Stepwise analysis of thyroid diagnostic modalities with genomic imprinting detection.

BACKGROUND: The current preoperative malignancy risk evaluation for thyroid nodules involves stepwise diagnostic modalities including ultrasonography, thyroid function serology and fine-needle aspiration (FNA) cytopathology, respectively. We aimed to substantiate the stepwise contributions of each diagnostic step and additionally investigate the diagnostic significance of quantitative chromogenic imprinted gene in-situ hybridization (QCIGISH)-an adjunctive molecular test based on epigenetic imprinting alterations. METHODS: A total of 114 cytopathologically-diagnosed and histopathologically-confirmed thyroid nodules with complete ultrasonographic and serological examination records were evaluated using QCIGISH in the study. Logistic regression models for thyroid malignancy prediction were developed with the stepwise addition of each diagnostic modality and the contribution of each step evaluated in terms of discrimination performance and goodness-of-fit. RESULTS: From the baseline model using ultrasonography [area under the receiver operating characteristics curve (AUROC): 0.79; 95% confidence interval (CI): 0.71-0.86], significant improvements in thyroid malignancy discrimination were observed with the stepwise addition of thyroid function serology (AUROC: 0.82; 95% CI: 0.74-0.90; P=0.23) and FNA cytopathology (AUROC: 0.88; 95% CI: 0.81-0.94; P=0.02), respectively. The inclusion of QCIGISH as an adjunctive molecular test further advanced the preceding model's diagnostic performance (AUROC: 0.95; 95% CI: 0.91-1.00, P=0.007). CONCLUSIONS: Our study demonstrated the significant stepwise diagnostic contributions of standard clinical assessments in the malignancy risk stratification of thyroid nodules. However, the addition of molecular imprinting detection further enabled a more accurate and definitive preoperative evaluation especially for morphologically indeterminate thyroid nodules and cases with potentially discordant results among standard modalities.

Construction of unique NiCoP/FeNiCoP hollow heterostructured ellipsoids with modulated electronic structure for enhanced overall water splitting.

Transition metal phosphides have been demonstrated to be promising non-noble catalysts for water splitting, yet their electrocatalytic performance is impeded by unfavorable free energies of adsorbed intermediates. The achievement of nanoscale modulation in morphology and electronic states is imperative for enhancing their intrinsic electrocatalytic activity. Herein, we propose a strategy to expedite the water splitting process over NiCoP/FeNiCoP hollow ellipsoids by modulating the electronic structure and d-band center. These unique phosphorus (P) vacancies-rich ellipsoids are synthesized through an ion-exchange reaction between uniform NiCo-nanoprisms and K3[Fe(CN)6], followed by NaH2PO2-assisted phosphorization under N2 atmosphere. Various characterizations reveals that the titled catalyst possesses high specific surface area, abundant porosity, and accessible inner surfaces, all of which are beneficial for efficient mass transfer and gas diffusion. Moreover, density functional theory (DFT) calculations further confirms that the NiCoP/FeNiCoP heterojunction associated with P vacancies regulate the electronic structures of d-electrons and p-electrons of Co and P atoms, respectively, resulting in a higher desorption efficiency of adsorbed H* intermediates with a lower energy barrier for water splitting. Due to the aforementioned advantages, the resultant NiCoP/FeNiCoP hollow ellipsoids exhibit remarkably low overpotentials of 45 and 266 mV for hydrogen and oxygen evolution reaction to achieve the current densities of 10 and 50 mA cm-2, respectively. This work not only reports the synthesis of a hollow double-shell structure of NiCoP/FeNiCoP but also introduces a novel strategy for constructing a multifunctional electrocatalyst for water splitting.

Ultrasound-guided fine needle aspiration thyroglobulin in the diagnosis of lymph node metastasis of differentiated papillary thyroid carcinoma and its influencing factors.

Background: Ultrasound-guided fine needle aspiration thyroglobulin (FNA-Tg) is recommended for the diagnosis of lymph node metastasis (LNM) in differentiated thyroid cancer (DTC), but its optimal cutoff value remains controversial, and the effect of potential influencing factors on FNA-Tg levels is unclear. Method: In this study, a retrospective analysis was conducted on 281 patients diagnosed with DTC, encompassing 333 lymph nodes. We analyze the optimal cutoff value and diagnostic efficacy of FNA-Tg, while also evaluating the potential influence of various factors on FNA-Tg. Results: For FNA-Tg, the optimal cutoff value was 16.1 ng/mL (area under the curve (AUC)= 0.942). The optimal cutoff value for FNA-Tg/sTg was 1.42 (AUC = 0.933). The AUC for FNA combined with FNA-Tg yielded the highest value compared to other combined diagnostic methods (AUC = 0.955). It has been found that serum thyroglobulin (sTg) is positively correlated with FNA-Tg (Rs = 0.318), while serum thyroglobulin antibodies (sTgAb) is negatively correlated with FNA-Tg (Rs = -0.147). In cases where the TNM stage indicated N1b, the presence of large or high volume lymph node metastasis(HVLNM), lymph node lateralization/suspicion (L/S) ratio ≤ 2, ultrasound findings indicating lymph node liquefaction, calcification, and increased blood flow, patients with coexisting Hashimoto's thyroiditis (HT), a tumor size ≥10 mm, and postoperative pathology confirming invasion of the thyroid capsule, higher levels of FNA-Tg were observed. However, the subgroup classification of DTC and the presence or absence of thyroid tissue did not demonstrate any significant impact on the levels of FNA-Tg. Conclusion: The findings of this study indicate that the utilization of FNA in conjunction with FNA-Tg is a crucial approach for detecting LNM in DTC. TNM stage indicated N1b, the presence of HVLNM, the presence of HT, lymph node L/S ratio, liquefaction, calcification, tumor diameter, sTg and sTgAb are factors that can impact FNA-Tg levels.In the context of clinical application, it is imperative to individualize the use of FNA-Tg.

Influence of cancer-directed surgery on the prognosis of liver metastases from gastric cancer

There are controversial about the application of cancer-directed surgery (CDS) in patients with liver metastases from gastric cancer, with improved responses to chemotherapy and targeted treatments, the role of CDS in metastatic gastric cancer to the liver needs to be revisited. This study aimed to evaluate the effect of CDS on patients with liver metastases from gastric cancer. Data for patients with liver metastases from gastric cancer were extracted from the population-based Surveillance, Epidemiology, and End Results (SEER) database. A total of 958 individuals were enrolled, 285 in the CDS group and 673 in the non-cancer guided surgery (Non-CDS) group. Following propensity score matching (PSM) analysis at 1:1 in the two groups,285 were included in the survival analysis for each group. Kaplan–Meier values and Cox proportional risk models were used to estimate the effect of CDS on patients' prognoses. Compared with the Non-CDS group, the CDS group significantly prolonged the median overall survival from 4 months (95% confidence interval [CI] 3–5) to 11 months (95% CI 8–12), p value < 0.001. Overall survival (OS) at 1 year was higher in the CDS group than in the Non-CDS group, at 44% (95 CI 38–50) and 25% (95 CI 20–30), respectively. OS at 3 years was also higher in the CDS group than in the Non-CDS group, at 24% (95 CI 19–29) and 6% (95 CI 3–9), respectively. Multivariate analysis showed that Non-CDS (hazard ratio[HR] = 2.26, 95% CI 1.88–2.72, p value < 0.001) was an adverse independent prognostic factor for patients (AU)

A comparative analysis of core needle biopsy and repeat fine needle aspiration in patients with inconclusive initial cytology of thyroid nodules.

Purpose: To assess and compare the effectiveness of ultrasound-guided core needle biopsy (CNB) in comparison to repeat fine-needle aspiration(rFNA) for thyroid nodules that yield inconclusive results following the initial fine-needle aspiration (FNA). Methods: A cohort of 471 patients who received an inconclusive cytological diagnosis following the initial FNA were included in this study. These patients subsequently underwent either CNB (n=242) or rFNA (n=229). The inconclusive FNA results encompassed categories I, III, and IV of The Bethesda System for Reporting Thyroid Cytopathology(TBSRTC), as well as the ultrasound images indicating malignancy despite FNA results falling under TBSRTC category II. This study assessed the sampling satisfaction rate, diagnostic efficacy, and complications associated with CNB compared to rFNA. Additionally, the impact of repeat puncture time and nodule size on diagnostic efficacy was analyzed. Results: Following repeat punctures, the satisfaction rate of the CNB sampling was found to be significantly higher than that of rFNA (83.9% vs 66.8%). The diagnostic rate in the CNB group was significantly greater compared to that of the rFNA group (70.7% vs 35.8%). In patients with nodule maximum diameters ranging from 5 mm to 20 mm, the diagnostic accuracy was significantly higher in the CNB group compared to that in the rFNA group. In patients with intervals less than 90 days, between 90 days and one year, the diagnostic rate in the CNB group was found to be higher compared to that in the rFNA group. In CNB, not immediately adjacent to the capsule was a risk factor for nodular puncture bleeding (37.0% vs 22.7%.). Conclusion: CNB demonstrated higher rates of satisfaction and diagnosis compared to the rFNA. The diagnostic effectiveness of CNB was not influenced by the time interval or the size of the thyroid nodule. Therefore, in cases where the initial FNA diagnosis of thyroid nodules is inconclusive, CNB should be considered as a viable option for re-puncture.

Clinical value of contrast-enhanced ultrasound quantitative analysis for differentiating thyroid lesions in Hashimoto's thyroiditis patients.

Background: The role of quantitative contrast-enhanced ultrasound (CEUS) in the evaluation of thyroid nodules with Hashimoto's thyroiditis (HT) has received little attention. Methods: This was a retrospective cohort study. We consecutively enrolled 242 patients (49 males, 193 females, average age 52 years) with a combined total of 248 thyroid nodules coexisting with HT who underwent biopsy/resection-proven pathology from December 2016 to June 2021. All patients underwent preoperative ultrasound (US) and CEUS examinations performed by 2 radiologists independently. Quantitative analysis of CEUS using time-intensity curves (TIC) was measured by an expert radiologist from the thyroid intra-nodule and the surrounding parenchyma and their ratios. Receiver operating characteristic (ROC) analysis was performed to evaluate their diagnostic performance. Results: The patients were divided into the nodular HT (NHT) group (n=42), the papillary thyroid carcinoma (PTC) group (n=154), and the primary thyroid lymphoma (PTL) group (n=52) according to their pathological results. TIC parameters revealed that PTC and PTL showed faster time to peak (TTP) (P=0.044, P=0.049), lower peak intensity (PI) (both P<0.001), and smaller areas under the curve (both P<0.001) than those of NHT. The intra nodule of PTL showed an obviously slower perfusion (ratio =0.90, P<0.001) and lower PI (ratio =0.84, P<0.001) compared with the thyroid parenchyma. TIC improved performance in distinguishing PTL from NHT [area under the curve (AUC): 0.947, 95% confidence interval (CI): 0.903-0.991], but inferior performance in differentiating PTC and NHT (AUC: 0.838, 95% CI: 0.759-0.917). Conclusions: CEUS quantitative analysis could be valuable in differentiating thyroid malignancies in patients with HT.

Influence of cancer-directed surgery on the prognosis of liver metastases from gastric cancer.

There are controversial about the application of cancer-directed surgery (CDS) in patients with liver metastases from gastric cancer, with improved responses to chemotherapy and targeted treatments, the role of CDS in metastatic gastric cancer to the liver needs to be revisited. This study aimed to evaluate the effect of CDS on patients with liver metastases from gastric cancer. Data for patients with liver metastases from gastric cancer were extracted from the population-based Surveillance, Epidemiology, and End Results (SEER) database. A total of 958 individuals were enrolled, 285 in the CDS group and 673 in the non-cancer guided surgery (Non-CDS) group. Following propensity score matching (PSM) analysis at 1:1 in the two groups,285 were included in the survival analysis for each group. Kaplan-Meier values and Cox proportional risk models were used to estimate the effect of CDS on patients' prognoses. Compared with the Non-CDS group, the CDS group significantly prolonged the median overall survival from 4 months (95% confidence interval [CI] 3-5) to 11 months (95% CI 8-12), p value < 0.001. Overall survival (OS) at 1 year was higher in the CDS group than in the Non-CDS group, at 44% (95 CI 38-50) and 25% (95 CI 20-30), respectively. OS at 3 years was also higher in the CDS group than in the Non-CDS group, at 24% (95 CI 19-29) and 6% (95 CI 3-9), respectively. Multivariate analysis showed that Non-CDS (hazard ratio[HR] = 2.26, 95% CI 1.88-2.72, p value < 0.001) was an adverse independent prognostic factor for patients. This study concludes that CDS prolonged survival in patients with gastric cancer with liver metastases. Due to the lack of information on the quality of life, biomarkers, targeted therapies, and immunotherapy in the SEER database, the observed improved survival rates following CDS of hepatic metastasis from gastric cancer requires prospective studies that take these factors into account to properly address the survival advantages and impact on quality of life of such a method.

Seeing the T cell Immunity of SARS-CoV-2 and SARS-CoV: Believing the Epitope-Oriented Vaccines.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the end of 2019 stimulated vigorous research efforts in immunology and vaccinology. In addition to innate immune responses, both virus-specific humoral and cellular immune responses are of importance for viral clearance. T cell epitopes play a central role in T cell-based immune responses. Herein, we summarized the peptide/major histocompatibility complex (pMHC) structures of the SARS-CoV-2-derived T cell epitopes available in the Protein Data Bank (PDB) and proposed the challenge and opportunities for using of T cell epitopes in future vaccine development efforts. A total of 27 SARS-CoV-2 related pMHC structures and five complexes with T cell receptors were retrieved. The peptides are mainly distributed on spike (S), nucleocapsid (N), and ORF1ab proteins. Most peptides are conserved among variants of concerns (VOCs) for SARS-CoV-2, except for several mutated peptides located in the S protein. The structures of human leukocyte antigen (HLA) complexed with seven epitopes derived from SARS-CoV were also retrieved, which showed a potential cross T cell immunity with SARS-CoV-2. Structural studies of antigenic peptides from SARS-CoV-2 and SARS-CoV help to visualize the processes and the mechanisms of cross T cell immunity. T cell epitope-oriented vaccines are potential next-generation vaccines for SARS-CoV-2, which are worthy of further investigation.

Inactivated vaccine fueled adaptive immune responses to Omicron in 2-year COVID-19 convalescents.

Over 3 years, humans have experienced multiple rounds of global transmission of SARS-CoV-2 and its variants. In addition, the widely used vaccines against SARS-CoV-2 involve multiple strategies of development and inoculation. Thus, the acquired immunity established among humans is complicated, and there is a lack of understanding within a panoramic vision. Here, we provided the special characteristics of the cellular and humoral responses in 2-year convalescents after inactivated vaccines, in parallel to vaccinated COVID-19 naïve persons and unvaccinated controls. The decreasing trends of the IgG, IgA, and NAb, but not IgM of the convalescents were reversed by the vaccination. Both cellular and humoral immunity in convalescents after vaccination were higher than the vaccinated COVID-19 naïve persons. Notably, inoculation with inactivated vaccine fueled the NAb to BA.1, BA.2, BA.4, and BA.5 in 2-year convalescents, much higher than the NAb during 6 months and 1 year after symptoms onset. And no obvious T cell escaping to the S protein was observed in 2-year convalescents after inoculation. The study provides insight into the complicated features of human acquired immunity to SARS-CoV-2 and variants in the real world, indicating that promoting vaccine inoculation is essential for achieving herd immunity against emerging variants, especially in convalescents.

Parallel T Cell Immunogenic Regions in Influenza B and A Viruses with Distinct Nuclear Export Signal Functions: The Balance between Viral Life Cycle and Immune Escape.

Influenza A viruses (IAVs) and influenza B viruses (IBVs) cause annual epidemics in human populations with seasonal circulation spikes. Peptide AM58-66GL9 located at residues 58-66 of M1 protein of IAVs has been recognized as an immunodominant T cell epitope with HLA-A*0201 restriction and broadly used as a positive reference in influenza immunity. This peptide also almost completely overlaps with a nuclear export signal (NES) 59-68 in IAV M1, which explains the limited escape mutations under the T cell immune pressure in this region. In this study, we investigated the potential immunogenicity and NES in the corresponding region of IBV. The long peptide covering this region can be recognized by specific T cells and induce robust expression of IFN-γ among HLA-B*1501 donors in vivo, but not in HLA-A*0201 donors. Among a series of truncated peptides derived from this region, we identified an immunodominant HLA-B*1501-restricted T cell epitope BM58-66AF9 (ALIGASICF) in the M1 protein of IBV. Furthermore, the structure of the HLA-B*1501/BM58-66AF9 complex shows that BM58-66AF9 performs a flat and featureless conformation that is similar to AM58-66GL9 presented by HLA-A*0201. In contrast with IAV, the sequence around residues 55-70 of IBV M1 does not contain an NES. Our comparative study on IBVs and IAVs provides new insights into the immune and evolution characteristics of IBVs and may shed light on vaccine development for influenza viruses.

A Wider and Deeper Peptide-Binding Groove for the Class I Molecules from B15 Compared with B19 Chickens Correlates with Relative Resistance to Marek's Disease.

The chicken MHC is known to confer decisive resistance or susceptibility to various economically important pathogens, including the iconic oncogenic herpesvirus that causes Marek's disease (MD). Only one classical class I gene, BF2, is expressed at a high level in chickens, so it was relatively easy to discern a hierarchy from well-expressed thermostable fastidious specialist alleles to promiscuous generalist alleles that are less stable and expressed less on the cell surface. The class I molecule BF2*1901 is better expressed and more thermostable than the closely related BF2*1501, but the peptide motif was not simpler as expected. In this study, we confirm for newly developed chicken lines that the chicken MHC haplotype B15 confers resistance to MD compared with B19. Using gas phase sequencing and immunopeptidomics, we find that BF2*1901 binds a greater variety of amino acids in some anchor positions than does BF2*1501. However, by x-ray crystallography, we find that the peptide-binding groove of BF2*1901 is narrower and shallower. Although the self-peptides that bound to BF2*1901 may appear more various than those of BF2*1501, the structures show that the wider and deeper peptide-binding groove of BF2*1501 allows stronger binding and thus more peptides overall, correlating with the expected hierarchies for expression level, thermostability, and MD resistance. Our study provides a reasonable explanation for greater promiscuity for BF2*1501 compared with BF2*1901, corresponding to the difference in resistance to MD.

Characterization of the enhanced infectivity and antibody evasion of Omicron BA.2.75.

Recently emerged SARS-CoV-2 Omicron subvariant, BA.2.75, displayed a growth advantage over circulating BA.2.38, BA.2.76, and BA.5 in India. However, the underlying mechanisms for enhanced infectivity, especially compared with BA.5, remain unclear. Here, we show that BA.2.75 exhibits substantially higher affinity for host receptor angiotensin-converting enzyme 2 (ACE2) than BA.5 and other variants. Structural analyses of BA.2.75 spike shows its decreased thermostability and increased frequency of the receptor binding domain (RBD) in the "up" conformation under acidic conditions, suggesting enhanced low-pH-endosomal cell entry. Relative to BA.4/BA.5, BA.2.75 exhibits reduced evasion of humoral immunity from BA.1/BA.2 breakthrough-infection convalescent plasma but greater evasion of Delta breakthrough-infection convalescent plasma. BA.5 breakthrough-infection plasma also exhibits weaker neutralization against BA.2.75 than BA.5, mainly due to BA.2.75's distinct neutralizing antibody (NAb) escape pattern. Antibody therapeutics Evusheld and Bebtelovimab remain effective against BA.2.75. These results suggest BA.2.75 may prevail after BA.4/BA.5, and its increased receptor-binding capability could support further immune-evasive mutations.

Chemotherapy- and Immune-Related Gene Panel in Prognosis Prediction and Immune Microenvironment of SCLC.

Small-cell lung cancer (SCLC) is a highly proliferative, invasive lung cancer with poor prognosis. Chemotherapy is still the standard first-line treatment for SCLC, but many patients relapse due to chemoresistance. Along with advances in immunology, it is essential to investigate potential indicators of the immune response and the prognosis of SCLC. Using bioinformatics analysis, we identified 313 differentially expressed genes (DEGs) in SCLC and normal lung samples, and we found that four upregulated genes (TOP2A, CDKN2A, BIRC5, and MSH2) were associated with platinum resistance, while immune-related genes (HLA family genes) were downregulated in SCLC. Then, a prognostic prediction model was constructed for SCLC based on those genes. Immune cell infiltration analysis showed that antigen presentation was weak in SCLC, and TOP2A expression was negatively correlated with CD8+ T cells, while HLA-ABC expression was positively correlated with M1 macrophages, memory B cells, and CD8+ T cells. We also found that TOP2A was related to poor prognosis and inversely correlated with HLA-ABC, which was verified with immunohistochemical staining in 151 SCLC specimens. Our study findings indicated that TOP2A may be a potential prognosis indicator and a target to reverse the immunosuppressive tumor microenvironment of SCLC.

Phosphosite-dependent presentation of dual phosphorylated peptides by MHC class I molecules.

Phosphopeptides presented by major histocompatibility complex (MHC) class I have been regarded as a pivotal type of cancer neoantigens that are recognized by T cells. The structural basis of single-phosphorylated peptide presentation has been well studied. Diphosphorylation with one interval between two sites is one of the prevalent forms of multisite-phosphorylated peptides. Herein, we determined the molecular basis of presentation of two P4/P6 double pS-containing peptides by HLA-B27 and compared them with unmodified and single-phosphorylated peptide complexes. These data clarified not only the HLA allele-specific presentation of phosphopeptides by MHC class I molecules but also the cooperativity of peptide conformation within P4 and P6 phosphorylation sites. The phosphorylation of P6 site can influence the binding mode of P4 phosphorylated site to HLA-B27. And we found the diphospho-dependent attenuated effect of peptide binding affinity. This study provides insights into the MHC presentation features of diphosphopeptides, which is different from monophosphopeptides.

Pseudoprogression in lung cancer patients treated with immunotherapy.

Lung cancer has attracted much attention because of its high morbidity and mortality worldwide. The advent of immunotherapy approaches, especially the application of immune checkpoint inhibitors (ICIs) has dramatically changed the treatment of lung cancer, but a novel and unexpected pattern of treatment response-- pseudoprogression, has been observed simultaneously which complicates the routine clinical evaluation and management. However, manifestations of pseudoprogression vary and there are many disputes on immune-related response assessment and corresponding treatments for lung cancer. Therefore, we summarized the possible mechanisms, clinical manifestations and corresponding treatment measures of pseudoprogression in lung cancer, as well as potential methods to differentiate pseudoprogression from true tumor progression.

Mooring Stone-Like Arg114 Pulls Diverse Bulged Peptides: First Insight into African Swine Fever Virus-Derived T Cell Epitopes Presented by Swine Major Histocompatibility Complex Class I.

African swine fever virus (ASFV) is the causative agent of African swine fever (ASF), which is a devastating pig disease threatening the global pork industry. However, currently, no commercial vaccines are available. During the pig immune response, major histocompatibility complex class I (MHC-I) molecules select viral peptide epitopes and present them to host cytotoxic T lymphocytes, thereby playing critical roles in eliminating viral infections. Here, we screened peptides derived from ASFV and determined the molecular basis of ASFV-derived peptides presented by the swine leukocyte antigen 1*0101 (SLA-1*0101). We found that peptide binding in SLA-1*0101 differs from the traditional mammalian binding patterns. Unlike the typical B and F pockets used by the common MHC-I molecule, SLA-1*0101 uses the D and F pockets as major peptide anchor pockets. Furthermore, the conformationally stable Arg114 residue located in the peptide-binding groove (PBG) was highly selective for the peptides. Arg114 draws negatively charged residues at positions P5 to P7 of the peptides, which led to multiple bulged conformations of different peptides binding to SLA-1*0101 and creating diversity for T cell receptor (TCR) docking. Thus, the solid Arg114 residue acts as a "mooring stone" and pulls the peptides into the PBG of SLA-1*0101. Notably, the T cell recognition and activation of p72-derived peptides were verified by SLA-1*0101 tetramer-based flow cytometry in peripheral blood mononuclear cells (PBMCs) of the donor pigs. These results refresh our understanding of MHC-I molecular anchor peptides and provide new insights into vaccine development for the prevention and control of ASF. IMPORTANCE The spread of African swine fever virus (ASFV) has caused enormous losses to the pork industry worldwide. Here, a series of ASFV-derived peptides were identified, which could bind to swine leukocyte antigen 1*0101 (SLA-1*0101), a prevalent SLA allele among Yorkshire pigs. The crystal structure of four ASFV-derived peptides and one foot-and-mouth disease virus (FMDV)-derived peptide complexed with SLA-1*0101 revealed an unusual peptide anchoring mode of SLA-1*0101 with D and F pockets as anchoring pockets. Negatively charged residues are preferred within the middle portion of SLA-1*0101-binding peptides. Notably, we determined an unexpected role of Arg114 of SLA-1*0101 as a "mooring stone" which pulls the peptide anchoring into the PBG in diverse "M"- or "n"-shaped conformation. Furthermore, T cells from donor pigs could activate through the recognition of ASFV-derived peptides. Our study sheds light on the uncommon presentation of ASFV peptides by swine MHC-I and benefits the development of ASF vaccines.

One-Year Sustained Cellular and Humoral Immunities in Coronavirus Disease 2019 (COVID-19) Convalescents.

BACKGROUND: The longitudinal antigen-specific immunity in COVID-19 convalescents is crucial for long-term protection upon individual re-exposure to SARS-CoV-2, and even more pivotal for ultimately achieving population-level immunity. We conducted this cohort study to better understand the features of immune memory in individuals with different disease severities at 1 year post-disease onset. METHODS: We conducted a systematic antigen-specific immune evaluation in 101 COVID-19 convalescents, who had asymptomatic, mild, moderate, or severe disease, through 2 visits at months 6 and 12 after disease onset. The SARS-CoV-2-specific antibodies, comprising neutralizing antibody (NAb), immunoglobulin (Ig) G, and IgM, were assessed by mutually corroborated assays (ie, neutralization, enzyme-linked immunosorbent assay [ELISA], and microparticle chemiluminescence immunoassay [MCLIA]). Meanwhile, T-cell memory against SARS-CoV-2 spike, membrane, and nucleocapsid proteins was tested through enzyme-linked immunospot assay (ELISpot), intracellular cytokine staining, and tetramer staining-based flow cytometry, respectively. RESULTS: SARS-CoV-2-specific IgG antibodies, and NAb, can persist among >95% of COVID-19 convalescents from 6 to 12 months after disease onset. At least 19/71 (26%) of COVID-19 convalescents (double positive in ELISA and MCLIA) had detectable circulating IgM antibody against SARS-CoV-2 at 12 months post-disease onset. Notably, numbers of convalescents with positive SARS-CoV-2-specific T-cell responses (≥1 of the SARS-CoV-2 antigen S1, S2, M, and N proteins) were 71/76 (93%) and 67/73 (92%) at 6 and 12 months, respectively. Furthermore, both antibody and T-cell memory levels in the convalescents were positively associated with disease severity. CONCLUSIONS: SARS-CoV-2-specific cellular and humoral immunities are durable at least until 1 year after disease onset.

Peptide Presentations of Marsupial MHC Class I Visualize Immune Features of Lower Mammals Paralleled with Bats.

Marsupials are one of three major mammalian lineages that include the placental eutherians and the egg-laying monotremes. The marsupial brushtail possum is an important protected species in the Australian forest ecosystem. Molecules encoded by the MHC genes are essential mediators of adaptive immune responses in virus-host interactions. Yet, nothing is known about the peptide presentation features of any marsupial MHC class I (MHC I). This study identified a series of possum MHC I Trvu-UB*01:01 binding peptides derived from wobbly possum disease virus (WPDV), a lethal virus of both captive and feral possum populations, and unveiled the structure of marsupial peptide/MHC I complex. Notably, we found the two brushtail possum-specific insertions, the 3-aa Ile52Glu53Arg54 and 1-aa Arg154 insertions are located in the Trvu-UB*01:01 peptide binding groove (PBG). The 3-aa insertion plays a pivotal role in maintaining the stability of the N terminus of Trvu-UB*01:01 PBG. This aspect of marsupial PBG is unexpectedly similar to the bat MHC I Ptal-N*01:01 and is shared with lower vertebrates from elasmobranch to monotreme, indicating an evolution hotspot that may have emerged from the pathogen-host interactions. Residue Arg154 insertion, located in the α2 helix, is available for TCR recognition, and it has a particular influence on promoting the anchoring of peptide WPDV-12. These findings add significantly to our understanding of adaptive immunity in marsupials and its evolution in vertebrates. Our findings have the potential to impact the conservation of the protected species brushtail possum and other marsupial species.

SCAMP2/5 as diagnostic and prognostic markers for acute myeloid leukemia.

The secretory carrier-associated membrane proteins (SCAMPs) are associated with the development of multiple human cancers. The role of SCAMPs in acute myeloid leukemia (AML), however, remains to be identified. In the present study, we explored expression patterns and prognostic value of SCAMPs and network analysis of SCAMPs-related signaling pathways in AML using Oncomine, GEPIA, cBioPortal, LinkedOmics, DAVID and Metascape databases. Genetic alteration analysis revealed that the mutation rate of SCAMP genes was below 1% (9/1272) in AML, and there was no significant correlation between SCAMPs gene mutation and AML prognosis. However, the SCAMP2/5 mRNA levels were significantly higher in AML patients than in healthy controls. Moreover, high mRNA expressions of SCAMP2/4/5 were associated with poor overall survival, which might be due to that SCAMP2/4/5 and their co-expressed genes were associated with multiple pathways related to tumorigenesis and progression, including human T-cell leukemia virus 1 infection, acute myeloid leukemia, mTOR and NF-kappa B signaling pathways. These results suggest that SCAMP2/4/5 are potential prognostic markers for AML, and that SCAMP2 and SCAMP5 individually or in combination may be used as diagnostic markers for AML.