bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical and immunological features of an APLAID patient caused by a novel mutation in PLCG2
Authors: Peng Qi , Luo Dong , Yang Yi , Zhu Yinghua , Luo Qingming , Chen Huan , Chen Dapeng , Zhou Zhongjun , Lu Xiaomei
Published: January 2023

Background

The APLAID syndrome is a rare primary immunodeficiency caused by gain-of-function mutations in the PLCG2 gene. We present a 7-year-old APLAID patient who has recurrent blistering skin lesions, skin infections in the perineum, a rectal perineal fistula, and inflammatory bowel disease.

Methods

To determine the genetic cause of our patient, WES and bioinformatics analysis were performed. Flow cytometry was used for phenotyping immune cell populations in peripheral blood. Cytokines released into plasma were analyzed using protein chip technology. The PBMCs of patient and a healthy child were subjected to single-cell RNA-sequencing analysis.

Results

The patient carried a novel de novo missense mutation c.2534T>C in exon 24 of the PLCG2 gene that causes a leucine to serine amino acid substitution (p.Leu845Ser). Bioinformatics analysis revealed that this mutation had a negative impact on the structure of the PLCγ2 protein, which is highly conserved in many other species. Immunophenotyping by flow cytometry revealed that in addition to the typical decrease in circulating memory B cells, the levels of myeloid dendritic cells (mDCs) in the children’s peripheral blood were significantly lower, as were the CD4+ effector T cells induced by their activation. Single-cell sequencing revealed that the proportion of different types of cells in the peripheral blood of the APLAID patient changed.

Conclusions

We present the first case of APLAID with severely reduced myeloid dendritic cells carrying a novel PLCG2 mutation, and conducted a comprehensive analysis of immunological features in the ALPAID patient, which has not been mentioned in previous reports. This study expands the spectrum of APLAID-associated immunophenotype and genotype. The detailed immune analyses in this patient may provide a basis for the development of targeted therapies for this severe autoinflammatory disease.
Medium chain fatty acid supplementation improves animal metabolic and immune status during the transition period: A study on dairy cattle
Authors: Wang Zhonghan , Wang Qianqian , Tang Chuanlan , Yuan Jing , Luo Chenglong , Li Dong , Xie Tian , Sun Xiaoge , Zhang Yan , Yang Zhantao , Guo Cheng , Cao Zhijun , Li Shengli , Wang Wei
Published: January 2023

The transition period is the stage of the high incidence of metabolic and infectious diseases in dairy cows. Improving transition dairy cows’ health is crucial for the industry. This study aimed to determine the effects of dietary supplementation medium-chain fatty acids (MCFAs) on immune function, metabolic status, performance of transition dairy cows. Twenty multiparous Holstein cows randomly assigned to two treatments at 35 d before calving. 1) CON (fed the basal 2) MCFA treatment (basal diet was supplemented at an additional 20 g MCFAs mixture every day) until 70 d after calving. The results showed that the serum amyloid A myeloperoxidase concentrations in the blood of cows in MCFA treatment significantly decreased during the early lactation (from 1 d to 28 d after calving) 0.03, 0.04, respectively) compared with the CON, while the tumor necrosis factor concentration was significantly decreased at 56 d after calving (P = 0.02). In addition, the concentration of insulin in the pre-calving (from 21 d before calving to calving) blood of cows in MCFA treatment was significantly decreased (P = 0.04), and concentration of triglyceride also showed a downward trend at 28 d after calving 0.07). Meanwhile, MCFAs supplementation significantly decreased the concentrations of lithocholic acid, hyodeoxycholic acid, and hyocholic acid in the blood at 1 d calving (P = 0.02, < 0.01, < 0.01, respectively), and the level of hyocholic acid taurocholic acid concentrations (P < 0.01, = 0.01, respectively) decreased dramatically at 14 d after calving. However, compared with the CON, the pre-calving dry matter intake and the early lactation milk yield in MCFA treatment were significantly decreased (P = 0.05, 0.02, respectively). In conclusion, MCFAs supplementation transition diet could improve the immune function and metabolic status of dairy cows, and the health of transition cows might be beneficial from the endocrine status.
Stimulation of the farnesoid X receptor promotes M2 macrophage polarization
Authors: Jaroonwitchawan Thiranut , Arimochi Hideki , Sasaki Yuki , Ishifune Chieko , Kondo Hiroyuki , Otsuka Kunihiro , Tsukumo Shin-ichi , Yasutomo Koji
Published: January 2023

FXR is a key molecule that modulates anti-inflammatory activity in the intestinal-liver axis. Although FXR has pleiotropic functions including regulation of liver inflammation and activation of macrophages, it remains unclear whether it is involved in macrophage polarization. In this paper we demonstrated that stimulation of macrophages derived from the bone marrow using an FXR agonist activated polarization toward M2 but not M1 macrophages. The treatment of mice with chitin skewed macrophage polarization towards M2 macrophages, while co-treatment with an FXR agonist further promoted the polarization toward M2 macrophages in vivo. This skewed polarization towards M2 macrophages by an FXR agonist was accompanied by increased expression of signaling molecules related to the retinoic acid receptor. Inhibition of the retinoic acid receptor suppressed FXR agonist-mediated M2 macrophage polarization, indicating that this polarization was, at least, partly dependent on the retinoic acid receptor pathway. These data demonstrate that FXR has a role in polarization toward M2 macrophages and suggest a possible therapeutic potential of FXR agonists in M2 macrophage-related conditions.
Case report: Advanced primary squamous cell carcinoma in the periampullary area with upregulation of programmed cell death-ligand 1 expression and response to sintilimab immunotherapy
Authors: Wang Baoshan , Li Dazhou , Zeng Dehua , Wang Wen , Jiang Chuanshen
Published: January 2023

Primary squamous cell carcinoma (SCC) of the periampullary area is exceedingly rare. We report a case of a 45-year-old woman who presented with progressive upper abdominal pain and melena. Laboratory testing revealed an elevated level of carcinoembryonic antigen. Esophagogastroduodenoscopy revealed a very large irregular ulcerated tumor in the periampullary area. Contrast-enhanced computed tomography (CT) of the chest, abdomen, and pelvis, 18 F-fluorodeoxyglucose positron emission tomography/CT, and thin-prep cytologic test excluded metastasis of the primary tumor to the periampullary area from other sites. Immunohistochemistry revealed positive p40 and cytokeratin (CK)5/6, indicating SCC. The expression of programmed cell death-ligand 1 (PD-L1) in tumor cells was upregulated, and the patient responded well to chemotherapy combined with immunotherapy. To the best of our knowledge, this is the first reported case of advanced primary SCC in the periampullary area with high expression of PD-L1.
NCAPG2 could be an immunological and prognostic biomarker: From pan-cancer analysis to pancreatic cancer validation
Authors: Wang Qi , Li Zhangzuo , Zhou Shujing , Li Zhengrui , Huang Xufeng , He Yiwei , Zhang Yuhan , Zhao Xiaoxian , Tang Yidan , Xu Min
Published: January 2023

More recently, NCAPG2 has emerged as an intrinsically essential participant of the condensin II complex involved in the process of chromosome cohesion and stabilization in mitosis, and its position in particular tumours is now being highlighted. Simultaneously, the genetic properties of NCAPG2 hint that it might have enormous potential to interpret the malignant progression of tumors in a broader perspective, that is, in pan-cancer. Yet, at present, this recognition remains merely superficial and there is a lack of more detailed studies to explore the underlying pathogenesis. To meet this need, the current study was undertaken to comprehensively elucidate the potential functions of NCAPG2 in pan-cancer, based on a combination of existing databases like TCGA and GTEx. NCAPG2 was identified to be overexpressed in almost every tumor and to exhibit significant prognostic and diagnostic efficacy. Furthermore, the correlation between NCAPG2 and selected immune features, namely immune cell infiltration, immune checkpoint genes, TMB, MSI, etc. also indicates that NCAPG2 could potentially be applied in guidance of immunotherapy. Subsequently, in pancreatic cancer, this study further clarified the utility of NCAPG2 that downregulation of its expression could result in reduced proliferation, invasion and metastasis of pancreatic cancer cells, among such phenotypical changes, the epithelial-mesenchymal transition disruption could be at least one of the possible mechanisms raising or enhancing tumorigenesis. Taken above, NCAPG2, as a member of pan-oncogenes, would serve as a biomarker and potential therapeutic target for a range of malignancies, sharing new insights into precision medicine.
Diagnostic and prognostic value of serum S100B in sepsis-associated encephalopathy: A systematic review and meta-analysis
Authors: Hu Jiyun , Xie Shucai , Li Wenchao , Zhang Lina
Published: January 2023

Background

In sepsis, brain dysfunction is known as Sepsis-associated encephalopathy (SAE), which often results in severe cognitive and neurological sequelae and increases the risk of death. Our systematic review and meta-analysis aimed to explore the diagnostic and prognostic value of serum S100 calcium-binding protein B (S100B) in SAE patients.

Methods

We conducted a systematic search of the databases PubMed, Web of Science, Embase, Cochrane databases, CNKI, VIP, and WFSD from their inception dates until August 20, 2022. A Meta-analysis of the included studies was also performed using Review Manager version 5.4 and Stata16.0.

Results

This meta-analysis included 28 studies with 1401 serum samples from SAE patients and 1591 serum samples from no-encephalopathy septic (NE) patients. The Meta-Analysis showed that individuals with SAE had higher serum S100B level than NE controls (MD, 0.49 [95% CI (0.37)-(0.60), Z =8.29, P < 0.00001]), and the baseline level of serum S100B in septic patients with burn was significantly higher than average (1.96 [95% CI (0.92)-(2.99), Z =3.71, P < 0.0002]) In addition, septic patients with favorable outcomes had lower serum S100B levels than those with unfavorable outcomes (MD, -0.35 [95% CI (-0.50)-(-0.20), Z =4.60, P < 0.00001]).

Conclusion

Our Meta-Analysis indicates that higher serum S100B level in septic patients are moderately associated with SAE and unfavorable outcomes (The outcomes here mainly refer to the mortality). The serum S100B level may be a useful diagnostic and prognostic biomarker of SAE.
Neutralizing antibodies to Omicron after the fourth SARS-CoV-2 mRNA vaccine dose in immunocompromised patients highlight the need of additional boosters
Authors: Rescigno Maria , Agrati Chiara , Salvarani Carlo , Giannarelli Diana , Costantini Massimo , Mantovani Alberto , Massafra Raffaella , Zinzani Pier Luigi , Morrone Aldo , Notari Stefania , Matusali Giulia , Pinter Giuseppe Lauria , Uccelli Antonio , Ciliberto Gennaro , Baldanti Fausto , Locatelli Franco , Silvestris Nicola , Sinno Valentina , Turola Elena , Lupo-Stanghellini Maria Teresa , Apolone Giovanni ,   the VAX4FRAIL study Group
Published: January 2023

Introduction

Immunocompromised patients have been shown to have an impaired immune response to COVID-19 vaccines.

Methods

Here we compared the B-cell, T-cell and neutralizing antibody response to WT and Omicron BA.2 SARS-CoV-2 virus after the fourth dose of mRNA COVID-19 vaccines in patients with hematological malignancies (HM, n=71), solid tumors (ST, n=39) and immune-rheumatological (IR, n=25) diseases. The humoral and T-cell responses to SARS-CoV-2 vaccination were analyzed by quantifying the anti-RBD antibodies, their neutralization activity and the IFN-γ released after spike specific stimulation.

Results

We show that the T-cell response is similarly boosted by the fourth dose across the different subgroups, while the antibody response is improved only in patients not receiving B-cell targeted therapies, independent on the pathology. However, 9% of patients with anti-RBD antibodies did not have neutralizing antibodies to either virus variants, while an additional 5.7% did not have neutralizing antibodies to Omicron BA.2, making these patients particularly vulnerable to SARS-CoV-2 infection. The increment of neutralizing antibodies was very similar towards Omicron BA.2 and WT virus after the third or fourth dose of vaccine, suggesting that there is no preferential skewing towards either virus variant with the booster dose. The only limited step is the amount of antibodies that are elicited after vaccination, thus increasing the probability of developing neutralizing antibodies to both variants of virus.

Discussion

These data support the recommendation of additional booster doses in frail patients to enhance the development of a B-cell response directed against Omicron and/or to enhance the T-cell response in patients treated with anti-CD20.
Defending against SARS-CoV-2: The T cell perspective
Authors: Almendro-Vázquez Patricia , Laguna-Goya Rocío , Paz-Artal Estela
Published: January 2023

SARS-CoV-2-specific T cell response has been proven essential for viral clearance, COVID-19 outcome and long-term memory. Impaired early T cell-driven immunity leads to a severe form of the disease associated with lymphopenia, hyperinflammation and imbalanced humoral response. Analyses of acute SARS-CoV-2 infection have revealed that mild COVID-19 course is characterized by an early induction of specific T cells within the first 7 days of symptoms, coordinately followed by antibody production for an effective control of viral infection. In contrast, patients who do not develop an early specific cellular response and initiate a humoral immune response with subsequent production of high levels of antibodies, develop severe symptoms. Yet, delayed and persistent bystander CD8+ T cell activation has been also reported in hospitalized patients and could be a driver of lung pathology. Literature supports that long-term maintenance of T cell response appears more stable than antibody titters. Up to date, virus-specific T cell memory has been detected 22 months post-symptom onset, with a predominant IL-2 memory response compared to IFN-γ. Furthermore, T cell responses are conserved against the emerging variants of concern (VoCs) while these variants are mostly able to evade humoral responses. This could be partly explained by the high HLA polymorphism whereby the viral epitope repertoire recognized could differ among individuals, greatly decreasing the likelihood of immune escape. Current COVID-19-vaccination has been shown to elicit Th1-driven spike-specific T cell response, as does natural infection, which provides substantial protection against severe COVID-19 and death. In addition, mucosal vaccination has been reported to induce strong adaptive responses both locally and systemically and to protect against VoCs in animal models. The optimization of vaccine formulations by including a variety of viral regions, innovative adjuvants or diverse administration routes could result in a desirable enhanced cellular response and memory, and help to prevent breakthrough infections. In summary, the increasing evidence highlights the relevance of monitoring SARS-CoV-2-specific cellular immune response, and not only antibody levels, as a correlate for protection after infection and/or vaccination. Moreover, it may help to better identify target populations that could benefit most from booster doses and to personalize vaccination strategies.
The ectonucleotidases CD39 and CD73 on T cells: The new pillar of hematological malignancy
Authors: Jiang Xuan , Wu Xiaofang , Xiao Yuxi , Wang Penglin , Zheng Jiamian , Wu Xiuli , Jin Zhenyi
Published: January 2023

Hematological malignancy develops and applies various mechanisms to induce immune escape, in part through an immunosuppressive microenvironment. Adenosine is an immunosuppressive metabolite produced at high levels within the tumor microenvironment (TME). Adenosine signaling through the A2A receptor expressed on immune cells, such as T cells, potently dampens immune responses. Extracellular adenosine generated by ectonucleoside triphosphate diphosphohydrolase-1 (CD39) and ecto-5’-nucleotidase (CD73) molecules is a newly recognized ‘immune checkpoint mediator’ and leads to the identification of immunosuppressive adenosine as an essential regulator in hematological malignancies. In this Review, we provide an overview of the detailed distribution and function of CD39 and CD73 ectoenzymes in the TME and the effects of CD39 and CD73 inhibition on preclinical hematological malignancy data, which provides insights into the potential clinical applications for immunotherapy.
The innate immune brakes of the lung
Authors: Sabatel Catherine , Bureau Fabrice
Published: January 2023

Respiratory mucosal surfaces are continuously exposed to not only innocuous non-self antigens but also pathogen-associated molecular patterns (PAMPs) originating from environmental or symbiotic microbes. According to either “self/non-self” or “danger” models, this should systematically result in homeostasis breakdown and the development of immune responses directed to inhaled harmless antigens, such as T helper type (Th)2-mediated asthmatic reactions, which is fortunately not the case in most people. This discrepancy implies the existence, in the lung, of regulatory mechanisms that tightly control immune homeostasis. Although such mechanisms have been poorly investigated in comparison to the ones that trigger immune responses, a better understanding of them could be useful in the development of new therapeutic strategies against lung diseases (e.g., asthma). Here, we review current knowledge on innate immune cells that prevent the development of aberrant immune responses in the lung, thereby contributing to mucosal homeostasis.
Research on the effects of complex terrain on the hydrodynamic performance of a deep-sea fishlike exploring and sampling robot moving near the sea bottom
Authors: Xue Gang , Bai Fagang , Guo Lei , Ren Pingshun , Liu Yanjun
Published: January 2023

Deep-sea exploring and sampling technologies have become frontier topics. Generally, the movable exploring mode near the seabed with low disturbance is an important way to improve the measurement accuracy and expand the measurement range. Inspired by fish, the fishlike propulsion method has the characteristics of low disturbance and high flexibility, which is very suitable for near-seabed detection under complex terrain conditions. However, the swimming mechanism and surrounding flow field evolution law of the robotic fish under the constraints of complex terrain are still unclear. In this paper, the confined terrain space is constructed with an undulating seabed and a narrow channel, and the hydrodynamic changing law and flow field evolution law of the autonomous swimming process of the fishlike swimmer in the confined space are analyzed. Moreover, the influence mechanism of the terrain on the motion performance of the robotic fish is revealed, and the optimal motion mode of the robotic fish under a complex terrain constraint is discussed. The results show that the propulsion force, Froude efficiency, and swimming stability of the robotic fish vary with the distance from the bottom under the undulating seabed condition lightly. When the distance from the bottom exceeds a certain value, it can be considered that the undulating seabed no longer affects the swimmer. Furthermore, when the robotic fish swims through a narrow channel with certain width, the swimming performance obviously varies with the distance from the boundary surface. During swimming in the confined terrain space, the propulsion force and swimming stability of robotic fish will decrease. In order to maintain the forward speed, the robotic fish should improve the tail-beat frequency in real time. However, considering the swimming stability, the tail-beat frequency is not the larger the better. The relevant conclusions of this paper could provide theoretical support for the development of low-disturbance bionic exploring and sampling platforms for deep-sea resources and environments.
Efficacy of ixekizumab in patients with moderate-to-severe plaque psoriasis and prediabetes or type 2 diabetes
Authors: Egeberg Alexander , Merola Joseph F. , Schäkel Knut , Puig Luis , Mahar Patrick D. , Wang Isabella Yali , Pavo Imre , Schuster Christopher , Griffiths Christopher E. M.
Published: January 2023

Objective

Patients with psoriasis have an increased prevalence of type 2 diabetes when compared to the general population. Research suggests that type 2 diabetes (T2D) as well as obesity may have an impact on patients' response to treatment. This post-hoc analysis reports the efficacy of ixekizumab in treating moderate-to-severe psoriasis in patients with prediabetes or T2D.

Method and materials

UNCOVER-1, UNCOVER-2, and UNCOVER-3 were three Phase 3, multicenter, randomized, double-blind, placebo-controlled trials that evaluated the efficacy and safety of ixekizumab in adult patients with moderate-to-severe psoriasis. Patients were aged ≥18 years with chronic moderate-to-severe psoriasis (defined as ≥10% body surface area affected, static Physician Global Assessment ≥3, and Psoriasis Area and Severity Index [PASI] ≥12 at screening and baseline) who were candidates for phototherapy or systemic therapy. UNCOVER-1, UNCOVER-2, and UNCOVER-3 participants received ixekizumab as per label (that is, an initial dose of two subcutaneous injections [160 mg in total] at Week 0, followed by 80 mg every 2 weeks through Week 12 and 80 mg every 4 weeks thereafter through Week 60).

Results

The proportions of patients with prediabetes, T2D and normoglycemia that achieved PASI75, PASI90, and PASI100 at Week 60 were similar. Results suggest that patients with T2D were slower to achieve PASI100 than patients with prediabetes or those with normoglycemia. Ixekizumab had no effect on any metabolic markers in patients receiving the treatment.

Conclusions

Despite the higher rate of obesity and extreme obesity in patients with prediabetes and T2D, ixekizumab was an efficacious treatment in treating patients with psoriasis.
When does doctor’s recommendation become patient’s resolution? The regulatory potential of procedural justice in the context of compliance with medical advice and the treatment process
Authors: Prusiński Tomasz
Published: January 2023

The main aim of the study was to find empirical evidence to answer the following question: If an important personal interest—namely, health and the prospect of a long life—is not enough to motivate a person to follow recommendations from doctors and medical experts, what factor plays a significant role? The author tested the regulatory potential of procedural justice in this context. The sample consisted of 210 participants, patients of independent primary healthcare facilities and specialist hospital outpatient clinics. The empirical data were analyzed by means of structural equation modeling (SEM). Seven SEM models were tested in the analyses. The adopted analytical strategy brought valuable results. The study supported the main hypothesized relationship, showing that procedural justice was a factor increasing the acceptance of and compliance with medical advice and doctor’s perceived competence. The results of analyses indicate that the fair treatment of patients in healthcare institutions can be regarded as a significant factor regulating patients’ health behavior. The procedural effect is significant for increasing patients’ positive evaluation of doctors’ competence. Also, the evaluation of a doctor as competent increases patient compliance.
Development and validation of a dynamic online nomogram for predicting acute kidney injury in cirrhotic patients upon ICU admission
Authors: Feng Lu-Huai , Lu Yang , Ren Shuang , Liang Hengkai , Wei Lu , Jiang Jianning
Published: January 2023

Background

Acute kidney injury (AKI) is one of the most common and deadly complications among cirrhotic patients at intensive care unit (ICU) admission. We aimed to develop and validate a simple and clinically useful dynamic nomogram for predicting AKI in cirrhotic patients upon ICU admission.

Methods

We analyzed the admission data of 4,375 patients with liver cirrhosis in ICU from 2008 to 2019 in the intensive care unit IV (MIMIC-IV) database. The eligible cirrhotic patients were non-randomly divided into derivation (n = 2,188) and validation (n = 2,187) cohorts at a ratio of 1:1, according to the order of admission. The least absolute shrinkage and selection operator regression model was used to identify independent predictors of AKI in the derivation cohort. A dynamic online nomogram was built using multivariate logistic regression analysis in the derivation cohort and then validated in the validation cohort. The C-index, calibration curve, and decision curve analysis were used to assess the nomogram’s discrimination, calibration, and clinical usefulness, respectively.

Results

The incidence of AKI in 4,375 patients was 71.3%. Ascites, chronic kidney disease, shock, sepsis, diuretic drugs, hepatic encephalopathy, bacterial infections, vasoactive drugs, admission age, total bilirubin, and blood urea nitrogen were identified using the multivariate logistic regression analysis as significant predictors of AKI upon ICU admission. In the derivation cohort, the model showed good discrimination (C-index, 0.786; 95% CI, 0.765–0.806) and good calibration. The model in the validation cohort yielded good discrimination (C-index, 0.774; 95% CI, 0.753–0.795) and good calibration. Decision curve analysis demonstrated that the dynamic online nomogram was clinically useful.

Conclusion

Our study presents a dynamic online nomogram that incorporates clinical predictors and can be conveniently used to facilitate the individualized prediction of AKI in cirrhotic patients upon ICU admission.
Prevalence of HDV infection in people living with HIV: Data from a multicenter Italian cohort
Authors: Nicolini Laura Ambra , Menzaghi Barbara , Ricci Elena , Pontali Emanuele , Cenderello Giovanni , Orofino Giancarlo , Cascio Antonio , Pellicanò Giovanni Francesco , Valsecchi Laura , Molteni Chiara , Vichi Francesca , Bonfanti Paolo , Di Biagio Antonio
Published: January 2023

Objectives

The development of novel antiviral agents active against Hepatitis Delta Virus (HDV) might change the natural history of chronic infection, reducing the risk for end-stage liver disease. People living with HIV (PWH) are at risk for bloodborne pathogens infection, but limited data on epidemiology of HDV infection is available in this setting. The aim of this study was to investigate HDV prevalence and attitude toward HDV testing and treatment in infectious diseases centers.

Methods

A cross sectional survey was performed among centers participating in the CISAI (Coordinamento Italiano per lo Studio dell’Allergia in Infezione da HIV) Group. The survey addressed anti-HDV prevalence and HDV-RNA detectability rates in PWH as well as perceived obstacles to treatment.

Results

Overall, responses from ten sites were collected. Among participating centers, 316 PWH with HBV chronic infection are currently followed. Of them, 15.2% had positive anti-HDV antibodies, while 13.9% were not tested yet. Overall, 17% of anti-HDV positive PWH tested at least once for HDV-RNA had active HDV infection, and 71% of them had advanced liver disease. Most infectious diseases centers intend to treat locally HDV infection with upcoming anti-HDV drugs, but some concerns exist regarding treatment schedule.

Discussion

HDV testing needs to be implemented in PWH. At present, few patients followed in the CISAI centers seem to be candidate to receive new direct active anti-HDV agents, but repeated HDV-RNA measures could change this proportion.
Novel and efficient method for the reconstruction of adenoviruses through isothermal assembly and its potential applications
Authors: Wen Ke , Resch Matthew D. , Mazboudi Ryan , Mulhall Maasz Hannah , Galarza Jose M.
Published: January 2023

Adenovirus based vectors are useful tools for vaccine development, gene therapy, and oncolytic virotherapy. Here we describe a novel approach for the genetic engineering of any portion of the adenovirus genome and the reconstruction of either fully replication competent or defective virions. This innovative strategy is rapid, effective and suitable for the manipulation of the entire genome broadening the spectrum of potential applications for the adenovirus system. Our strategy involved insertion of restriction enzyme recognition sequences absent in the native virus into the termini of the adenovirus genome in order to facilitate recovery. These restriction enzyme sites, together with the two inverted terminal repeats and packaging sequences, were synthesized and then subcloned into the pBR322 vector. The remaining internal portion of the adenovirus genome was separated and amplified via PCR into six segments, of which groups of two were joined together by PCR and then subcloned into pBR322 plasmids. During the PCR reaction, an overlap of 30–40 bp was added to the termini of the adjacent fragments, allowing for the subsequent isothermal assembly and correct orientation of all fragments. This approach allows for the genetic modification of each genomic fragment according to the specific research goals, (e.g., deletion, substitution, addition, etc.) To recreate the entire viral genome, the four engineered fragments (each comprised of two adenovirus genomic sections) as well as the pBR322 backbone, were reassembled into a single construct utilizing an isothermal assembly reaction. Finally, the reassembled plasmid containing the entire genome was linearized and transfected into HEK293 cells to recover the complete reconstructed adenoviral vector. Using this approach, we have successfully generated two recombinant reporter adenoviruses, one of human adenovirus serotype 14 and another of serotype 55. The E3 region was replaced by the reporter genes (GFP and Luciferase) to visualize and track the recovery process. Subsequent infection of A549 cells with these reconstructed adenovirus vectors demonstrated that they were replication competent. This method shortens the viral reconstruction process because the one-step isothermal assembly requires less than 4 days, and recombinant adenovirus recovery occurs within 10 days. This new method allows for single or multiple genetic modifications within any portion of the viral genome and can be used to construct or manipulate any adenovirus whose complete genome sequence is known.
Novel TLR7/8 agonists promote activation of HIV-1 latent reservoirs and human T and NK cells
Authors: Li Yangyang , Wang Zhisong , Hou Ying , Liu Xiaoyu , Hong Junxian , Shi Xuanling , Huang Xiaojie , Zhang Tong , Liao Xuebin , Zhang Linqi
Published: January 2023

Antiretroviral therapy can successfully suppress HIV-1 replication to undetectable levels but fails to eliminate latent and persistent HIV-1 reservoirs. Recent studies have focused on the immunomodulatory agents such as Toll-like receptor 7 and 8 (TLR7 and TLR8) capable of activating, thereby rendering the reservoir susceptible to antiretroviral inhibition and immune recognition and elimination. In this context, this study focused on generating a diverse repertoire of TLR7/8 agonists to identify more potent candidates for activating latent HIV-1 and immune cells’ response. Through combinational strategies of computer-aided design and biological characterization, 159 pyrido [3,2-d] pyrimidine and pyridine-2-amine-based derivatives were synthesized. Of which, two TLR7/8 dual and one TLR8-specific agonists with exceptionally high potency in activating HIV-1 latent reservoirs in cell lines and PBMCs of patients with persistent and durable virologic controls were identified. Particularly, these agonists appeared to enhance NK and T cells activity, which were correlated with the degree of surface activation markers. The outcome of this study highlights the remarkable potential of TLR7/8 agonists in simultaneously activating HIV-1 from the latently infected cells and augmenting immune effector cells.
Prevalence and contamination patterns of Listeria monocytogenes in Pleurotus eryngii (king oyster mushroom) production plants
Authors: Xu Jiang , Wu Shi , Liu Ming , Xiao Zitian , Peng Yangyang , He Huanqing
Published: January 2023

Listeria monocytogenes is a major foodborne pathogen that is well-known for its high mortality rate upon infection. In recent years, the edible mushroom has also been found to be an important source of L. monocytogenes, but the contamination sources in Pleurotus eryngii (the king oyster mushroom) were unclear. In this study, a total of 203 edible mushrooms and environmental samples from four P. eryngii production plants were obtained. As a result, 29 samples (14.3%) were positive for L. monocytogenes, including eight mushroom samples (13.3%, 8/60) and 21 associated environmental samples (14.7%, 21/143). The contamination of L. monocytogenes in plants A and B was more severe and was likely to originate from the mycelium stimulation machine. The isolates belonged to serogroups II.1 (4b-4d-4e), I.1 (1/2a-3a), and I.2 (1/2c-3c), and multilocus sequence typing (MLST) revealed that these L. monocytogenes strains belonged to five different sequence types (ST3, ST121, ST9, ST87, and ST224). The ST121 and ST3 isolates were only found in plants A and B, respectively. The isolates were carried by hly (29/29, 100%), inlB (23/29, 79.3%), inlA (29/29, 100%), inlC (29/29, 100%), inlJ (29/29, 100%), actA (19/29, 65.5%), iap (29/29, 100%), plcA (26/29, 100%), plcB (29/29, 100%), prfA (27/29, 93.1%), and mpl (29/29, 100%). Further study of inlA sequencing showed that 65.5% of strains (19/29) contained full-length InlA that was required for host cell invasion, whereas the mutation led to premature stop codons (PMSCs) at position 492 (type 6) on inlA alleles. All isolates in this survey were sensitive to gentamicin, kanamycin, sulbactam/ampicillin, trimethoprim-sulfamethoxazole, tetracycline, and doxycycline. The drug with the highest resistance is rifampicin (37.9%), followed by penicillin (24.1%) and ciprofloxacin (10.3%). Most multiply resistant strains are isolated from raw materials and equipment of the P. eryngii processing lines. Our study reflects the contamination patterns and potential risk of L. monocytogenes infection in P. eryngii production plants. The persistence of specific L. monocytogenes isolates (such as ST121 and ST3) may assist with contamination. In accordance with these results, the control of L. monocytogenes should focus on the environmental materials, especially in the mycelium stimulation stage. However, effective Listeria monitoring programs will allow for the improved development of Listeria control measures to minimize cross-contamination in the processing of P. eryngii.
Mycobacterial protein PE_PGRS30 induces macrophage apoptosis through prohibitin 2 mitochondrial function interference
Authors: Matsumura Kazunori , Takaki Satoshi , Kirikae Teruo
Published: January 2023

PE_PGRS30 belongs to the PE_PGRS protein family and is characterized by a conserved Pro-Glu (PE) domain and a typically polymorphic GC-rich sequence (PGRS) domain. PE_PGRS30 is a virulence factor of Mycobacterium tuberculosis that induces macrophage cell death. We found that RAW264.7 cells and murine alveolar macrophages underwent apoptosis in response to PE_PGRS30. The host protein prohibitin 2 (PHB2) was identified as a target molecule. PE_PGRS30 and PHB2 interact via the PGRS domain and mitochondrial targeting sequence, respectively. PHB2 overexpression reduced macrophage apoptosis in response to PE_PGRS30. PE_PGRS30 co-localized with PHB2, not in mitochondria, but in lysosomes. The maintenance of mitochondrial structure by PHB2 was impaired in response to the PGRS domain. These results indicated that PE_PGRS30 reduces PHB2 in mitochondria, resulting in mitochondrial dysfunction and cellular apoptosis.
Dopaminergic regulation of hippocampal plasticity, learning, and memory
Authors: Tsetsenis Theodoros , Broussard John I. , Dani John A.
Published: January 2023

The hippocampus is responsible for encoding behavioral episodes into short-term and long-term memory. The circuits that mediate these processes are subject to neuromodulation, which involves regulation of synaptic plasticity and local neuronal excitability. In this review, we present evidence to demonstrate the influence of dopaminergic neuromodulation on hippocampus-dependent memory, and we address the controversy surrounding the source of dopamine innervation. First, we summarize historical and recent retrograde and anterograde anatomical tracing studies of direct dopaminergic projections from the ventral tegmental area and discuss dopamine release from the adrenergic locus coeruleus. Then, we present evidence of dopaminergic modulation of synaptic plasticity in the hippocampus. Plasticity mechanisms are examined in brain slices and in recordings from in vivo neuronal populations in freely moving rodents. Finally, we review pharmacological, genetic, and circuitry research that demonstrates the importance of dopamine release for learning and memory tasks while dissociating anatomically distinct populations of direct dopaminergic inputs.
Diagnostic performance of dynamic 3D magnetic resonance angiography in daily practice for the detection of intracranial arteriovenous shunts in patients with non-traumatic intracranial hemorrhage
Authors: Roumi Arnaud , Ben Hassen Wagih , Hmeydia Ghazi , Posener Sacha , Pallud Johan , Sharshar Tarek , Calvet David , Mas Jean-Louis , Baron Jean-Claude , Oppenheim Catherine , Naggara Olivier , Turc Guillaume
Published: January 2023

Introduction

Identification of treatable causes of intracranial hemorrhage (ICH) such as intracranial arteriovenous shunt is crucial to prevent recurrence. However, diagnostic approaches vary considerably across centers, partly because of limited knowledge of the diagnostic performance of first-line vascular imaging techniques. We assessed the diagnostic performance of dynamic three-dimensional magnetic resonance angiography (dynamic 3D MRA) in daily practice to detect intracranial arteriovenous shunts in ICH patients against subsequent digital subtraction angiography (DSA) as reference standard.

Methods

We reviewed all adult patients who underwent first-line dynamic 3D MRA and subsequent DSA for non-traumatic ICH between January 2016 and September 2021 in a tertiary center. Sensitivity, specificity, accuracy, positive and negative predictive values of dynamic 3D MRA for the detection of intracranial arteriovenous shunt were calculated with DSA as reference standard.

Results

Among 104 included patients, 29 (27.9%) had a DSA-confirmed arteriovenous shunt [19 pial arteriovenous malformations, 10 dural arteriovenous fistulae; median onset-to-DSA: 17 (IQR: 3–88) days]. The sensitivity and specificity of dynamic 3D MRA [median onset-to-dynamic 3D MRA: 14 (3–101) h] for the detection of intracranial arteriovenous shunt were 66% (95% CI: 48–83) and 91% (95% CI: 84–97), respectively. The corresponding accuracy, positive and negative predictive values were 84% (95% CI: 77–91), 73% (95% CI: 56–90), and 87% (95% CI: 80–95), respectively.

Conclusion

This study suggests that although first-line evaluation with dynamic 3D MRA may be helpful for the detection of intracranial arteriovenous shunts in patients with ICH, additional vascular imaging work-up should not be withheld if dynamic 3D MRA is negative. Comparative prospective studies are needed to determine the best imaging strategy to diagnose arteriovenous shunts after non-traumatic ICH.
Opportunities and barriers to translating the hibernation phenotype for neurocritical care
Authors: Drew Kelly L. , Bhowmick Saurav , Laughlin Bernard W. , Goropashnaya Anna V. , Tøien Øivind , Sugiura M. Hoshi , Wong Ardy , Pourrezaei Kambiz , Barati Zeinab , Chen Chao-Yin
Published: January 2023

Targeted temperature management (TTM) is standard of care for neonatal hypoxic ischemic encephalopathy (HIE). Prevention of fever, not excluding cooling core body temperature to 33°C, is standard of care for brain injury post cardiac arrest. Although TTM is beneficial, HIE and cardiac arrest still carry significant risk of death and severe disability. Mammalian hibernation is a gold standard of neuroprotective metabolic suppression, that if better understood might make TTM more accessible, improve efficacy of TTM and identify adjunctive therapies to protect and regenerate neurons after hypoxic ischemia brain injury. Hibernating species tolerate cerebral ischemia/reperfusion better than humans and better than other models of cerebral ischemia tolerance. Such tolerance limits risk of transitions into and out of hibernation torpor and suggests that a barrier to translate hibernation torpor may be human vulnerability to these transitions. At the same time, understanding how hibernating mammals protect their brains is an opportunity to identify adjunctive therapies for TTM. Here we summarize what is known about the hemodynamics of hibernation and how the hibernating brain resists injury to identify opportunities to translate these mechanisms for neurocritical care.
Cerebral microdialysis and glucopenia in traumatic brain injury: A review
Authors: Sharma Himanshu , McGinnis John P. , Kabotyanski Katherine E. , Gopinath Shankar P. , Goodman Jerry C. , Robertson Claudia , Cruz Navarro Jovany
Published: January 2023

Traditionally, intracranial pressure (ICP) and partial brain tissue oxygenation (PbtO2) have been the primary invasive intracranial measurements used to guide management in patients with severe traumatic brain injury (TBI). After injury however, the brain develops an increased metabolic demand which may require an increment in the oxidative metabolism of glucose. Simultaneously, metabolic, and electrical dysfunction can lead to an inability to meet these demands, even in the absence of ischemia or increased intracranial pressure. Cerebral microdialysis provides the ability to accurately measure local concentrations of various solutes including lactate, pyruvate, glycerol and glucose. Experimental and clinical data demonstrate that such measurements of cellular metabolism can yield critical missing information about a patient's physiologic state and help limit secondary damage. Glucose management in traumatic brain injury is still an unresolved question. As cerebral glucose metabolism may be uncoupled from systemic glucose levels due to the metabolic dysfunction, measurement of cerebral extracellular glucose concentrations could provide more predictive information and prove to be a better biomarker to avoid secondary injury of at-risk brain tissue. Based on data obtained from cerebral microdialysis, specific interventions such as ICP-directed therapy, blood glucose increment, seizure control, and/or brain oxygen optimization can be instituted to minimize or prevent secondary insults. Thus, microdialysis measurements of parenchymal metabolic function provides clinically valuable information that cannot be obtained by other monitoring adjuncts in the standard ICU setting.
Pituitary stalk changes on magnetic resonance imaging following pituitary adenoma resection using a transsphenoidal approach
Authors: Zhang Huijian , Zhang Shuai , Shang Mingchao , Wang Jiaxing , Wei Liangfeng , Wang Shousen
Published: January 2023

Objective

We aimed to investigate the magnetic resonance imaging (MRI) findings and clinical significance of position and changes in morphology of the pituitary stalk following pituitary adenoma (PA) resection using a transsphenoidal approach.

Methods

We collected clinical and MRI data of 108 patients with PA after transsphenoidal surgery. Diameter, length, and coronal deviation of the pituitary stalk were measured pre-, post-, and mid-term post-operatively, to observe pituitary stalk morphology.

Results

Of 108 patients, 53 pituitary stalks were recognisable pre-operatively. The angle between the pituitary stalk and the median line was 7.22°-50.20° (average, 25.85°) in 22 patients with left-sided pituitary stalks and 5.32°-64.05° (average, 21.63°) in 20 patients with right-sided pituitary stalks. Of 42 patients with preoperative pituitary stalk deviation, 41 had an early postoperative recovery and 1 had increased deviation. In the mid-term postoperative period, 21 of 42 patients had pituitary stalks located centrally. In 53 patients, the pituitary stalk length was 1.41–11.74 mm (mean, 6.12 mm) pre-operatively, 3.61–11.63 mm (mean, 6.93 mm) in the early postoperative period, and 5.37–17.57 mm (mean, 8.83 mm) in the mid-term postoperative period. In the early postoperative period, 58 (53.70%) patients had posterior pituitary bright spots (PPBS) and 28 (25.92%) had diabetes insipidus (DI).

Conclusion

Pre-operatively, the pituitary stalk was compressed and thinned. Post-operatively, it could be stretched to a “normal state”, and its position showed a gradual centring trend. Post-operatively, the length of the pituitary stalk gradually increased. The PPBS in the early postoperative period negatively correlated with postoperative DI.
Case report: Adult-onset limb girdle muscular dystrophy in sibling pair due to novel homozygous LAMA2 missense variant
Authors: Katz Matthew , Waddell Leigh B. , Yuen Michaela , Bryen Samantha J. , Oates Emily , Garton Fleur C. , Robertson Thomas , Henderson Robert David , Cooper Sandra T. , McCombe Pamela A.
Published: January 2023

Recessive pathogenic variants in the laminin subunit alpha 2 (LAMA2) gene cause a spectrum of disease ranging from severe congenital muscular dystrophy to later-onset limb girdle muscular dystrophy (LGMDR23). The phenotype of LGMDR23 is characterized by slowly progressive proximal limb weakness, contractures, raised creatine kinase, and sometimes distinctive cerebral white matter changes and/or epilepsy. We present two siblings, born to consanguineous parents, who developed adult-onset LGMDR23 associated with typical cerebral white matter changes and who both later developed dementia. The male proband also had epilepsy and upper motor neuron signs when he presented at age 72. Merosin immunohistochemistry and Western blot on muscle biopsies taken from both subjects was normal. Whole exome sequencing revealed a previously unreported homozygous missense variant in LAMA2 [Chr6(GRCh38):g.129297734G>A; NM_000426.3:c.2906G>A; p.(Cys969Tyr)] in the proband. The same homozygous LAMA2 variant was confirmed by Sanger sequencing in the proband's affected sister. These findings expand the genotypic and phenotypic spectrum of LGMDR23.