bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization and genome analysis of phage vB_KpnS_SXFY507 against Klebsiella pneumoniae and efficacy assessment in Galleria mellonella larvae
Authors: Feng Jiao , Li Fei , Sun Li , Dong Lina , Gao Liting , Wang Han , Yan Liyong , Wu Changxin
Published: January 2023

Carbapenem-resistant Klebsiella pneumoniae is one of the primary bacterial pathogens that pose a significant threat to global public health because of the lack of available therapeutic options. Phage therapy shows promise as a potential alternative to current antimicrobial chemotherapies. In this study, we isolated a new Siphoviridae phage vB_KpnS_SXFY507 against KPC-producing K. pneumoniae from hospital sewage. It had a short latent period of 20 min and a large burst size of 246 phages/cell. The host range of phage vB_KpnS_SXFY507 was relatively broad. It has a wide range of pH tolerance and high thermal stability. The genome of phage vB_KpnS_SXFY507 was 53,122 bp in length with a G + C content of 49.1%. A total of 81 open-reading frames (ORFs) and no virulence or antibiotic resistance related genes were involved in the phage vB_KpnS_SXFY507 genome. Phage vB_KpnS_SXFY507 showed significant antibacterial activity in vitro. The survival rate of Galleria mellonella larvae inoculated with K. pneumoniae SXFY507 was 20%. The survival rate of K. pneumonia-infected G. mellonella larvae was increased from 20 to 60% within 72 h upon treatment with phage vB_KpnS_SXFY507. In conclusion, these findings indicate that phage vB_KpnS_SXFY507 has the potential to be used as an antimicrobial agent for the control of K. pneumoniae.
Emergence of microbial resistance against nanoparticles: Mechanisms and strategies
Authors: Kamat Siya , Kumari Madhuree
Published: January 2023

Antimicrobial nanoparticles have gained the status of a new generation of drugs that can kill bacterial pathogens by multiple means; however, nanoparticle resistance acquired by some bacterial pathogens has evoked a cause of concern. Several reports suggested that bacteria can develop nanoparticles, specifically metal nanoparticle resistance, by mechanisms: nanoparticle transformation-induced oxidative stress, membrane alterations, reversible adaptive resistance, irreversible modifications to cell division, and a change in bacterial motility and resistance. Surface properties, concentration and aggregation of nanoparticles, biofilm forming and metal exclusion capacity, and R plasmid and flagellin synthesis by bacteria are crucial factors in the development of nanoparticle resistance in bacteria. Studies reported the resistance reversal by modifying the surface corona of nanoparticles or inhibiting flagellin production by bacterial pathogens. Furthermore, strict regulation regarding the use and disposal of nano-waste across the globe, the firm knowledge of microbe–nanoparticle interaction, and the regulated disposal of nanoparticles in soil and water is required to prevent microbes from developing nanoparticle resistance.
Structure-guided design of a potent Clostridioides difficile toxin A inhibitor
Authors: Hussack Greg , Rossotti Martin A. , van Faassen Henk , Murase Tomohiko , Eugenio Luiz , Schrag Joseph D. , Ng Kenneth K.-S. , Tanha Jamshid
Published: January 2023

Crystal structures of camelid heavy-chain antibody variable domains (VHHs) bound to fragments of the combined repetitive oligopeptides domain of Clostridioides difficile toxin A (TcdA) reveal that the C-terminus of VHH A20 was located 30 Å away from the N-terminus of VHH A26. Based on this observation, we generated a biparatopic fusion protein with A20 at the N-terminus, followed by a (GS)6 linker and A26 at the C-terminus. This A20-A26 fusion protein shows an improvement in binding affinity and a dramatic increase in TcdA neutralization potency (>330-fold [IC50]; ≥2,700-fold [IC99]) when compared to the unfused A20 and A26 VHHs. A20-A26 also shows much higher binding affinity and neutralization potency when compared to a series of control antibody constructs that include fusions of two A20 VHHs, fusions of two A26 VHHs, a biparatopic fusion with A26 at the N-terminus and A20 at the C-terminus (A26-A20), and actoxumab. In particular, A20-A26 displays a 310-fold (IC50) to 29,000-fold (IC99) higher neutralization potency than A26-A20. Size-exclusion chromatography-multiangle light scattering (SEC-MALS) analyses further reveal that A20-A26 binds to TcdA with 1:1 stoichiometry and simultaneous engagement of both A20 and A26 epitopes as expected based on the biparatopic design inspired by the crystal structures of TcdA bound to A20 and A26. In contrast, the control constructs show varied and heterogeneous binding modes. These results highlight the importance of molecular geometric constraints in generating highly potent antibody-based reagents capable of exploiting the simultaneous binding of more than one paratope to an antigen.
Vanoxerine kills mycobacteria through membrane depolarization and efflux inhibition
Authors: Kingdon Alexander D. H. , Meosa-John Asti-Rochelle , Batt Sarah M. , Besra Gurdyal S.
Published: January 2023

Mycobacterium tuberculosis is a deadly pathogen, currently the leading cause of death worldwide from a single infectious agent through tuberculosis infections. If the End TB 2030 strategy is to be achieved, additional drugs need to be identified and made available to supplement the current treatment regimen. In addition, drug resistance is a growing issue, leading to significantly lower treatment success rates, necessitating further drug development. Vanoxerine (GBR12909), a dopamine re-uptake inhibitor, was recently identified as having anti-mycobacterial activity during a drug repurposing screening effort. However, its effects on mycobacteria were not well characterized. Herein, we report vanoxerine as a disruptor of the membrane electric potential, inhibiting mycobacterial efflux and growth. Vanoxerine had an undetectable level of resistance, highlighting the lack of a protein target. This study suggests a mechanism of action for vanoxerine, which will allow for its continued development or use as a tool compound.
Biochemical characterization and identification of ferulenol and embelin as potent inhibitors of malate:quinone oxidoreductase from Campylobacter jejuni
Authors: Kabongo Augustin Tshibaka , Acharjee Rajib , Sakura Takaya , Bundutidi Gloria Mavinga , Hartuti Endah Dwi , Davies Cadi , Gundogdu Ozan , Kita Kiyoshi , Shiba Tomoo , Inaoka Daniel Ken
Published: January 2023

Campylobacter jejuni infection poses a serious global threat to public health. The increasing incidence and antibiotic resistance of this bacterial infection have necessitated the adoption of various strategies to curb this trend, primarily through developing new drugs with new mechanisms of action. The enzyme malate:quinone oxidoreductase (MQO) has been shown to be essential for the survival of several bacteria and parasites. MQO is a peripheral membrane protein that catalyses the oxidation of malate to oxaloacetate, a crucial step in the tricarboxylic acid cycle. In addition, MQO is involved in the reduction of the quinone pool in the electron transport chain and thus contributes to cellular bioenergetics. The enzyme is an attractive drug target as it is not conserved in mammals. As a preliminary step in assessing the potential application of MQO from C. jejuni (CjMQO) as a new drug target, we purified active recombinant CjMQO and conducted, for the first time, biochemical analyses of MQO from a pathogenic bacterium. Our study showed that ferulenol, a submicromolar mitochondrial MQO inhibitor, and embelin are nanomolar inhibitors of CjMQO. We showed that both inhibitors are mixed-type inhibitors versus malate and noncompetitive versus quinone, suggesting the existence of a third binding site to accommodate these inhibitors; indeed, such a trait appears to be conserved between mitochondrial and bacterial MQOs. Interestingly, ferulenol and embelin also inhibit the in vitro growth of C. jejuni, supporting the hypothesis that MQO is essential for C. jejuni survival and is therefore an important drug target.
Defining the role of Interleukin-6 for the development of perioperative neurocognitive disorders: Evidence from clinical and preclinical studies
Authors: Barreto Chang Odmara L. , Maze Mervyn
Published: January 2023

For most, staying “mentally sharp” as they age is a very high priority that may be thwarted by the consequences of a postoperative complication unrelated to the disorder which necessitated the surgical intervention. Perioperative neurocognitive disorder (PND) is an overarching term for cognitive impairment in surgical patients, that includes conditions from delirium to dementia, affecting more than 7 million patients annually in the US, and which threatens both functional independence and life. Clinical trials and meta-analyses have identified the association between PNDs and increased perioperative levels of Interleukin-6 (IL-6), a pleiotropic cytokine that is both necessary and sufficient for postoperative memory decline in a preclinical model of PND. Recently, we reported that, in adult male wild-type mice subjected to tibial fracture under general anesthesia, IL-6 trans-signaling in hippocampal CA1 neurons mediates surgery-induced memory impairment. As there are no therapeutic options for preventing or reversing PNDs, patients and their caregivers, as well as the healthcare industry, endure staggering costs. Olamkicept, a highly selective IL-6 trans-signaling blocker has shown to be efficacious and safe in clinical trials involving patients with inflammatory bowel disease, another condition for which IL-6 trans-signaling is the mediating mechanism. Subject to a demonstration that olamkicept is effective in preventing cognitive impairment in vulnerable (aged and Alzheimer’s Disease) preclinical PND models, clinical trials involving aged and/or cognitively impaired surgical patients should be undertaken to study olamkicept’s utility for PNDs.
Brain blood vessel autoantibodies in patients with NMDA and GABAA receptor encephalitis: identification of unconventional Myosin-X as target antigen
Authors: Li Lucie Y. , Kreye Jakob , Burek Malgorzata , Cordero-Gomez César , Barthel Paula C. , Sánchez-Sendín Elisa , Kornau Hans-Christian , Schmitz Dietmar , Scharf Madeleine , Meybohm Patrick , Reincke S. Momsen , Prüss Harald , Höltje Markus
Published: January 2023

Introduction: The antibody repertoire from CSF-derived antibody-secreting cells and memory B-cells in patients with encephalitis contains a considerable number of antibodies that do not target the disease-defining autoantigen such as the GABA or NMDA receptors. This study focuses on the functional relevance of autoantibodies to brain blood vessels in patients with GABAA and NMDA receptor encephalitis.

Methods: We tested 149 human monoclonal IgG antibodies from the cerebrospinal fluid of six patients with different forms of autoimmune encephalitis on murine brain sections for reactivity to blood vessels using immunohistochemistry. Positive candidates were tested for reactivity with purified brain blood vessels, effects on transendothelial electrical resistance (TEER), and expression of tight junction proteins as well as gene regulation using human brain microvascular endothelial hCMEC/D3 cells as in vitro blood-brain barrier model. One blood-vessel reactive antibody was infused intrathecally by pump injection in mice to study in vivo binding and effects on tight junction proteins such as Occludin. Target protein identification was addressed using transfected HEK293 cells.

Results: Six antibodies reacted with brain blood vessels, three were from the same patient with GABAAR encephalitis, and the other three were from different patients with NMDAR encephalitis. One antibody from an NMDAR encephalitis patient, mAb 011-138, also reacted with cerebellar Purkinje cells. In this case, treatment of hCMEC/D3 cells resulted in decreased TEER, reduced Occludin expression, and mRNA levels. Functional relevance in vivo was confirmed as Occludin downregulation was observed in mAb 011-138-infused animals. Unconventional Myosin-X was identified as a novel autoimmune target for this antibody.

Discussion: We conclude that autoantibodies to blood vessels occur in autoimmune encephalitis patients and might contribute to a disruption of the blood-brain barrier thereby suggesting a potential pathophysiological relevance of these antibodies.
APPsα rescues CDK5 and GSK3β dysregulation and restores normal spine density in Tau transgenic mice
Authors: Baltissen Danny , Bold Charlotte S. , Rehra Lena , Banićević Marija , Fricke Justus , Just Jennifer , Ludewig Susann , Buchholz Christian J. , Korte Martin , Müller Ulrike C.
Published: January 2023

The Tau protein can be phosphorylated by numerous kinases. In Alzheimer’s disease (AD) hyperphosphorylated Tau species accumulate as neurofibrillary tangles that constitute a major hallmark of AD. AD is further characterized by extracellular Aβ plaques, derived from the β-amyloid precursor protein APP. Whereas Aβ is produced by amyloidogenic APP processing, APP processing along the competing non-amyloidogenic pathway results in the secretion of neurotrophic and synaptotrophic APPsα. Recently, we demonstrated that APPsα has therapeutic effects in transgenic AD model mice and rescues Aβ-dependent impairments. Here, we examined the potential of APPsα to regulate two major Tau kinases, GSK3β and CDK5 in THY-Tau22 mice, a widely used mouse model of tauopathy. Immunohistochemistry revealed a dramatic increase in pathologically phosphorylated (AT8 and AT180) or misfolded Tau species (MC1) in the hippocampus of THY-Tau22 mice between 3 and 12 months of age. Using a highly sensitive radioactive kinase assay with recombinant human Tau as a substrate and immunoblotting, we demonstrate an increase in GSK3β and CDK5 activity in the hippocampus of THY-Tau22 mice. Interestingly, AAV-mediated intracranial expression of APPsα in THY-Tau22 mice efficiently restored normal GSK3β and CDK5 activity. Western blot analysis revealed upregulation of the CDK5 regulatory proteins p35 and p25, indicating CDK5 hyperactivation in THY-Tau22 mice. Strikingly, AAV-APPsα rescued p25 upregulation to wild-type levels even at stages of advanced Tau pathology. Sarkosyl fractionation used to study the abundance of soluble and insoluble phospho-Tau species revealed increased soluble AT8-Tau and decreased insoluble AT100-Tau species upon AAV-APPsα injection. Moreover, AAV-APPsα reduced misfolded (MC1) Tau species, particularly in somatodendritic compartments of CA1 pyramidal neurons. Finally, we show that AAV-APPsα upregulated PSD95 expression and rescued deficits in spine density of THY-Tau22 mice. Together our findings suggest that APPsα holds therapeutic potential to mitigate Tau-induced pathology.
Gene panel analysis of 119 index patients with suspected periodic paralysis in Japan
Authors: Yuan Jun-Hui , Higuchi Yujiro , Hashiguchi Akihiro , Ando Masahiro , Yoshimura Akiko , Nakamura Tomonori , Hiramatsu Yu , Sakiyama Yusuke , Takashima Hiroshi
Published: January 2023

Introduction

Genetic factors are recognized as the major reason for patients with periodic paralysis. The goal of this study was to determine the genetic causes of periodic paralysis in Japan.

Methods

We obtained a Japanese nationwide case series of 119 index patients (108 men and 11 women) clinically suspected of periodic paralysis, and a gene panel analysis, targeting CACNA1S, SCN4A, and KCNJ2 genes, was conducted.

Results

From 34 cases, 25 pathogenic/likely pathogenic/unknown significance variants were detected in CACNA1S (nine cases), SCN4A (19 cases), or KCNJ2 (six cases), generating a molecular diagnostic rate of 28.6%. In total, seven variants have yet been found linked to periodic paralysis previously. The diagnostic yield of patients with hypokalemic and hyperkalemic periodic paralyzes was 26.2 (17/65) and 32.7% (17/52), respectively. A considerably higher yield was procured from patients with than without positive family history (18/25 vs. 16/94), onset age ≤20 years (24/57 vs. 9/59), or recurrent paralytic attacks (31/94 vs. 3/25).

Discussion

The low molecular diagnostic rate and specific genetic proportion of the present study highlight the etiological complexity of patients with periodic paralysis in Japan.
Givinostat for Becker muscular dystrophy: A randomized, placebo-controlled, double-blind study
Authors: Comi Giacomo P. , Niks Erik H. , Vandenborne Krista , Cinnante Claudia M. , Kan Hermien E. , Willcocks Rebecca J. , Velardo Daniele , Magri Francesca , Ripolone Michela , van Benthem Jules J. , van de Velde Nienke M. , Nava Simone , Ambrosoli Laura , Cazzaniga Sara , Bettica Paolo U.
Published: January 2023

Objective

No treatments are approved for Becker muscular dystrophy (BMD). This study investigated the efficacy and safety of givinostat, a histone deacetylase pan-inhibitor, in adults with BMD.

Methods

Males aged 18–65 years with a diagnosis of BMD confirmed by genetic testing were randomized 2:1 to 12 months treatment with givinostat or placebo. The primary objective was to demonstrate statistical superiority of givinostat over placebo for mean change from baseline in total fibrosis after 12 months. Secondary efficacy endpoints included other histological parameters, magnetic resonance imaging and spectroscopy (MRI and MRS) measures, and functional evaluations.

Results

Of 51 patients enrolled, 44 completed treatment. At baseline, there was greater disease involvement in the placebo group than givinostat, based on total fibrosis (mean 30.8 vs. 22.8%) and functional endpoints. Mean total fibrosis did not change from baseline in either group, and the two groups did not differ at Month 12 (least squares mean [LSM] difference 1.04%; p = 0.8282). Secondary histology parameters, MRS, and functional evaluations were consistent with the primary. MRI fat fraction in whole thigh and quadriceps did not change from baseline in the givinostat group, but values increased with placebo, with LSM givinostat–placebo differences at Month 12 of −1.35% (p = 0.0149) and −1.96% (p = 0.0022), respectively. Adverse events, most mild or moderate, were reported by 88.2% and 52.9% patients receiving givinostat and placebo.

Conclusion

The study failed to achieve the primary endpoint. However, there was a potential signal from the MRI assessments suggesting givinostat could prevent (or slow down) BMD disease progression.
Time since onset might be of essence: A recommendation to assess the effects of combination of non-pharmacological neuromodulatory approaches at early stage since symptoms onset
Authors: Agostinho Mariana , Weissman Fogel Irit , Treister Roi
Published: January 2023

In the past decade researchers began to assess the potential beneficial effects of non-invasive brain stimulation (NIBS) combined with a behavioral task as a treatment approach for various medical conditions. Transcranial direct current stimulation (tDCS) applied to the motor cortex combined with another treatment approach has been assessed as analgesic treatment in neuropathic and non-neuropathic pain conditions, and was found to exert only modest pain relief. Our group results show that combined tDCS and mirror therapy dramatically reduced acute phantom limb pain intensity with long-lasting effects, potentially preventing pain chronification. A review of the scientific literature indicates that our approach differs from that of others: We applied the intervention at the acute stage of the disease, whereas other studies applied the intervention in patients whose disease had already been established. We suggest that the timing of administration of the combined intervention is critical. Unlike in patients with chronic painful condition, in which the maladaptive plasticity associated with pain chronification and chronicity is well-consolidated, early treatment at the acute pain stage may be more successful in counterbalancing the not-yet consolidated maladaptive plasticity. We encourage the research community to test our hypothesis, both in the treatment of pain, and beyond.
Abnormal posterior semicircular canal function may predict poor prognosis in patients with severe and profound ISSNHL
Authors: Yang Yang , Gao Dekun , Ma Xiaobao , Shen Jiali , Zhang Qin , Chen Xiangping , Zhang Qing , Jin Yulian , Chen Jianyong , Duan Maoli , Yang Jun
Published: January 2023

Background

Severe and profound idiopathic sudden sensorineural hearing loss (ISSNHL) generally leads to unfavorable prognosis, and has a considerable impact on patient quality of life. However, related prognostic factors remain controversial.

Objective

To elaborate the relationship between vestibular function impairment and the prognosis of patients with severe and profound ISSNHL, and investigated the relevant factors affecting prognosis.

Methods

Forty-nine patients with severe and profound ISSNHL were divided into good outcome group [GO group, pure tone average (PTA) improvement > 30 dB] and poor outcome group (PO group, PTA improvement ≤ 30 dB) according to hearing outcomes. The clinical characteristics and the proportion of abnormal vestibular function tests in these two groups were analyzed by univariate analysis, and multivariable logistic regression analysis was performed for parameters with significant differences.

Results

Forty-six patients had abnormal vestibular function test results (46/49, 93.88%). The number of vestibular organ injuries was 1.82 ± 1.29 in all patients, with higher mean numbers in PO group (2.22 ± 1.37) than in GO group (1.32 ± 0.99). Univariate analysis revealed no statistical differences between the GO and PO groups in terms of gender, age, side of the affected ear, vestibular symptoms, delayed treatment, instantaneous gain value of horizontal semicircular canal, regression gain value of vertical semicircular canal, abnormal rates of oVEMP, cVEMP, caloric test and vHIT in anterior and horizontal semicircular canal, however, significant differences were found in the initial hearing loss and abnormal vHIT of posterior semicircular canal (PSC). Multivariable analysis revealed that only PSC injury was an independent risk factor for predicting the prognosis of patients with severe and profound ISSNHL. Patients with abnormal PSC function had worse initial hearing impairment and prognosis than patients with normal PSC function. The sensitivity of abnormal PSC function in predicting poor prognosis in patients with severe and profound ISSNHL was 66.67%, specificity was 95.45%, and positive and negative likelihood ratios were 14.65 and 0.35, respectively.

Conclusion

Abnormal PSC function is an independent risk factor for poor prognosis in patients with severe and profound ISSNHL. Ischemia in the branches of the internal auditory artery supplying the cochlea and PSC may be the underlying mechanism.
The classification of brain network for major depressive disorder patients based on deep graph convolutional neural network
Authors: Zhu Manyun , Quan Yu , He Xuan
Published: January 2023

Introduction

The early diagnosis of major depressive disorder (MDD) is very important for patients that suffer from severe and irreversible consequences of depression. It has been indicated that functional connectivity (FC) analysis based on functional magnetic resonance imaging (fMRI) data can provide valuable biomarkers for clinical diagnosis. However, previous studies mainly focus on brain disease classification in small sample sizes, which may lead to dramatic divergences in classification accuracy.

Methods

This paper attempts to address this limitation by applying the deep graph convolutional neural network (DGCNN) method on a large multi-site MDD dataset. The resting-state fMRI data are acquired from 830 MDD patients and 771 normal controls (NC) shared by the REST-meta-MDD consortium.

Results

The DGCNN model trained with the binary network after thresholding, identified MDD patients from normal controls and achieved an accuracy of 72.1% with 10-fold cross-validation, which is 12.4%, 9.8%, and 7.6% higher than SVM, RF, and GCN, respectively. Moreover, the process of dataset reading and model training is faster. Therefore, it demonstrates the advantages of the DGCNN model with low time complexity and sound classification performance.

Discussion

Based on a large, multi-site dataset from MDD patients, the results expressed that DGCNN is not an extremely accurate method for MDD diagnosis. However, there is an improvement over previous methods with our goal of better understanding brain function and ultimately providing a biomarker or diagnostic capability for MDD diagnosis.
Quality control practices in FMRI analysis: Philosophy, methods and examples using AFNI
Authors: Reynolds Richard C. , Taylor Paul A. , Glen Daniel R.
Published: January 2023

Quality control (QC) is a necessary, but often an under-appreciated, part of FMRI processing. Here we describe procedures for performing QC on acquired or publicly available FMRI datasets using the widely used AFNI software package. This work is part of the Research Topic, “Demonstrating Quality Control (QC) Procedures in fMRI.” We used a sequential, hierarchical approach that contained the following major stages: (1) GTKYD (getting to know your data, esp. its basic acquisition properties), (2) APQUANT (examining quantifiable measures, with thresholds), (3) APQUAL (viewing qualitative images, graphs, and other information in systematic HTML reports) and (4) GUI (checking features interactively with a graphical user interface); and for task data, and (5) STIM (checking stimulus event timing statistics). We describe how these are complementary and reinforce each other to help researchers stay close to their data. We processed and evaluated the provided, publicly available resting state data collections (7 groups, 139 total subjects) and task-based data collection (1 group, 30 subjects). As specified within the Topic guidelines, each subject’s dataset was placed into one of three categories: Include, exclude or uncertain. The main focus of this paper, however, is the detailed description of QC procedures: How to understand the contents of an FMRI dataset, to check its contents for appropriateness, to verify processing steps, and to examine potential quality issues. Scripts for the processing and analysis are freely available.
An in vitro analysis of how lactose modifies the gut microbiota structure and function of adults in a donor-independent manner
Authors: Firrman Jenni , Liu LinShu , Mahalak Karley , Hu Weiming , Bittinger Kyle , Moustafa Ahmed , Jones Steven M. , Narrowe Adrienne , Tomasula Peggy
Published: January 2023

Introduction

Following consumption of milk, lactose, a disaccharide of glucose and galactose, is hydrolyzed and absorbed in the upper gastrointestinal tract. However, hydrolysis and absorption are not always absolute, and some lactose will enter the colon where the gut microbiota is able to hydrolyze lactose and produce metabolic byproducts.

Methods

Here, the impact of lactose on the gut microbiota of healthy adults was examined, using a short-term, in vitro strategy where fecal samples harvested from 18 donors were cultured anaerobically with and without lactose. The data were compiled to identify donor-independent responses to lactose treatment.

Results and discussion

Metagenomic sequencing found that the addition of lactose decreased richness and evenness, while enhancing prevalence of the β-galactosidase gene. Taxonomically, lactose treatment decreased relative abundance of Bacteroidaceae and increased lactic acid bacteria, Lactobacillaceae, Enterococcaceae, and Streptococcaceae, and the probiotic Bifidobacterium. This corresponded with an increased abundance of the lactate utilizers, Veillonellaceae. These structural changes coincided with increased total short-chain fatty acids (SCFAs), specifically acetate, and lactate. These results demonstrated that lactose could mediate the gut microbiota of healthy adults in a donor-independent manner, consistent with other described prebiotics, and provided insight into how dietary milk consumption may promote human health through modifications of the gut microbiome.
Field-friendly MUNNG® optima simple test kit for quick qualitative assessment of iodine and iron presence in double-fortified salt
Authors: Godbole Ujwala , Gupta Divya , Godbole Nachiket , Godbole Madan
Published: January 2023

Background

Data from several efficacy studies and a long-term effectiveness study have encouraged the governments to adopt a policy of providing double-fortified salt (DFS) in the Mid-Day Meal (MDM) programs in government schools across India. These envisaged food security events are likely to boost the manufacturing of DFS in a big way. Thus, it becomes pertinent to come up with a robust monitoring system involving community and field workers for quality checks. It is imperative to equip these field workers with simple testing kits (STKs) capable of qualitative detection of iron and iodine in DFS. As the consumer acceptance of foods is based on several factors including sensory characteristics, performance, convenience, cost, nutrition, and product image, a variety of iron compounds are in use for fortification. However, it becomes challenging to provide a kit that can overcome the chemical masking of iodine detection by iron compounds.

Objectives

We aimed at (1) the development of a field-friendly STK for quick qualitative assessment of iodine and various forms of iron present in DFS, (2) to check its validity under field conditions.

Methods

We put in place reagents combined using known chemical reactions and balanced use of oxidants to overcome the problems of encapsulation and to maximize the use, by enabling reagent combination to react with all forms of iron.

Results

The kit reagents successfully detect iodine as well as three commonly used iron fortificants in DFS. Published field trials confirmed the specificity and sensitivity of the developed kit. The simplicity and use of the kit by a field worker can be seen in the enclosed video.

Conclusion

The combination of improvised kit reagents allows early detection of iron and iodine in DFS. Iron is detected in a variety of iron-containing fortifications. The provision of diluted H2O2ensures the presence of oxygen-free radicals that enhances iodine release captured by concentrated KI making iodine detection an easy task.
Characteristics and clinical course of patients referred to the NST
Authors: Bong Jeong Bin , Chung Ji Yeon , Kim So-Yeong , Ryu Han Uk , Shin Byoung-Soo , Kang Hyun Goo
Published: January 2023

Background and aims

The nutrition support team (NST) comprises doctors, nutritionists, pharmacists, and nurses who provide intensive nutritional treatment designed for each patient by evaluating their nutritional status of hospitalized patients. This study aimed to identify the clinical characteristics of patients referred to the NST among those admitted to a tertiary hospital and to understand the factors affecting their clinical course and changes in pressure sore grades.

Methods

This study included 1,171 adult patients aged 18 years or older referred to the NST at a tertiary hospital in a metropolitan city between 1 January 2019 and 31 December 2020. Patients were divided into five age groups, neuro department and non-neuro department, those treated in the intensive care unit (ICU), and those not treated in the ICU. Patients were also compared based on the presence of pressure sores at the time of NST referral and changes in pressure sore grades at the first time of NST referral and discharge (improved pressure sores, no change in pressure sores, and aggravated pressure sores). In addition, this study examined the factors affecting changes in pressure sore grades.

Results

As age increased, the proportion of both low albumin levels and pressure sores significantly increased (p < 0.001), and the neuro department showed a significantly lower proportion of low albumin levels and pressure sores (p < 0.001). The proportion of patients with pressure sores was higher (64.9%), and this patient group showed significantly higher rates of low albumin levels (p < 0.001) and treatment in the ICU (p < 0.001). The group with aggravated pressure sore grades had a significantly higher proportion of patients in the surgery department (p = 0.009) and those treated in the ICU (p < 0.001). Admission to the surgery department was a factor that aggravated the grade of pressure sores [adjusted odds ratio (aOR) = 1.985, 95% confidence interval (CI) = 1.168–3.371]. When patients were not treated in the ICU, the grade of the pressure sores was less likely to worsen (aOR = 0.364, 95% CI = 0.217–0.609).

Conclusion

Pressure sores and low albumin levels are closely related, and the risk of developing and aggravating pressure sores is particularly high in patients in the surgery department and those receiving ICU treatment. Therefore, it is necessary to actively implement NST referral to ensure that overall nutrition, including albumin, is well supplied, especially for patients in the surgery department and treated in the ICU, as they are at high risk of pressure sore development and aggravation. Moreover, since low albumin levels frequently occur in elderly patients, it is necessary to consider including the elderly in the indications for referral to the NST.
Patient-derived models: Advanced tools for precision medicine in neuroblastoma
Authors: Aaltonen Kristina , Radke Katarzyna , Adamska Aleksandra , Seger Alexandra , Mañas Adriana , Bexell Daniel
Published: January 2023

Neuroblastoma is a childhood cancer derived from the sympathetic nervous system. High-risk neuroblastoma patients have a poor overall survival and account for ~15% of childhood cancer deaths. There is thus a need for clinically relevant and authentic models of neuroblastoma that closely resemble the human disease to further interrogate underlying mechanisms and to develop novel therapeutic strategies. Here we review recent developments in patient-derived neuroblastoma xenograft models and in vitro cultures. These models can be used to decipher mechanisms of metastasis and treatment resistance, for drug screening, and preclinical drug testing. Patient-derived neuroblastoma models may also provide useful information about clonal evolution, phenotypic plasticity, and cell states in relation to neuroblastoma progression. We summarize current opportunities for, but also barriers to, future model development and application. Integration of patient-derived models with patient data holds promise for the development of precision medicine treatment strategies for children with high-risk neuroblastoma.
SHP-2-induced M2 polarization of tumor associated macrophages via IL-4 regulate colorectal cancer progression
Authors: Li Zhihan , Xi Jinchuan , Li Baokun , Liu Youqiang , Wang Guiying , Yu Bin , Ma Hongqing , Li Zhilin , Zhang Zhenya
Published: January 2023

Objective

To explore the effect and molecular mechanism of Src homology region 2 domain-containing protein tyrosine phosphatase-2 (SHP-2) in tumor-associated macrophages (TAMs) repressing the migration and invasion of colorectal cancer (CRC) cells.

Methods

The relevant data sets of human colon specimens were obtained from GEO database, and then the performed correlation analysis, principal component analysis and differentially expressed gene (DEGs) analysis on the samples were conducted. GO and KEGG enrichment analysis were performed on the common DEGs, and then functional interaction prediction was performed to verify the gene regulatory circuit of SHP-2. Furthermore, western blot was used to detect the effect of low expression of SHP-2 on related proteins, including the markers of promoting M2 polarization and exosome secretion, and keys proteins of the PI3K pathway. The relationship between SHP-2 and PI3K pathway was further verified by adding PI3K inhibitor LY294002. Finally, the effect of SHP-2 on the function of colon cancer cells was confirmed by wound healing assay and Transwell assay.

Results

Through bioinformatics analysis, SHP-2 was screened as a possible key gene affecting CRC. The low expression of SHP-2 promoted the protein levels of Arginase-1 and IL-10 in IL-4 induced M2 macrophages, while inhibited the protein levels of IL-1β and TNF-α. Meanwhile, low expression of SHP-2 was found to similarly promote the expression of p-PI3K, p-AKT, and the release of exosomes. Interestingly, the promotion was suppressed after the addition of the PI3K inhibitor LY294002. In terms of cellular behavior, wound healing and transwell data showed that low expression of SHP-2 enhanced the migration and invasion abilities of CRC cells.

Conclusion

The low expression of SHP-2 induced by PHPS1 may regulate M2 polarization of TAMs and release of exosomes through PI3K/AKT pathway, thereby enhancing the migration and invasion ability of CRC cells.
Addressing blood-brain-tumor-barrier heterogeneity in pediatric brain tumors with innovative preclinical models
Authors: Morris Elysse K. , Daignault-Mill Sheena , Stehbens Samantha J. , Genovesi Laura A. , Lagendijk Anne K.
Published: January 2023

Brain tumors represent the leading cause of disease-related mortality and morbidity in children, with effective treatments urgently required. One factor limiting the effectiveness of systemic therapy is the blood-brain-barrier (BBB), which limits the brain penetration of many anticancer drugs. BBB integrity is often compromised in tumors, referred to as the blood-brain-tumor-barrier (BBTB), and the impact of a compromised BBTB on the therapeutic sensitivity of brain tumors has been clearly shown for a few selected agents. However, the heterogeneity of barrier alteration observed within a single tumor and across distinct pediatric tumor types represents an additional challenge. Herein, we discuss what is known regarding the heterogeneity of tumor-associated vasculature in pediatric brain tumors. We discuss innovative and complementary preclinical model systems that will facilitate real-time functional analyses of BBTB for all pediatric brain tumor types. We believe a broader use of these preclinical models will enable us to develop a greater understanding of the processes underlying tumor-associated vasculature formation and ultimately more efficacious treatment options.
Pathologic and molecular insights in nodal T-follicular helper cell lymphomas
Authors: Marques-Piubelli Mario L. , Amador Catalina , Vega Francisco
Published: January 2023

T-follicular helper (TFH) cells are one of the T-cell subsets with a critical role in the regulation of germinal center (GC) reactions. TFH cells contribute to the positive selection of GC B-cells and promote plasma cell differentiation and antibody production. TFH cells express a unique phenotype characterized by PD-1hi, ICOShi, CD40Lhi, CD95hi, CTLAhi, CCR7lo, and CXCR5hi. Three main subtypes of nodal TFH lymphomas have been described: 1) angioimmunoblastic-type, 2) follicular-type, and 3) not otherwise specified (NOS). The diagnosis of these neoplasms can be challenging, and it is rendered based on a combination of clinical, laboratory, histopathologic, immunophenotypic, and molecular findings. The markers most frequently used to identify a TFH immunophenotype in paraffin-embedded tissue sections include PD-1, CXCL13, CXCR5, ICOS, BCL6, and CD10. These neoplasms feature a characteristic and similar, but not identical, mutational landscape with mutations in epigenetic modifiers (TET2, DNMT3A, IDH2), RHOA, and T-cell receptor signaling genes. Here, we briefly review the biology of TFH cells and present a summary of the current pathologic, molecular, and genetic features of nodal lymphomas. We want to highlight the importance of performing a consistent panel of TFH immunostains and mutational studies in TCLs to identify TFH lymphomas.
Prognostic value of systemic immune-inflammation index in non-metastatic clear cell renal cell carcinoma with tumor thrombus
Authors: Gu Yufeng , Fu Yao , Pan Xin , Zhou Yulin , Ji Changwei , Zhao Tangliang , Miao He , Lv Huichen , Da Jianping , Ge Jingping , Wang Linhui , Qu Le , Ge Silun , Guo Hongqian , Zhou Wenquan
Published: January 2023

This study aims to determine the prognostic value of SII for non-metastatic clear cell renal cell carcinoma (ccRCC) patients with venous tumor thrombus (VTT). We retrospectively collected and analyzed 328 non-metastatic ccRCC patients with VTT who underwent radical nephrectomy and thrombectomy from 3 tertiary centers in China between 2011 to 2021. Kaplan-Meier analyses and Cox proportional hazard analyses were used to determine its prognostic value for overall survival (OS) and disease free survival (DFS). The Harrell concordance index (C-index), receiver operating characteristic curve (ROC) analysis, and decision curve analysis (DCA) were used to evaluate its role in the improvement of prognostic accuracy of the existing models. Nomogram models containing the SII were then developed and evaluated by R. Patients were divided into low-SII and high-SII groups based on the SII optimal cut-off value 912 calculated by the Youden index in all patients. Higher SII was correlated with more symptoms, longer surgical time, higher WHO/ISUP grade, and longer tumor diameter. Kaplan-Meier analyses revealed significant differences in OS and DFS between two groups. Multivariate analyses revealed that SII was an independent prognostic factor for OS (HR:2.220, p=0.002) and DFS (HR:1.846, p=0.002). Compared with other indicators, SII had a superior accuracy (c-index=0.630 for OS and 0.595 for DFS). It also improved the performance of models for predicting OS and DFS (all p <0.01). Based on the results of LASSO Cox regression analysis, we constructed a nomogram to predict OS and it performed well on both the training cohort (AUC=0.805) and the validation cohort (AUC=0.795). Risk stratification based on nomogram can distinguish patients with different risks (all p <0.001). Preoperative SII is an independent predictive factor for OS and DFS of non-metastatic ccRCC patients with VTT. It can be used to improve the performance of current risk models.
Six-month multidisciplinary follow-up in multisystem inflammatory syndrome in children: An Italian single-center experience
Authors: Zuccotti Gianvincenzo , Calcaterra Valeria , Mannarino Savina , D’Auria Enza , Bova Stefania Maria , Fiori Laura , Verduci Elvira , Milanese Alberto , Marano Giuseppe , Garbin Massimo , Zirpoli Salvatore , Fabiano Valentina , Carlucci Patrizia , Olivotto Sara , Gianolio Laura , De Santis Raffaella , Pelizzo Gloria , Zoia Elena , Dilillo Dario , Biganzoli Elia Mario
Published: January 2023

Background

A severe multisystem inflammatory syndrome in children (MIS-C) related to SARS-CoV-2 has been described after infection. A limited number of reports have analyzed the long-term complications related to pro-inflammatory status in MIS-C. We evaluated multiorgan impairment at the 6-month follow-up in MIS-C.

Methods

We enrolled 33 pediatric patients consecutively hospitalized for MIS-C and monitored for almost 6 months. The inter-relationship of patient's features and disease severity at admission with long term complications was studied by multivariate analysis.

Results

Endo-metabolic derangement, cardiac injury, respiratory, renal and gastrointestinal manifestations and neurological involvement are part of the initial presentation. The most abnormalities appear to resolve within the first few weeks, without significant long term dysfunction at the 6-months follow-up, except for endocrine (non-thyroidal illness syndrome in 12.1%, insulin resistance in 21.2%) and neurological system (27.3% cognitive or psychological, behavioral, adaptive difficulties). Endocrine and heart involvement at admission represent a significant factor on the long term sequelae; however no association between severity score and long-term outcome was noted.

Conclusions

The severity of initial clinical presentation may be associated to organ domain, however it is not related to long term sequelae. The prevalent organ restoration supports a predominant indirect immune-mediated injury triggered by a systemic inflammatory response; however a direct damage due to the viral entry could be not excluded. Eventhought our preliminary results seem to suggest that MIS-C is not a long-term risk condition for children health, a longer follow-up is mandatory to confirm this hypothesis.
The relationship between father absence and hostility among Chinese depressed youths: A serial mediation model and the role of self-esteem and frustration tolerance
Authors: Liu Xiao-Ge , Li Yang , Xiong Fang , Li Wen-Tian , Liu Lian-Zhong , John S. Sullivan
Published: January 2023

Background

While the association between father absence and youth hostility has been well-documented among depressed youths, there is a lack of research on the potential mechanism underlying such an association. This study aimed to test a serial mediation model of self-esteem and frustration tolerance on the link between father absence and youth hostility.

Methods

A total of 137 Chinese youths with major depressive disorder were recruited from Wuhan Mental Health Center. They completed a survey including the Father Absence Questionnaire to measure father absence, the Chinese Hostility Inventory (CHI) to measure hostility, the Psychological Endurance Questionnaire to measure frustration tolerance, and the Self-esteem Scale (SES) to measure self-esteem. A series of multiple linear regression models were employed to assess the associations among father absence, self-esteem, frustration tolerance, and hostility.

Results

Although father absence was modestly associated with hostility (r = 0.30, p < 0.001), subsequent serial mediation analysis showed that father absence was not directly related to hostility (β = 0.06, p = 0.29) when self-esteem and frustration tolerance were included in the model. High levels of father absence had an adverse effect on levels of self-esteem, which decreased levels of frustration tolerance, and thus higher levels of hostility among depressed youths. The indirect effects of father absence on hostility through self-esteem, frustration tolerance, as well as through self-esteem and frustration tolerance serially accounted for 28%, 24%, and 24% of the total effect, respectively.

Conclusion

Our study tested a serial mediation model of self-esteem and frustration tolerance as mediators between father absence and hostility among depressed youths. The findings strengthened our understanding of the potential mechanism underlying the association between self-esteem and frustration tolerance, which may provide useful guidance for future intervention programs.
Mutations and clinical characteristics of dRTA caused by SLC4A1 mutations: Analysis based on published patients
Authors: Yang Mengge , Sheng Qiqi , Ge Shenghui , Song Xinxin , Dong Jianjun , Guo Congcong , Liao Lin
Published: January 2023

Background and Aims

The genetic and clinical characteristics of patients with distal renal tubular acidosis (dRTA) caused by SLC4A1 mutations have not been systematically recorded before. Here, we summarized the SLC4A1 mutations and clinical characteristics associated with dRTA.

Methods

Database was searched, and the mutations and clinical manifestations of patients were summarized from the relevant articles.

Results

Fifty-three eligible articles involving 169 patients were included and 41 mutations were identified totally. Fifteen mutations involving 100 patients were autosomal dominant inheritance, 21 mutations involving 61 patients were autosomal recessive inheritance. Nephrocalcinosis or kidney stones were found in 72.27%, impairment in renal function in 14.29%, developmental disorders in 61.16%, hematological abnormalities in 33.88%, and muscle weakness in 13.45% of patients. The age of onset was younger (P < 0.01), urine pH was higher (P < 0.01), and serum potassium was lower (P < 0.001) in recessive patients than patients with dominant SLC4A1 mutations. Autosomal recessive inheritance was more often found in Asian patients (P < 0.05).

Conclusions

The children present with metabolic acidosis with high urinary pH, accompanying hypokalemia, hyperchloremia, nephrocalcinosis, growth retardation and hematological abnormalities should be suspected as dRTA and suggested a genetic testing. The patients with recessive dRTA are generally more severely affected than that with dominant SLC4A1 mutations. Autosomal recessive inheritance was more often found in Asian patients, and more attentions should be paid to the Asian patients.