CD23+IgG1+ memory B cells are poised to switch to pathogenic IgE production in food allergy.

Food allergy is caused by allergen-specific immunoglobulin E (IgE) antibodies, but little is known about the B cell memory of persistent IgE responses. Here, we describe, in human pediatric peanut allergy, a population of CD23+IgG1+ memory B cells arising in type 2 immune responses that contain high-affinity peanut-specific clones and generate IgE-producing cells upon activation. The frequency of CD23+IgG1+ memory B cells correlated with circulating concentrations of IgE in children with peanut allergy. A corresponding population of "type 2-marked" IgG1+ memory B cells was identified in single-cell RNA sequencing experiments. These cells differentially expressed interleukin-4 (IL-4)- and IL-13-regulated genes, such as FCER2/CD23+, IL4R, and germline IGHE, and carried highly mutated B cell receptors (BCRs). In children with high concentrations of serum peanut-specific IgE, high-affinity B cells that bind the main peanut allergen Ara h 2 mapped to the population of "type 2-marked" IgG1+ memory B cells and included clones with convergent BCRs across different individuals. Our findings indicate that CD23+IgG1+ memory B cells transcribing germline IGHE are a unique memory population containing precursors of high-affinity pathogenic IgE-producing cells that are likely to be involved in the long-term persistence of peanut allergy.

Organocatalyzed ring-opening reactions of γ-carbonyl-substituted ε-caprolactones.

Side-chain-functionalized aliphatic polyesters are promising as functional biodegradable polymers. We have investigated ring-opening reactions of γ-carbonyl-substituted ε-caprolactones (gCCLs) to obtain poly(ε-caprolactone) (PCL) analogues. Organic catalysts and Sn(Oct)2 often used for the ring-opening polymerization (ROP) of ε-caprolactone (CL) have been explored to find the conditions for the formation of polymeric products of gCCLs. We confirmed the consumption of gCCLs in all catalyzed reactions. However, chain propagation hardly occurs, as the propagating species are preferentially transformed to α-substituted five-membered lactones when the substituents are linked by ester or not sterically hindered. Intramolecular cyclization to form thermodynamically stable five-membered lactones releases alcohols and amines, serving as nucleophiles for the subsequent ring opening of other gCCLs. Thus, apparent chain reactions are realized for continuous consumption of gCCLs. The reaction preference remains unchanged independent of the catalysts, although the reactions of the amide-linked gCCLs by acidic catalysts are slightly mitigated. Finally, copolymerization of CL and a gCCL catalyzed by diphenyl phosphate has been investigated, which enables the chain propagation reaction to yield the linear oligomers of PCL analogues containing up to 16 mol% of gCCL units. This study contributes to understanding the chemistry of ring-opening reactions of substituted lactones for designing functional degradable polymers.

Fusion of the molecular adjuvant C3d to cleavage-independent native-like HIV-1 Env trimers improves the elicited antibody response.

An effective HIV vaccine likely requires the elicitation of neutralizing antibodies (NAbs) against multiple HIV-1 clades. The recently developed cleavage-independent native flexibly linked (NFL) envelope (Env) trimers exhibit well-ordered conformation and elicit autologous tier 2 NAbs in multiple animal models. Here, we investigated whether the fusion of molecular adjuvant C3d to the Env trimers can improve B- cell germinal center (GC) formation and antibody responses. To generate Env-C3d trimers, we performed a glycine-serine- based (G4S) flexible peptide linker screening and identified a linker range that allowed native folding. A 30-60- amino- acid- long linker facilitates Env-to-C3d association and achieves the secretion of well-ordered trimers and the structural integrity and functional integrity of Env and C3d. The fusion of C3d did not dramatically affect the antigenicity of the Env trimers and enhanced the ability of the Env trimers to engage and activate B cells in vitro. In mice, the fusion of C3d enhanced germinal center formation, the magnitude of Env-specific binding antibodies, and the avidity of the antibodies in the presence of an adjuvant. The Sigma Adjuvant System (SAS) did not affect the trimer integrity in vitro but contributed to altered immunogenicity in vivo, resulting in increased tier 1 neutralization, likely by increased exposure of variable region 3 (V3). Taken together, the results indicate that the fusion of the molecular adjuvant, C3d, to the Env trimers improves antibody responses and could be useful for Env-based vaccines against HIV.

The memory of pathogenic IgE is contained within CD23 + IgG1 + memory B cells poised to switch to IgE in food allergy.

Food allergy is caused by allergen-specific IgE antibodies but little is known about the B cell memory of persistent IgE responses. Here we describe in human pediatric peanut allergy CD23 + IgG1 + memory B cells arising in type 2 responses that contain peanut specific clones and generate IgE cells on activation. These 'type2-marked' IgG1 + memory B cells differentially express IL-4/IL-13 regulated genes FCER2 / CD23, IL4R , and germline IGHE and carry highly mutated B cell receptors (BCRs). Further, high affinity memory B cells specific for the main peanut allergen Ara h 2 mapped to the population of 'type2-marked' IgG1 + memory B cells and included convergent BCRs across different individuals. Our findings indicate that CD23 + IgG1 + memory B cells transcribing germline IGHE are a unique memory population containing precursors of pathogenic IgE. One-Sentence Summary: We describe a unique population of IgG + memory B cells poised to switch to IgE that contains high affinity allergen-specific clones in peanut allergy.

Klebsiella invasive liver abscess syndrome presenting with a central nervous system manifestation secondary to latent cholecystitis: a case report.

BACKGROUND: Brain abscess is a life-threatening event. Moreover, when Klebsiella pneumoniae is the cause, rapid diagnosis and appropriate treatment are required. Klebsiella invasive liver abscess syndrome, a bloodstream metastatic infection of potentially aggressive nature, has been recognized to cause infection in the central nervous system, and concern for Klebsiella liver abscess syndrome is increasing globally. CASE PRESENTATION: A 73-year-old Japanese woman was admitted to the institution complaining of aggravated dysarthria and weakness in the right upper extremities with onset 5 days earlier. Magnetic resonance imaging revealed a brain abscess in the left basal ganglia, and abdominal computed tomography revealed a liver abscess in liver segment 7. The patient's dysarthria symptoms became increasingly worse over the next few days, so surgical drainage via frontotemporal craniotomy was performed on admission day 3, and subsequent culture from the brain abscess showed growth of Klebsiella pneumoniae. On admission day 9, percutaneous transhepatic drainage of the liver segment 7 abscess was undertaken. The pus culture also showed growth of Klebsiella pneumoniae, thus associating the liver abscess with the brain abscess. Following long-term conservative treatment with antibiotics and abscess drainage, the liver abscess disappeared. However, the patient continuously presented with right upper quadrant pain, and abdominal computed tomography showed swelling of the gallbladder. Consequently, percutaneous transhepatic gallbladder drainage was initially administered, and the bile culture was also positive for Klebsiella pneumoniae. For radical treatment, a laparoscopic cholecystectomy was performed on admission day 99. The postoperative period was complicated by an intraabdominal abscess; however, conservative therapy was successful. She was subsequently discharged, and 12-month follow-up revealed no further sequelae. CONCLUSIONS: We describe a rare case of Klebsiella liver abscess syndrome, which first presented with a central nervous system manifestation. Our patient was successfully treated via an early surgical intervention and subsequent antibiotic therapy. Although surgical drainage remains the cornerstone treatment for brain abscess, when a brain abscess is found, and there is a high index of suspicion for the existence of a liver abscess, Klebsiella liver abscess syndrome should be considered as a possible diagnosis.

Water-soluble dietary fiber alleviates cancer-induced muscle wasting through changes in gut microenvironment in mice.

Cancer cachexia and the associated skeletal muscle wasting are considered poor prognostic factors, although effective treatment has not yet been established. Recent studies have indicated that the pathogenesis of skeletal muscle loss may involve dysbiosis of the gut microbiota and the accompanying chronic inflammation or altered metabolism. In this study, we evaluated the possible effects of modifying the gut microenvironment with partially hydrolyzed guar gum (PHGG), a soluble dietary fiber, on cancer-related muscle wasting and its mechanism using a colon-26 murine cachexia model. Compared with a fiber-free (FF) diet, PHGG contained fiber-rich (FR) diet-attenuated skeletal muscle loss in cachectic mice by suppressing the elevation of the major muscle-specific ubiquitin ligases Atrogin-1 and MuRF1, as well as the autophagy markers LC3 and Bnip3. Although tight-junction markers were partially reduced in both FR and FF diet-fed cachectic mice, the abundance of Bifidobacterium, Akkermansia, and unclassified S24-7 family increased by FR diet, contributing to the retention of the colonic mucus layer. The reinforcement of the gut barrier function resulted in the controlled entry of pathogens into the host system and reduced circulating levels of lipopolysaccharide-binding protein (LBP) and IL-6, which in turn led to the suppression of proteolysis by downregulating the ubiquitin-proteasome system and autophagy pathway. These results suggest that dietary fiber may have the potential to alleviate skeletal muscle loss in cancer cachexia, providing new insights for developing effective strategies in the future.

The first case of SMARCA4-deficient sarcoma of stomach.

SMARCA4-deficient sarcoma was first reported in the chest and recently in the uterus, but not in the stomach. Here, we present a patient diagnosed with SMARCA4-deficient sarcoma of the stomach, using histochemistry. An emergency operation was performed due to perforation of the tumor. However, one month after the operation, two nodes recurred, and six cycles of combination chemotherapy consisting of adriamycin and ifosfamide were administered. The combination chemotherapy showed a remarkable effect, and complete remission was achieved. The patient was alive without recurrence after 48-month follow-up. SMARCA4-deficient sarcoma is an exceedingly rare tumor with an extremely poor therapeutic response to anticancer drugs. Herein, we present the first case of SMARCA4-deficient sarcoma of the stomach, where a complete response to chemotherapy was achieved.

Treatment with broad-spectrum antibiotics upregulates Sglt1 and induces small intestinal villous hyperplasia in mice.

Although extensive evidence indicates that the gut microbiota plays a crucial role in regulating glucose homeostasis, the exact regulatory mechanism remains unclear. This study aimed to investigate the effect of broad-spectrum antibiotics on the expression of glucose transporters, histomorphology of the small intestine, and glucose metabolism in mice. C57BL/6 mice were administered drinking water with or without a broad-spectrum antibiotic combination for 4 weeks. Thereafter, an oral glucose tolerance test was performed. Body weight, small intestine histopathology, mRNA levels of glucose transporters (SGLT1 and GLUT2) and intestinal transcription factors (CDX1 and CDX2) were evaluated. SGLT1 and CDX1 were upregulated in the small intestine upon antibiotic administration compared with that in the control group. The height and surface area of the jejunal villi were significantly higher upon antibiotic administration than in the control group. Fasting glucose levels were significantly higher upon antibiotic administration than in the control group. The present results indicate that treatment with broad-spectrum antibiotics upregulates SGLT1 and CDX1 and induces hyperplasia in the small intestine, thus increasing fasting blood glucose levels. Our results further the current understanding of the effects of broad-spectrum antibiotics on the gut microbiota and glucose homeostasis that may have future clinical implications.

Methoxy-Functionalized Glycerol-Based Aliphatic Polycarbonate: Organocatalytic Synthesis, Blood Compatibility, and Hydrolytic Property.

Polymers that are biocompatible and degradable are desired for tissue engineering approaches in the treatment of vascular diseases, especially for those involving small-diameter blood vessels. Herein, we report the compatibility of a newly developed glycerol-based aliphatic polycarbonate possessing simple methoxy side groups, named poly(5-methoxy-1,3-dioxan-2-one) (PMDO), with blood cells and plasma proteins as well as its susceptibility to hydrolysis. As a consequence of the organocatalytic ring-opening polymerization (ROP) of a methoxy-functionalized cyclic carbonate derived from glycerol, PMDO with a sufficiently high molecular weight (Mn 14 kg/mol) and a narrow distribution (D̵M 1.12) was obtained for evaluation as a bulk biomaterial. This study demonstrates for the first time the organocatalytic ROP of a glycerol-based cyclic carbonate in a controlled manner. Compared with the clinically applied aliphatic polycarbonate poly(trimethylene carbonate) (PTMC), PMDO inhibits platelet adhesion by 33% and denaturation of fibrinogen by 23%. Although the wettability of PMDO based on water contact angle was almost comparable to those of PTMC and poly(ethylene terephthalate), the reason for the inhibited platelet adhesion and protein denaturation appeared to be related to the presence of specific hydrated water formed in the hydrated polymer. The improved hydration of PMDO also enhanced the susceptibility to hydrolysis, with PMDO demonstrating a slightly higher hydrolytic property than PTMC. This simple glycerol-based aliphatic polycarbonate has the following benefits: bio-based characteristics of glycerol and improved blood compatibility and hydrolytic biodegradability stemming from moderate hydration of the methoxy side groups.

Metformin inhibits TGF­ß1­induced epithelial­mesenchymal transition and liver metastasis of pancreatic cancer cells.

Epithelial­mesenchymal transition (EMT) is considered a crucial event in the development of cancer metastasis. Metformin is a drug used in the treatment of type 2 diabetes. Recently, increasing evidence has indicated that metformin possesses anti­tumor activities. However, the effects of metformin on EMT and metastases in pancreatic cancer remain unknown. Thus, the present study investigated whether metformin inhibits EMT of human pancreatic cancer cell lines. Pancreatic cancer cells were stimulated with transforming growth factor ß1 (TGF­ß1), an activator of EMT signaling, with or without metformin. After 48 h, the levels of epithelial and mesenchymal markers were evaluated by western blot analysis, immunocytochemistry and RT­qPCR. Cancer cell migration was evaluated by an in vitro wound healing assay. The cells stimulated with TGF­ß1 acquired an elongated and fusiform morphology, which was inhibited by metformin. The wound healing assay revealed that metformin significantly suppressed the TGF­ß1­stimulated migration of pancreatic cancer cells. Following treatment with metformin, E­cadherin expression (epithelial marker) was upregulated, and the levels of mesenchymal markers were downregulated, which had been increased by TGF­ß1 in these cells. Exposure of the cells to TGF­ß1 activated the Smad2/3 and Akt/mammalian target of rapamycin (mTOR) pathways, and this effect was inhibited by metformin, suggesting that metformin inhibits TGF­ß1­induced­EMT through the down­regulation of the Smad pathway in PANC­1 cells and the downregulation of the Akt/mTOR pathway in BxPC­3 cells. In an animal model of surgical orthotopic implantation, metformin inhibited liver metastasis without a significant reduction in the size of the primary pancreatic tumor. On the whole, the findings of the present study suggest that metformin inhibits EMT and cancer metastasis through the Smad or Akt/mTOR pathway.

Effects of L-Menthol and Carbon Dioxide on the Adenoma Detection Rate during Colonoscopy: L-Menthol and Carbon Dioxide on Colonoscopy.

BACKGROUND AND AIMS: We examined the efficacy of the combined use of L-menthol spraying (L-mentholS) as an antispasmodic agent and carbon dioxide insufflation (CO2I) on the adenoma detection rate (ADR) in a prospective, single-center trial with a 2 × 2 factorial design. METHODS: We randomly assigned 611 patients scheduled to undergo colonoscopy to 4 groups: (1) the L-mentholS + CO2I (n = 153), (2) L-mentholS + air insufflation (AI; n = 156), (3) CO2I (n = 153), and (4) AI (n = 149) groups. We used 20 mL of 0.8%-L-menthol solution for the L-mentholS. The primary outcome was the difference in the ADR, and the secondary outcomes were the differences in colonic peristalsis and abdominal pain. -Results: The ADRs were not different among the groups: 1/2/3/4; 39.9%/43.6%/41.2%/51.0%. CO2I was associated with a significant decrease in the ADR (OR 0.57; 95% CI 0.35- 0.93) with a multiple logistic regression. The interaction between L-mentholS and CO2I was associated with a suppression of the decrease in the ADR. Both L-mentholS and CO2I were associated with a significant decrease in abdominal pain, and L-mentholS was associated with a significant improvement of peristalsis. CONCLUSIONS: The fact that CO2I was associated with significant decreases in the ADR was a problem. The combined use of L-mentholS and CO2I could help to suppress the decrease in the ADR.

Detection and activation of HIV broadly neutralizing antibody precursor B cells using anti-idiotypes.

Many tested vaccines fail to provide protection against disease despite the induction of antibodies that bind the pathogen of interest. In light of this, there is much interest in rationally designed subunit vaccines that direct the antibody response to protective epitopes. Here, we produced a panel of anti-idiotype antibodies able to specifically recognize the inferred germline version of the human immunodeficiency virus 1 (HIV-1) broadly neutralizing antibody b12 (iglb12). We determined the crystal structure of two anti-idiotypes in complex with iglb12 and used these anti-idiotypes to identify rare naive human B cells expressing B cell receptors with similarity to iglb12. Immunization with a multimerized version of this anti-idiotype induced the proliferation of transgenic murine B cells expressing the iglb12 heavy chain in vivo, despite the presence of deletion and anergy within this population. Together, our data indicate that anti-idiotypes are a valuable tool for the study and induction of potentially protective antibodies.

[Long-Term Survival of a Patient with Small Cell Esophageal Carcinoma Who Underwent Multidisciplinary Therapy-ACase Report].

The patient was a 69-year-old woman.Upper gastrointestinal endoscopy showed a protruding tumor in the mid-thoracic esophagus, and biopsy revealed small cell carcinoma in November 2012. Four courses of neoadjuvant chemotherapy comprising CDDP and CPT-11 were administered, and radical resection was performed in March 2013.I n March 2014, chest computed tomography revealed the recurrence of mediastinal lymph nodes; thus, we administered chemoradiotherapy comprising 5- FU and CDDP, and the size of the recurrent tumors decreased.However, in February 2015, positron emission tomographycomputed tomography revealed liver metastases.Therefore, we switched to a new chemotherapy regimen containing CDDP and VP-16.Although the treatment was very effective and the liver metastases significantly decreased in size, it was discontinued after 9 courses owing to neurotoxicity.Next, 7 courses of chemotherapy comprising amrubicin, which is administered for treating small cell lung carcinoma, were administered, which suppressed tumor growth for approximately 8 months.However, the tumor then re-grew.Chemotherapy comprising S-1 was administered; however, the tumor gradually progressed.The patient died 51 months after the initial treatment.

Fulminant type 1 diabetes mellitus associated with Coxsackievirus type B1 infection during pregnancy: a case report.

BACKGROUND: Fulminant type 1 diabetes is characterized by an intrinsic insulin deficiency resulting from the severe destruction of pancreatic ß cells and it rapidly leads to ketoacidosis. However, the association between fulminant type 1 diabetes in pregnancy and specific viral infections has not been reported. CASE PRESENTATION: The patient in this study was a 31-year-old Japanese woman, and at 30 weeks of pregnancy she was admitted with marked fatigue. Fetal bradycardia was noted, and the child was delivered by emergency cesarean section but was stillborn. The maternal blood sugar level was high (427 mg/dL), but the glycated hemoglobin value was 6.2%; therefore, fulminant type 1 diabetes was suspected. Serum antibody testing confirmed a Coxsackievirus B1 infection. The patient in this case had fulminant type 1 diabetes in pregnancy associated with Coxsackievirus B1. CONCLUSION: This case highlights that fulminant type 1 diabetes in pregnancy may be associated with Coxsackievirus B1 infection.

Clinical significance of soluble forms of immune checkpoint molecules in advanced esophageal cancer.

Immune checkpoint molecules are expressed on cancer cells and regulate tumor immunity by binding to ligands on immune cells. Although soluble forms of immune checkpoint molecules have been detected in the blood of patients with some types of tumors, their roles have not been fully elucidated. Soluble PD-L1, PD-1, CD155, LAG3, and CD226 (sPD-L1, sPD-1, sCD155, sLAG3, and sCD226, respectively) were measured in the sera of 47 patients with advanced esophageal cancer and compared with those of 24 control subjects. Pretreatment levels of sPD-1 and sCD155 were significantly higher in the patients with cancer than in the control subjects (P = 0.023, P = 0.001). The sPD-1 levels tended to be higher in the patients with lymph node metastasis, a large tumor diameter, and higher levels of serum SCC antigen (P = 0.150, P = 0.189, and P = 0.078, respectively). However, higher levels of sCD155 were associated with a better response to chemotherapy and favorable overall survival (P = 0.111 and P = 0.068, respectively). After 2 courses of chemotherapy, the levels of sCD155 and sCD226 were significantly increased (P < 0.001 and P = 0.002, respectively). Moreover, the increase in sCD226 during chemotherapy was associated with poor treatment response (P = 0.019). sPD-1 levels are possibly dependent on the tumor aggressiveness of the esophageal cancer. Furthermore, the pretreatment levels of sCD155 and kinetic change of sCD226 after chemotherapy may be used as biomarkers of the treatment response and prognosis in patients with esophageal cancer.

First Case Report of Possible Sarcocystis truncata-induced Food Poisoning in Venison.

Along with the increase in consumption of raw animal meat, the prevalence of food poisoning is increasing. A 67-year-old Japanese man had eaten raw venison 4 hours prior to the beginning of vomiting. Many white cysts were discovered in the venison, with numerous bradyzoites being detected after the cysts were punctured. The presence of the Sarcocystis spp. 18S rRNA gene was detected by polymerase chain reaction, and Sarcocystis truncata was isolated from the venison. Sarcocystis truncata has not previously been identified in sika deer (Cervus nippon) in Japan. This is the first report of possible Sarcocystis truncata-induced food poisoning following consumption of venison.

Skeletal muscle mass as a predictor of the response to neo-adjuvant chemotherapy in locally advanced esophageal cancer.

Undernutrition and sarcopenia are associated with a higher incidence of chemotherapy-related toxicity and a poor prognosis in several kinds of cancer, but the impact of sarcopenia on the outcomes of chemotherapy for esophageal cancer remains unclear. Thus, the purpose of this retrospective study was to investigate whether sarcopenia affects the efficacy and toxicities of chemotherapy for advanced esophageal cancer patients. Data were collected from 31 esophageal cancer patients who underwent neo-adjuvant chemotherapy followed by surgery. Body composition was assessed at the start of chemotherapy by bioelectrical impedance analysis, and outcomes of chemotherapy were compared between sarcopenic and non-sarcopenic groups. Of the 31 patients, sarcopenia was observed in 16 (51.6%). The incidence of toxicities was not different between the two groups. However, as for pathologic response, a good therapeutic effect (Grade 2 or higher) was more common in the non-sarcopenic group than in the sarcopenic group (53.3% vs. 25.0%). Multivariate analysis showed that sarcopenia was an independent predictor of poor pathological response (odds ratio 8.02; P = 0.037). The results of this study suggest the potential utility of sarcopenia assessment in neoadjuvant patient selection strategies.

Thyrotoxicosis and Adrenocortical Hormone Deficiency During Immune-checkpoint Inhibitor Treatment for Malignant Melanoma.

BACKGROUND: Immune-checkpoint inhibitors (ICIs) are novel promising agents for the treatment of malignant tumors. However, critical endocrine immune-related adverse events (irAEs) by ICIs often occur. CASE REPORT: A 63-year-old woman with advanced malignant melanoma had received anti-PD-1 antibody (nivolumab, 2 mg/kg every 3 weeks) for 8 cycles (from day 0 to day 147). On day 168, nivolumab was switched to anti-CTLA-4 antibody (ipilimumab, 3mg/kg every 3 weeks). Twenty-eight days later, she was diagnosed with thyrotoxicosis due to painless thyroiditis (day 196). Thirty-five days later (day 231), thyrotoxicosis turned to hypothyroidism. In addition, twenty-five days later (day 256), she was diagnosed with adrenocortical insufficiency due to adrenocortical hormone (ACTH) deficiency. Hormone replacements with levothyroxine and hydrocortisone were administered. She showed eosinophilia, ESR/CRP/LDH elevation, liver dysfunction and hyponatremia before diagnosis of ACTH insufficiency. Eosinophilia, thrombocytopenia, ESR/CRP/LDH elevation, and liver dysfunction might be important for early detection of thyrotoxicosis in our case. CONCLUSION: The present report provides the first detailed presentation of combined thyrotoxicosis and isolated ACTH deficiency induced by ICIs. Since rapidly progressive fatal endocrine system failure may be provoked during ICI therapy, precise diagnosis and prompt treatment as well as close follow-up is critical. We propose routine monitoring of endocrine functions and related symptoms (worsened fatigue, hypoglycemia, hypotension or hyponatremia), as well as other laboratory tests during ICI therapy.

Precursor Frequency and Affinity Determine B Cell Competitive Fitness in Germinal Centers, Tested with Germline-Targeting HIV Vaccine Immunogens.

How precursor frequencies and antigen affinities impact interclonal B cell competition is a particularly relevant issue for candidate germline-targeting HIV vaccine designs because of the in vivo rarity of naive B cells that recognize broadly neutralizing epitopes. Knowing the frequencies and affinities of HIV-specific VRC01-class naive human B cells, we transferred B cells with germline VRC01 B cell receptors into congenic recipients to elucidate the roles of precursor frequency, antigen affinity, and avidity on B cell responses following immunization. All three factors were interdependently limiting for competitive success of VRC01-class B cells. In physiological high-affinity conditions using a multivalent immunogen, rare VRC01-class B cells successfully competed in germinal centers (GC), underwent extensive somatic hypermutation, and differentiated into memory B cells. The data reveal dominant influences of precursor frequency, affinity, and avidity for interclonal GC competition and indicate that germline-targeting immunogens can overcome these challenges with high-affinity multimeric designs.

Monoether-Tagged Biodegradable Polycarbonate Preventing Platelet Adhesion and Demonstrating Vascular Cell Adhesion: A Promising Material for Resorbable Vascular Grafts and Stents.

We developed a biodegradable polycarbonate that demonstrates antithrombogenicity and vascular cell adhesion via organocatalytic ring-opening polymerization of a trimethylene carbonate (TMC) analogue bearing a methoxy group. The monoether-tagged polycarbonate demonstrates a platelet adhesion property that is 93 and 89% lower than those of poly(ethylene terephthalate) and polyTMC, respectively. In contrast, vascular cell adhesion properties of the polycarbonate are comparable to those controls, indicating a potential for selective cell adhesion properties. This difference in the cell adhesion property is well associated with surface hydration, which affects protein adsorption and denaturation. Fibrinogen is slightly denatured on the monoether-tagged polycarbonate, whereas fibronectin is highly activated to expose the RGD motif for favorable vascular cell adhesion. The surface hydration, mainly induced by the methoxy side chain, also contributes to slowing the enzymatic degradation. Consequently, the polycarbonate exhibits decent blood compatibility, vascular cell adhesion properties, and biodegradability, which is promising for applications in resorbable vascular grafts and stents.