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Within a multi-state viral genomic surveillance program, we evaluated whether proportions of SARS-CoV-2 infections attributed to the JN.1 variant and to XBB-lineage variants (including HV.1 and EG.5) differed between inpatient and outpatient care settings during periods of cocirculation. Both JN.1 and HV.1 were less likely than EG.5 to account for infections among inpatients versus outpatients (aOR=0.60 [95% CI: 0.43-0.84; p=0.003] and aOR=0.35 [95% CI: 0.21-0.58; p<0.001], respectively). JN.1 and HV.1 variants may be associated with a lower risk of severe illness. The severity of COVID-19 may have attenuated as predominant circulating SARS-CoV-2 lineages shifted from EG.5 to HV.1 to JN.1.
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This cross-sectional survey study aimed to explore the knowledge, attitude, and practice (KAP) toward total neoadjuvant therapy (TNT) for rectal cancer (RC) among specialists in Hainan Province, China. RC specialists working in Hainan Province (China) were enrolled in this cross-sectional study between March and June 2023. A self-designed questionnaire was used to collect the participants' characteristics and KAP toward TNT for RC. A total of 279 valid questionnaires were collected. The KAP scores were 15.91 ± 6.02 (possible range: 0-24), 34.16 ± 5.11 (possible range: 10-50), and 12.42 ± 1.83 (possible range: 3-15), respectively. The KAP scores of specialists who had applied TNT in clinical practice or research and had evaluated RC patients treated with TNT were significantly higher than those who had not (all P < 0.05). The structural equation model showed that knowledge of TNT directly affected attitude (ß = 0.292, P = 0.007) and practice (ß = 0.912, P = 0.007), and attitude toward TNT also had a direct effect on practice (ß = 1.047, P = 0.008). In conclusion, RC specialists in Hainan (China) had inadequate knowledge, negative attitudes, and sufficient practice toward TNT in Hainan Province, China. It is necessary to enhance education for RC specialists to improve their knowledge and attitude toward TNT.
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In this study, we investigated how Radix pseudostellariae polysaccharide (RPP) enhances the immune response of the inactivated porcine reproductive and respiratory syndrome virus (PRRSV) vaccine through interactions with the microbiome and metabolome. We pretreated sows with 10 mg/kg body weight of RPP via drinking water for 7 days prior to intramuscular injection of the PRRSV vaccine. This significantly increased the concentrations of PRRSV GP5 protein antibody, interleukin (IL)-2, IL-4, IL-10, and interferon (IFN)-γ. Oral administration of RPP also significantly improved the abundance of beneficial bacteria in the stool, such as Parabacteroides distasonis, Prevotella_copri, Eubacterium_sp., and Clostridium_sp._CAG:226, and decreased the levels of potentially pathogenic bacteria, such as Paraeggerthella and [Clostridium] innocuum, compared to the vaccine alone. These bacterial changes were confirmed using quantitative real-time polymerase chain reaction (Q-PCR). Moreover, RPP treatment significantly increased the blood concentrations of L-theanine, taurodeoxycholic acid (TDCA), and N-arachidonoyl proline, and decreased the levels of L-glutamine, oclacitinib, lipoxin C4, and leukotriene C5 in sows after immunization (p< 0.05). The concentrations of various blood metabolites were validated using sandwich enzyme-linked immunosorbent assay (ELISA), confirming the accuracy of the metabolomics data. Intriguingly, the integration of microbiome and metabolome analyses highlighted the significance of Prevotella_copri and TDCA. We consequently developed a mouse immunity model using GP5 protein and discovered that oral administration of RPP significantly enhanced the levels of GP5 protein antibodies, IL-2, IL-4, IL-10, and IFN-γ in mouse serum. It also increased the number of CD3+ and CD3+CD4+ cells in the spleen. Additionally, Prevotella_copri was administered into the large intestine via the anus for 7 days prior to the intramuscular injection of the PRRSV GP5 protein. The results demonstrated a significant increase in TDCA and GP5 antibody concentration in the mouse serum, indicating that RPP modulates Prevotella_copri to elevate its metabolite TDCA, thereby enhancing the GP5 antibody level. In conclusion, oral administration of 10 mg/kg RPP optimizes gut flora diversity and blood metabolites, particularly Prevotella_copri and TDCA, thereby improving the immune response to the inactivated PRRSV vaccine.
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Metaboloma , Polisacáridos , Síndrome Respiratorio y de la Reproducción Porcina , Virus del Síndrome Respiratorio y Reproductivo Porcino , Vacunas de Productos Inactivados , Vacunas Virales , Animales , Porcinos , Virus del Síndrome Respiratorio y Reproductivo Porcino/inmunología , Síndrome Respiratorio y de la Reproducción Porcina/inmunología , Síndrome Respiratorio y de la Reproducción Porcina/prevención & control , Vacunas Virales/inmunología , Femenino , Vacunas de Productos Inactivados/inmunología , Anticuerpos Antivirales/sangre , Citocinas/metabolismo , Microbiota/efectos de los fármacos , Microbiota/inmunología , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/inmunología , Adyuvantes InmunológicosRESUMEN
Ventricular meningiomas are neoplastic cells originating from the ependymal lining of the central canal of the spinal cord and the ventricles of the brain. These tumorigenic cells predominantly manifest in the fourth ventricle, followed by the spinal cord. Most intraparenchymal ventricular meningiomas are located within the brain tissue, exhibiting a higher degree of malignancy compared to their intracerebroventricular counterparts. While intracranial dissemination and metastasis to the spinal cord can occur, extra-neurologic metastasis is an exceedingly rare phenomenon that lacks a clear elucidation regarding its underlying mechanism. The authors presented a case of supratentorial brain parenchymal type ventricular meningioma surgical treatment in a young female patient, occurring two years after the development of multiple metastases in both lungs, pleura, and mediastinum. This may be attributed to the high malignancy degree and strong invasiveness of this lesion, as well as its proximity to the dura mater and venous sinus. The craniotomy provided an opportunity for tumor cells to invade the adjacent venous sinus, leading to dissemination through the blood system. Additionally, postoperative radiation and chemotherapy were administered to inhibit tumor angiogenesis; however, these treatments also increased the likelihood of tumor cell invasion into neighboring brain tissues and distant metastasis.
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Background: Viral SARS-CoV-2 rebound (viral RNA rebound) is challenging to characterize in large cohorts due to the logistics of collecting frequent and regular diagnostic test results. Pharmacy-based testing data provide an opportunity to study the phenomenon in a large population, also enabling subgroup analyses. The current real-world evidence approach complements approaches focused on smaller, prospective study designs. Methods: We linked real-time reverse transcription quantitative polymerase chain reaction test data from national pharmacy-based testing to health care claims data via tokenization to calculate the cumulative incidence of viral RNA rebound within 28 days following positive test results in nirmatrelvir/ritonavir (NMV-r)-treated and untreated individuals during the Omicron era (December 2021-November 2022) and prior to the Omicron era (October 2020-November 2021). Results: Among 30 646 patients, the rate of viral RNA rebound was 3.5% (95% CI, 2.0%-5.7%) in NMV-r-treated infections as compared with 1.5% (95% CI, 1.3%-1.7%) in untreated infections during the Omicron era and 1.9% (95% CI, 1.7%-2.1%) prior to the Omicron era. Viral RNA rebound in patients who were vaccinated (n = 8151), high risk (n = 4411), or older (≥65 years, n = 4411) occurred at comparable rates to the overall cohort (range, 1.1%-4.8%). Viral rebounds to high RNA levels in NMV-r-treated infections occurred in 8% of viral rebounds as compared with 5% to 11% in untreated infections. Rates of hospitalization were comparable between patients with NMV-r-treated infections with viral RNA rebound (0%) and untreated patients with viral RNA rebound (0%-1.2%). Conclusions: Our findings suggest viral RNA rebound is rare (< 5%), with rates that were consistent with those from the EPIC-HR trial (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients). Most occurrences of viral RNA rebound were associated with low viral RNA levels, and viral RNA rebound progression to severe disease was not observed.
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OBJECTIVE: Portal hypertension leads to hepatic artery dilatation and a higher risk of bleeding. We tried to identify the bleeding risk after gastroesophageal varices (GOV) treatment using hepatic artery diameter of contrast-enhanced CT. METHODS: Retrospective retrieval of 258 patients with cirrhosis who underwent contrast-enhanced CT from January 2022 to May 2023 and endoscopy within one month thereafter at Hainan Affiliated Hospital of Hainan Medical University. Cirrhotic patients before GOV treatment were used as the test cohort (n = 199), and cirrhotic patients after GOV treatment were used as the validation cohort (n = 59). The grading and bleeding risk was classified according to the endoscopic findings. Arterial-phase images of contrast-enhanced CT were used for coronal reconstruction, and the midpoint diameter of the hepatic artery was measured on coronal images. The optimal cutoff value for identifying bleeding risk was analyzed and calculated in the test cohort, and its diagnostic performance was evaluated in the validation cohort. RESULTS: In the test cohort, hepatic artery diameters were significantly higher in high-risk GOV than in low-risk GOV [4.69 (4.31, 5.56) vs. 3.10 (2.59, 3.77), P < 0.001]. With a hepatic artery diameter cutoff value of 4.06 mm, the optimal area under the operating characteristic curve was 0.940 (95% confidence interval: 0.908-0.972), with a sensitivity of 0.887, a specificity of 0.892, a positive predictive value of 0.904, and a negative predictive value of 0.874 for identifying bleeding risk in the test cohort, while in the validation cohort, the sensitivity was 0.885, specificity was 0.939, positive predictive value was 0.920, and negative predictive value was 0.912. CONCLUSION: Hepatic artery diameter has high diagnostic performance in identifying bleeding risk after GOV treatment.
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Within a multistate clinical cohort, SARS-CoV-2 antiviral prescribing patterns were evaluated from April 2022-June 2023 among nonhospitalized patients with SARS-CoV-2 with risk factors for severe COVID-19. Among 3247 adults, only 31.9% were prescribed an antiviral agent (87.6% nirmatrelvir/ritonavir, 11.9% molnupiravir, 0.5% remdesivir), highlighting the need to identify and address treatment barriers.
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Antivirales , Tratamiento Farmacológico de COVID-19 , SARS-CoV-2 , Humanos , Antivirales/uso terapéutico , Masculino , Persona de Mediana Edad , Femenino , Adulto , Anciano , Factores de Riesgo , Ritonavir/uso terapéutico , COVID-19/epidemiología , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/uso terapéutico , Alanina/uso terapéutico , Alanina/análogos & derivados , Pautas de la Práctica en Medicina/estadística & datos numéricos , Citidina/análogos & derivados , HidroxilaminasRESUMEN
U6 and 7SK snRNAs have a 5' cap, believed to be essential for their stability and maintained by mammalian MePCE or Drosophila Bin3 enzymes. Although both proteins are required for 7SK stability, loss of neither destabilizes U6, casting doubts on the function of capping U6. Here, we show that the Drosophila Amus protein, homologous to both proteins, is essential for U6 but not 7SK stability. The loss of U6 is rescued by the expression of an Amus-MePCE hybrid protein harboring the methyltransferase domain from MePCE, highlighting the conserved function of the two proteins as the U6 capping enzyme. Our investigations in human cells establish a dependence of both U6 and 7SK stability on MePCE, resolving a long-standing uncertainty. While uncovering a division of labor of Bin3/MePCE/Amus proteins, we found a "Bin3-Box" domain present only in enzymes associated with 7SK regulation. Targeted mutagenesis confirms its importance for Bin3 function, revealing a possible conserved element in 7SK but not U6 biology.
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Proteínas de Drosophila , Drosophila , Animales , Humanos , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Mamíferos/metabolismo , Metiltransferasas/genética , Metiltransferasas/metabolismoRESUMEN
Parkinson's disease (PD) is the second most common neurodegenerative disease with currently no cure. Most PD cases are sporadic, and about 5-10% of PD cases present a monogenic inheritance pattern. Mutations in more than 20 genes are associated with genetic forms of PD. Mitochondrial dysfunction is considered a prominent player in PD pathogenesis. Post-translational modifications (PTMs) allow rapid switching of protein functions and therefore impact various cellular functions including those related to mitochondria. Among the PD-associated genes, Parkin, PINK1, and LRRK2 encode enzymes that directly involved in catalyzing PTM modifications of target proteins, while others like α-synuclein, FBXO7, HTRA2, VPS35, CHCHD2, and DJ-1, undergo substantial PTM modification, subsequently altering mitochondrial functions. Here, we summarize recent findings on major PTMs associated with PD-related proteins, as enzymes or substrates, that are shown to regulate important mitochondrial functions and discuss their involvement in PD pathogenesis. We will further highlight the significance of PTM-regulated mitochondrial functions in understanding PD etiology. Furthermore, we emphasize the potential for developing important biomarkers for PD through extensive research into PTMs.
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BACKGROUND: Between November 2021 and February 2022, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta and Omicron variants co-circulated in the United States, allowing for co-infections and possible recombination events. METHODS: We sequenced 29,719 positive samples during this period and analyzed the presence and fraction of reads supporting mutations specific to either the Delta or Omicron variant. FINDINGS: We identified 18 co-infections, one of which displayed evidence of a low Delta-Omicron recombinant viral population. We also identified two independent cases of infection by a Delta-Omicron recombinant virus, where 100% of the viral RNA came from one clonal recombinant. In the three cases, the 5' end of the viral genome was from the Delta genome and the 3' end from Omicron, including the majority of the spike protein gene, though the breakpoints were different. CONCLUSIONS: Delta-Omicron recombinant viruses were rare, and there is currently no evidence that Delta-Omicron recombinant viruses are more transmissible between hosts compared with the circulating Omicron lineages. FUNDING: This research was supported by the NIH RADx initiative and by the Centers for Disease Control Contract 75D30121C12730 (Helix).
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COVID-19 , Coinfección , Orthopoxvirus , Humanos , SARS-CoV-2/genética , Genoma Viral/genéticaRESUMEN
PURPOSE: Adult skeletal age estimation is an active research field. To evaluate the performance of a pubic CT radiomics-based machine learning model for estimating age, we established a multiple linear regression model based on radiomics and machine learning methods. METHODS: A total of 355 subjects were enrolled in this retrospective study from August 2016 to August 2021, and divided into a training cohort (N = 325) and a testing cohort (N = 30). Computerized texture analysis of the semi-automatically segmentation was performed and 107 texture features were extracted from the regions. Then we used univariate linear regression and multivariate stepwise regression to assess correlations of texture parameters with age. The most vital features were used to make the best predictive model. Eventually, the established radiomics model was tested with an additional 30 patients. RESULTS: Clinical characteristics include age, sex, height, weight and BMI were not statistically significant different between training and testing cohort (p = 0.098-0.888). Through a multivariate regression analysis using stepwise regression, six texture parameters were found to have significant correlations with age. The regression formula estimating the age was constructed. CONCLUSIONS: The radiomics model using machine learning is considered as a new approach forage estimation frompubic symphysis CT features.Digital osteology is obtained in a non-invasive way so that it can be an ideal collection for anthropological studies.
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Background: Although anterior cruciate ligament reconstruction (ACLR) can restore the stability and function of the knee joint, patellofemoral joint cartilage damage still progresses. Currently, the clinically important factors that lead to the progression of patellofemoral articular cartilage damage are not fully understood. Purpose: To investigate the factors that affect the progression of patellofemoral articular cartilage damage after ACLR. Study Design: Cohort study; Level of evidence, 2. Methods: Among 160 patients who underwent ACLR between January 2015 and December 2019, the authors evaluated 129 patients for at least 1 year after surgery. Within 1 week before ACLR and at the last follow-up, patients underwent subjective functional assessment and magnetic resonance imaging evaluations of articular cartilage damage (modified Outerbridge assessment). At the last follow-up, the side-to-side difference on KT-2000 arthrometer and bilateral quadriceps muscle strength were measured. Univariate and multivariate logistic regression analyses were performed. Results: The mean follow-up was 24.69 ± 10.74 months. Progression of patellar cartilage damage from preoperatively to final follow-up was seen in 45 patients (P < .001). Logistic regression analysis revealed that the follow-up period (P = .047; odds radio (OR) = 0.953) (improvement of patellar cartilage damage with longer follow-up), partial lateral meniscal resection (P = .004; OR = 6.929), partial medial meniscal resection (P = .004; OR = 6.032), and quadriceps muscle strength <80% of the contralateral side (P = .001; OR = 4.745) were risk factors for the progression of patellar cartilage damage. Conclusion: Cartilage damage at the patellofemoral joint, especially the patellar cartilage, still progresses after ACLR. At a mean follow-up of 24.69 months after ACLR, partial meniscal resection and quadriceps femoris muscle strength were found to be the main risk factors for the progression of patellofemoral articular cartilage damage after ACLR.
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We report on the sequencing of 74,348 SARS-CoV-2 positive samples collected across the United States and show that the Delta variant, first detected in the United States in March 2021, made up the majority of SARS-CoV-2 infections by July 1, 2021 and accounted for >99.9% of the infections by September 2021. Not only did Delta displace variant Alpha, which was the dominant variant at the time, it also displaced the Gamma, Iota, and Mu variants. Through an analysis of quantification cycle (Cq) values, we demonstrate that Delta infections tend to have a 1.7× higher viral load compared to Alpha infections (a decrease of 0.8 Cq) on average. Our results are consistent with the hypothesis that the increased transmissibility of the Delta variant could be due to the ability of the Delta variant to establish a higher viral load earlier in the infection as compared to the Alpha variant.
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COVID-19 , SARS-CoV-2 , COVID-19/epidemiología , Humanos , SARS-CoV-2/genética , Estados Unidos/epidemiología , Carga Viral/genéticaRESUMEN
Genomic-guided pharmaceutical prescribing is increasingly recognized as an important clinical application of genetics. Accurate genotyping of pharmacogenomic (PGx) genes can be difficult, owing to their complex genetic architecture involving combinations of single-nucleotide polymorphisms and structural variation. Here, we introduce the Helix PGx database, an open-source star allele, genotype, and resulting metabolic phenotype frequency database for CYP2C9, CYP2C19, CYP2D6, and CYP4F2, based on short-read sequencing of >86,000 unrelated individuals enrolled in the Helix DNA Discovery Project. The database is annotated using a pipeline that is clinically validated against a broad range of alleles and designed to call CYP2D6 structural variants with high (98%) accuracy. We find that CYP2D6 has greater allelic diversity than the other genes, manifest in both a long tail of low-frequency star alleles, as well as a disproportionate fraction (36%) of all novel predicted loss-of-function variants identified. Across genes, we observe that many rare alleles (<0.1% frequency) in the overall cohort have 10 times higher frequency in one or more subgroups with non-European genetic ancestry. Extending these PGx genotypes to predicted metabolic phenotypes, we demonstrate that >90% of the cohort harbors a high-risk variant in one of the four pharmacogenes. Based on the recorded prescriptions for >30,000 individuals in the Healthy Nevada Project, combined with predicted PGx metabolic phenotypes, we anticipate that standard-of-care screening of these 4 pharmacogenes could impact nearly half of the general population.
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Sistema Enzimático del Citocromo P-450/genética , ADN/genética , Frecuencia de los Genes/genética , Alelos , Bases de Datos de Ácidos Nucleicos , Genómica/métodos , Genotipo , Humanos , Farmacogenética/métodos , Fenotipo , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Purpose: To determine whether the early assessment of temporal lobe microstructural changes using diffusion kurtosis imaging (DKI) can predict late delayed neurocognitive decline after radiotherapy in nasopharyngeal carcinoma (NPC) patients. Methods and Materials: Fifty-four NPC patients undergoing intensity-modulated radiotherapy (IMRT) participated in a prospective DKI magnetic resonance (MR) imaging study. MR imaging was acquired prior to IMRT (-0), 1 month (-1), and 3 (-3) months after IMRT. Kurtosis (Kmean, Kax, Krad) and Diffusivity (Dmean, Dax, Drad) variables in the temporal lobe gray and white matter were computed. Neurocognitive function tests (MoCA) were administered pre-radiotherapy and at 2 years post-IMRT follow-up. All the patients were divided into neurocognitive function decline (NFD group) and neurocognitive function non-decline groups (NFND group) according to whether the MoCA score declined ≥3 2 years after IMRT. All the DKI metrics were compared between the two groups, and the best imaging marker was chosen for predicting a late delayed neurocognitive decline. Results: Kurtosis (Kmean-1, Kmean-3, Kax-1, Kax-3, Krad-1, and Krad-3) and Diffusivity (Dmean-1 and Dmean-3) of white matter were significantly different between the two groups (p<0.05). Axial Kurtosis (Kax-1, Kax-3) of gray matter was significantly different between the two groups (p<0.05). By receiver operating characteristic (ROC) curves, Kmean-1 of white matter performed best in predicting of MoCA scores delayed decline (p<0.05). The radiation dose was also significantly different between NFD and NFND group (p=0.031). Conclusions: Temporal lobe white matter is more vulnerable to microstructural changes and injury following IMRT in NPC. Metrics derived from DKI should be considered as imaging markers for predicting a late delayed neurocognitive decline. Both temporal lobe white and gray matter show microstructural changes detectable by DKI. The Kmean early after radiotherapy has the best prediction performance.
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The circuitry associated with the visual cortex is particularly sensitive to experiences during the early stages of life, which are collectively known as critical periods. Critical period of ocular dominance plasticity is regulated by both environmental and genetic factors. Previous studies demonstrated that IGF-1 significantly influenced the regulation of visual cortex synaptic plasticity. IGF-2 can reportedly regulate synapse formation, dendritic spine maturation, and memory consolidation in rodents. Association between IGF-2 and the regulation of visual cortex synaptic plasticity remains unclear. Here, we first aimed to elucidate the normal expression patterns of IGF-2 and its laminar expression pattern during the process of visual cortex development in mice. This confirmed that IGF-2 may influence the regulation of ocular dominance plasticity in mice. We further elucidated the role of IGF-2 in the regulation of visual cortex synaptic plasticity by examining the effect of monocular deprivation (MD) on IGF-2 expression in the visual cortex. Interestingly, we observed that MD remarkably reduced IGF-2 expression in the visual cortex. Rodents reared in an enriched environment, with enhanced sensory, motor, and social experiences, were capable of effectively accelerating the development of the visual system and could restore normal visual acuity. Although the enriched environment facilitated the restoration of normal visual acuity in the MD mice, IGF-2 expression levels in the visual cortex remained unchanged. Therefore, we considered the possibility that IGF-2 may have a different role with regard to the modulation of plasticity in the visual cortex of the mice, which we aim to study in the future.
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Factor II del Crecimiento Similar a la Insulina/biosíntesis , Privación Sensorial/fisiología , Visión Monocular/fisiología , Corteza Visual/crecimiento & desarrollo , Corteza Visual/metabolismo , Animales , Expresión Génica , Factor II del Crecimiento Similar a la Insulina/genética , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: There have been no reliable scientific studies examining whether the interval between induction chemotherapy (IC) and initiating radiotherapy is associated with poor outcomes of nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: In this retrospective study, we included a total of 239 local advanced NPC patients who underwent concurrent chemoradiotherapy and IC. Based on the interval between IC and intensity-modulated radiation therapy (IMRT), the patients were classified into three groups as follows: Group A (≤7 vs >7 days), Group B (≤14 vs >14 days), and Group C (≤ 21 vs >21 days). Univariate and multivariate regression analyses were performed to determine the prognostic factors of survival outcomes. The differences between the two groups were compared by the log-rank test. RESULTS: The median IC-IMRT interval was 9 days (range, 1-76 days). The median follow-up time was 40 months (range, 4-58 months). The IC-IMRT interval including Group A, Group B, and Group C was not significantly associated with overall survival (OS), distant metastasis-free survival (DMFS), locoregional relapse-free survival (LRFS), or disease-free survival (DFS). Multivariate analysis showed that the tumor stage was the independent significant predictor for OS, DMFS, LRFS, and DFS. But it appears that there was a trend toward improvement in the outcome of ≤7 days group in OS from the Kaplan-Meier curves. CONCLUSION: It is also feasible to postpone radiotherapy for 1-3 weeks if patients were unable to receive treatment immediately due to chemotherapy complications such as bone marrow suppression. However, we suggest that patients should start IMRT as soon as possible after IC.
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The immunoglobulin heavy variable (IGHV) and T cell beta variable (TRBV) loci are among the most complex and variable regions in the human genome. Generated through a process of gene duplication/deletion and diversification, these loci can vary extensively between individuals in copy number and contain genes that are highly similar, making their analysis technically challenging. Here, we present a comprehensive study of the functional gene segments in the IGHV and TRBV loci, quantifying their copy number and single-nucleotide variation in a globally diverse sample of 109 (IGHV) and 286 (TRBV) humans from over a 100 populations. We find that the IGHV and TRBV gene families exhibit starkly different patterns of variation. In addition to providing insight into the different evolutionary paths of the IGHV and TRBV loci, our results are also important to the adaptive immune repertoire sequencing community, where the lack of frequencies of common alleles and copy number variants is hampering existing analytical pipelines.
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Reordenamiento Génico de la Cadena beta de los Receptores de Antígenos de los Linfocitos T/genética , Genoma Humano/genética , Región Variable de Inmunoglobulina/genética , Polimorfismo de Nucleótido Simple/genética , Inmunidad Adaptativa/genética , Alelos , Secuencia de Bases/genética , Variaciones en el Número de Copia de ADN , Bases de Datos Genéticas , Duplicación de Gen , Frecuencia de los Genes , Sitios Genéticos , Haplotipos , Humanos , Mutación/genéticaRESUMEN
The dynamics of a population undergoing selection is a central topic in evolutionary biology. This question is particularly intriguing in the case where selective forces act in opposing directions at two population scales. For example, a fast-replicating virus strain outcompetes slower-replicating strains at the within-host scale. However, if the fast-replicating strain causes host morbidity and is less frequently transmitted, it can be outcompeted by slower-replicating strains at the between-host scale. Here we consider a stochastic ball-and-urn process which models this type of phenomenon. We prove the weak convergence of this process under two natural scalings. The first scaling leads to a deterministic nonlinear integro-partial differential equation on the interval [0, 1] with dependence on a single parameter, λ. We show that the fixed points of this differential equation are Beta distributions and that their stability depends on λ and the behavior of the initial data around 1. The second scaling leads to a measure-valued Fleming-Viot process, an infinite dimensional stochastic process that is frequently associated with a population genetics.