindomar José , Pinto Marcelo Alves , Gil Laura Helena Vega Gonzalez , de Oliveira-Filho Edmilson Ferreira 
Published: May 2023

AbstractHepatitis E virus (HEV) circulation in humans and swine has been extensively studied in South America over the last two decades. Nevertheless, only 2.1% of reported HEV strains are available as complete genome sequences. Therefore, many clinical, epidemiological, and evolutionary aspects of circulating HEV in the continent still need to be clarified. Here, we conducted a retrospective evolutionary analysis of one human case and six swine HEV strains previously reported in northeastern, southern, and southeastern Brazil. We obtained two complete and four nearly complete genomic sequences. Evolutionary analysis comparing the whole genomic and capsid gene sequences revealed high genetic variability. This included the circulation of at least one unrecognized unique South American subtype. Our results corroborate that sequencing the whole capsid gene could be used as an alternative for HEV subtype assignment in the absence of complete genomic sequences. Moreover, our results substantiate the evidence for zoonotic transmission by comparing a larger genomic fragment recovered from the sample of the autochthonous human hepatitis E case. Further studies should continuously investigate HEV genetic diversity and zoonotic transmission of HEV in South America.
Newly arrived migrants did not represent an additional COVID-19 burden for Italy: data from the italian information flow
Authors: Sisti Leuconoe Grazia , Di Napoli Anteo , Petrelli Alessio , Diodati Alessandra , Cavani Andrea , Mirisola Concetta , Costanzo Gianfranco 
Published: May 2023

Abstract
Background
During the COVID-19 pandemic, migrants arriving in host countries irregularly have not infrequently been perceived as increasing the COVID-19 burden. Italy is a transit and destination country for migrants who cross the Central Mediterranean route and, during the pandemic, all migrants who landed on Italian shores were COVID-19 tested and quarantined. Our study aimed to investigate the impact of the SARS-CoV-2 infection among migrants who landed on the Italian coasts by analyzing both incidence and health outcomes.

Methods
A retrospective observational study has been designed. The population of interest was represented by 70,512 migrants (91% male, 99% <60 years old) who landed in Italy between January 2021 and 2022. SARS-CoV-2 incidence rate per 1,000 (with 95%CI) in migrants and the resident population in Italy of the corresponding age group was computed. The incidence rate ratio (IRR) was used to compare the incidence rates in migrants and the resident population.

Results
2,861 migrants out of those landed in Italy during the observation period tested positive, with an incidence rate of 40.6 (39.1–42.1) cases per 1,000. During the same period, 177.6 (177.5-177.8) cases per 1,000 were reported in the resident population, with an IRR of 0.23 (0.22–0.24). 89.7% of cases were male and 54.6% belonged to the 20–29 age group. 99% of cases reported no symptoms, no relevant comorbidities were reported and no cases were hospitalized.

Conclusions
Our study found a low rate of SARS-CoV-2 infection in migrants reaching Italy by sea with an incidence rate that is roughly a quarter of that of the resident population. Thus, irregular migrants who arrived in Italy during the observation period did not increase the COVID-19 burden. Further studies are needed to investigate possible reasons for the low incidence observed in this population.
Breastfeeding practices in Northeast China in 2008 and 2018: cross-sectional surveys to explore determinants over a decade
Authors: Zhou Qianling , Feng Xing Lin 
Published: May 2023

Abstract
Background
This study was conducted to investigate the prevalence and determinants of breastfeeding in 2008 and 2018, respectively, in Northeast China, where health service efficiency is at the lowest national level and regional data on breastfeeding are lacking. The influence of early initiation of breastfeeding on later feeding practices was specifically explored.

Methods
Data from the China National Health Service Survey in Jilin Province in 2008 (n = 490) and 2018 (n = 491) were analysed. Multistage stratified random cluster sampling procedures were used to recruit the participants. Data collection was conducted in the selected villages and communities in Jilin. Early initiation of breastfeeding was defined as the proportion of children born in the last 24 months who were put to the breast within one hour after birth in both the 2008 and 2018 surveys. Exclusive breastfeeding was defined as the proportion of infants 0–5 months of age who were fed exclusively with breast milk in the 2008 survey; while defined as the proportion of infants 6–60 months of age who had been fed exclusively with breast milk within the first six months of life in the 2018 survey.

Results
The prevalence of early initiation of breastfeeding (27.6% in 2008 and 26.1% in 2018) and exclusive breastfeeding during the first six months (< 50%) were low in two surveys. Logistic regression revealed that exclusively breastfeeding at six months was positively associated with early initiation of breastfeeding (OR 2.65; 95% confidence interval (CI) 1.65, 4.26) and negatively associated with caesarean section (OR 0.65; 95% CI 0.43, 0.98) in 2018. Continued breastfeeding at one year and timely introduction of complementary foods were associated with maternal residence and place of delivery, respectively, in 2018. Early initiation of breastfeeding was associated with mode and place of delivery in 2018 but residence in 2008.

Conclusion
Breastfeeding practices in Northeast China are far from optimal. The negative effect of caesarean section and positive effect of early initiation of breastfeeding on exclusive breastfeeding suggest that an institution-based approach should not be substituted by the community-based one in the formulation of breastfeeding strategies in China.
Mutations in α-synuclein, TDP-43 and tau prolong protein half-life through diminished degradation by lysosomal proteases
Authors: Sampognaro Paul J. , Arya Shruti , Knudsen Giselle M. , Gunderson Emma L. , Sandoval-Perez Angelica , Hodul Molly , Bowles Kathryn , Craik Charles S. , Jacobson Matthew P. , Kao Aimee W. 
Published: May 2023

Abstract
Background
Autosomal dominant mutations in α-synuclein, TDP-43 and tau are thought to predispose to neurodegeneration by enhancing protein aggregation. While a subset of α-synuclein, TDP-43 and tau mutations has been shown to increase the structural propensity of these proteins toward self-association, rates of aggregation are also highly dependent on protein steady state concentrations, which are in large part regulated by their rates of lysosomal degradation. Previous studies have shown that lysosomal proteases operate precisely and not indiscriminately, cleaving their substrates at very specific linear amino acid sequences. With this knowledge, we hypothesized that certain coding mutations in α-synuclein, TDP-43 and tau may lead to increased protein steady state concentrations and eventual aggregation by an alternative mechanism, that is, through disrupting lysosomal protease cleavage recognition motifs and subsequently conferring protease resistance to these proteins.

Results
To test this possibility, we first generated comprehensive proteolysis maps containing all of the potential lysosomal protease cleavage sites for α-synuclein, TDP-43 and tau. In silico analyses of these maps indicated that certain mutations would diminish cathepsin cleavage, a prediction we confirmed utilizing in vitro protease assays. We then validated these findings in cell models and induced neurons, demonstrating that mutant forms of α-synuclein, TDP-43 and tau are degraded less efficiently than wild type despite being imported into lysosomes at similar rates.

Conclusions
Together, this study provides evidence that pathogenic mutations in the N-terminal domain of α-synuclein (G51D, A53T), low complexity domain of TDP-43 (A315T, Q331K, M337V) and R1 and R2 domains of tau (K257T, N279K, S305N) directly impair their own lysosomal degradation, altering protein homeostasis and increasing cellular protein concentrations by extending the degradation half-lives of these proteins. These results also point to novel, shared, alternative mechanism by which different forms of neurodegeneration, including synucleinopathies, TDP-43 proteinopathies and tauopathies, may arise. Importantly, they also provide a roadmap for how the upregulation of particular lysosomal proteases could be targeted as potential therapeutics for human neurodegenerative disease.
The Notch signaling pathway: a potential target for cancer immunotherapy
Authors: Li Xinxin , Yan Xianchun , Wang Yufeng , Kaur Balveen , Han Hua , Yu Jianhua 
Published: May 2023

AbstractDysregulation of the Notch signaling pathway, which is highly conserved across species, can drive aberrant epigenetic modification, transcription, and translation. Defective gene regulation caused by dysregulated Notch signaling often affects networks controlling oncogenesis and tumor progression. Meanwhile, Notch signaling can modulate immune cells involved in anti- or pro-tumor responses and tumor immunogenicity. A comprehensive understanding of these processes can help with designing new drugs that target Notch signaling, thereby enhancing the effects of cancer immunotherapy. Here, we provide an up-to-date and comprehensive overview of how Notch signaling intrinsically regulates immune cells and how alterations in Notch signaling in tumor cells or stromal cells extrinsically regulate immune responses in the tumor microenvironment (TME). We also discuss the potential role of Notch signaling in tumor immunity mediated by gut microbiota. Finally, we propose strategies for targeting Notch signaling in cancer immunotherapy. These include oncolytic virotherapy combined with inhibition of Notch signaling, nanoparticles (NPs) loaded with Notch signaling regulators to specifically target tumor-associated macrophages (TAMs) to repolarize their functions and remodel the TME, combining specific and efficient inhibitors or activators of Notch signaling with immune checkpoint blockers (ICBs) for synergistic anti-tumor therapy, and implementing a customized and effective synNotch circuit system to enhance safety of chimeric antigen receptor (CAR) immune cells. Collectively, this review aims to summarize how Notch signaling intrinsically and extrinsically shapes immune responses to improve immunotherapy.
miR-92a-1-5p enriched prostate cancer extracellular vesicles regulate osteoclast function via MAPK1 and FoxO1
Authors: Yu Lijuan , Sui Bingdong , Zhang Xin , Liu Jiayun , Hao Xiaoke , Zheng Lei 
Published: May 2023

Abstract
Background
We have previously reported that extracellular vesicles (EVs) derived from osteoblastic, osteoclastic and mixed prostate cancer cells promote osteoclast differentiation and inhibit osteoblast differentiation via transferring miR-92a-1-5p. In the present study, we focused on engineering miR-92a-1-5p into EVs and determining any therapeutic roles and mechanisms of the engineered EVs.

Methods
A stable prostate cancer cell line (MDA PCa 2b) overexpressing miR-92a-1-5p was constructed by lentivirus, and EVs were isolated by ultracentrifugation. The overexpression of miR-92a-1-5p in both cells and EVs was tested using qPCR. Osteoclast function was evaluated by Trap staining, mRNA expression of osteoclastic markers ctsk and trap, immunolabeling of CTSK and TRAP and microCT using either in vitro and in vivo assays. Target gene of miR-92a-1-5p was proved by a dual-luciferase reporter assay system. siRNAs were designed and used for transient expression in order to determine the role of downstream genes on osteoclast differentiation.

Results
Stable overexpression cells of miRNA-92a-5p was associated with EVs upregulating this microRNA, as confirmed by qPCR. Further, miR-92a-1-5p enriched EVs promote osteoclast differentiation in vitro by reducing MAPK1 and FoxO1 expression, associated with increased osteoclast function as shown by TRAP staining and mRNA expression of osteoclast functional genes. siRNA targeting MAPK1 or FoxO1 resulted in similar increase in osteoclast function. In vivo, the miR-92a-1-5p enriched EVs given via i.v. injection promote osteolysis, which was associated with reduction of MAPK1 and FoxO1 expression in bone marrow.

Conclusion
These experiments suggest that miR-92a-1-5p enriched EVs regulate osteoclast function via reduction of MAPK1 and FoxO1.

Graphical Abstract
Cutaneous lesions in psoriatic arthritis are enriched in chemokine transcriptomic pathways
Authors: Johnsson Hanna , Cole John , Siebert Stefan , McInnes Iain B. , Graham Gerard 
Published: May 2023

Abstract
Objectives
Skin from people with psoriasis has been extensively studied and is assumed to be identical to skin from those with psoriatic arthritis (PsA). Chemokines and the CC chemokine scavenger receptor ACKR2 are upregulated in uninvolved psoriasis. ACKR2 has been proposed as a regulator of cutaneous inflammation in psoriasis. The aim of this study was to compare the transcriptome of PsA skin to healthy control (HC) skin and evaluate ACKR2 expression in PsA skin.

Methods
Full-thickness skin biopsies from HC, lesional and uninvolved skin from participants with PsA were sequenced on NovaSeq 6000. Findings were validated using qPCR and RNAscope.

Results
Nine HC and nine paired PsA skin samples were sequenced. PsA uninvolved skin was transcriptionally similar to HC skin, and lesional PsA skin was enriched in epidermal and inflammatory genes. Lesional PsA skin was enriched in chemokine-mediated signalling pathways, but uninvolved skin was not. ACKR2 was upregulated in lesional PsA skin but had unchanged expression in uninvolved compared with HC skin. The expression of ACKR2 was confirmed by qPCR, and RNAscope demonstrated strong expression of ACKR2 in the suprabasal layer of the epidermis in PsA lesions.

Conclusion
Chemokines and their receptors are upregulated in lesional PsA skin but relatively unchanged in uninvolved PsA skin. In contrast to previous psoriasis studies, ACKR2 was not upregulated in uninvolved PsA skin. Further understanding of the chemokine system in PsA may help to explain why inflammation spreads from the skin to the joints in some people with psoriasis.
A biomarker-validated time scale in years of disease progression has identified early- and late-onset subgroups in sporadic Alzheimer’s disease
Authors: Almkvist Ove , Nordberg Agneta 
Published: May 2023

Abstract
Background
It is possible to calculate the number of years to the expected clinical onset (YECO) of autosomal-dominant Alzheimer’s disease (adAD). A similar time scale is lacking for sporadic Alzheimer’s disease (sAD). The purpose was to design and validate a time scale in YECO for patients with sAD in relation to CSF and PET biomarkers.

Methods
Patients diagnosed with Alzheimer’s disease (AD, n = 48) or mild cognitive impairment (MCI, n = 46) participated in the study. They underwent a standardized clinical examination at the Memory clinic, Karolinska University Hospital, Stockholm, Sweden, which included present and previous medical history, laboratory screening, cognitive assessment, CSF biomarkers (Aβ42, total-tau, and p-tau), and an MRI of the brain. They were also assessed with two PET tracers, 11C-Pittsburgh compound B and 18F-fluorodeoxyglucose. Assuming concordance of cognitive decline in sAD and adAD, YECO for these patients was calculated using equations for the relationship between cognitive performance, YECO, and years of education in adAD (Almkvist et al. J Int Neuropsychol Soc 23:195-203, 2017).

Results
The mean current point of disease progression was 3.2 years after the estimated clinical onset in patients with sAD and 3.4 years prior to the estimated clinical onset in patients with MCI, as indicated by the median YECO from five cognitive tests. The associations between YECO and biomarkers were significant, while those between chronological age and biomarkers were nonsignificant. The estimated disease onset (chronological age minus YECO) followed a bimodal distribution with frequency maxima before (early-onset) and after (late-onset) 65 years of age. The early- and late-onset subgroups differed significantly in biomarkers and cognition, but after control for YECO, this difference disappeared for all except the APOE e4 gene (more frequent in early- than in late-onset).

Conclusions
A novel time scale in years of disease progression based on cognition was designed and validated in patients with AD using CSF and PET biomarkers. Two early- and late-disease onset subgroups were identified differing with respect to APOE e4.
Centralizing prescreening data collection to inform data-driven approaches to clinical trial recruitment
Authors: Kirn Dylan R. , Grill Joshua D. , Aisen Paul , Ernstrom Karin , Gale Seth , Heidebrink Judith , Jicha Gregory , Jimenez-Maggiora Gustavo , Johnson Leigh , Peskind Elaine , McCann Kelly , Shaffer Elizabeth , Sultzer David , Wang Shunran , Sperling Reisa , Raman Rema 
Published: May 2023

Abstract
Background
Recruiting to multi-site trials is challenging, particularly when striving to ensure the randomized sample is demographically representative of the larger disease-suffering population. While previous studies have reported disparities by race and ethnicity in enrollment and randomization, they have not typically investigated whether disparities exist in the recruitment process prior to consent. To identify participants most likely to be eligible for a trial, study sites frequently include a prescreening process, generally conducted by telephone, to conserve resources. Collection and analysis of such prescreening data across sites could provide valuable information to improve understanding of recruitment intervention effectiveness, including whether traditionally underrepresented participants are lost prior to screening.

Methods
We developed an infrastructure within the National Institute on Aging (NIA) Alzheimer’s Clinical Trials Consortium (ACTC) to centrally collect a subset of prescreening variables. Prior to study-wide implementation in the AHEAD 3–45 study (NCT NCT04468659), an ongoing ACTC trial recruiting older cognitively unimpaired participants, we completed a vanguard phase with seven study sites. Variables collected included age, self-reported sex, self-reported race, self-reported ethnicity, self-reported education, self-reported occupation, zip code, recruitment source, prescreening eligibility status, reason for prescreen ineligibility, and the AHEAD 3–45 participant ID for those who continued to an in-person screening visit after study enrollment.

Results
Each of the sites was able to submit prescreening data. Vanguard sites provided prescreening data on a total of 1029 participants. The total number of prescreened participants varied widely among sites (range 3–611), with the differences driven mainly by the time to receive site approval for the main study. Key learnings instructed design/informatic/procedural changes prior to study-wide launch.

Conclusion
Centralized capture of prescreening data in multi-site clinical trials is feasible. Identifying and quantifying the impact of central and site recruitment activities, prior to participants signing consent, has the potential to identify and address selection bias, instruct resource use, contribute to effective trial design, and accelerate trial enrollment timelines.
Rare and heterogeneous manifestations of leucocyte adhesion deficiency type 1: report of two cases with diagnostic dilemmas and novel ITGB2 mutation
Authors: Anis Sabiha , Abid Aiysha , Kodwavwala Sadaf Aba Umer , Sarfaraz Sabahat , Junejo Samina , Shahid Saba , Sultan Sajid , Rizvi Adibul Hasan 
Published: May 2023

Abstract
Background
Primary immunodeficiency disorders (PID) are rare disorders with heterogeneous manifestations, overlapping with other diseases such as autoimmunity, malignancy, and infections. This makes the diagnosis very challenging and delays management. Leucocyte adhesion defects (LAD) are a group of PIDs in which patients lack adhesion molecules on leukocytes needed for their emigration through blood vessels to the site of infection. Patients with LAD can present with diverse clinical features including severe and life-threatening infections, early in life, and the absence of pus formation around infection or inflammation. There is often delayed umbilical cord separation, omphalitis, late wound healing, and a high white blood cell count. If not recognized and managed early, can lead to life-threatening complications and death.

Case Presentation
LAD 1 is characterized by homozygous pathogenic variants in the integrin subunit beta 2 (ITGB2) gene. We report two cases of LAD1 with unusual presentations (post-circumcision excessive bleeding and chronic inflammation of the right eye) which were confirmed by flow cytometric analysis and genetic testing. We found two disease-causing ITGB2 pathogenic variants in both cases.

Conclusions
These cases highlight the importance of a multidisciplinary approach to recognizing clues in patients with uncommon manifestations of a rare disease. This approach initiates a proper diagnostic workup of primary immunodeficiency disorder leading to a better understanding of the disease, and appropriate patient counseling, and helps clinicians to be better equipped to deal with complications.
Peptide-based PET imaging agent of tumor TIGIT expression
Authors: Weng Dinghu , Guo Rong , Zhu Ziyang , Gao Yu , An Rui , Zhou Xiuman 
Published: May 2023

Abstract
Background
Accumulating studies have demonstrated that elevated TIGIT expression in tumor microenvironment correlates with better therapeutic response to TIGIT-based immunotherapy in pre-clinical studies. Therefore, a non-invasive method to detect tumor TIGIT expression is crucial to predict the therapeutic effect.

Methods
In this study, a peptide-based PET imaging agent, 68Ga-DOTA-DTBP-3, was developed to non-invasively detect TIGIT expression by micro-PET in tumor-bearing BALB/c mice. DTBP-3, a D-peptide comprising of 12 amino acids, was radiolabeled with 68Ga through a DOTA chelator. In vitro studies were performed to evaluate the affinity of 68Ga-DOTA-DTBP-3 to TIGIT and its stability in fetal bovine serum. In vivo studies were assessed by micro-PET, biodistribution, and immunohistochemistry on tumor-bearing BALB/c mice.

Results
The in vitro studies showed the equilibrium dissociation constant of 68Ga-DOTA-DTBP-3 for TIGIT was 84.21 nM and its radiochemistry purity was 89.24 ± 1.82% in FBS at 4 h in room temperature. The results of micro-PET, biodistribution and immunohistochemistry studies indicated that 68Ga-DOTA-DTBP-3 could be specifically targeted in 4T1 tumor-bearing mice, with a highest uptake at 0.5 h.

Conclusion
68Ga-DOTA-DTBP-3 holds potential for non-invasively detect tumor TIGIT expression and for timely assessment of the therapeutic effect of immune checkpoint blockade.