bluuebunny/crossref_metadata_2025 huggingface dataset:
A New Method Based on the von Mises-Fisher Distribution Shows that a Minority of Liver-Localized CD8 T Cells Display Hard-To-Detect Attraction to Plasmodium-Infected Hepatocytes
Authors: Zenkov Viktor S. , O’Connor James H. , Cockburn Ian A. , Ganusov Vitaly V.
Published: January 2022

Malaria is a disease caused byPlasmodiumparasites, resulting in over 200 million infections and 400,000 deaths every year. A critical step of malaria infection is when sporozoites, injected by mosquitoes, travel to the liver and form liver stages. Malaria vaccine candidates which induce large numbers of malaria-specific CD8 T cells in mice are able to eliminate all liver stages, preventing fulminant malaria. However, how CD8 T cells find all parasites in 48 h of the liver stage lifespan is not well understood. Using intravital microscopy of murine livers, we generated unique data on T cell search for malaria liver stages within a few hours after infection. To detect attraction of T cells to an infection site, we used the von Mises-Fisher distribution in 3D, similar to the 2D von Mises distribution previously used in ecology. Our results suggest that the vast majority (70–95%) of malaria-specific and non-specific liver-localized CD8 T cells did not display attraction towards the infection site, suggesting that the search for malaria liver stages occurs randomly. However, a small fraction (15–20%) displayed weak but detectable attraction towards parasites which already had been surrounded by several T cells. We found that speeds and turning angles correlated with attraction, suggesting that understanding mechanisms that determine the speed of T cell movement in the liver may improve the efficacy of future T cell-based vaccines. Stochastic simulations suggest that a small movement bias towards the parasite dramatically reduces the number of CD8 T cells needed to eliminate all malaria liver stages, but to detect such attraction by individual cells requires data from long imaging experiments which are not currently feasible. Importantly, as far as we know this is the first demonstration of how activated/memory CD8 T cells might search for the pathogen in nonlymphoid tissues a few hours after infection. We have also established a framework for how attraction of individual T cells towards a location in 3D can be rigorously evaluated.
Role of SVEP1 in Stroma-Dependent Hematopoiesis In vitro
Authors: Tran Vinson , O’Neill Helen C.
Published: January 2022

Study of the microenvironment that supports hematopoietic stem cell (HSC) development in vivo is very difficult involving small numbers of interacting cells which are usually not well defined. While much is known about HSC niches located within the bone marrow in terms of contributing cell types and signalling molecules, very little is known about equivalent niches within spleen. Extramedullary hematopoiesis in spleen contributes myeloid cells important in the mobilisation of an immune response. As a result, it is important to develop in vitro models to identify the cells which constitute HSC niches in spleen and to identify the regulatory molecules supporting myeloid cell development. Studies described here document a model system to study the maintenance and differentiation of HSC by splenic stromal cells in vitro. The splenic stromal lines 5G3 and 3B5 differ in hematopoietic support capacity. SVEP1 and IGF2 are molecules of interest specifically expressed by 5G3 stroma. Gene knockdown technology using shRNA plasmids has been used to reduce gene expression in 5G3 and to determine specific effects on myeloid cell development following co-culture with overlaid hematopoietic progenitors in vitro. Knockdown of Svep1 gave specific inhibition of a dendritic cell (DC) population described previously in spleen (L-DC). Knockdown of Igf2 resulted in loss of production of a minor subset of conventional (c) DC. SVEP1 is now considered a marker of mesenchymal stromal cells with osteogenic differentiative capacity reflective of perivascular stromal cells. The power of this in vitro model is evidenced by the fact that it has been used to define SVEP1 as a specific adhesion molecule that regulates the hematopoietic process dependent on stromal niche interaction. The identification of stromal cells and molecules that contribute to the hematopoietic process in spleen, brings us closer to the realm of therapeutically regulating hematopoiesis in vivo, and to inhibiting niches which support cancer stem cells.
A Ferroptosis-Related Gene Prognostic Index to Predict Temozolomide Sensitivity and Immune Checkpoint Inhibitor Response for Glioma
Authors: Cai Yonghua , Liang Xianqiu , Zhan Zhengming , Zeng Yu , Lin Jie , Xu Anqi , Xue Shuaishuai , Xu Wei , Chai Peng , Mao Yangqi , Song Zibin , Han Lei , Xiao Jianqi , Song Ye , Zhang Xian
Published: January 2022

Background: Gliomas are highly lethal brain tumors. Despite multimodality therapy with surgery, radiotherapy, chemotherapy, and immunotherapy, glioma prognosis remains poor. Ferroptosis is a crucial tumor suppressor mechanism that has been proven to be effective in anticancer therapy. However, the implications of ferroptosis on the clinical prognosis, chemotherapy, and immune checkpoint inhibitor (ICI) therapy for patients with glioma still need elucidation.

Methods: Consensus clustering revealed two distinct ferroptosis-related subtypes based on the Cancer Genome Atlas (TCGA) glioma dataset (n = 663). Subsequently, the ferroptosis-related gene prognostic index (FRGPI) was constructed by weighted gene co-expression network analysis (WGCNA) and “stepAIC” algorithms and validated with the Chinese Glioma Genome Atlas (CGGA) dataset (n = 404). Subsequently, the correlation among clinical, molecular, and immune features and FRGPI was analyzed. Next, the temozolomide sensitivity and ICI response for glioma were predicted using the “pRRophetic” and “TIDE” algorithms, respectively. Finally, candidate small molecular drugs were defined using the connectivity map database based on FRGPI.

Results: The FRGPI was established based on the HMOX1, TFRC, JUN, and SOCS1 genes. The distribution of FRGPI varied significantly among the different ferroptosis-related subtypes. Patients with high FRGPI had a worse overall prognosis than patients with low FRGPI, consistent with the results in the CGGA dataset. The final results showed that high FRGPI was characterized by more aggressive phenotypes, high PD-L1 expression, high tumor mutational burden score, and enhanced temozolomide sensitivity; low FRGPI was associated with less aggressive phenotypes, high microsatellite instability score, and stronger response to immune checkpoint blockade. In addition, the infiltration of memory resting CD4+ T cells, regulatory T cells, M1 macrophages, M2 macrophages, and neutrophils was positively correlated with FRGPI. In contrast, plasma B cells and naïve CD4+ T cells were negatively correlated. A total of 15 potential small molecule compounds (such as depactin, physostigmine, and phenacetin) were identified.

Conclusion: FRGPI is a promising gene panel for predicting the prognosis, immune characteristics, temozolomide sensitivity, and ICI response in patients with glioma.
STEP-UP: Enabling Low-Cost IMU Sensors to Predict the Type of Dementia During Everyday Stair Climbing
Authors: Holloway Catherine , Bhot William , Yong Keir X. X. , McCarthy Ian , Suzuki Tatsuto , Carton Amelia , Yang Biao , Serougne Robin , Boampong Derrick , Tyler Nick , Crutch Sebastian J. , Berthouze Nadia , Cho Youngjun
Published: January 2022

Posterior Cortical Atrophy is a rare but significant form of dementia which affects people's visual ability before their memory. This is often misdiagnosed as an eyesight rather than brain sight problem. This paper aims to address the frequent, initial misdiagnosis of this disease as a vision problem through the use of an intelligent, cost-effective, wearable system, alongside diagnosis of the more typical Alzheimer's Disease. We propose low-level features constructed from the IMU data gathered from 35 participants, while they performed a stair climbing and descending task in a real-world simulated environment. We demonstrate that with these features the machine learning models predict dementia with 87.02% accuracy. Furthermore, we investigate how system parameters, such as number of sensors, affect the prediction accuracy. This lays the groundwork for a simple clinical test to enable detection of dementia which can be carried out in the wild.
Association Between Trypanosoma cruzi DNA in Peripheral Blood and Chronic Chagasic Cardiomyopathy: A Systematic Review
Authors: Bosch-Nicolau Pau , Espinosa-Pereiro Juan , Salvador Fernando , Sánchez-Montalvá Adrián , Molina Israel
Published: January 2022

Chronic chagasic cardiomyopathy (CCC) is the most important complication of patients with Chagas disease (CD). The role of persistent detection of DNA in peripheral blood and its association to CCC is unknown. We performed a systematic review up to July 2021, including studies that reported ratios of CCC and PCR positivity among non-treated adult patients. We identified 749 records and selected 12 for inclusion corresponding to 1,686 patients. Eight studies were performed in endemic countries and 4 in non-endemic countries. Only two studies showed an association between CCC and Trypanosoma cruzi parasitemia by means of PCR detection. Six studies reported greater positive PCR ratios among patients with CCC than in the patients with indeterminate chagas disease (ICD) with no statistical significance. A significant risk of bias has been detected among most of the studies. Therefore, while we performed a meta-analysis, wide inter-study heterogeneity impeded its interpretation.

Conclusions

With the available information, we could not establish a correlation between PCR-detectable parasitemia and CCC.

Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020216072, identifier: CRD42020216072.
Study of Water Huff-n-Puff in Low-Permeability Oil Reservoirs With Horizontal Fractures: A Case Study of Chang 6 Reservoir in Yanchang, China
Authors: Meng Xuangang , Hang Song , Zhang Heng , Gao Feilong , Gao Yong , Li Xiangfang
Published: January 2022

Water huff-n-puff is an effective technology to enhance oil recovery (EOR) of low-permeability reservoirs, which are usually developed with hydraulic fracturing. Fluid exchange between fractures and the matrix is the main EOR mechanism. However, the presented water huff-n-puff simulations usually assume vertical fracture morphology, while the horizontal fractures formed in shallow reservoirs are rarely reported. In this study, we first introduced the water huff-n-puff process in a low-permeability oil reservoir with horizontal fractures and described the multiphase flow characteristics during the huff, soak, and puff stages. Then combined with a series of experiments, a comprehensive method is used to determine the key flow parameters, that is, capillary pressure and relative permeability. Finally, using the Chang 6 reservoir as an example, a series of numerical simulations were conducted to demonstrate the effect of water huff-n-puff on the well performance in this field. The simulation results showed that oil production is mainly affected by the injection volume and injection rate, while water production mainly depends on the well shut-in time. For a typical well in this field, the optimal injection volume, injection rate, and well shut-in time are 300 m3, 10 m3/d, and 30 days, respectively. In addition, our results showed that increasing the number of cycles not only benefits fluid exchange but also enhances the formation pressure. Both of them can accelerate the development of low-permeability oil reservoirs.
Validation of Controlled Attenuation Parameter Measured by FibroScan as a Novel Surrogate Marker for the Evaluation of Metabolic Derangement
Authors: Huang Zhimin , Ng Kaka , Chen Hongyan , Deng Wanping , Li Yanbing
Published: January 2022

Background/Objectives

Renaming non-alcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MAFLD) suggests a shift of emphasis to the accompanying metabolic disturbance. Controlled attenuation parameter (CAP) measured by FibroScan has been shown to be correlated with hepatic steatosis. We aim to validate its usefulness as a novel surrogate marker for evaluating metabolic derangement.

Subjects/Methods

Volunteers were recruited from medical staff at our hospital to undergo CAP measurements. Anthropometrics, CAP, and laboratory assessments for metabolic profiles and insulin resistance were collected. CAP < 238 dB/m denoted no hepatic steatosis, 238 ≤ CAP ≤ 259 dB/m denoted mild, 260 ≤ CAP ≤ 291 dB/m denoted moderate, and CAP > 291 dB/m denoted severe hepatic steatosis according to previous reports.

Results

Data of 824 participants were included for analysis. The age was 53.2 ± 15.4 years, body mass index (BMI) was 23.6 ± 3.1 kg/m2, 24.4% were male subjects, and 22.0% met the criteria for metabolic syndrome (MetS). Taking the group with CAP < 238 dB/m as control, subjects with mild, moderate, and severe hepatic steatosis had increased odds of MetS by 3.51-, 3.32-, and 5.12-fold, respectively, after adjusting for multiple confounders (p = 0.020). Metabolic profiles, insulin resistance, and presence of MetS were similar between normal-weight subjects with CAP ≥ 238 dB/m and overweight subjects with CAP < 238 dB/m. Even in subjects with no MetS components, those with CAP ≥ 238 dB/m had higher BMI, waist circumferences, uric acid, triglyceride, white blood cell count, and insulin resistance, whereas lower adiponectin and estimated glomerular filtration rate. Waist circumference [OR 1.11 (1.04, 1.18), p = 0.001] and homeostatic model assessment of insulin resistance (HOMA-IR) [OR 2.39 (1.18, 4.83), p = 0.016] were predictive of hepatic steatosis according to CAP ≥ 238 dB/m.

Conclusions

CAP is a convenient, sensitive, and non-invasive indicator for metabolic derangement. Prospective studies are needed to further validate its usefulness as a surrogate marker for the transition of metabolic status over time.
Denosumab for the Treatment of Hypercalcemia in a Patient With Parathyroid Carcinoma: A Case Report
Authors: Roukain Abdallah , Alwan Heba , Bongiovanni Massimo , Sykiotis Gerasimos P. , Kopp Peter A.
Published: January 2022

Background

Refractory hypercalcemia is one of the major complications of parathyroid carcinoma.

Case report

An 84-year old female patient presented with an acute confusional state due to hypercalcemia. This led to the diagnosis of primary hyperparathyroidism for which she underwent surgery. The initial histological diagnosis was interpreted as atypical parathyroid adenoma; the resection was microscopically incomplete. One year later, the patient presented with elevated calcium levels up to 3.89 mmol/l. Recurrent severe hypercalcemia required multiple hospitalizations. Review of the histology slides revealed that the initially resected lesion was in fact a parathyroid carcinoma. Treatment with the calcimimetic drug cinacalcet was poorly tolerated. Repeated administration of zoledronic acid only had transient effects on calcium levels, and bisphosphonate treatment was ultimately discontinued because of chronic renal failure. The patient then received denosumab (60 or 120 mg) when needed (nine doses over twenty months), the last dose in November 2020, which led to a reduction and control of here calcium levels. Currently, at three years after initial surgery, calcium levels are stable between 2.7-2.8 mmol/l and the patient has not required hospitalization for hypercalcemia for 10 months.

Discussion

In case of parathyroid carcinoma, en-bloc resection is the first treatment. Denosumab has proven its efficiency in treating hypercalcemia in malignancy. Several case reports studied denosumab in hypercalcemia due to parathyroid carcinoma, and the treatment were efficient to decrease levels of calcium when repeated as needed or monthly. We report another case of refractory hypercalcemia treated with several doses of denosumab in a patient with parathyroid carcinoma.
A Data-Driven Genetic Algorithm for Power Flow Optimization in the Power System With Phase Shifting Transformer
Authors: Li Zuohong , Li Feng , Liu Ruoping , Yu Mengze , Chen Zhiying , Xie Zihao , Du Zhaobin
Published: January 2022

Phase-shifting transformer (PST) is one of the flexible AC transmission technologies to solve the problem of uneven power transmission. Considering that PST can also be used as a regulation means for the economic operation of the system, it is necessary to study the power flow optimization of power systems with PST. In order to find a more efficient power flow optimization method, an improved genetic algorithm including a data-driven module is proposed. This method uses the deep belief network (DBN) to train the sample set of the power flow and obtains a high-precision proxy model. Then, the calculation of the DBN model replaces the traditional adaptation function calculation link which is very time-consuming due to a great quantity of AC power flow solution work. In addition, the sectional power flow reversal elimination mechanism in the genetic algorithm is introduced and appropriately co-designed with DBN to avoid an unreasonable power flow distribution of the grid section with PST. Finally, by comparing with the traditional model-driven genetic algorithm and traditional mathematical programming method, the feasibility and the validity of the method proposed in this paper are verified on the IEEE 39-node system.
Hypoxia Induced Sex-Difference in Zebrafish Brain Proteome Profile Reveals the Crucial Role of H3K9me3 in Recovery From Acute Hypoxia
Authors: Das Tapatee , Kamle Avijeet , Kumar Arvind , Chakravarty Sumana
Published: January 2022

Understanding the molecular basis of sex differences in neural response to acute hypoxic insult has profound implications for the effective prevention and treatment of ischemic stroke. Global hypoxic-ischemic induced neural damage has been studied recently under well-controlled, non-invasive, reproducible conditions using a zebrafish model. Our earlier report on sex difference in global acute hypoxia-induced neural damage and recovery in zebrafish prompted us to conduct a comprehensive study on the mechanisms underlying the recovery. An omics approach for studying quantitative changes in brain proteome upon hypoxia insult following recovery was undertaken using iTRAQ-based LC-MS/MS approach. The results shed light on the altered expression of many regulatory proteins in the zebrafish brain upon acute hypoxia following recovery. The sex difference in differentially expressed proteins along with the proteins expressed in a uniform direction in both the sexes was studied. Core expression analysis by Ingenuity Pathway Analysis (IPA) showed a distinct sex difference in the disease function heatmap. Most of the upstream regulators obtained through IPA were validated at the transcriptional level. Translational upregulation of H3K9me3 in males led us to elucidate the mechanism of recovery by confirming transcriptional targets through ChIP-qPCR. The upregulation of H3K9me3 level in males at 4 h post-hypoxia appears to affect the early neurogenic markers nestin, klf4, and sox2, which might explain the late recovery in males, compared to females. Acute hypoxia-induced sex-specific comparison of brain proteome led us to reveal many differentially expressed proteins, which can be further studied for the development of novel targets for better therapeutic strategy.
Multi-Trait Multi-Environment Genomic Prediction for End-Use Quality Traits in Winter Wheat
Authors: Sandhu Karansher S. , Patil Shruti Sunil , Aoun Meriem , Carter Arron H.
Published: January 2022

Soft white wheat is a wheat class used in foreign and domestic markets to make various end products requiring specific quality attributes. Due to associated cost, time, and amount of seed needed, phenotyping for the end-use quality trait is delayed until later generations. Previously, we explored the potential of using genomic selection (GS) for selecting superior genotypes earlier in the breeding program. Breeders typically measure multiple traits across various locations, and it opens up the avenue for exploring multi-trait–based GS models. This study’s main objective was to explore the potential of using multi-trait GS models for predicting seven different end-use quality traits using cross-validation, independent prediction, and across-location predictions in a wheat breeding program. The population used consisted of 666 soft white wheat genotypes planted for 5 years at two locations in Washington, United States. We optimized and compared the performances of four uni-trait– and multi-trait–based GS models, namely, Bayes B, genomic best linear unbiased prediction (GBLUP), multilayer perceptron (MLP), and random forests. The prediction accuracies for multi-trait GS models were 5.5 and 7.9% superior to uni-trait models for the within-environment and across-location predictions. Multi-trait machine and deep learning models performed superior to GBLUP and Bayes B for across-location predictions, but their advantages diminished when the genotype by environment component was included in the model. The highest improvement in prediction accuracy, that is, 35% was obtained for flour protein content with the multi-trait MLP model. This study showed the potential of using multi-trait–based GS models to enhance prediction accuracy by using information from previously phenotyped traits. It would assist in speeding up the breeding cycle time in a cost-friendly manner.
GPR174 mRNA Acts as a Novel Prognostic Biomarker for Patients With Sepsis via Regulating the Inflammatory Response
Authors: Wang Jianli , Hu Yanyan , Kuang Zhongshu , Chen Yao , Xing Lingyu , Wei Wei , Xue Mingming , Mu Sucheng , Tong Chaoyang , Yang Yilin , Song Zhenju
Published: January 2022

Previous studies indicated that G-protein coupled receptor 174 (GPR174) is involved in the dysregulated immune response of sepsis, however, the clinical value and effects of GPR174 in septic patients are still unknown. This study is aimed to evaluate the potential value of GPR174 as a prognostic biomarker for sepsis and explore the pathological function of GPR174 in cecal ligation and puncture (CLP)-induced septic mice. In this prospective longitudinal study, the expressions of peripheral GPR174 mRNA were measured in 101 septic patients, 104 non-septic ICU controls, and 46 healthy volunteers at Day 1, 7 after ICU (Intensive Care Unit) admission, respectively. Then, the clinical values of GPR174 for the diagnosis, severity assessment, and prognosis of sepsis were analyzed. Moreover, the expressions of GPR174 mRNA in CLP-induced septic mice were detected, and Gpr174-knockout (KO) mice were used to explore its effects on inflammation. The results showed that the levels of GPR174 mRNA were significantly decreased in septic patients compared with non-septic ICU and healthy controls. In addition, the expressions of GPR174 mRNA were correlated with the lymphocyte (Lym) counts, C-reactive protein (CRP), and APACHE II and SOFA scores. The levels of GPR174 mRNA at Day 7 had a high AUC in predicting the death of sepsis (0.83). Further, we divided the septic patients into the higher and lower GPR174 mRNA expression groups by the ROC cut-off point, and the lower group was significantly associated with poor survival rate (P = 0.00139). Similarly, the expressions of peripheral Gpr174 mRNA in CLP-induced septic mice were also significantly decreased, and recovered after 72 h. Intriguingly, Gpr174-deficient could successfully improve the outcome with less multi-organ damage, which was mainly due to an increased level of IL-10, and decreased levels of IL-1β and TNF-α. Further, RNA-seq showed that Gpr174 deficiency significantly induced a phenotypic shift toward multiple immune response pathways in septic mice. In summary, our results indicated that the expressions of GPR174 mRNA were associated with the severity of sepsis, suggesting that GPR174 could be a potential prognosis biomarker for sepsis. In addition, GPR174 plays an important role in the development of sepsis by regulating the inflammatory response.
Gut Microbiota Composition Is Related to AD Pathology
Authors: Verhaar Barbara J. H. , Hendriksen Heleen M. A. , de Leeuw Francisca A. , Doorduijn Astrid S. , van Leeuwenstijn Mardou , Teunissen Charlotte E. , Barkhof Frederik , Scheltens Philip , Kraaij Robert , van Duijn Cornelia M. , Nieuwdorp Max , Muller Majon , van der Flier Wiesje M.
Published: January 2022

Introduction

Several studies have reported alterations in gut microbiota composition of Alzheimer’s disease (AD) patients. However, the observed differences are not consistent across studies. We aimed to investigate associations between gut microbiota composition and AD biomarkers using machine learning models in patients with AD dementia, mild cognitive impairment (MCI) and subjective cognitive decline (SCD).

Materials and Methods

We included 170 patients from the Amsterdam Dementia Cohort, comprising 33 with AD dementia (66 ± 8 years, 46%F, mini-mental state examination (MMSE) 21[19-24]), 21 with MCI (64 ± 8 years, 43%F, MMSE 27[25-29]) and 116 with SCD (62 ± 8 years, 44%F, MMSE 29[28-30]). Fecal samples were collected and gut microbiome composition was determined using 16S rRNA sequencing. Biomarkers of AD included cerebrospinal fluid (CSF) amyloid-beta 1-42 (amyloid) and phosphorylated tau (p-tau), and MRI visual scores (medial temporal atrophy, global cortical atrophy, white matter hyperintensities). Associations between gut microbiota composition and dichotomized AD biomarkers were assessed with machine learning classification models. The two models with the highest area under the curve (AUC) were selected for logistic regression, to assess associations between the 20 best predicting microbes and the outcome measures from these machine learning models while adjusting for age, sex, BMI, diabetes, medication use, and MMSE.

Results

The machine learning prediction for amyloid and p-tau from microbiota composition performed best with AUCs of 0.64 and 0.63. Highest ranked microbes included several short chain fatty acid (SCFA)-producing species. Higher abundance of [Clostridium] leptum and lower abundance of [Eubacterium] ventriosum group spp., Lachnospiraceae spp., Marvinbryantia spp., Monoglobus spp., [Ruminococcus] torques group spp., Roseburia hominis, and Christensenellaceae R-7 spp., was associated with higher odds of amyloid positivity. We found associations between lower abundance of Lachnospiraceae spp., Lachnoclostridium spp., Roseburia hominis and Bilophila wadsworthia and higher odds of positive p-tau status.

Conclusions

Gut microbiota composition was associated with amyloid and p-tau status. We extend on recent studies that observed associations between SCFA levels and AD CSF biomarkers by showing that lower abundances of SCFA-producing microbes were associated with higher odds of positive amyloid and p-tau status.
Long-Term Outcome After Adoptive Immunotherapy With Natural Killer Cells: Alloreactive NK Cell Dose Still Matters
Authors: Parisi Sarah , Ruggeri Loredana , Dan Elisa , Rizzi Simonetta , Sinigaglia Barbara , Ocadlikova Darina , Bontadini Andrea , Giudice Valeria , Urbani Elena , Ciardelli Sara , Sartor Chiara , Cristiano Gianluca , Nanni Jacopo , Zannoni Letizia , Chirumbolo Gabriella , Arpinati Mario , Lewis Russell E. , Bonifazi Francesca , Marconi Giovanni , Martinelli Giovanni , Papayannidis Cristina , Paolini Stefania , Velardi Andrea , Cavo Michele , Lemoli Roberto M. , Curti Antonio
Published: January 2022

Recently, many reports were published supporting the clinical use of adoptively transferred natural killer (NK) cells as a therapeutic tool against cancer, including acute myeloid leukemia (AML). Our group demonstrated promising clinical response using adoptive immunotherapy with donor-derived alloreactive KIR-ligand-mismatched NK cells in AML patients. Moreover, the antileukemic effect was correlated with the dose of infused alloreactive NK cells (“functional NK cell dose”). Herein, we update the results of our previous study on a cohort of adult AML patients (median age at enrollment 64) in first morphological complete remission (CR), not eligible for allogeneic stem cell transplantation. After an extended median follow-up of 55.5 months, 8/16 evaluable patients (50%) are still off-therapy and alive disease-free. Overall survival (OS) and disease-free survival (DFS) are related with the dose of infused alloreactive NK cells (≥2 × 105/kg).
All-Trans Retinoic Acid Attenuates Transmissible Gastroenteritis Virus-Induced Inflammation in IPEC-J2 Cells via Suppressing the RLRs/NF‐κB Signaling Pathway
Authors: Pu Junning , Chen Daiwen , Tian Gang , He Jun , Huang Zhiqing , Zheng Ping , Mao Xiangbing , Yu Jie , Luo Junqiu , Luo Yuheng , Yan Hui , Yu Bing
Published: January 2022

Transmissible gastroenteritis virus (TGEV) infection can cause transmissible gastroenteritis (TGE), especially in suckling piglets, resulting in a significant economic loss for the global pig industry. The pathogenesis of TGEV infection is closely related to intestinal inflammation. All-trans retinoic acid (ATRA) has anti-inflammatory activity and immunomodulatory properties, but it is unclear whether ATRA can attenuate the inflammatory response induced by TGEV. This study aimed to investigate the protective effect of ATRA on TGEV-induced inflammatory injury in intestinal porcine epithelial cells (IPEC-J2) and to explore the underlying molecular mechanism. The results showed that TGEV infection triggered inflammatory response and damaged epithelial barrier integrity in IPEC-J2 cells. However, ATRA attenuated TGEV-induced inflammatory response by inhibiting the release of pro-inflammatory cytokines, including IL-1β, IL-6, IL-8 and TNF-α. ATRA also significantly reversed the reduction of ZO-1 and Occludin protein levels induced by TGEV infection and maintained epithelial barrier integrity. Moreover, ATRA treatment significantly prevented the upregulation of IкBα and NF-κB p65 phosphorylation levels and the nuclear translocation of NF-кB p65 induced by TGEV. On the other hand, treatment of TGEV-infected IPEC-J2 cells with the NF-κB inhibitors (BAY11-7082) significantly decreased the levels of inflammatory cytokines. Furthermore, ATRA treatment significantly downregulated the mRNA abundance and protein levels of TLR3, TLR7, RIG-I and MDA5, and downregulated their downstream signaling molecules TRIF, TRAF6 and MAVS mRNA expressions in TGEV-infected IPEC-J2 cells. However, the knockdown of RIG-I and MDA5 but not TLR3 and TLR7 significantly reduced the NF-κB p65 phosphorylation level and inflammatory cytokines levels in TGEV-infected IPEC-J2 cells. Our results indicated that ATRA attenuated TGEV-induced IPEC-J2 cells damage via suppressing inflammatory response, the mechanism of which is associated with the inhibition of TGEV-mediated activation of the RLRs/NF‐κB signaling pathway.
Don’t Let It Get Under Your Skin! – Vaccination Protects the Skin Barrier of Common Carp From Disruption Caused by Cyprinid Herpesvirus 3
Authors: Adamek Mikolaj , Matras Marek , Rebl Alexander , Stachnik Magdalena , Falco Alberto , Bauer Julia , Miebach Anne-Carina , Teitge Felix , Jung-Schroers Verena , Abdullah Muhammad , Krebs Torben , Schröder Lars , Fuchs Walter , Reichert Michal , Steinhagen Dieter
Published: January 2022

Vaccination is the best form of protecting fish against viral diseases when the pathogen cannot be contained by biosecurity measures. Vaccines based on live attenuated viruses seem to be most effective for vaccination against challenging pathogens like Cyprinid herpesvirus 3. However, there are still knowledge gaps how these vaccines effectively protect fish from the deadly disease caused by the epitheliotropic CyHV-3, and which aspects of non-direct protection of skin or gill integrity and function are important in the aquatic environment. To elucidate some elements of protection, common carp were vaccinated against CyHV-3 using a double deletion vaccine virus KHV-T ΔDUT/TK in the absence or presence of a mix of common carp beta-defensins 1, 2 and 3 as adjuvants. Vaccination induced marginal clinical signs, low virus load and a minor upregulation of cd4, cd8 and igm gene expression in vaccinated fish, while neutralisation activity of blood serum rose from 14 days post vaccination (dpv). A challenge infection with CyHV-3 induced a severe disease with 80-100% mortality in non-vaccinated carp, while in vaccinated carp, no mortality was recorded and the virus load was >1,000-fold lower in the skin, gill and kidney. Histological analysis showed strongest pathological changes in the skin, with a complete destruction of the epidermis in non-vaccinated carp. In the skin of non-vaccinated fish, T and B cell responses were severely downregulated, inflammation and stress responses were increased upon challenge, whereas vaccinated fish had boosted neutrophil, T and B cell responses. A disruption of skin barrier elements (tight and adherence junction, desmosomes, mucins) led to an uncontrolled increase in skin bacteria load which most likely exacerbated the inflammation and the pathology. Using a live attenuated virus vaccine, we were able to show that increased neutrophil, T and B cell responses provide protection from CyHV-3 infection and lead to preservation of skin integrity, which supports successful protection against additional pathogens in the aquatic environment which foster disease development in non-vaccinated carp.
Photochemically-Mediated Inflammation and Cross-Presentation of Mycobacterium bovis BCG Proteins Stimulates Strong CD4 and CD8 T-Cell Responses in Mice
Authors: Waeckerle-Men Ying , Kotkowska Zuzanna K. , Bono Géraldine , Duda Agathe , Kolm Isabel , Varypataki Eleni M. , Amstutz Beat , Meuli Michael , Høgset Anders , Kündig Thomas M. , Halin Cornelia , Sander Peter , Johansen Pål
Published: January 2022

Conventional vaccines are very efficient in the prevention of bacterial infections caused by extracellular pathogens due to effective stimulation of pathogen-specific antibodies. In contrast, considering that intracellular surveillance by antibodies is not possible, they are typically less effective in preventing or treating infections caused by intracellular pathogens such asMycobacterium tuberculosis. The objective of the current study was to use so-called photochemical internalization (PCI) to deliver a live bacterial vaccine to the cytosol of antigen-presenting cells (APCs) for the purpose of stimulating major histocompatibility complex (MHC) I-restricted CD8 T-cell responses. For this purpose,Mycobacterium bovisBCG (BCG) was combined with the photosensitiser tetraphenyl chlorine disulfonate (TPCS2a) and injected intradermally into mice. TPCS2a was then activated by illumination of the injection site with light of defined energy. Antigen-specific CD4 and CD8 T-cell responses were monitored in blood, spleen, and lymph nodes at different time points thereafter using flow cytometry, ELISA and ELISPOT. Finally, APCs were infected and PCI-treatedin vitrofor analysis of their activation of T cellsin vitroorin vivoafter autologous vaccination of mice. Combination of BCG with PCI induced stronger BCG-specific CD4 and CD8 T-cell responses than treatment with BCG only or with BCG and TPCS2a without light. The overall T-cell responses were multifunctional as characterized by the production of IFN-γ, TNF-α, IL-2 and IL-17. Importantly, PCI induced cross-presentation of BCG proteins for stimulation of antigen-specific CD8 T-cells that were particularly producing IFN-γ and TNF-α. PCI further facilitated antigen presentation by causing up-regulation of MHC and co-stimulatory proteins on the surface of APCs as well as their production of TNF-α and IL-1βin vivo. Furthermore, PCI-based vaccination also caused local inflammation at the site of vaccination, showing strong infiltration of immune cells, which could contribute to the stimulation of antigen-specific immune responses. This study is the first to demonstrate that a live microbial vaccine can be combined with a photochemical compound and light for cross presentation of antigens to CD8 T cells. Moreover, the results revealed that PCI treatment strongly improved the immunogenicity ofM. bovisBCG.
Healthcare Workers in South Korea Maintain a SARS-CoV-2 Antibody Response Six Months After Receiving a Second Dose of the BNT162b2 mRNA Vaccine
Authors: Choi Jae Hong , Kim Young Ree , Heo Sang Taek , Oh Hyunjoo , Kim Misun , Lee Hyang Ran , Yoo Jeong Rae
Published: January 2022

Background

Effective vaccines against coronavirus disease 2019 (COVID-19) are available worldwide; however, the longevity of vaccine effectiveness is not known.

Objective

We performed a prospective observational study to assess the antibody response of healthcare workers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after BNT162b2 mRNA COVID-19 vaccination.

Methods

SARS-CoV-2 neutralizing antibody (nAb) and spike (S) protein-IgG (S-IgG) antibody titers were examined in participants who received two doses of the BNT162b2 mRNA COVID-19 vaccine in a single center between March 1, 2021, and October 11, 2021. Antibody levels were analyzed at four times: before vaccination (visit 1), 4 weeks after the first vaccination (visit 2), 3 months after the second vaccination (visit 3), and 6 months after the second vaccination (visit 4).

Results

A total of 249 healthcare workers at Jeju National University Hospital were enrolled in this study, and 982 blood samples were analyzed. The mean age was 38.1 ± 9.5 years, and 145 (58.2%) participants were females. Positive nAbs (inhibition rates ≥ 20%) were measured in 166/249 (66.7%) subjects at visit 2, 237/243 (97.5%) subjects at visit 3, and 150/237 (63.3%) subjects at visit 4. A S-IgG (≥50 AU/mL) positivity was detected in 246/249 (98.8%) subjects at visit 1, and all participants had positive S-IgG antibody levels at visits 3 and 4 after being fully vaccinated. Further analysis of S-IgG levels revealed a median quantitative antibody level of 1275.1 AU/mL (interquartile range [IQR] 755.5–2119.0) at visit 2, 2765.9 AU/mL (IQR 1809.8–4138.4) at visit 3, and 970.1 AU/mL (IQR 606.0–1495.9) at visit 4. Patient characteristics, such as age, body mass index, and comorbidity, had no relationship with nAb or S-IgG levels at any of the visits. Considering the change in antibody levels over time, both nAb and S-IgG levels at visit 4 decreased compared with the corresponding levels at visit 3. No evidence of SARS-CoV-2 infection was found among any of the participants throughout the study.

Conclusions

The BNT162b2 mRNA vaccine was effective in protecting healthcare personnel working in COVID-19-related departments. While the level of S-IgG antibodies was maintained for 6 months after the second vaccination, nAb levels waned over this 6-month period, indicating the need for a booster vaccination in some healthcare workers 6 months after full vaccination. Herein, we suggest that further studies are needed to evaluate the need for an interval of booster vaccination after full vaccination.
The Spectrum of Inborn Errors of Immunity in the United Arab Emirates: 5 Year Experience in a Tertiary Center
Authors: Shendi Hiba Mohammed , Al Kuwaiti Amna Ali , Al Dhaheri Ahmed Darwaish , Al-Hammadi Suleiman
Published: January 2022

Purpose

Inborn Errors of Immunity (IEI) are heterogeneous disorders of immunity with variable clinical presentation and outcome. This is the first comprehensive report from the United Arab Emirates aiming to describe the demographics, clinical characteristics, categories, treatment modalities and outcome of patients with IEI.

Methods

This retrospective study was conducted on patients who attended Tawam Hospital between 2016-2020.

Results

We identified 162 patients with IEI, of whom 152 were children. The age of onset of symptoms ranged between birth to 38 years. About two-thirds of patients were Emirati nationals, 64.2% had consanguineous parents and 38.3% of cases were familial. Patients were classified as; immunodeficiencies affecting cellular and humoral immunity (20.4%), combined immunodeficiencies with associated or syndromic features (38.3%), predominantly antibody deficiencies (16%), immune dysregulation (4.3%), congenital defects of phagocytes number or function (8.6%), defects in intrinsic and innate immunity (1.9%) autoinflammatory disorders (1.9%), complement deficiency (6.2%), bone marrow failure (1.9%) and phenocopies of inborn errors of immunity (0.6%). Genetic testing was performed in 85.2% of patients with a diagnostic yield of 92.7%. Complications included bronchiectasis, neoplasia, and vaccine-related infections. Immunoglobulin therapy and antimicrobial prophylaxis were both used in (51.9%) of patients while (20.4%) underwent hematopoietic stem cell transplantation (HSCT). The overall mortality rate was 10.5%.

Conclusion

This report highlights the burden of IEI in the UAE. Ongoing education of physicians, establishment of a national registry and considering changes to early BCG vaccination are measures recommended to improve outcomes.
A Coordinated Public Health Laboratory Response to COVID-19 in Mali
Authors: Diarra Bassirou , Kone Amadou , Guindo Ibrehima , Bane Sidy , Doumbia Lassina , Timbine Lassana , Diallo Dramane , Sanogo Moumine , Togo Antieme Combo Georges , Coulibaly Tenin Aminatou , Diallo Fatimata Amath , Kone Mahamadou , Somboro Anou Moise , Togo Josue , Coulibaly Mariam , Camara Fatoumata A. , Coulibaly Gagni , Diarra Hawa Boukary , Diakite Mahamane Talphi , Abdou Mohamed , Somboro Amadou , Dolo Oumar , Maiga Oumou Ousmane , Keita Daouda , Coulibaly Youssouf , Degoga Boureima , Drame Hawa MBaye , Sow Mariame , Goumane Mariam , Traore Fah Gaoussou , Kone Kadidia , Sanogo Fanta , Diallo Ibrahima B. , Denou Larissa , Sarro Yeya Sadio , Shaw-Saliba Katy , Lau Chuen-Yen , Neal Aaron , Sow Idrissa , Kouriba Bourema , Koita Ousmane , Diakite Mahamadou , Iknane Akory Ag , Doumbia Seydou
Published: January 2022

Ability to rapidly and accurate diagnose pathogens during disease outbreaks is essential for public health. Diagnosis depends largely on laboratory capacity, which can be challenging in resource limited settings. We report Mali’s experience involving four research laboratories in response to the COVID-19 pandemic. This coordinated effort leveraged the emerging infectious pathogens diagnostic capacity and partnerships built from the 2014/2015 Ebola outbreak. Since Mali’s first two COVID-19 cases in March 2020, 349,292 suspected cases were tested in the four Bamako laboratories as of July 31, 2021. Laboratory operation, safety considerations, diagnostic assays, and challenges are described herein from the perspective of a participating laboratory, the Mali University Clinical Research Center (UCRC). We also highlight additional roles of the UCRC laboratory in the COVID-19 response, including roll out of vaccination and research efforts. Mali’s readiness to detect the index cases early in the epidemic and continued response to the COVID-19 pandemic highlight the need for strengthening the critical role and capacity of clinical research laboratories for response to emerging infectious disease epidemics in Africa.
Submersibles Greatly Enhance Research on the Diversity of Deep-Reef Fishes in the Greater Caribbean
Authors: Robertson D. Ross , Tornabene Luke , Lardizabal Claudia C. , Baldwin Carole C.
Published: January 2022

Understanding the diversity and ecology of deep-reef fishes is challenging. Due to intensive and widely dispersed sampling, the Greater Caribbean (GC) fauna of species found on shallow reefs is much better characterized than the fauna of deep-reef species restricted to mesophotic (40–130 m) and rariphotic (130–300 m) depths. Our knowledge about deep-reef fishes is based on ship-board sampling and the recent use of rebreather diving, remotely operated vehicles (ROVs), baited remote underwater videos, and crewed submersibles. Submersible research on GC deep-reef fishes began in the 1960s and has flourished over the last decade through research by the Smithsonian Institution’s Deep Reef Observation Project (DROP). Here we quantify the contribution of submersible research, particularly the surge by DROP, to our understanding of the diversity of the deep-reef fish fauna of the GC. We compared shallow- and deep-reef fish faunas of three GC sites subjected to DROP research to faunas of three sites without such research. DROP increased the size of the deep faunas at three islands ∼9-fold, and they have deep-reef faunas ∼2–4 times the size of those of the other three sites. Those deep-reef faunas have high proportions of small cryptobenthic fishes, which also represent a major component of shallow faunas. That research increased the rate of discovery (collection) of new species of deep-reef fishes ∼6-fold and accounts for 31% of the deep-reef species first discovered within the GC. Substantial numbers of new species at each of the three DROP islands were not found at the other two. This indicates that other parts of the GC likely harbor many undetected deep-reef fishes, and that the size of the deep-reef fauna of the GC is significantly underestimated. These results show that small research submersibles are versatile, highly productive tools for deep-reef studies. They allow long-duration dives at any depth, while offering unparalleled views of their surroundings to study the ecology of deep-reef fishes (e.g., DROP’s definition of the rariphotic assemblage from fish depth distributions). Submersibles can efficiently collect reef fishes of a broad range of taxa, ecotypes and sizes, leading to a more comprehensive understanding of the regional GC deep-reef fish fauna.
Numerous Sublinear Sets of Holes in Sediment on the Northern Mid-Atlantic Ridge Point to Knowledge Gaps in Understanding Mid-Ocean Ridge Ecosystems
Authors: Vecchione Michael , Bergstad Odd Aksel
Published: January 2022

On 13 July 2004, during an expedition exploring biodiversity along the northern Mid-Atlantic Ridge, an ROV dive recorded videos of numerous sublinear sets of holes in sediment at ca. 2,082 m depth. The location was north of the Azores. Each set appeared track-like. Lengths of individual series ranged from < 1 m to many meters. Each was straight or gently curved. Some series intersected or crossed. Close examination of the holes showed them to be elongate, with the long axis parallel to the axis of the series. The holes were ca. 6 × 1.5 cm, with distance between holes similar to hole length. The holes that appeared to be most recently formed were each surrounded by raised sediment. Holes that appeared older were partly filled with sediment and the raised surrounding sediment was less obvious. Overall, these lebensspuren created small-scale heterogeneity in the local soft-bottom benthic ecosystem. The source of the holes or how they were constructed is unknown, but the raised sediment may indicate excavation by an infaunal organism or digging and removal by e.g., a feeding appendage of a large epifaunal animal. None of our closeups showed any sign of living organisms inhabiting the holes. Whether the holes were connected beneath the sediment surface was not visible. The traces observed are reminiscent of ichnofossils reported from deep marine facies. We hope that future studies of the lebensspuren we report here will resolve the mystery of what created them.