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Changes in the epidemiology and ecology of H5N1 highly pathogenic avian influenza are devastating wild bird and poultry populations, farms and communities, and wild mammals worldwide. Having originated in farmed poultry, H5N1 viruses are now spread globally by wild birds, with transmission to many mammal and avian species, resulting in 2024 in transmission among dairy cattle with associated human cases. These ecological changes pose challenges to mitigating the impacts of H5N1 highly pathogenic avian influenza on wildlife, ecosystems, domestic animals, food security, and humans. H5N1 highly pathogenic avian influenza highlights the need for One Health approaches to pandemic prevention and preparedness, emphasising multisectoral collaborations among animal, environmental, and public health sectors. Action is needed to reduce future pandemic risks by preventing transmission of highly pathogenic avian influenza among domestic and wild animals and people, focusing on upstream drivers of outbreaks, and ensuring rapid responses and risk assessments for zoonotic outbreaks. Political commitment and sustainable funding are crucial to implementing and maintaining prevention programmes, surveillance, and outbreak responses.
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Four types of influenza virus have been identified in nature: influenza A, B, and C viruses are capable of infecting humans, and influenzas A and B cause annual epidemics (seasonal flu) in humans; however, influenza D is currently known to infect only pigs and cattle. The influenza A viruses (IAVs) are of greatest importance to humans, causing widespread significant morbidity and mortality, and have been responsible for at least five pandemics documented since the beginning of the 20th century (Table 1). The H1N1 and H3N2 IAVs continue to circulate in humans as seasonal influenza. In addition to humans, IAVs have a wide range of host animal species in nature, especially wild aquatic birds, the reservoir hosts of IAVs. The IAVs isolated from or adapted to an avian host are named avian influenza viruses (AIVs), and are of great concern owing to their involvement in the genesis of pandemic and outbreak strains. Moreover, the majority of AIVs persist in wild birds and domestic poultry, and novel variants continue to emerge in birds and other hosts, posing non-negligible threats to host ecology and public health.
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Aves , Vírus da Influenza A , Influenza Aviária , Influenza Humana , Animais , Influenza Aviária/virologia , Influenza Aviária/epidemiologia , Influenza Aviária/transmissão , Aves/virologia , Vírus da Influenza A/fisiologia , Vírus da Influenza A/patogenicidade , Humanos , Influenza Humana/virologia , Influenza Humana/epidemiologia , Influenza Humana/transmissão , Evolução Molecular , Evolução BiológicaRESUMO
PURPOSE: Adolescent and young adult cancer survivors (AYACS) are patients diagnosed with cancer between 15 and 39 years of age. AYACS are often derailed from planned educational and occupational endeavors due to disruption from cancer treatment and its consequences. The study objective was to examine how a personal cancer diagnosis impacted AYACS' experiences related to these endeavors. METHODS: Semi-structured interviews were conducted as part of a larger study assessing psychosocial challenges among a younger AYACS subset aged 15-25 years old at the time of cancer diagnosis. Interviews were coded based on responses and were used to develop themes related to educational and occupational endeavors. RESULTS: Data were collected from 35 participants. Five themes emerged: (1) Pauses in educational attainment had a detrimental effect on educational goals for some participants, but further solidified and sculpted educational plans for others; (2) Although participants experienced challenges accomplishing educational goals, supportive school environments helped surmount these challenges; (3) Participants reflected on rethinking career aspirations, though some desired to pursue the same occupation planned before cancer diagnosis; (4) Participants experienced challenges, including physical and cognitive limitations, upon returning to work; and (5) Participants valued autonomy and normalcy through work and appreciated supportive and flexible work environments. CONCLUSIONS: AYACS prioritize professional achievement, yet encounter challenges in achieving professional goals. Our findings create a foundation for developing and testing prospective interventions to promote continuance of school and work during cancer treatment when feasible, and proactive reintegration strategies for those who paused professional goals due to cancer treatment.
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Sobreviventes de Câncer , Pesquisa Qualitativa , Humanos , Sobreviventes de Câncer/psicologia , Adolescente , Masculino , Feminino , Adulto Jovem , Adulto , Neoplasias/psicologia , Entrevistas como Assunto , Escolaridade , Escolha da ProfissãoRESUMO
We report three new polymers, based on mechanically interlocked inorganic-organic rotaxanes. They are made in very mild conditions and involve pyrimidine head groups binding to copper(ii) linking units. A two-dimensional 6,3 net and a three-dimensional 10,3b net are found depending on the solvent used in the reaction.
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Preferentially Expressed Antigen in Melanoma (PRAME) and Ten-Eleven Translocation (TET) dioxygenase-mediated 5-hydroxymethylcytosine (5hmC) are emerging melanoma biomarkers. We observed an inverse correlation between PRAME expression and 5hmC levels in benign nevi, melanoma in situ, primary invasive melanoma, and metastatic melanomas via immunohistochemistry and multiplex immunofluorescence: nevi exhibited high 5hmC and low PRAME, whereas melanomas showed the opposite pattern. Single-cell multiplex imaging of melanoma precursors revealed that diminished 5hmC coincides with PRAME upregulation in premalignant cells. Analysis of TCGA and GTEx databases confirmed a negative relationship between TET2 and PRAME mRNA expression in melanoma. Additionally, 5hmC levels were reduced at the PRAME 5' promoter in melanoma compared to nevi, suggesting a role for 5hmC in PRAME transcription. Restoring 5hmC levels via TET2 overexpression notably reduced PRAME expression in melanoma cell lines. These findings establish a function of TET2-mediated DNA hydroxymethylation in regulating PRAME expression and demonstrate epigenetic reprogramming as pivotal in melanoma tumorigenesis. Teaser: Melanoma biomarker PRAME expression is negatively regulated epigenetically by TET2-mediated DNA hydroxymethylation.
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[This corrects the article DOI: 10.3389/fcimb.2024.1407246.].
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Prior studies found hand preference trajectories predict preschool language outcomes. However, this approach has been limited to examining bimanual manipulation in toddlers. It is not known whether hand preference during infancy for acquiring objects (i.e., reach-to-grasp) similarly predicts childhood language ability. The current study explored this motor-language developmental cascade in 90 children. Hand preference for acquiring objects was assessed monthly from 6 to 14 months and language skill was assessed at 5 years. Latent class growth analysis identified three infant hand preference classes: left, early right, and late right. Infant hand preference classes predicted 5-year language skills. Children in the left and early right classes, who were categorized as having a consistent hand preference, had higher expressive and receptive language scores relative to children in the inconsistent late right class. Consistent classes did not differ from each other on language outcomes. Infant hand preference patterns explained more variance for expressive and receptive language relative to previously reported toddler hand preference patterns, above and beyond socioeconomic status (SES). Results suggest that hand preference, measured at different time points across development using a trajectory approach, is reliably linked to later language.
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The human brain undergoes rapid development during the first years of life. Beginning in utero, a wide array of biological, social, and environmental factors can have lasting impacts on brain structure and function. To understand how prenatal and early life experiences alter neurodevelopmental trajectories and shape health outcomes, several NIH Institutes, Centers, and Offices collaborated to support and launch the HEALthy Brain and Child Development (HBCD) Study. The HBCD Study is a multi-site prospective longitudinal cohort study, that will examine human brain, cognitive, behavioral, social, and emotional development beginning prenatally and planned through early childhood. Influenced by the success of the ongoing Adolescent Brain Cognitive DevelopmentSM Study (ABCD Study®) and in partnership with the NIH Helping to End Addiction Long-term® Initiative, or NIH HEAL Initiative®, the HBCD Study aims to establish a diverse cohort of over 7000 pregnant participants to understand how early life experiences, including prenatal exposure to addictive substances and adverse social environments as well as their interactions with an individual's genes, can affect neurodevelopmental trajectories and outcomes. Knowledge gained from the HBCD Study will help identify targets for early interventions and inform policies that promote resilience and mitigate the neurodevelopmental effects of adverse childhood experiences and environments.
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Chronic motor impairments are a leading cause of disability after stroke. Previous studies have associated motor outcomes with the degree of damage to predefined structures in the motor system, such as the corticospinal tract. However, such theory-based approaches may not take full advantage of the information contained in clinical imaging data. The present study uses data-driven approaches to model chronic motor outcomes after stroke and compares the accuracy of these associations to previously-identified theory-based biomarkers. Using a cross-validation framework, regression models were trained using lesion masks and motor outcomes data from 789 stroke patients from the Enhancing NeuroImaging Genetics through Meta Analysis (ENIGMA) Stroke Recovery Working Group. Using the explained variance metric to measure the strength of the association between chronic motor outcomes and imaging biomarkers, we compared theory-based biomarkers, like lesion load to known motor tracts, to three data-driven biomarkers: lesion load of lesion-behaviour maps, lesion load of structural networks associated with lesion-behaviour maps, and measures of regional structural disconnection. In general, data-driven biomarkers had stronger associations with chronic motor outcomes accuracy than theory-based biomarkers. Data-driven models of regional structural disconnection performed the best of all models tested (R 2 = 0.210, P < 0.001), performing significantly better than the theory-based biomarkers of lesion load of the corticospinal tract (R 2 = 0.132, P < 0.001) and of multiple descending motor tracts (R 2 = 0.180, P < 0.001). They also performed slightly, but significantly, better than other data-driven biomarkers including lesion load of lesion-behaviour maps (R 2 = 0.200, P < 0.001) and lesion load of structural networks associated with lesion-behaviour maps (R 2 = 0.167, P < 0.001). Ensemble models - combining basic demographic variables like age, sex, and time since stroke - improved the strength of associations for theory-based and data-driven biomarkers. Combining both theory-based and data-driven biomarkers with demographic variables improved predictions, and the best ensemble model achieved R 2 = 0.241, P < 0.001. Overall, these results demonstrate that out-of-sample associations between chronic motor outcomes and data-driven imaging features, particularly when lesion data is represented in terms of structural disconnection, are stronger than associations between chronic motor outcomes and theory-based biomarkers. However, combining both theory-based and data-driven models provides the most robust associations.
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OBJECTIVE: Antimicrobial resistance (AMR), together with multidrug resistance (MDR), mainly among Gram-negative bacteria, has been on the rise. Colistin (polymyxin E) remains one of the primary available last resorts to treat infections caused by MDR bacteria during the rapid emergence of global resistance. As the exact mechanism of bacterial resistance to colistin remains undetermined, this study warranted elucidation of the underlying mechanisms of colistin resistance and heteroresistance among carbapenem-resistant Klebsiella pneumoniae isolates. METHODS: Molecular analysis was carried out on the resistant isolates using a genome-wide characterisation approach, as well as MALDI-TOF mass spectrometry, to identify lipid A. RESULTS: Among the 32 carbapenem-resistant K. pneumoniae isolates, several isolates showed resistance and intermediate resistance to colistin. The seven isolates with intermediate resistance exhibited the "skip-well" phenomenon, attributed to the presence of resistant subpopulations. The three isolates with full resistance to colistin showed ions using MALDI-TOF mass spectrometry at m/z of 1840 and 1824 representing bisphosphorylated and hexa-acylated lipid A, respectively, with or without hydroxylation at position C'-2 of the fatty acyl chain. Studying the genetic environment of mgrB locus revealed the presence of two insertion sequences that disrupted the mgrB locus in the three colistin-resistant isolates: IS1R and IS903B. CONCLUSIONS: Our findings show that colistin resistance/heteroresistance was inducible with mutations in chromosomal regulatory networks controlling the lipid A moiety and insertion sequences disrupting the mgrB gene, leading to elevated minimum inhibitory concentration values and treatment failure. Different treatment strategies should be employed to avoid colistin heteroresistance-linked treatment failures, mainly through combination therapy using colistin with carbapenems, aminoglycosides, or tigecycline.
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The recently emerged BA.2.86, JN.1, EG.5, EG.5.1, and HV.1 variants have a growth advantage. In this study, we explore the structural bases of receptor binding and immune evasion for the Omicron BA.2.86, JN.1, EG.5, EG.5.1, and HV.1 sub-variants. Our findings reveal that BA.2.86 exhibits strong receptor binding, whereas its JN.1 sub-lineage displays a decreased binding affinity to human ACE2 (hACE2). Through complex structure analyses, we observed that the reversion of R493Q in BA.2.86 receptor binding domain (RBD) plays a facilitating role in receptor binding, while the L455S substitution in JN.1 RBD restores optimal affinity. Furthermore, the structure of monoclonal antibody (mAb) S309 complexed with BA.2.86 RBD highlights the importance of the K356T mutation, which brings a new N-glycosylation motif, altering the binding pattern of mAbs belonging to RBD-5 represented by S309. These findings emphasize the importance of closely monitoring BA.2.86 and its sub-lineages to prevent another wave of SARS-CoV-2 infections.
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Enzima de Conversão de Angiotensina 2 , Anticorpos Monoclonais , COVID-19 , Evasão da Resposta Imune , Ligação Proteica , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Humanos , SARS-CoV-2/imunologia , SARS-CoV-2/metabolismo , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/química , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/genética , COVID-19/imunologia , COVID-19/virologia , COVID-19/metabolismo , Sítios de Ligação , Modelos Moleculares , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/metabolismo , MutaçãoRESUMO
We report the synthesis of a right-handed (Δ-stereochemistry of strand crossings) trefoil knot from a single molecular strand containing three pyrazine-2,5-dicarboxamide units adjacent to point-chiral centers and six pyridine moieties. The oligomeric ligand strand folds into an overhand (open-trefoil) knot through the assistance of coordinatively dynamic Co(II) "chaperones" that drive the formation of a three-metal-ion circular helicate. The entangled structure is kinetically locked by oxidation to Co(III) and covalently captured by ring-closing olefin metathesis to generate a trefoil knot of single topological handedness. The stereochemistry of the strand crossings in the metal-coordinated overhand knot is governed by the stereochemistry of the point-chiral carbon centers in the ligand strand. The overhand and trefoil knots were characterized by NMR spectroscopy, mass spectrometry, and X-ray crystallography. Removal of the metal ions from the knot, followed by hydrogenation of the alkene, yielded the wholly organic trefoil knot. The metal-free knot and parent ligand were investigated by circular dichroism (CD) spectroscopy. The CD spectra indicate that the topological stereochemistry of the knot has a greater effect on the asymmetry of the chromophore environment than do the point-chiral centers of the strand.
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Introduction: In the battle against multidrug-resistant bacterial infections, ceftazidime- avibactam (CZA) stands as a pivotal defense, particularly against carbapenemresistant (CR) Gram-negative pathogens. However, the rise in resistance against this drug poses a significant threat to its effectiveness, highlighting the critical need for in-depth studies about its resistance mechanisms. Methods: This research focuses on the genomic characterization of CR- and CZA-resistant Escherichia coli (n=26) and Klebsiella pneumoniae (n=34) strains, harboring the blaNDM and/or blaOXA-48-like genes, at a major Lebanese tertiary care medical center, using whole genome sequencing (WGS). Results: Our findings revealed a notable prevalence of blaNDM in all K. pneumoniae strains isolates, with 27 of these also harboring blaOXA-48. On the other hand, E. coli strains predominantly carried the blaNDM-5 gene. Whole genome sequencing (WGS) identified a predominance of ST383 among K. pneumoniae strains, which possessed a multi-replicon IncFIB-IncHI1B plasmid harboring the blaNDM-5. Additionally, various Inc group plasmids in K. pneumoniae across multiple sequence types were found to carry the blaNDM. Similarly, diverse STs of E. coli were observed to carry blaNDM-5 on different plasmids. Discussion: The study underscores NDM carbapenemases as a paramount resistance mechanism in Lebanon,jeopardizing critical last-resort treatments. It also illuminates the role of varied sequence types and mobile genetic elements in the spread of NDM resistance,stressing the urgent need for strategies to mitigate this threat, especially in nosocomial infections.
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Antibacterianos , Compostos Azabicíclicos , Carbapenêmicos , Ceftazidima , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla , Escherichia coli , Klebsiella pneumoniae , Sequenciamento Completo do Genoma , beta-Lactamases , Ceftazidima/farmacologia , Compostos Azabicíclicos/farmacologia , Humanos , Líbano , beta-Lactamases/genética , beta-Lactamases/metabolismo , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/efeitos dos fármacos , Antibacterianos/farmacologia , Escherichia coli/genética , Escherichia coli/efeitos dos fármacos , Carbapenêmicos/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Plasmídeos/genética , Testes de Sensibilidade Microbiana , Transferência Genética Horizontal , Genoma Bacteriano , Enterobacteriáceas Resistentes a Carbapenêmicos/genética , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Enterobacteriáceas Resistentes a Carbapenêmicos/isolamento & purificação , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Centros de Atenção TerciáriaRESUMO
OBJECTIVES: The objective of this study was to determine the difference in failure rates of surgical repair for displaced femoral neck fractures in patients younger than 60 years of age according to fixation strategy. DESIGN: This is a retrospective, comparative cohort study. SETTING: Twenty-six Level 1 North American trauma centers. PATIENT SELECTION CRITERIA: Patients younger than 60 years of age with a displaced femoral neck fracture (OTA 31-B2, B3) undergoing surgical repair from 2005 to 2017. OUTCOME MEASURES AND COMPARISONS: Patient demographics, injury characteristics, repair methods used, and treatment failure (nonunion/failed fixation, avascular necrosis, and need for secondary surgery) were compared according to fixation strategy. RESULTS: Five hundred and sixty-five patients met inclusion criteria and were studied. The mean age was 42 years, 36% were female, and the average Pauwels' angle of fractures was 55 degrees. There were 305 patients treated with multiple cannulated screws (MCS) and 260 treated with a fixed-angle (FA) construct. Treatment failures were 46% overall, but was more likely to occur in MCS constructs versus FA devices (55% vs. 36%, P < 0.001). When FA constructs were substratified, the use of a sliding hip screw with addition of a medial femoral neck buttress plate (FNBP) and "antirotation" (AR) screw demonstrated better results than either FNBP or AR screw alone or neither with the lowest overall construct failure rate of 11% (P < 0.036). CONCLUSIONS: Historically used fixation constructs for femoral neck fractures (eg, multiple cannulated screws and sliding hip screw) in young and middle-aged adults performed poorly compared with more recently proposed constructs, including those using a medial femoral neck buttress plate and an antirotation screw. Fixed-angle constructs outperformed multiple cannulated screws overall, and augmentation of fixed-angle constructs with a medial femoral neck buttress plate and antirotation screw improved the likelihood of successful treatment. Surgeons should prioritize fixation decisions when repairing displaced femoral neck fractures in patients. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
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Fraturas do Colo Femoral , Fixação Interna de Fraturas , Centros de Traumatologia , Humanos , Fraturas do Colo Femoral/cirurgia , Feminino , Masculino , Estudos Retrospectivos , Pessoa de Meia-Idade , Adulto , Fixação Interna de Fraturas/métodos , Fixação Interna de Fraturas/instrumentação , Adolescente , Adulto Jovem , Parafusos Ósseos , Estudos de Coortes , Falha de Tratamento , Resultado do TratamentoRESUMO
OBJECTIVES: To study the results of displaced femoral neck fractures (FNFs) in adults less than 60 years of age by comparing patients, injury, treatment, and the characteristics of treatment failure specifically according to patients' age at injury, that is, by their "decade of life" [ie, "under 30" (29 years and younger), "the 30s" (30-39 years), "the 40s" (40-49 years), and "the 50s" (50-59 years)]. DESIGN: Multicenter retrospective comparative cohort series. SETTING: Twenty-six North American Level 1 Trauma Centers. PATIENT SELECTION CRITERIA: Skeletally mature patients aged 18-59 years with operative repair of displaced FNFs. OUTCOME MEASURES AND COMPARISONS: Main outcome measures were treatment failures (fixation failure and/or nonunion, osteonecrosis, malunion, and the need for subsequent major reconstructive surgery (arthroplasty or proximal femoral osteotomy). These were compared across decades of adult life through middle age (<30 years, 30-39 years, 40-49 years, and 50-59 years). RESULTS: Overall, treatment failure was observed in 264 of 565 (47%) of all hips. The mean age was 42.2 years, 35.8% of patients were women, and the mean Pauwels angle was 53.8 degrees. Complications and the need for major secondary surgeries increased with each increasing decade of life assessed: 36% of failure occurred in patients <30 years of age, 40% in their 30s, 48% in their 40s, and 57% in their 50s (P < 0.001). Rates of osteonecrosis increased with decades of life (under 30s and 30s vs. 40s vs. 50s developed osteonecrosis in 10%, 10%, 20%, and 27% of hips, P < 0.001), while fixation failure and/or nonunion only increased by decade of life to a level of trend (P = 0.06). Reparative methods varied widely between decade-long age groups, including reduction type (open vs. closed, P < 0.001), reduction quality (P = 0.030), and construct type (cannulated screws vs. fixed angle devices, P = 0.024), while some variables evaluated did not change with age group. CONCLUSIONS: Displaced FNFs in young and middle-aged adults are a challenging clinical problem with a high rate of treatment failure. Major complications and the need for complex reconstructive surgery increased greatly by decade of life with the patients in their sixth decade experiencing osteonecrosis at the highest rate seen among patients in the decades studied. Interestingly, treatments provided to patients in their 50s were notably different than those provided to younger patient groups. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
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Fraturas do Colo Femoral , Falha de Tratamento , Humanos , Fraturas do Colo Femoral/cirurgia , Adulto , Pessoa de Meia-Idade , Feminino , Masculino , Adulto Jovem , Estudos Retrospectivos , Adolescente , Fixação Interna de Fraturas/métodos , Fatores EtáriosRESUMO
The Addictions Neuroclinical Assessment (ANA) is a neurobiologically-informed framework designed to understand the etiology and heterogeneity of Alcohol Use Disorder (AUD). Previous studies validated the three neurofunctional domains of ANA: Incentive Salience (IS), Negative Emotionality (NE) and Executive Function (EF) using secondary data. The present cross-sectional observational study assessed these domains in an independent, prospective clinical sample. Adults across the drinking spectrum (N = 300) completed the ANA battery, a standardized collection of behavioral tasks and self-report assessments. Factor analyses were used to identify latent factors underlying each domain. Associations between identified domain factors were evaluated using structural equation models. Receiver operating characteristics analyses were used to determine factors with the strongest ability to classify individuals with problematic drinking and AUD. We found (1) two factors underlie the IS domain: alcohol motivation and alcohol insensitivity. (2) Three factors were identified for the NE domain: internalizing, externalizing, and psychological strength. (3) Five factors were found for the EF domain: inhibitory control, working memory, rumination, interoception, and impulsivity. (4) These ten factors showed varying degrees of cross-correlations, with alcohol motivation, internalizing, and impulsivity exhibiting the strongest correlations. (5) Alcohol motivation, alcohol insensitivity, and impulsivity showed the greatest ability in classifying individuals with problematic drinking and AUD. Thus, the present study identified unique factors underlying each ANA domain assessed using a standardized assessment battery. These results revealed additional dimensionality to the ANA domains, bringing together different constructs from the field into a single cohesive framework and advancing the field of addiction phenotyping. Future work will focus on identifying neurobiological correlates and identifying AUD subtypes based on these factors.
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Alcoolismo , Função Executiva , Motivação , Testes Neuropsicológicos , Humanos , Masculino , Feminino , Adulto , Estudos Transversais , Alcoolismo/fisiopatologia , Alcoolismo/psicologia , Função Executiva/fisiologia , Pessoa de Meia-Idade , Estudos Prospectivos , Comportamento Impulsivo/fisiologia , Adulto Jovem , Comportamento Aditivo/psicologia , Comportamento Aditivo/fisiopatologia , Emoções/fisiologia , Análise FatorialRESUMO
Genome transcription and replication of influenza A virus (FluA), catalyzed by viral RNA polymerase (FluAPol), are delicately controlled across the virus life cycle. A switch from transcription to replication occurring at later stage of an infection is critical for progeny virion production and viral non-structural protein NS2 has been implicated in regulating the switch. However, the underlying regulatory mechanisms and the structure of NS2 remained elusive for years. Here, we determine the cryo-EM structure of the FluAPol-NS2 complex at ~3.0 Å resolution. Surprisingly, three domain-swapped NS2 dimers arrange three symmetrical FluPol dimers into a highly ordered barrel-like hexamer. Further structural and functional analyses demonstrate that NS2 binding not only hampers the interaction between FluAPol and the Pol II CTD because of steric conflicts, but also impairs FluAPol transcriptase activity by stalling it in the replicase conformation. Moreover, this is the first visualization of the full-length NS2 structure. Our findings uncover key molecular mechanisms of the FluA transcription-replication switch and have implications for the development of antivirals.
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Drs. John and Ford reported in biomedicines that a variant transcript encoding receptor tyrosine kinase-like orphan receptor 1 (ROR1), namely ENST00000545203 or variant 3 (ROR1V3), was a predominant ROR1 transcript of neoplastic or normal cells in the Bioinformatic database, including GTEx and the 33 datasets from TCGA. Unlike the full-length ROR1 transcript, Drs. John and Ford deduced that ROR1V3 encoded a cytoplasmic ROR1 protein lacking an apparent signal peptide necessary for transport to the cell surface, which they presumed made it unlikely to function as a surface receptor for Wingless/Integrated (Wnt) factors. Moreover, they speculated that studies evaluating ROR1 via immunohistochemistry using any one of several anti-ROR1 mAbs actually may have detected cytoplasmic protein encoded by ROR1V3 and that anti-cancer therapies targeting surface ROR1 thus would be ineffective against "cytoplasmic ROR1-positive" cancers that express predominately ROR1V3. We generated lentivirus vectors driving the expression of full-length ROR1 or the ROR1v3 upstream of an internal ribosome entry site (IRES) of the gene encoding a red fluorescent reporter protein. Although we find that cells that express ROR1 have surface and cytoplasmic ROR1 protein, cells that express ROR1v3 neither have surface nor cytoplasmic ROR1, which is consistent with our finding that ROR1v3 lacks an in-frame initiation codon for ribosomal translation into protein. We conclude that the detection of ROR1 protein in various cancers cannot be ascribed to the expression of ROR1v3.
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Influenza A/H9 viruses circulate worldwide in wild and domestic avian species, continuing to evolve and posing a zoonotic risk. A substantial increase in human infections with A/H9N2 subtype avian influenza viruses (AIVs) and the emergence of novel reassortants carrying A/H9N2-origin internal genes has occurred in recent years. Different names have been used to describe the circulating and emerging A/H9 lineages. To address this issue, an international group of experts from animal and public health laboratories, endorsed by the WOAH/FAO Network of Expertise on Animal Influenza, has created a practical lineage classification and nomenclature system based on the analysis of 10,638 hemagglutinin sequences from A/H9 AIVs sampled worldwide. This system incorporates phylogenetic relationships and epidemiologic characteristics designed to trace emerging and circulating lineages and clades. To aid in lineage and clade assignment, an online tool has been created. This proposed classification enables rapid comprehension of the global spread and evolution of A/H9 AIVs.