[Characteristics of serum autoantibodies in patients with lupus nephritis and tubulointerstitial damage].

OBJECTIVE: To observe the tubulointerstitial damage (TID) in lupus nephritis (LN) and investigate the relationship between autoantibodies and TID in lupus nephritis. METHODS: This cross-sectional study was conducted in a comprehensive tertiary hospital in Peking University Shenzhen Hospital. From March 2012 to July 2021, LN patients who performed renal biopsy were enrolled in the study. Clinical, laboratory and pathology data were collected. We classified the patients into none-or-mild group and moderate-to-severe groups according to the severity of interstitial fibrosis (IF) /tubular atrophy (TA) or tubulointerstitial inflammation (TII). The t test, U test and Chi-square test were used for statistical analysis as appropriate. RESULTS: A total of 226 patients were included, of who 190 (84%) were female with a median age of 32 (26, 39) years. 89% (201/226) of the patients who pathologically proved to be proliferative LN by renal biopsy. The frequency of moderate-to-severe TII and moderate-to-severe IF/TA was 30% (67/226) and 34% (76/226) respectively. For autoantibodies, the patients with moderate-to-severe TII had a lower rate of positive serum anti-ribonucleoprotein (anti-RNP) antibodies than the patients with none-or-mild TII (34% vs. 51%), and moderate-to-severe IF/TA had a lower rate of positive anti-ribosomal P protein (anti-P) antibodies than patients with none-or-mild IF/TA (19% vs. 33%). For other clinical indicators, the patients with moderate-to-severe TII and moderate-to-severe IF/TA were more often combined with proliferative LN, hypertension and anemia than the patients with none-or-mild TII and none-or-mild IF/TA, respectively. The patients with moderate-to-severe TII had higher serum creatinine values and lower glomerular filtration rates than the patients with none-or-mild TII. The patients with moderate-to-severe IF/TA had higher serum creatinine values, and lower glomerular filtration rates than the patients with none-or-mild IF/TA. CONCLUSION: In patients with LN in Southern China, anti-RNP antibodies and anti-P antibodies may be potential protective factors for TII and IF/TA, respectively. More studies are needed to identify the risk factors of lupus patients with TID and investigate the correlation between autoantibodies and TID, which are critical for developing better preventive and therapeutic strategies to improve the survival rate of LN.

Structure of trimeric pre-fusion rabies virus glycoprotein in complex with two protective antibodies.

Rabies virus (RABV) causes lethal encephalitis and is responsible for approximately 60,000 deaths per year. As the sole virion-surface protein, the rabies virus glycoprotein (RABV-G) mediates host-cell entry. RABV-G's pre-fusion trimeric conformation displays epitopes bound by protective neutralizing antibodies that can be induced by vaccination or passively administered for post-exposure prophylaxis. We report a 2.8-Å structure of a RABV-G trimer in the pre-fusion conformation, in complex with two neutralizing and protective monoclonal antibodies, 17C7 and 1112-1, that recognize distinct epitopes. One of these antibodies is a licensed prophylactic (17C7, Rabishield), which we show locks the protein in pre-fusion conformation. Targeted mutations can similarly stabilize RABV-G in the pre-fusion conformation, a key step toward structure-guided vaccine design. These data reveal the higher-order architecture of a key therapeutic target and the structural basis of neutralization by antibodies binding two key antigenic sites, and this will facilitate the development of improved vaccines and prophylactic antibodies.

Contrasting Modes of New World Arenavirus Neutralization by Immunization-Elicited Monoclonal Antibodies.

Transmission of the New World hemorrhagic fever arenaviruses Junín virus (JUNV) and Machupo virus (MACV) to humans is facilitated, in part, by the interaction between the arenavirus GP1 glycoprotein and the human transferrin receptor 1 (hTfR1). We utilize a mouse model of live-attenuated immunization with envelope exchange viruses to isolate neutralizing monoclonal antibodies (NAbs) specific to JUNV GP1 and MACV GP1. Structures of two NAbs, termed JUN1 and MAC1, demonstrate that they neutralize through disruption of hTfR1 recognition. JUN1 utilizes a binding mode common to all characterized infection- and vaccine-elicited JUNV-specific NAbs, which involves mimicking hTfR1 binding through the insertion of a tyrosine into the receptor-binding site. In contrast, MAC1 undergoes a tyrosine-mediated mode of antigen recognition distinct from that used by the reported anti-JUNV NAbs and the only other characterized anti-MACV NAb. These data reveal the varied modes of GP1-specific recognition among New World arenaviruses by the antibody-mediated immune response. IMPORTANCE The GP1 subcomponent of the New World arenavirus GP is a primary target of the neutralizing antibody response, which has been shown to be effective in the prevention and treatment of infection. Here, we characterize the structural basis of the antibody-mediated immune response that arises from immunization of mice against Junín virus and Machupo virus, two rodent-borne zoonotic New World arenaviruses. We isolate a panel of GP1-specific monoclonal antibodies that recognize overlapping epitopes and exhibit neutralizing behavior, in vitro. Structural characterization of two of these antibodies indicates that antibody recognition likely interferes with GP1-mediated recognition of the transferrin receptor 1. These data provide molecular-level detail for a key region of vulnerability on the New World arenavirus surface and a blueprint for therapeutic antibody development.

Neutralization potency of monoclonal antibodies recognizing dominant and subdominant epitopes on SARS-CoV-2 Spike is impacted by the B.1.1.7 variant.

Interaction of the SARS-CoV-2 Spike receptor binding domain (RBD) with the receptor ACE2 on host cells is essential for viral entry. RBD is the dominant target for neutralizing antibodies, and several neutralizing epitopes on RBD have been molecularly characterized. Analysis of circulating SARS-CoV-2 variants has revealed mutations arising in the RBD, N-terminal domain (NTD) and S2 subunits of Spike. To understand how these mutations affect Spike antigenicity, we isolated and characterized >100 monoclonal antibodies targeting epitopes on RBD, NTD, and S2 from SARS-CoV-2-infected individuals. Approximately 45% showed neutralizing activity, of which ∼20% were NTD specific. NTD-specific antibodies formed two distinct groups: the first was highly potent against infectious virus, whereas the second was less potent and displayed glycan-dependant neutralization activity. Mutations present in B.1.1.7 Spike frequently conferred neutralization resistance to NTD-specific antibodies. This work demonstrates that neutralizing antibodies targeting subdominant epitopes should be considered when investigating antigenic drift in emerging variants.

Impact of the B.1.1.7 variant on neutralizing monoclonal antibodies recognizing diverse epitopes on SARS-CoV-2 Spike.

The interaction of the SARS-CoV-2 Spike receptor binding domain (RBD) with the ACE2 receptor on host cells is essential for viral entry. RBD is the dominant target for neutralizing antibodies and several neutralizing epitopes on RBD have been molecularly characterized. Analysis of circulating SARS-CoV-2 variants has revealed mutations arising in the RBD, the N-terminal domain (NTD) and S2 subunits of Spike. To fully understand how these mutations affect the antigenicity of Spike, we have isolated and characterized neutralizing antibodies targeting epitopes beyond the already identified RBD epitopes. Using recombinant Spike as a sorting bait, we isolated >100 Spike-reactive monoclonal antibodies from SARS-CoV-2 infected individuals. ≈45% showed neutralizing activity of which ≈20% were NTD-specific. None of the S2-specific antibodies showed neutralizing activity. Competition ELISA revealed that NTD-specific mAbs formed two distinct groups: the first group was highly potent against infectious virus, whereas the second was less potent and displayed glycan-dependant neutralization activity. Importantly, mutations present in B.1.1.7 Spike frequently conferred resistance to neutralization by the NTD-specific neutralizing antibodies. This work demonstrates that neutralizing antibodies targeting subdominant epitopes need to be considered when investigating antigenic drift in emerging variants.

Impact of the B.1.1.7 variant on neutralizing monoclonal antibodies recognizing diverse epitopes on SARS-CoV-2 Spike

The interaction of the SARS-CoV-2 Spike receptor binding domain (RBD) with the ACE2 receptor on host cells is essential for viral entry. RBD is the dominant target for neutralizing antibodies and several neutralizing epitopes on RBD have been molecularly characterized. Analysis of circulating SARS-CoV-2 variants has revealed mutations arising in the RBD, the N-terminal domain (NTD) and S2 subunits of Spike. To fully understand how these mutations affect the antigenicity of Spike, we have isolated and characterized neutralizing antibodies targeting epitopes beyond the already identified RBD epitopes. Using recombinant Spike as a sorting bait, we isolated >100 Spike-reactive monoclonal antibodies from SARS-CoV-2 infected individuals. ~45% showed neutralizing activity of which ~20% were NTD-specific. None of the S2-specific antibodies showed neutralizing activity. Competition ELISA revealed that NTD-specific mAbs formed two distinct groups: the first group was highly potent against infectious virus, whereas the second was less potent and displayed glycan-dependant neutralization activity. Importantly, mutations present in B.1.1.7 Spike frequently conferred resistance to neutralization by the NTD-specific neutralizing antibodies. This work demonstrates that neutralizing antibodies targeting subdominant epitopes need to be considered when investigating antigenic drift in emerging variants.

[Nomenclature correction of "incidental gallbladder cancer" and its prevention strategies].

Incidental gallbladder cancer(IGBC) originated in the West more than half a century ago.IGBC was translated and introduced into China afterwards with widespread clinical application.With the popularization of laparoscopic cholecystectomy, the trend of "abuse" of IGBC has become increasingly apparent worldwide.Many advanced gallbladder cancers have been categorized as IGBC which actually become the synonym of "missed diagnosis" . From the point of the pathology, the diagnosis of IGBC may cause delays in treatment and adversely affect the patient's prognosis.For country like China with relatively high incidences of chronic cholecystitis, cholelithiasis, and gallbladder cancer, the concept of IGBC, however, is no longer applicable to our diagnosis treat model.For improving the prognosis of gallbladder patients, it is necessary to update and rename the concept of IGBC and more attention should be paid to improve the diagnostic level of early stage tumor.

Results of a global, patient-based survey assessing the impact of psoriatic arthritis discussed in the context of the Psoriatic Arthritis Impact of Disease (PsAID) questionnaire.

BACKGROUND: Psoriatic arthritis (PsA) is a chronic immune-mediated inflammatory musculoskeletal disease, manifesting as peripheral arthritis, enthesitis, dactylitis, spondylitis, and skin and nail psoriasis. A core set of domains for measuring the impact of PsA has been developed, including pain, patient global assessment, physical function, health-related quality of life (HRQoL), and fatigue. To understand the impact of PsA on health domains from a patient's perspective, a global survey was developed and results reported in the context of the 12-item Psoriatic Arthritis Impact of Disease (PsAID-12) questionnaire. METHODS: An online patient-based global survey was conducted by The Harris Poll in Australia, Brazil, Canada, France, Spain, Taiwan, the UK, and the US between November 2, 2017 and March 12, 2018. Eligible patients were ≥ 18 years old with a diagnosis of PsA for > 1 year, had visited a rheumatologist/dermatologist in the past 12 months and reported using ≥ 1 synthetic/biologic disease-modifying antirheumatic drug for PsA. Patients reported on PsA severity and symptoms, and the impact of PsA on HRQoL. After survey completion, responses were aligned with PsAID health domains. Descriptive statistics and chi-square tests were conducted. RESULTS: This analysis included 1286 patients from eight countries. Most patients (97%) reported musculoskeletal symptoms relating to PsA in the past year. Common moderate/major impacts of PsA were on physical activity (78%), ability to perform certain activities (76%), work productivity (62%), and career path (57%). Skin/nail symptoms occurred in 80% of patients. Overall, 69% of patients reported that PsA had a moderate/major impact on emotional/mental wellbeing, 56% on romantic relationships/intimacy, and 44% on relationships with family and friends. Social impacts included emotional distress (58%), social shame or disapproval (32%), and ceased participation in social activities (45%). Over half of all patients experienced unusual fatigue over the past 12 months (52%). The health domains that patients reported as being impacted by PsA aligned with life impact domains of the patient-derived PsAID health domains. CONCLUSION: These results highlight the impact of PsA on multiple health domains from a patient perspective that should be considered during shared decision-making processes between healthcare providers and patients.

[Pathological changes of the spleen in ten patients with coronavirus disease 2019(COVID-19) by postmortem needle autopsy].

Objective: To study the pathological changes of the spleen in patients with COVID-19 and to analyze the relationship between the weakened immune system and splenic lesions. Methods: Postmortem needle autopsies from the spleen were carried out on 10 patients who died from COVID-19 in Wuhan. Routine hematoxylin and eosin (HE) staining was used to observe the pathological changes. The changes of lymphocytes were studied further with immunohistochemistry.RT-PCR was used to detect 2019-nCoV RNA in the spleen. In addition,the Epstein-Barr virus (EBV) was detected by in situ hybridization, and coronavirus particles were detected by transmission electron microscopy in 2 cases. Results: There were 7 males and 3 females, with an average age of 68.3 years.Of the 10 cases, 4 had cancer history and another 4 had other underlying diseases respectively.Cough, fever, malaise and dyspnea were the main clinical symptoms.The time from onset to death was 15-45 days.Ten cases patients had normal or slight increase in peripheral blood leukocyte count in the early stage of the disease, 6 cases had significant increase before death. Five patients' peripheral blood lymphocyte count decreased in the early stage of the disease, and 10 patients' peripheral blood lymphocyte count decreased significantly before the disease progressed or died. Seven cases were treated with corticosteroid (methylprednisolone ≤40 mg/d, not more than 5 days). Histopathological examination showed that the cell composition of the spleen decreased, white pulp atrophied at different levels, meanwhile lymphoid follicles decreased or absent;in addition, the ratio of red pulp to white pulp increased with varying degrees. In 7 cases, more neutrophil infiltration was found, and in 5 cases, scattered plasma cell infiltration was found. Macrophage proliferation and hemophagocytic phenomena in a few cells were found in a case. Meanwhile, necrosis and lymphocyte apoptosis were detected in 2 cases, small artery thrombosis and spleen infarction in 1 case, and fungal infection in 1 case. The results of immunohistochemistry showed that the T and B lymphocyte components of the spleen in all cases decreased in varying degrees. CD20(+) B cells were found to accumulate in the lymphoid sheath around the splenic artery in 8 cases. However, CD20 and CD21 immunostaining in 2 cases showed that the number of white pulp was almost normal, and splenic nodules were atrophic. CD3(+), CD4(+) and CD8(+)T cells were decreased. In 9 cases,CD68(+) macrophages were no significant changes in the distribution and quantity. While more CD68(+) cells were found in the medullary sinuses of 1 case (related to fungal infection). Few CD56(+) cells were found. EBV was negative by in situ hybridization. RT-PCR was used to detect the nucleic acid of 2019-nCoV. One of 10 cases was positive, 39 years old,who was the youngest patient in this group, and the other 9 cases were negative. Coronavirus particles were found in the cytoplasm of macrophage under electron microscope in 2 cases. Conclusions: The death of COVID-19 occurs mainly in the elderly, and some cases have no underlying diseases. Spleen may be one of the organs directly attacked by the virus in some patients who died from COVID-19. T and B lymphocyte in the spleen decrease in varying degrees, lymphoid follicles are atrophied, decreased or absent, and the number of NK cells do not change significantly. And the pathological changes of the spleen are not related to the use of low dose corticosteroid, which may be related to the direct attack of virus and the attack of immune system on its own tissues.

Unraveling virus relationships by structure-based phylogenetic classification.

Delineation of the intricacies of protein function from macromolecular structure constitutes a continual obstacle in the study of cell and pathogen biology. Structure-based phylogenetic analysis has emerged as a powerful tool for addressing this challenge, allowing the detection and quantification of conserved architectural properties between proteins, including those with low or no detectable sequence homology. With a focus on viral protein structure, we highlight how a number of investigations have utilized this powerful method to infer common functionality and ancestry.

Randomized clinical trial of continuous transversus abdominis plane block, epidural or patient-controlled analgesia for patients undergoing laparoscopic colorectal cancer surgery.

BACKGROUND: The optimal analgesia regimen after laparoscopic colorectal cancer surgery is unclear. The aim of the study was to characterize the beneficial effects of continuous transversus abdominis plane (TAP) blocks initiated before operation on outcomes following laparoscopic colorectal cancer surgery. METHODS: Patients undergoing surgery for colorectal cancer were divided randomly into three groups: combined general-TAP anaesthesia (TAP group), combined general-thoracic epidural anaesthesia (TEA group) and standard general anaesthesia (GA group). The primary endpoint was duration of hospital stay. Secondary endpoints included gastrointestinal motility, pain scores and plasma levels of cytokines. RESULTS: In total, 180 patients were randomized and 165 completed the trial. The intention-to-treat analysis showed that duration of hospital stay was significantly longer in the TEA group than in the TAP and GA groups (median 4·1 (95 per cent c.i. 3·8 to 4·3) versus 3·1 (3·0 to 3·3) and versus 3·3 (3·2 to 3·6) days respectively; both P < 0·001). Time to first flatus was earlier in the TAP group (P < 0·001). Visual analogue scale (VAS) scores during coughing were lower in the TAP and TEA groups than the GA group (P < 0·001). Raised plasma levels of vascular endothelial growth factor C, interleukin 6, adrenaline and cortisol were attenuated significantly by continuous TAP block. CONCLUSION: Continuous TAP analgesia not only improved gastrointestinal motility but also shortened duration of hospital stay. A decreased opioid requirement and attenuating surgical stress response may be potential mechanisms. Registration number: ChiCTR-TRC-1800015535 ( http://www.chictr.org.cn).

ANTECEDENTES: El régimen analgésico óptimo para los pacientes tras cirugía laparoscópica del cáncer colorrectal se desconoce. El objetivo de este estudio fue caracterizar los efectos beneficiosos del bloqueo continuo del plano transverso abdominal (transversus abdominis plane, TAP) iniciado preoperatoriamente sobre los resultados después de cirugía laparoscópica del cáncer colorrectal. MÉTODOS: Los pacientes sometidos a cirugía del cáncer colorrectal fueron divididos aleatoriamente en tres grupos: anestesia combinada general-TAP (grupo TAP), anestesia epidural combinada general-torácica (grupo TEA) y anestesia general estándar (grupo GA). El resultado primario fue la duración de la estancia hospitalaria. Los resultados secundarios incluyeron la motilidad gastrointestinal, puntuaciones de dolor y niveles plasmáticos de citocinas. RESULTADOS: En total, 180 pacientes fueron aleatorizados y 165 completaron el ensayo. El análisis por intención de tratar mostró que la duración de la estancia hospitalaria en el grupo TEA fue significativamente más larga que en el grupo TAP y GA respectivamente (4,1 (3,8-4,3) versus 3,1 (3,0-3,3) días, P < 0,001; 4,1 (3,8-4,3) versus 3,3 (3,2-3,6) días, P < 0,001). El tiempo hasta la primera eliminación de gases fue más precoz en el grupo TAP (P < 0,001). Las puntuaciones de la escala analógica visual (visual analogue scale, VAS) durante la tos en el grupo TAP y TEA fueron inferiores (P < 0,01). Los niveles elevados en plasma del factor de crecimiento endotelial C (VEGF-C), interleucina (IL)-6, epinefrina y cortisol fueron atenuados significativamente por el bloque TAP continuo. CONCLUSIÓN: La analgesia TAP continua no solo mejora la motilidad gastrointestinal, sino que también acorta la estancia hospitalaria. Una disminución en los requerimientos de opiáceos y la atenuación de la respuesta al estrés quirúrgico podrían ser mecanismos potenciales de la acción de TAP.

[Evaluating the impact of preoperative anemia on the prognosis of upper tract urothelial carcinoma following radical nephroureterectomy: A single-center retrospective study of 686 patients].

OBJECTIVE: To identify the effect of preoperative anemia on the prognosis of patients with upper tract urothelial carcinoma (UTUC) following radical nephroureterectomy. METHODS: Clinicopathological and prognosis data on 686 patients with UTUC who underwent RNU at Peking University First Hospital between January 2000 and December 2013 were retrospectively analyzed. Preoperative anemia was defined as hemoglobin <130 g/L in men and <120 g/L in women based on the World Health Organization classification. The Kaplan-Meier method with log-rank test was applied to estimate the effect of anemia on survival. The associations of clinicopathologic features with overall survival and cancer-specific survival were evaluated using univariate and multivariate Cox regression models. RESULTS: There were 303(44.2%, 303/686) male and 383(55.8%, 383/686) female patients, and the median age was 68 years (interquartile range: 60-74 years). In all, 320 (46.6%, 320/686) patients were anemic before surgery. The median follow-up duration was 47 months. In all, 160 (23.3%) patients died, 141 (20.6%) died of cancer and 19 (2.7%) died of other disease or accidents. Preoperative anemia was associated with gender (P=0.002), age (P<0.001), lymph node positive (P=0.026), increased tumor grade (P=0.018), concomitant carcinoma in situ (P=0.038), tumor necrosis (P=0.007) and poor renal function (P<0.001). In univariate analysis, overall mortality was correlated with pre-operative anemia (P<0.001), gender (P=0.009), hydronephrosis (P=0.024), tumor stage (P<0.001), lymph node positive (P<0.001), tumor grade (P<0.001), tumor architecture(P<0.001), sarcomatoid differentiation (P=0.013), history of ureteroscope (P=0.033) and tumor hemorrhage (P<0.001); cancer-specific mortality was correlated with preoperative anemia (P=0.001), gender (P=0.001), hydronephrosis (P=0.043), tumor stage (P<0.001), lymph node positive (P<0.001), tumor grade (P<0.001), tumor architecture (P<0.001), sarcomatoid differentiation (P=0.016), history of ureteroscope (P=0.028) and tumor hemorrhage (P=0.003). A multivariate Cox proportional hazards model indicated that preoperative anemia was an independent prognositic predictor for overall mortality (P<0.001, HR=1.861) and cancer-specific mortality (P=0.003, HR=1.688). CONCLUSION: The preoperative anemia is an independent risk factor for cancer-specific survival and overall survival. Hemoglobin levels should be considered during patient counseling and in decision-making for further therapy.

Structures of enveloped virions determined by cryogenic electron microscopy and tomography.

Enveloped viruses enclose their genomes inside a lipid bilayer which is decorated by membrane proteins that mediate virus entry. These viruses display a wide range of sizes, morphologies and symmetries. Spherical viruses are often isometric and their envelope proteins follow icosahedral symmetry. Filamentous and pleomorphic viruses lack such global symmetry but their surface proteins may display locally ordered assemblies. Determining the structures of enveloped viruses, including the envelope proteins and their protein-protein interactions on the viral surface, is of paramount importance. These structures can reveal how the virions are assembled and released by budding from the infected host cell, how the progeny virions infect new cells by membrane fusion, and how antibodies bind surface epitopes to block infection. In this chapter, we discuss the uses of cryogenic electron microscopy (cryo-EM) in elucidating structures of enveloped virions. Starting from a detailed outline of data collection and processing strategies, we highlight how cryo-EM has been successfully utilized to provide unique insights into enveloped virus entry, assembly, and neutralization.

Risk factors for community-associated Clostridioides difficile infection in young children.

The majority of paediatric Clostridioides difficile infections (CDI) are community-associated (CA), but few data exist regarding associated risk factors. We conducted a case-control study to evaluate CA-CDI risk factors in young children. Participants were enrolled from eight US sites during October 2014-February 2016. Case-patients were defined as children aged 1-5 years with a positive C. difficile specimen collected as an outpatient or ⩽3 days of hospital admission, who had no healthcare facility admission in the prior 12 weeks and no history of CDI. Each case-patient was matched to one control. Caregivers were interviewed regarding relevant exposures. Multivariable conditional logistic regression was performed. Of 68 pairs, 44.1% were female. More case-patients than controls had a comorbidity (33.3% vs. 12.1%; P = 0.01); recent higher-risk outpatient exposures (34.9% vs. 17.7%; P = 0.03); recent antibiotic use (54.4% vs. 19.4%; P < 0.0001); or recent exposure to a household member with diarrhoea (41.3% vs. 21.5%; P = 0.04). In multivariable analysis, antibiotic exposure in the preceding 12 weeks was significantly associated with CA-CDI (adjusted matched odds ratio, 6.25; 95% CI 2.18-17.96). Improved antibiotic prescribing might reduce CA-CDI in this population. Further evaluation of the potential role of outpatient healthcare and household exposures in C. difficile transmission is needed.

Structure-Based Classification Defines the Discrete Conformational Classes Adopted by the Arenaviral GP1.

The emergence of Old and New World arenaviruses from rodent reservoirs persistently threatens human health. The GP1 subunit of the envelope-displayed arenaviral glycoprotein spike complex (GPC) mediates host cell recognition and is an important determinant of cross-species transmission. Previous structural analyses of Old World arenaviral GP1 glycoproteins, alone and in complex with a cognate GP2 subunit, have revealed that GP1 adopts two distinct conformational states distinguished by differences in the orientations of helical regions of the molecule. Here, through comparative study of the GP1 glycoprotein architectures of Old World Loei River virus and New World Whitewater Arroyo virus, we show that these rearrangements are restricted to Old World arenaviruses and are not induced solely by the pH change that is associated with virus endosomal trafficking. Our structure-based phylogenetic analysis of arenaviral GP1s provides a blueprint for understanding the discrete structural classes adopted by these therapeutically important targets.IMPORTANCE The genetically and geographically diverse group of viruses within the family Arenaviridae includes a number of zoonotic pathogens capable of causing fatal hemorrhagic fever. The multisubunit GPC glycoprotein spike complex displayed on the arenavirus envelope is a key determinant of species tropism and a primary target of the host humoral immune response. Here, we show that the receptor-binding GP1 subcomponent of the GPC spike from Old World but not New World arenaviruses adopts a distinct, pH-independent conformation in the absence of the cognate GP2. Our analysis provides a structure-based approach to understanding the discrete conformational classes sampled by these therapeutically important targets, informing strategies to develop arenaviral glycoprotein immunogens that resemble GPC as presented on the mature virion surface.

The Function and Regulatory Network of Pax9 Gene in Palate Development.

Cleft palate, a common congenital deformity, can arise from disruptions in any stage of palatogenesis, including palatal shelf growth, elevation, adhesion, and fusion. Paired box gene 9 (Pax9) is recognized as a vital regulator of palatogenesis with great relevance to cleft palate in humans and mice. Pax9-deficient murine palatal shelves displayed deficient elongation, postponed elevation, failed contact, and fusion. Pax9 is expressed in epithelium and mesenchyme, exhibiting a dynamic expression pattern that changes according to the proceeding of palatogenesis. Recent studies highlighted the Pax9-related genetic interactions and their critical roles during palatogenesis. During palate growth, PAX9 interacts with numerous molecules and members of pathways (e.g., OSR2, FGF10, SHOS2, MSX1, BARX1, TGFß3, LDB1, BMP, WNT ß-catenin dependent, and EDA) in the mesenchyme and functions as a key mediator in epithelial-mesenchymal communications with FGF8, TBX1, and the SHH pathway. During palate elevation, PAX9 is hypothesized to mediate the time point of the elevation event in the anterior and posterior parts of the palatal shelves. The delayed elevation of Pax9 mutant palatal shelves probably results from abnormal expressions of a series of genes ( Osr2 and Bmpr1a) leading to deficient palate growth, abnormal tongue morphology, and altered hyaluronic acid distribution. The interactions between PAX9 and genes encoding the OSR2, TGFß3, and WNT ß-catenin-dependent pathways provide evidence that PAX9 might participate in the regulation of palate fusion. This review summarizes the current understanding of PAX9's functions and emphasizes the interactions between PAX9 and vital genes during palatogenesis. We hope to provide some clues for further exploration of the function and mechanism of PAX9, especially during palate elevation and fusion events.

[Endoscopicretrograde cholangio-pancreatography management of long-term complications after pancreaticoduodenectomy].

Objective: To investigate the feasibility and effectiveness of endoscopicretrograde cholangio-pancreatography(ERCP)in the management of long-term complications after pancreaticoduodenectomy. Methods: From January 2009 to July 2018, the clinical data of 62 patients with biliary or pancreatic long-term complications after pancreatoduodenectomy were reviewed at Department of General Surgery, and the corresponding ERCP were carried out in the multi-disciplinary cooperation.There were 39 males and 24 females.The age was 56.5 years(aging from 13 to 76 years). The time of treatment was 3 months to 20 years after pancreatoduodenectomy.The long-term biliopancreatic complications after pancreatoduodenectomy included 51 cases of biliary calculi, 42 cases of bilioenteric anastomotic stenosis with proximal bile duct dilatation, and 11 cases of pancreaticointestinal anastomosis stenosis with distal pancreatic duct dilatation.All patients received conventional duodenoscopy or single-balloon enteroscopy assisted ERCP under general anesthesia. Results: A total of 95 ERCP were performed in 62 patients, averaging 1.5 times per case.The long-term complications of cholangiopancreatic after pancreatoduodenectomy(ERCP indications) included 56 times of bile duct stones(58.9%), 45 times of bilioenteric anastomatic stricture(47.4%), 11 times of recurrent pancreatitis(11.6%), 6 cases(6.3%) of bilioenteric anastomatic foreign body, 3 times of intrahepatic bile duct stenosis(3.2%). Among the 95 times, 82 times(86.3%) achieved endoscopic endoscopy, 76 times(80.0%) were diagnosed successfully, and 72 times(75.8%) were successfully treated with ERCP.Small intestinal perforation occurred in 1 patient undergoing duodenoscopy, and then healed by surgical repair. Conclusion: Multi-disciplinary collaboration of ERCP is safe and effective in the treatment of long-term complications after pancreaticoduodenectomy, but the long-term effect still needs further clinical follow-up.

Early Detection of a Hepatic Artery Pseudoaneurysm After Liver Transplantation Is the Determinant of Survival.

BACKGROUND: Hepatic artery pseudoaneurysm (PA) after liver transplantation (LT) is a rare but potentially fatal complication. Among a series of 50 patients of LT, we experienced 3 such cases. Some authors also have reported cases of PA, either intrahepatic or extrahepatic. The aim of this study was to investigate the important factors that affect the treatment outcome. METHODS: Three patients were presented. To analyze the factors, not only our patients but also the patients with PA reported in the literature (including 10 case series and 23 case reports) were enrolled for analysis. The possible factors probably affecting the survival were compared statistically, including age, sex, clinical manifestation as bleeding (including gastrointestinal bleeding, hemobilia, or intra-abdominal bleeding), treatment (with embolization or surgical exploration or stent), diagnosis establishment before or after bleeding, and so forth. RESULTS: From univariate analysis, the significant factors that affect survival are sex (female) (P = .036), stent treatment (P = .006), and early detection (P = .036), whereas age (P = .493) and presentation with hemorrhage (P = .877) are not significant factors. However, according to multivariate analysis, stent treatment has a borderline significance (P = .056). CONCLUSIONS: Early detection of such a life-threatening complication is a key determinant of survival. "Early" does not refer to early postoperative days but means the detection prior to the rupture of the pseudoaneurysm. Postoperative imaging studies such as computed tomographic scan or magnetic resonance cholangiopancreatography early and periodically to follow up the graft status is recommended, especially for those who had received other interventions before or after the liver transplantation.

Autologous dermal graft combined with a modified degloving procedure for penile augmentation in young adults: a preliminary study.

In order to evaluate the effect of penile enhancement, we retrospectively reviewed the data of the patients operated with autologous dermal graft implantation combined with a modified penile degloving procedure. The patients with the complaints of small penis, asking for penile augmentation, and normal erectile function were psychologically screened and enrolled. Data of follow-up visit including patient demographics, medical history, surgical procedure, patient-reported outcomes were analysed. In all, 30 eligible persons were operated. After degloving of the penis, the suspensory ligament was incised and the tunica albuginea was fixed to the proximal tunica dartos at the penile base. Then, the dermis graft was implanted on the dorsal surface of the tunica albuginea. The file of follow-up visit was available in 17 (57%) patients. The mean age was 23.7 years (19-35 years) and the mean follow-up was 13 months (range, 4-24 months). During the follow-up period, the average gain in the penis length was 2.7 cm in flaccid and 0.8 cm in erection, respectively. And the average gain in the penis circumference was 1.5 cm in flaccid and 1.2 cm in erection, respectively. Also, psychosexual sexual self-esteem and confidence of the patients were significantly improved (p < 0.001). Overall, 13 (76%) patients reported satisfaction with the penile appearance. We believe that the surgery is both safe and effective in the enhancement of the penis, however, further clinical studies with a larger patient population are necessary.

Hes1 Increases the Invasion Ability of Colorectal Cancer Cells via the STAT3-MMP14 Pathway.

The Notch pathway contributes to self-renewal of tumor-initiating cell and inhibition of normal colonic epithelial cell differentiation. Deregulated expression of Notch1 and Jagged1 is observed in colorectal cancer. Hairy/enhancer of split (HES) family, the most characterized targets of Notch, involved in the development of many cancers. In this study, we explored the role of Hes1 in the tumorigenesis of colorectal cancer. Knocking down Hes1 induced CRC cell senescence and decreased the invasion ability, whereas over-expression of Hes1 increased STAT3 phosphorylation activity and up-regulated MMP14 protein level. We further explored the expression of Hes1 in human colorectal cancer and found high Hes1 mRNA expression is associated with poor prognosis in CRC patients. These findings suggest that Hes1 regulates the invasion ability through the STAT3-MMP14 pathway in CRC cells and high Hes1 expression is a predictor of poor prognosis of CRC.