S100A4 exerts robust mucosal adjuvant activity for co-administered antigens in mice

The lack of clinically applicable mucosal adjuvants is a major hurdle in designing effective mucosal vaccines. We hereby report that the calcium-binding protein S100A4, which regulates a wide range of biological functions, is a potent mucosal adjuvant in mice for co-administered antigens, including the SARS-CoV-2 spike protein, with comparable or even superior efficacy as cholera toxin but without causing any adverse reactions. Intranasal immunization with recombinant S100A4 elicited antigen-specific antibody and pulmonary cytotoxic T cell responses, and these responses were remarkably sustained for longer than six months. As a self-protein, S100A4 did not stimulate antibody responses against itself, a quality desired of adjuvants. S100A4 prolonged nasal residence of intranasally delivered antigens and promoted migration of antigen-presenting cells. S100A4-pulsed dendritic cells potently activated cognate T cells. Furthermore, S100A4 induced strong germinal center responses revealed by both microscopy and mass spectrometry, a novel technique for measuring germinal center activity. In conclusion, S100A4 may be a promising adjuvant in formulating mucosal vaccines, including vaccines against pathogens that infect via the respiratory tract, such as SARS-CoV-2.

The Genomic Landscape of Waldenström Macroglobulinemia Reveals Sustained Germinal Center Activity and Late-Developing Copy Number Aberrations

The genomic landscape of Waldenström Macroglobulinemia (WM) is characterized by recurrent somatic mutations in MYD88, with a lower incidence of mutations affecting CXCR4, ARID1A, CD79B and the NFKB signaling pathway (Hunter et. al. Blood 2014). We aimed to characterize the relationship between single base substitutions (SBS), mutational signatures, copy number aberrations (CNA) and structural variants (SV) in WM. We performed whole genome sequencing (WGS) on 14 primary samples from WM patients at various clinical stages, including IgM monoclonal gammopathy (n=1), smoldering (n=5), newly diagnosed (n=7) and relapsed WM (n=1). We identified a median of 2806 clonal SBS per sample (IQR 1870-3079), and 12/14 (85%) samples harbored MYD88 mutations. To investigate which mutational processes are involved in shaping the genomic landscape of WM we performed a mutational signature analysis. Four previously reported SBS signatures were detected: SBS1 and SBS5 (aging), SBS9 (germinal center; GC) and SBS8, with the contribution of age-related signatures SBS1/SBS5 being directly correlated with age at presentation (R 2=0.44, p=0.014). The GC signature SBS9 demonstrated sustained GC activity, as evidenced by the same proportion of mutations attributable to SBS9 at both the clonal and subclonal level (24%). At the immunoglobulin loci, we observed evidence of clustered SBS84 (AID), reflecting somatic hypermutation, with SBS84 accounting for 30% of signature contribution from subclonal mutations. Overall, these data suggest that, similarly to MM and other hematological malignancies, the interaction between WM and the GC is sustained over time. We have previously demonstrated that SV and complex events are critical in the pathogenesis and clinical outcomes of multiple myeloma. In contrast, in this WM WGS cohort, we found a low prevalence of complex SV, with no chromothripsis detected, and a single chromoplexy event found in 3 patients (21%), all of whom had progressed to symptomatic WM. To explore WM CNA features in a larger cohort, we examined the WGS data together with 38 MYD88-mutated WM samples for which targeted sequencing was available (MSK-IMPACT-Heme 400 gene panel). In this combined dataset (n=52), GISTIC analysis identified significantly deleted regions at 6q16.1, 7q34, 17p13.1 (TP53) and 21q22.2, along with significant amplification at 6p22.1 (HLA-A). To better characterize the HLA loci using the loss of heterozygosity in human leukocyte antigen (LOHHLA) tool (McGranahan et. al. Cell 2017) we found the presence of HLA-specific loss of heterozygosity in 1 sample, while 4 samples had HLA CN >2.5 (all from patients who progressed to symptomatic WM). CNA analysis demonstrated that while some samples harbored typical CNA features, others had minimal changes, with MGUS / smoldering WM samples having less CNA compared with those who progressed to symptomatic WM. The 2 MYD88 wild type WGS contained a clonal gain affecting chromosome 12, which is typically an early event in chronic lymphocytic leukemia. Molecular time analysis (the corrected ratio between duplicated and non-duplicated clonal mutations within large chromosomal gains [Maura et al. Nat Comm 2019]) demonstrated that these 2 chromosomal gain events occurred early in cancer development (relative timing <0.5), while multiple other CNA changes occurred later in the disease course (timing >0.5) and tended to be subclonal. This data suggests that, while MYD88-mutations are central to WM clone establishment and can be observed in precursor disease, CNA may contribute to later phases and disease progression. In summary, WGS in WM allows the demonstration that germinal center activity is sustained over time. CNA in WM are not random in distribution, with specific loci being significantly amplified or deleted, and a potential role for HLA CNA. In contrast to MYD88 mutations, which are carried by stable precursor patients, the subclonal status and late molecular time of most CNA changes suggest a late role in cancer progression. Disclosures Kastritis: Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Diamond: Sanofi: Honoraria; Medscape: Honoraria. Kazandjian: Arcellx: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Papaemmanuil: Isabl Technologies: Divested equity in a private or publicly-traded company in the past 24 months; Kyowa Hakko Kirin Pharma: Consultancy. Dogan: Roche: Consultancy, Research Funding; Seattle Genetics: Consultancy; EUSA Pharma: Consultancy; Peer View: Honoraria; Takeda: Consultancy, Research Funding; Physicians' Education Resource: Honoraria. Lesokhin: Trillium Therapeutics: Consultancy; Serametrix, Inc: Patents & Royalties; Genetech: Research Funding; Iteos: Consultancy; bristol myers squibb: Research Funding; Behringer Ingelheim: Honoraria; pfizer: Consultancy, Research Funding; Janssen: Honoraria, Research Funding. Landgren: Janssen: Other: IDMC; Janssen: Honoraria; Celgene: Research Funding; Amgen: Honoraria; Janssen: Research Funding; Amgen: Research Funding; Takeda: Other: IDMC; GSK: Honoraria. Palomba: Rheos: Honoraria; Pluto: Honoraria; Lygenesis: Honoraria; Ceramedix: Honoraria; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Nektar: Honoraria; PCYC: Consultancy; Wolters Kluwer: Patents & Royalties; Notch: Honoraria, Other: Stock; Priothera: Honoraria; Kite: Consultancy; Novartis: Consultancy; Magenta: Honoraria; WindMIL: Honoraria; BeiGene: Consultancy; Juno: Patents & Royalties. Maura: OncLive: Honoraria; Medscape: Consultancy, Honoraria. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; BeiGene: Honoraria.

Movement Patterns of Commuterline Users in the Medan City Train Station Area Based on Transit

At the time of this research, Medan City was threatened with the gridlock, a situation where the number of vehicles exceeds the available road capacity. To prevent the gridlock happens, Medan Train Station (Medan ts.) area as the center activity of Medan City, will be developed into an area based on the Transit-Oriented Development (TOD) concept by adding Light Rail Transit (LRT) and Bus Rapid Transit (BRT). The addition is hoped to encourage walking and public transportation usage for visitors in Medan ts. area. This study aims to determine and mapping the movement patterns of commuterline users, in this case Medan – Binjai line which is the only line available, as the basis for the application of the concept of TOD in the Medan ts. area. The research uses observation and interview as the methods. The results of the study showed that the majority of commuterline users of the Medan ts. relied on paratransit when heading or leaving the station than walking. This can be seen from 70% of users (weekday) and 83.3% of users (weekends) using paratransit when heading to the station and 86.6% of users (weekday) and 66.6% of users (weekends) using paratransit when leaving the station.

Germinal center activity and B cell maturation promote protective antibody responses against Plasmodium pre-erythrocytic infection

Blocking Plasmodium, the causative agent of malaria, at the asymptomatic pre-erythrocytic stage would abrogate disease pathology and prevent transmission. Rodent-infectious species of Plasmodium such as P. yoelii (Py) serve as key tools to study vaccine efficacy and disease biology in immune-competent experimental animals. Here we evaluated the differences in vaccine-elicited humoral immunity in two widely used, and vastly diverged, inbred mouse strains, BALB/cJ and C57BL/6J, and identified immunological factors associated with protection. We vaccinated with Py circumsporozoite protein (CSP), the major surface antigen on the sporozoite, and evaluated protective efficacy after mosquito bite challenge. Vaccination achieved 60% sterile protection and otherwise delayed blood stage patency in BALB/cJ mice, whereas; all C57BL/6J mice were infected similar to controls. Interestingly, protection was mediated by antibodies, and could be passively transferred from immunized BALB/cJ mice into naïve C57BL/6J. Dissection of the underlying immunological features of protection revealed early deficits in antibody titers and polyclonal avidity in C57BL/6J mice. Additionally, PyCSP-vaccination in BALB/cJ induced a significantly higher proportion of antigen-specific B-cells and class-switched memory B-cell (MBCs) populations than in C57BL/6J mice. Strikingly, C57BL/6J mice also had markedly fewer germinal center experienced, CSP-specific class-switched MBCs compared to BALB/cJ mice. Analysis of the IgG γ chain repertoires by next generation sequencing in PyCSP-specific memory B-cell repertoires also revealed higher somatic hypermutation rates in BALB/cJ mice than in C57BL/6J mice. These findings indicate that BALB/cJ mice achieved higher levels of B cell maturation in response to vaccination with PyCSP, which likely enabled the development of protective antibody responses. Overall, our study indicates that germinal center activity and B cell maturation are key processes in the development of vaccine-elicited protective antibodies against CSP.

Uterine Sensitization-Associated Gene-1 in the Progression of Kidney Diseases

Uterine sensitization-associated gene-1 (USAG-1), originally identified as a secretory protein preferentially expressed in the sensitized rat endometrium, has been determined to modulate bone morphogenetic protein (BMP) and Wnt expression to play important roles in kidney disease. USAG-1 affects the progression of acute and chronic kidney damage and the recovery of allograft kidney function by regulating the BMP and Wnt signaling pathways. Moreover, USAG-1 has been found to be involved in the process of T cell immune response, and its ability to inhibit germinal center activity and reduce humoral immunity is of great significance for the treatment of autoimmune nephropathy and antibody-mediated rejection (AMR) after renal transplantation. This article summarizes the many advances made regarding the roles of USAG-1 in the progression of kidney disease and outlines potential treatments.

Edukasi Strategi Koping Sebagai Upaya Dalam Menurunkan Tingkat Stres Pada Siswa Smkn 4 Garut Selama Pandemi Covid-19

ABSTRAK Menanggapi bahayanya virus Covid-19, pemerintah Indonesia mengeluarkan beberapan peraturan mengenai protokol kesehatan, salah satunya ialah protokol mennjaga jarak atau social distancing yang kemudian ditindaklanjuti dengan kebijakan PSBB yang justru menyebabkan terganggunya kesehatan mental, terutama pada remaja sekolah yang diisukan mengalami stress dengan adanya sistem PJJ. Pada penkes ini kami memberikan edukasi pada siswa/i SMKN 4 Garut mengenai pengelolaan stres dengan strategi koping. Ruang lingkup dalam kegiatan Penkes ini ialah siswa dan siswi SMKN 4 Garut. Tujuan: Kegiatan penkes ini bertujuan untuk meningkatkan pengetahuan siswa dan siswi SMKN 4 Garut dalam melakukan pengelolaan stress dengan strategi koping selama masa pandemi covid-19. Metode: Kegiatan penkes ini mengintegrasikan konsep teori HBM. Penkes ini menggunakan metode lecture atau ceramah dengan menggunakan media powerpoint yang dilaksanakan secara daring menggunakan platform Zoom Meeting. Hasil yang ditemukan dari kegiatan penkes ini ialah persentase pengetahuan peserta mengenai stress dan strategi koping meningkat setelah diberikan materi yang dapat dilihat dari hasil post test sebagian besar peserta penkes. Simpulan yang dapat diambil dari kegiatan penkes ini ialah, terdapat peningkatan pengetahuan pada siswa dan siswi SMKN 4 Garut mengenai stress dan pengelolaan stress dengan strategi koping, setelah peserta diberikan pretest sebelum pemberian materi dan diberikan post test setelah pemberian materi. Kata Kunci: Health Belief Model, Pandemi Covid-19, Strategi koping, Stres ABSTRACT Responding to the dangers of the Covid-19 virus, the Indonesian government issued several regulations regarding health protocols, one of which is the social distancing protocol which is then followed up with the PSBB policy which actually causes mental health disruption, especially for school teenagers who are rumored to be experiencing stress with the PJJ system. . At this health center we provide education to students of SMKN 4 Garut about stress management with coping strategies. The scope of this Penkes activity is students and students of SMKN 4 Garut. Purpose: This Health Center activity aims to increase the knowledge of students and students of SMKN 4 Garut in managing stress with coping strategies during the Covid-19 pandemic. Methods: This health center activity integrates the HBM theory concept. This Health Center uses the lecture method or lectures using powerpoint media which are held online using the Zoom Meeting platform. The results found from this Health Center activity were that the percentage of participants' knowledge about stress and coping strategies increased after being given the material which can be seen from the post test results of most of the Health Center participants. The conclusions that can be taken from this Health Center activity are, there is an increase in knowledge of students of SMKN 4 Garut about stress and stress management with coping strategies, after participants are given a pretest before giving material and given a post test after giving the material. Keywords: Health Belief Model, Covid-19 Pandemic, Coping Strategy, Stress

Osteochondrosis of Primary Center of Patella: A Case Report

Introduction: Osteochondrosis of the primary ossification center of the patella (Kohler’s Disease) is a rare and self-limiting condition of unknown etiology. Sometimes it may be found as normal variant. Case Report: A 7-year-old boy presented with anterior right knee pain. On radiological examination, there was increased density, irregularity, and fragmentation of the patellar primary ossification center. Activity modification and exercise led to marked symptomatic improvement after 1 year. Conclusion: It was concluded that the disease either physiological or pathological, diagnosis is usually difficult. However, the treatment is simple. There was improvement functionally as well as radiologically with activity modification. Keywords: Osteochondrosis, primary center, patella.

Evaluation and Transplantation of a SARS-CoV-2 Seropositive Kidney Candidate

The COVID-19 pandemic affected transplant center activity in areas with high number of cases such as New York City and prompted reevaluation of patients awaiting organ transplant diagnosed with SARS-CoV-2 infection. To resume safe transplantation at our center, we found it necessary to (1) identify transplant candidates with possible exposure to or history of COVID-19 infection, (2) outline a clinical and laboratory assessment to determine adequate clinical recovery from COVID-19 for transplantation, and (3) determine whether the possibility of perioperative COVID-19 transmission from the patient to staff would pose unacceptable risk. Here, we describe our center’s approach to proceeding with transplantation in a SARS-CoV-2 seropositive living donor kidney transplant recipient and describe early posttransplant outcomes.

Vasculature-Associated Lymphoid Tissue: A Unique Tertiary Lymphoid Tissue Correlates With Renal Lesions in Lupus Nephritis Mouse Model

Lupus nephritis (LN) is a common complication in young patients and the most predominant cause of glomerulonephritis. Infiltrating immune cells and presence of immunocomplexes in the kidney are hallmarks of LN, which is closely associated with renal lesions (RLs). However, their regulatory mechanism in the kidney remains unclear, which is valuable for prevention of RL development. Here, we show the development of vasculature-associated lymphoid tissue (VALT) in LN, which is related to renal inflammatory cytokines, indicating that VALT is a unique tertiary lymphoid tissue. Transcriptomic analysis revealed different chemokines and costimulatory molecules for VALT induction and organization. Vascular and perivascular structures showed lymphoid tissue organization through lymphorganogenic chemokine production. Transcriptional profile and intracellular interaction also demonstrated antigen presentation, lymphocyte activity, clonal expansion, follicular, and germinal center activity in VALT. Importantly, VALT size was correlated with infiltrating immune cells in kidney and RLs, indicating its direct correlation with the development of RLs. In addition, dexamethasone administration reduced VALT size. Therefore, inhibition of VALT formation would be a novel therapeutic strategy against LN.