bluuebunny/crossref_metadata_2025 huggingface dataset:
Complete variable domain sequences of monoclonal antibody light chains identified from untargeted RNA sequencing data
Authors: Nau Allison , Shen Yun , Sanchorawala Vaishali , Prokaeva Tatiana , Morgan Gareth J.
Published: April 2023

Introduction

Monoclonal antibody light chain proteins secreted by clonal plasma cells cause tissue damage due to amyloid deposition and other mechanisms. The unique protein sequence associated with each case contributes to the diversity of clinical features observed in patients. Extensive work has characterized many light chains associated with multiple myeloma, light chain amyloidosis and other disorders, which we have collected in the publicly accessible database, AL-Base. However, light chain sequence diversity makes it difficult to determine the contribution of specific amino acid changes to pathology. Sequences of light chains associated with multiple myeloma provide a useful comparison to study mechanisms of light chain aggregation, but relatively few monoclonal sequences have been determined. Therefore, we sought to identify complete light chain sequences from existing high throughput sequencing data.

Methods

We developed a computational approach using the MiXCR suite of tools to extract complete rearranged IGVL-IGJL sequences from untargeted RNA sequencing data. This method was applied to whole-transcriptome RNA sequencing data from 766 newly diagnosed patients in the Multiple Myeloma Research Foundation CoMMpass study.

Results

Monoclonal IGVL-IGJL sequences were defined as those where >50% of assigned IGK or IGL reads from each sample mapped to a unique sequence. Clonal light chain sequences were identified in 705/766 samples from the CoMMpass study. Of these, 685 sequences covered the complete IGVL-IGJL region. The identity of the assigned sequences is consistent with their associated clinical data and with partial sequences previously determined from the same cohort of samples. Sequences have been deposited in AL-Base.

Discussion

Our method allows routine identification of clonal antibody sequences from RNA sequencing data collected for gene expression studies. The sequences identified represent, to our knowledge, the largest collection of multiple myeloma-associated light chains reported to date. This work substantially increases the number of monoclonal light chains known to be associated with non-amyloid plasma cell disorders and will facilitate studies of light chain pathology.
Case Report: Blinatumomab therapy for the treatment of B-cell acute lymphoblastic leukemia patients with central nervous system infiltration
Authors: Cao Han-Yu , Chen Hui , Liu Song-Bai , Gong Wen-Jie , Qian Chong-Sheng , Zhang Tong-Tong , Wan Chao-Ling , Huang Si-Man , Xu Nan , Dai Hai-Ping , Xue Sheng-Li
Published: April 2023

The treatment of B-cell acute lymphoblastic leukemia (B-ALL) with central nervous system (CNS) involvement poses a significant clinical challenge because most chemotherapeutic agents exhibit weak permeability to the blood-brain barrier (BBB). In addition, current anti-CNS leukemia treatments often bring short or long-term complications. Immunotherapy including chimeric antigen T-cell therapy and bispecific antibody have shown profound treatment responses in relapsed/refractory B-ALL. However, there is a lack of data on the efficacy of bispecific antibody in treating B-ALL with CNS involvement. Here, we report two ALL patients with CNS leukemia who received blinatumomab. Case 1 was diagnosed with chronic myeloid leukemia in lymphoid blast phase. The patient developed CNS leukemia and bone marrow relapse during the treatment with dasatinib. Case 2 was diagnosed with B-ALL and suffered early hematologic relapse and cerebral parenchyma involvement. After treatment with one cycle of blinatumomab, both patients achieved complete remission in the bone marrow and CNS. Furthermore, this is the first report on the efficacy of blinatumomab in treating CNS leukemia with both of the cerebral spinal fluid and the cerebral parenchymal involvement. Our results suggest that blinatumomab might be a potential option for the treatment of CNS leukemia.
State-of-the-art of data analyses in environmental DNA approaches towards its applicability to sustainable fisheries management
Authors: Petit-Marty Natalia , Casas Laura , Saborido-Rey Fran
Published: April 2023

An increasing number of studies using marine environmental DNA (eDNA) approaches are showing its potential application in marine fisheries management by helping and simplifying some of the labor-intensive traditional surveys required to assess exploited populations and ecosystem status. eDNA approaches (i.e. metabarcoding and targeted) can support to ecosystem-based fisheries management by providing information on species composition; surveillance of invasive, rare and/or endangered species; and providing estimates of species abundance. Due to these potential uses in fisheries and conservation sciences, the number of studies applying eDNA approaches in marine habitats has expanded in the very last few years. However, a lack of consistency across studies when applying pipelines for data analyses, makes results difficult to compare among them. Such lack of consistency is partially caused by poor knowledge in the management of raw sequences data, and analytical methods allowing comparative results. Hence, we review here the essential steps of eDNA data processing and analyses to get sound, reproducible, and comparable results, providing a set of bioinformatics tools useful for each step. Altogether this review presents the state of the art of eDNA data analyses towards a comprehensive application in fisheries management promoting sustainability.
Characteristics and mechanisms of long-lasting 2021–2022 summer Northeast Pacific warm blobs
Authors: Chen Jiajie , Li Ronglin , Xie Shen , Wei Jiaqi , Shi Jian
Published: April 2023

Warm blobs are persistently warmer-than-normal seawaters over the Northeast Pacific (NEP), which cause substantial impacts on marine ecosystems and climate. Recently, the warm blobs occurred consecutively in spring and summer of 2021 and 2022. The warm blob in 2021 was mostly located east of 155°W, while it shifted to west of 155°W in 2022. Based on a mixed-layer heat budget analysis, we find that atmospheric processes positively and dominantly contributed in May 2021 and July 2022. Specifically, less latent heat loss from the ocean caused by reducing background westerlies and evaporation intensified the 2021 warm blob, while more shortwave radiation heating due to decreased low clouds intensified the one in 2022. However, the positive contribution of the atmospheric processes cannot maintain a season due to their strong internal variability. The seasonal persistence of the warm blobs, instead, is owing to the offset between the atmospheric and oceanic processes. We highlight the importance of atmospheric processes in the evolution of the NEP warm blobs in spring and summer, which lacks sufficient investigation but can provide more potential predictability for the NEP warm blobs.
Nomogram to predict postpartum hemorrhage in cesarean delivery for twin pregnancies: a retrospective cohort study in China
Authors: Zhang Yanhua , Chen Lu , Zhou Weixiao , Lin Jun , Wen Hong
Published: April 2023

Background

Postpartum hemorrhage (PPH) is the most common cause of maternal morbidity and mortality worldwide. A reliable risk assessment tool for PPH could optimize available interventions to reduce adverse maternal outcomes.

Objective

The objective of this study was to explore a nomogram predicting the risk of postpartum hemorrhage after cesarean delivery for twin pregnancies.

Methods

This single-center retrospective cohort study conducted twin pregnancies who underwent cesarean delivery between January 2014 and July 2021. Propensity score matching at baseline was used to match PPH (blood loss ≥1000 mL) and non-PPH group (blood loss <1000 mL). A nomogram was developed to predict the risk of PPH in cesarean delivery for twin pregnancies. The receiver operating characteristic curve (ROC), calibration plot, and decision curve analysis (DCA) were, respectively, used to evaluate the discrimination, calibration, and clinical utility of the prediction models.

Results

After propensity score matching, 186 twin pregnancies in the PPH group were matched with 186 controls in the non-PPH group. Seven independent prognostic variables, including antepartum albumin, assisted reproductive technology, hypertensive disorders of pregnancy, placenta previa, placenta accrete spectrum, intrapartum cesarean delivered, and estimated weights of twins, were used to build the nomogram. Based on the performance of the model, it appears that a good calibration (Hosmer–Lemeshow χ2 = 4.84, P > 0.05), an excellent predictive ability (area under the curve: 0.778, 95% CI: 0.732–0.825), and a good positive net benefit in the predictive model have been achieved.

Conclusion

The nomogram was first generated to predict PPH in cesarean delivery for twin pregnancies, which could help clinicians to provide a reference for the preoperative surgical plan, choose optimal treatments, optimize healthcare resources, and thereby reduce the associated adverse maternal outcomes.
An update on the role of thioredoxin-interacting protein in diabetic kidney disease: A mini review
Authors: Sun Hong , Sun Rong , Hua Yulin , Lu Qianyi , Shao Xinyu
Published: April 2023

Thioredoxin-interacting protein (TXNIP) was first isolated from Vitamin D3-exposed HL60 cells. TXNIP is the main redox-regulating factor in various organs and tissues. We begin with an overview of the TXNIP gene and protein information, followed by a summary of studies that have shown its expression in human kidneys. Then, we highlight our current understanding of the effect of TXNIP on diabetic kidney disease (DKD) to improve our understanding of the biological roles and signal transduction of TXNIP in DKD. Based on the recent review, the modulation of TXNIP may be considered as a new target in the management of DKD.
The hidden sentinel of the skin: An overview on the role of interleukin-13 in atopic dermatitis
Authors: Napolitano Maddalena , di Vico Francesca , Ruggiero Angelo , Fabbrocini Gabriella , Patruno Cataldo
Published: April 2023

Recent evidence suggests that interleukin (IL)-13 is a crucial cytokine involved in the pathogenesis of atopic dermatitis (AD). It is a central driver of type-2 T-helper inflammation and is overexpressed in lesional skin of AD patients. Upon release in peripheral skin, IL-13 activates its receptors, recruits inflammatory cells, and modifies the skin microbiome. IL-13 also reduces the expression of epidermal barrier proteins and activates sensory nerve mediating the itch transmission signal. Novel therapeutics that target IL-13 seem to be efficacious and safe for the treatment of patients with moderate-to-severe AD. The aim of our manuscript is to review the role that IL-13 plays in AD immunopathogenesis.
Streptomyces catenulae as a Novel Marine Actinobacterium Mediated Silver Nanoparticles: Characterization, Biological Activities, and Proposed Mechanism of Antibacterial Action
Authors: Khalil Maha A. , El-Shanshoury Abd El-Raheem R. , Alghamdi Maha A. , Sun Jianzhong , Ali Sameh S.
Published: April 2023

Graphical Abstract

Biological applications of silver nanoparticles derived from Streptomyces catenulae.
Endophytic Trichoderma species from rubber trees native to the Brazilian Amazon, including four new species
Authors: Nascimento Brito Vanessa , Lana Alves Janaina , Sírio Araújo Kaliane , de Souza Leite Tiago , Borges de Queiroz Casley , Liparini Pereira Olinto , de Queiroz Marisa Vieira
Published: April 2023

Fungi belonging to the genus Trichoderma have been widely recognized as efficient controllers of plant diseases. Although the majority of isolates currently deployed, thus far, have been isolated from soil, endophytic Trichoderma spp. is considered to be a promising option for application in biocontrol. In this study, 30 endophytic Trichoderma isolates—obtained from the leaves, stems, and roots of wild Hevea spp. in the Brazilian Amazon—were analyzed using specific DNA barcodes: sequences of internal transcribed spacers 1 and 2 of rDNA (ITS region), genes encoding translation elongation factor 1-α (TEF1-α), and the second largest subunit of RNA polymerase II (RPB2). The genealogical concordance phylogenetic species recognition (GCPSR) concept was used for species delimitation. A phylogenetic analysis showed the occurrence of Trichoderma species, such as T. erinaceum, T. ovalisporum, T. koningiopsis, T. sparsum, T. lentiforme, T. virens, and T. spirale. Molecular and morphological features resulted in the discovery of four new species, such as T. acreanum sp. nov., T. ararianum sp. nov., T. heveae sp. nov., and T. brasiliensis sp. nov. The BI and ML analyses shared a similar topology, providing high support to the final trees. The phylograms show three distinct subclades, namely, T. acreanum and T. ararianum being paraphyletic with T. koningiopsis; T. heveae with T. subviride; and T. brasiliensis with T. brevicompactum. This study adds to our knowledge of the diversity of endophytic Trichoderma species in Neotropical forests and reveals new potential biocontrol agents for the management of plant diseases.
Fecal microbiota transplantation inhibits colorectal cancer progression: Reversing intestinal microbial dysbiosis to enhance anti-cancer immune responses
Authors: Yu Hao , Li Xing-Xiu , Han Xing , Chen Bin-Xin , Zhang Xing-Hua , Gao Shan , Xu Dan-Qi , Wang Yao , Gao Zhan-Kui , Yu Lei , Zhu Song-Ling , Yao Li-Chen , Liu Gui-Rong , Liu Shu-Lin , Mu Xiao-Qin
Published: April 2023

Many lines of evidence demonstrate the associations of colorectal cancer (CRC) with intestinal microbial dysbiosis. Recent reports have suggested that maintaining the homeostasis of microbiota and host might be beneficial to CRC patients, but the underlying mechanisms remain unclear. In this study, we established a CRC mouse model of microbial dysbiosis and evaluated the effects of fecal microbiota transplantation (FMT) on CRC progression. Azomethane and dextran sodium sulfate were used to induce CRC and microbial dysbiosis in mice. Intestinal microbes from healthy mice were transferred to CRC mice by enema. The vastly disordered gut microbiota of CRC mice was largely reversed by FMT. Intestinal microbiota from normal mice effectively suppressed cancer progression as assessed by measuring the diameter and number of cancerous foci and significantly prolonged survival of the CRC mice. In the intestine of mice that had received FMT, there were massive infiltration of immune cells, including CD8+ T and CD49b+ NK, which is able to directly kill cancer cells. Moreover, the accumulation of immunosuppressive cells, Foxp3+ Treg cells, seen in the CRC mice was much reduced after FMT. Additionally, FMT regulated the expressions of inflammatory cytokines in CRC mice, including down-regulation of IL1a, IL6, IL12a, IL12b, IL17a, and elevation of IL10. These cytokines were positively correlated with Azospirillum_sp._47_25, Clostridium_sensu_stricto_1, the E. coli complex, Akkermansia, Turicibacter, and negatively correlated with Muribaculum, Anaeroplasma, Candidatus_Arthromitus, and Candidatus Saccharimonas. Furthermore, the repressed expressions of TGFb, STAT3 and elevated expressions of TNFa, IFNg, CXCR4 together promoted the anti-cancer efficacy. Their expressions were positively correlated with Odoribacter, Lachnospiraceae-UCG-006, Desulfovibrio, and negatively correlated with Alloprevotella, Ruminococcaceae UCG-014, Ruminiclostridium, Prevotellaceae UCG-001 and Oscillibacter. Our studies indicate that FMT inhibits the development of CRC by reversing gut microbial disorder, ameliorating excessive intestinal inflammation and cooperating with anti-cancer immune responses.
Virotyping and genetic antimicrobial susceptibility testing of porcine ETEC/STEC strains and associated plasmid types
Authors: Vereecke Nick , Van Hoorde Sander , Sperling Daniel , Theuns Sebastiaan , Devriendt Bert , Cox Eric
Published: April 2023

Introduction

EnterotoxigenicEscherichia coli(ETEC) infections are the most common cause of secretory diarrhea in suckling and post-weaning piglets. For the latter, Shiga toxin-producingEscherichia coli(STEC) also cause edema disease. This pathogen leads to significant economic losses. ETEC/STEC strains can be distinguished from generalE. coliby the presence of different host colonization factors (e.g., F4 and F18 fimbriae) and various toxins (e.g., LT, Stx2e, STa, STb, EAST-1). Increased resistance against a wide variety of antimicrobial drugs, such as paromomycin, trimethoprim, and tetracyclines, has been observed. Nowadays, diagnosing an ETEC/STEC infection requires culture-dependent antimicrobial susceptibility testing (AST) and multiplex PCRs, which are costly and time-consuming.

Methods

Here, nanopore sequencing was used on 94 field isolates to assess the predictive power, using the meta R package to determine sensitivity and specificity and associated credibility intervals of genotypes associated with virulence and AMR.

Results

Genetic markers associated with resistance for amoxicillin (plasmid-encoded TEM genes), cephalosporins (ampCpromoter mutations), colistin (mcrgenes), aminoglycosides (aac(3)andaph(3)genes), florfenicol (floR), tetracyclines (tetgenes), and trimethoprim-sulfa (dfrAgenes) could explain most acquired resistance phenotypes. Most of the genes were plasmid-encoded, of which some collocated on a multi-resistance plasmid (12 genes against 4 antimicrobial classes). For fluoroquinolones, AMR was addressed by point mutations within the ParC and GyrA proteins and theqnrS1gene. In addition, long-read data allowed to study the genetic landscape of virulence- and AMR-carrying plasmids, highlighting a complex interplay of multi-replicon plasmids with varying host ranges.

Conclusion

Our results showed promising sensitivity and specificity for the detection of all common virulence factors and most resistance genotypes. The use of the identified genetic hallmarks will contribute to the simultaneous identification, pathotyping, and genetic AST within a single diagnostic test. This will revolutionize future quicker and more cost-efficient (meta)genomics-driven diagnostics in veterinary medicine and contribute to epidemiological studies, monitoring, tailored vaccination, and management.
Traditional mineral medicine realgar and Realgar-Indigo naturalis formula potentially exerted therapeutic effects by altering the gut microbiota
Authors: Luo Lu , Li Chaofeng , Huang Nanxi , Wang Qiaochu , Zhang Zihao , Song Chen , Yang Hui , Yuan Maowen , Xu Ziwen , Sun Jialei , Zhang Zhijie
Published: April 2023

Introduction

Realgar has a long history ofuse in traditional medicines. However, the mechanism through which Realgar or Realgar-Indigo naturalis formula (RIF) exert therapeutic effects is only partially understood.

Methods

In this study, 60 feces and 60 ileum samples from rats administered with realgar or RIF were collected to examine the gut microbiota.

Results

The results showed that realgar and RIF influenced different microbiota in both feces and ileum. Compared with realgar, RIF at low dosage (0.1701 g/3 ml) significantly increased the microbiota diversity. LEfSe and random forest analyses showed that the bacterium Bacteroidales was significantly altered after RIF administration, and it was predicted that these microorganisms contribute to the inorganic arsenic metabolic process.

Discussion

Our results suggest that realgar and RIF may exert their therapeutic effects through influencing microbiota. The low dose of RIF had greater effects on increasing the diversity of microbiota, and Bacteroidales in feces might participate in the inorganic arsenic metabolic process to exert therapeutic effects for realgar.
The chemical neighborhood of cells in a diffusion-limited system
Authors: Gesztesi Juliana , Broddrick Jared T. , Lannin Timothy , Lee Jessica A.
Published: April 2023

Microorganisms follow us everywhere, and they will be essential to sustaining long-term human space exploration through applications such as vitamin synthesis, biomining, and more. Establishing a sustainable presence in space therefore requires that we better understand how stress due to the altered physical conditions of spaceflight affects our companion organisms. In microgravity environments such as orbital space stations, microorganisms likely experience the change in gravity primarily through changes in fluid mixing processes. Without sedimentation and density-driven convection, diffusion becomes the primary process governing the movement of growth substrates and wastes for microbial cells in suspension culture. Non-motile cells might therefore develop a substrate-deficient “zone of depletion” and experience stress due to starvation and/or waste build-up. This would in turn impact the concentration-dependent uptake rate of growth substrates and could be the cause of the altered growth rates previously observed in microorganisms in spaceflight and in ground-simulated microgravity. To better understand the extent of these concentration differences and their potential influence on substrate uptake rates, we used both an analytical solution and finite difference method to visualize concentration fields around individual cells. We modeled diffusion, using Fick’s Second Law, and nutrient uptake, using Michaelis–Menten kinetics, and assessed how that distribution varies in systems with multiple cells and varied geometries. We determined the radius of the zone of depletion, within which cells had reduced the substrate concentration by 10%, to be 5.04 mm for an individual Escherichia coli cell in the conditions we simulated. However, we saw a synergistic effect with multiple cells near each other: multiple cells in close proximity decreased the surrounding concentration by almost 95% from the initial substrate concentration. Our calculations provide researchers an inside look at suspension culture behavior in the diffusion-limited environment of microgravity at the scale of individual cells.
Alanine-mediated P cycle boosting enhances the killing efficiency of kasugamycin on antibiotic-resistant Xanthomonas oryzae
Authors: Guan Yi , Lin Meiyun , Shen Peihua , Zou Zhenyu
Published: April 2023

The outbreak of Bacterial blight (BB) caused by Xanthomonas oryzae (Xoo) generates substantial economic losses to agricultural production. Antibiotics application is a valuable measure to control this bacterial disease. However, microbial antibiotic resistance dramatically reduced antibiotic effectiveness. Identifying the resistance mechanism of Xoo to antibiotics and restoring antibiotic susceptibility is one of the crucial ways to solve this problem. This study employed a GC-MS-based metabolomic approach to reveal the differential metabolomics between a kasugamycin-susceptible Xoo strain (Z173-S) and a kasugamycin-resistant strain (Z173-RKA). The metabolic mechanism of kasugamycin (KA) resistance in Xoo by GC–MS showed that the downregulation of the pyruvate cycle (P cycle) is a crucial feature of Z173-RKA resistance to KA. This conclusion was confirmed by the decreased enzyme activities and the related gene transcriptional level in the P cycle. Furfural (an inhibitor of pyruvate dehydrogenase) can effectively inhibit the P cycle and increase the resistance of Z173-RKA to KA. Moreover, exogenous alanine can reduce the resistance of Z173-RKA to KA by promoting the P cycle. Our work seems to be the first exploration of the mechanism of KA resistance in Xoo by GC–MS-based metabonomics approach. These results provide a new idea for developing metabolic regulation to address KA resistance in Xoo.
Specific DNA binding of archaeal histones HMfA and HMfB
Authors: Erkelens Amanda M. , Henneman Bram , van der Valk Ramon A. , Kirolos Nancy C. S. , Dame Remus T.
Published: April 2023

In archaea, histones play a role in genome compaction and are involved in transcription regulation. Whereas archaeal histones bind DNA without sequence specificity, they bind preferentially to DNA containing repeats of alternating A/T and G/C motifs. These motifs are also present on the artificial sequence “Clone20,” a high-affinity model sequence for binding of the histones from Methanothermus fervidus. Here, we investigate the binding of HMfA and HMfB to Clone20 DNA. We show that specific binding at low protein concentrations (<30 nM) yields a modest level of DNA compaction, attributed to tetrameric nucleosome formation, whereas nonspecific binding strongly compacts DNA. We also demonstrate that histones impaired in hypernucleosome formation are still able to recognize the Clone20 sequence. Histone tetramers indeed exhibit a higher binding affinity for Clone20 than nonspecific DNA. Our results indicate that a high-affinity DNA sequence does not act as a nucleation site, but is bound by a tetramer which we propose is geometrically different from the hypernucleosome. Such a mode of histone binding might permit sequence-driven modulation of hypernucleosome size. These findings might be extrapolated to histone variants that do not form hypernucleosomes. Versatile binding modes of histones could provide a platform for functional interplay between genome compaction and transcription.
Discovery of a cryptic pocket in the AI-predicted structure of PPM1D phosphatase explains the binding site and potency of its allosteric inhibitors
Authors: Meller Artur , De Oliveira Saulo , Davtyan Aram , Abramyan Tigran , Bowman Gregory R. , van den Bedem Henry
Published: April 2023

Virtual screening is a widely used tool for drug discovery, but its predictive power can vary dramatically depending on how much structural data is available. In the best case, crystal structures of a ligand-bound protein can help find more potent ligands. However, virtual screens tend to be less predictive when only ligand-free crystal structures are available, and even less predictive if a homology model or other predicted structure must be used. Here, we explore the possibility that this situation can be improved by better accounting for protein dynamics, as simulations started from a single structure have a reasonable chance of sampling nearby structures that are more compatible with ligand binding. As a specific example, we consider the cancer drug target PPM1D/Wip1 phosphatase, a protein that lacks crystal structures. High-throughput screens have led to the discovery of several allosteric inhibitors of PPM1D, but their binding mode remains unknown. To enable further drug discovery efforts, we assessed the predictive power of an AlphaFold-predicted structure of PPM1D and a Markov state model (MSM) built from molecular dynamics simulations initiated from that structure. Our simulations reveal a cryptic pocket at the interface between two important structural elements, the flap and hinge regions. Using deep learning to predict the pose quality of each docked compound for the active site and cryptic pocket suggests that the inhibitors strongly prefer binding to the cryptic pocket, consistent with their allosteric effect. The predicted affinities for the dynamically uncovered cryptic pocket also recapitulate the relative potencies of the compounds (τb = 0.70) better than the predicted affinities for the static AlphaFold-predicted structure (τb = 0.42). Taken together, these results suggest that targeting the cryptic pocket is a good strategy for drugging PPM1D and, more generally, that conformations selected from simulation can improve virtual screening when limited structural data is available.
Identifying genetic variants for amyloid β in subcortical vascular cognitive impairment
Authors: Kim Hang-Rai , Jung Sang-Hyuk , Kim Beomsu , Kim Jaeho , Jang Hyemin , Kim Jun Pyo , Kim So Yeon , Na Duk L. , Kim Hee Jin , Nho Kwangsik , Won Hong-Hee , Seo Sang Won
Published: April 2023

Background

The genetic basis of amyloid β (Aβ) deposition in subcortical vascular cognitive impairment (SVCI) is still unknown. Here, we investigated genetic variants involved in Aβ deposition in patients with SVCI.

Methods

We recruited a total of 110 patients with SVCI and 424 patients with Alzheimer’s disease-related cognitive impairment (ADCI), who underwent Aβ positron emission tomography and genetic testing. Using candidate AD-associated single nucleotide polymorphisms (SNPs) that were previously identified, we investigated Aβ-associated SNPs that were shared or distinct between patients with SVCI and those with ADCI. Replication analyses were performed using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and Religious Orders Study and Rush Memory and Aging Project cohorts (ROS/MAP).

Results

We identified a novel SNP, rs4732728, which showed distinct associations with Aβ positivity in patients with SVCI (Pinteraction = 1.49 × 10–5); rs4732728 was associated with increased Aβ positivity in SVCI but decreased Aβ positivity in ADCI. This pattern was also observed in ADNI and ROS/MAP cohorts. Prediction performance for Aβ positivity in patients with SVCI increased (area under the receiver operating characteristic curve = 0.780; 95% confidence interval = 0.757–0.803) when rs4732728 was included. Cis-expression quantitative trait loci analysis demonstrated that rs4732728 was associated with EPHX2 expression in the brain (normalized effect size = −0.182, P = 0.005).

Conclusion

The novel genetic variants associated with EPHX2 showed a distinct effect on Aβ deposition between SVCI and ADCI. This finding may provide a potential pre-screening marker for Aβ positivity and a candidate therapeutic target for SVCI.
Diaphragmatic ultrasound can help evaluate pulmonary dysfunction in patients with stroke
Authors: Chen Yifei , Zhou Shuyan , Liao Lixia , He Jinyan , Tang Danzhe , Wu Wen , Wang Kangling
Published: April 2023

Objective

Pulmonary dysfunction after stroke is increasingly gaining attention from clinical and rehabilitation specialists. However, owing to cognitive and motor dysfunction in patients with stroke, determining the pulmonary function of these patients remains challenging. The present study aimed to devise a simple method for an early evaluation of pulmonary dysfunction in patients with stroke.

Methods

Overall, 41 patients with stroke in the recovery period (stroke group) and 22 matched healthy controls (control group) were included in the study. We first collected data regarding baseline characteristics for all participants. Furthermore, the participants with stroke were examined using additional scales, such as the National Institutes of Health Stroke Scale (NIHSS), Fugl–Meyer assessment scale (FMA), and modified Barthel Index (MBI). Subsequently, we examined the participants with simple pulmonary function detection and diaphragm ultrasound (B-mode). Ultrasound indices calculated were as follows: the thickness of the diaphragm under the position of functional residual capacity (TdiFRC), the thickness of the diaphragm under the position of forced vital capacity (TdiFVC), thickness fraction, and diaphragmatic mobility. Finally, we compared and analyzed all data to identify group differences, the correlation between pulmonary function and diaphragmatic ultrasound indices, and the correlation between pulmonary function and assessment scale scores in patients with stroke, respectively.

Results

Compared with the control group, patients in the stroke group exhibited lower values for indices of pulmonary and diaphragmatic function (p < 0.001), except for TdiFRC (p > 0.05). The majority of the patients with stroke had restrictive ventilatory dysfunction, as indicated by a significantly higher incidence ratio (36 in 41 patients) than that in the control group (0 in 22 patients) (p < 0.001). Moreover, significant correlations were found between pulmonary function and diaphragmatic ultrasound indices (p < 0.05), with the strongest correlation between TdiFVC and pulmonary indices. In the stroke group, pulmonary function indices were negatively correlated with the NIHSS scores (p < 0.001) and positively correlated with the FMA scores (p < 0.001). No (p > 0.05) or weak (p < 0.05) correlation was found between pulmonary function indices and the MBI scores.

Conclusion

We found that patients with stroke had pulmonary dysfunction even in the recovery period. Diaphragmatic ultrasound can be used as a simple and effective tool for detecting pulmonary dysfunction in patients with stroke, with TdiFVC being the most effective index.
Plasma levels of VIP are not elevated during PACAP- and VIP-induced cluster headache attacks: an exploratory study
Authors: Deligianni Christina , Pellesi Lanfranco , Chaudhry Basit Ali , Haulund Vollesen Anne Luise , Snoer Agneta Henriette , Hannibal Jens , Jensen Rigmor Højland , Ashina Messoud
Published: April 2023

Background

Pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) provoked cluster headache attacks in individuals with episodic cluster headache during their active phase and individuals with chronic cluster headache. In this study, we investigated whether infusions of PACAP and VIP caused alterations in plasma levels of VIP and their potential contribution to induced cluster headache attacks.

Methods

Participants received either PACAP or VIP infusion for 20 min on 2 separate days with an interval of at least 7 days in between. Blood collection was performed at T0, T20, T30, and T90. Plasma levels of VIP were measured using a validated radioimmunoassay method.

Results

Blood samples were collected from participants with episodic cluster headache in the active phase (eCHA, n = 14), remission (eCHR, n = 15), and from participants with chronic cluster headache (cCH, n = 15). Baseline levels of VIP did not differ among the three groups (p = 0.1161). During PACAP infusion, mixed-effects analysis revealed a significant increase in plasma levels of VIP in eCHA (p = 0.0300) and eCHR (p = 0.0058) but not in cCH (p = 0.2930). We found no difference in the increase of plasma VIP levels between patients who developed PACAP38- or VIP-induced attacks.

Conclusion

Cluster headache attacks induced by PACAP38 or VIP infusion are not associated with changes in plasma levels of VIP. Further studies are needed to investigate the role of VIP and the parasympathetic system in cluster headache.

Clinical trial registration

The parent study is registered at ClinicalTrials.gov (NCT03814226).
Serum microRNAs associated with concussion in football players
Authors: Wyczechowska Dorota , Harch Paul G. , Mullenix Shelly , Fannin Erin S. , Chiappinelli Brenda B. , Jeansonne Duane , Lassak Adam , Bazan Nicolas G. , Peruzzi Francesca
Published: April 2023

Mild Traumatic Brain Injury (mild TBI)/concussion is a common sports injury, especially common in football players. Repeated concussions are thought to lead to long-term brain damage including chronic traumatic encephalopathy (CTE). With the worldwide growing interest in studying sport-related concussion the search for biomarkers for early diagnosis and progression of neuronal injury has also became priority. MicroRNAs are short, non-coding RNAs that regulate gene expression post-transcriptionally. Due to their high stability in biological fluids, microRNAs can serve as biomarkers in a variety of diseases including pathologies of the nervous system. In this exploratory study, we have evaluated changes in the expression of selected serum miRNAs in collegiate football players obtained during a full practice and game season. We found a miRNA signature that can distinguish with good specificity and sensitivity players with concussions from non-concussed players. Furthermore, we found miRNAs associated with the acute phase (let-7c-5p, miR-16-5p, miR-181c-5p, miR-146a-5p, miR-154-5p, miR-431-5p, miR-151a-5p, miR-181d-5p, miR-487b-3p, miR-377-3p, miR-17-5p, miR-22-3p, and miR-126-5p) and those whose changes persist up to 4 months after concussion (miR-17-5p and miR-22-3p).
The endocannabinoid system and breathing
Authors: Wiese Beth M. , Alvarez Reyes Angelica , Vanderah Todd W. , Largent-Milnes Tally M.
Published: April 2023

Recent changes in cannabis accessibility have provided adjunct therapies for patients across numerous disease states and highlights the urgency in understanding how cannabinoids and the endocannabinoid (EC) system interact with other physiological structures. The EC system plays a critical and modulatory role in respiratory homeostasis and pulmonary functionality. Respiratory control begins in the brainstem without peripheral input, and coordinates the preBötzinger complex, a component of the ventral respiratory group that interacts with the dorsal respiratory group to synchronize burstlet activity and drive inspiration. An additional rhythm generator: the retrotrapezoid nucleus/parafacial respiratory group drives active expiration during conditions of exercise or high CO2. Combined with the feedback information from the periphery: through chemo- and baroreceptors including the carotid bodies, the cranial nerves, stretch of the diaphragm and intercostal muscles, lung tissue, and immune cells, and the cranial nerves, our respiratory system can fine tune motor outputs that ensure we have the oxygen necessary to survive and can expel the CO2waste we produce, and every aspect of this process can be influenced by the EC system. The expansion in cannabis access and potential therapeutic benefits, it is essential that investigations continue to uncover the underpinnings and mechanistic workings of the EC system. It is imperative to understand the impact cannabis, and exogenous cannabinoids have on these physiological systems, and how some of these compounds can mitigate respiratory depression when combined with opioids or other medicinal therapies. This review highlights the respiratory system from the perspective of central versus peripheral respiratory functionality and how these behaviors can be influenced by the EC system. This review will summarize the literature available on organic and synthetic cannabinoids in breathing and how that has shaped our understanding of the role of the EC system in respiratory homeostasis. Finally, we look at some potential future therapeutic applications the EC system has to offer for the treatment of respiratory diseases and a possible role in expanding the safety profile of opioid therapies while preventing future opioid overdose fatalities that result from respiratory arrest or persistent apnea.
GAP-43 closely interacts with BDNF in hippocampal neurons and is associated with Alzheimer's disease progression
Authors: Lee Ye Ji , Jeong Ye Ji , Kang Eun Ji , Kang Beom Seok , Lee Song Hee , Kim You Jin , Kang Seong Su , Suh Sang Won , Ahn Eun Hee
Published: April 2023

Introduction

Growth-associated protein 43 (GAP-43) is known as a neuronal plasticity protein because it is widely expressed at high levels in neuronal growth cones during axonal regeneration. GAP-43 expressed in mature adult neurons is functionally important for the neuronal communication of synapses in learning and memory. Brain-derived neurotrophic factor (BDNF) is closely related to neurodegeneration and synaptic plasticity during the aging process. However, the molecular mechanisms regulating neurodegeneration and synaptic plasticity underlying the pathogenesis and progression of Alzheimer's disease (AD) still remain incompletely understood.

Methods

Remarkably, the expressions of GAP-43 and BDNF perfectly match in various neurons in the Human Brain Atlas database. Moreover, GAP-43 and BDNF are highly expressed in a healthy adults' hippocampus brain region and are inversely correlated with the amyloid beta (Aβ), which is the pathological peptide of amyloid plaques found in the brains of patients with AD.

Results

These data led us to investigate the impact of the direct molecular interaction between GAP-43 and BDNF in hippocampal neuron fate. In this study, we show that GAP-43 and BDNF are inversely associated with pathological molecules for AD (Tau and Aβ). In addition, we define the three-dimensional protein structure for GAP-43 and BDNF, including the predictive direct binding sites via analysis using ClusPro 2.0, and demonstrate that the deprivation of GAP-43 and BDNF triggers hippocampal neuronal death and memory dysfunction, employing the GAP-43 or BDNF knock-down cellular models and 5XFAD mice.

Conclusion

These results show that GAP-43 and BDNF are direct binding partners in hippocampal neurons and that their molecular signaling might be potential therapeutic targets for AD.
Role of cerebellum in sleep-dependent memory processes
Authors: Jackson Andrew , Xu Wei
Published: April 2023

The activities and role of the cerebellum in sleep have, until recently, been largely ignored by both the sleep and cerebellum fields. Human sleep studies often neglect the cerebellum because it is at a position in the skull that is inaccessible to EEG electrodes. Animal neurophysiology sleep studies have focussed mainly on the neocortex, thalamus and the hippocampus. However, recent neurophysiological studies have shown that not only does the cerebellum participate in the sleep cycle, but it may also be implicated in off-line memory consolidation. Here we review the literature on cerebellar activity during sleep and the role it plays in off-line motor learning, and introduce a hypothesis whereby the cerebellum continues to compute internal models during sleep that train the neocortex.
Integration of advanced 3D SPECT modelling for pinhole collimators into the open-source STIR framework
Authors: Strugari Matthew , Falcon Carles , Erlandsson Kjell , Hutton Brian F. , Brewer Kimberly , Thielemans Kris
Published: April 2023

Single-photon emission computed tomography (SPECT) systems with pinhole collimators are becoming increasingly important in clinical and preclinical nuclear medicine investigations as they can provide a superior resolution-sensitivity trade-off compared to conventional parallel-hole and fanbeam collimators. Previously, open-source software did not exist for reconstructing tomographic images from pinhole-SPECT datasets. A 3D SPECT system matrix modelling library specific for pinhole collimators has recently been integrated into STIR, an open-source software package for tomographic image reconstruction. The pinhole-SPECT library enables corrections for attenuation and the spatially variant collimator–detector response by incorporating their effects into the system matrix. Attenuation correction can be calculated with a simple single line of response or a full model. The spatially variant collimator–detector response can be modelled with a point spread function and depth of interaction corrections for increased system matrix accuracy. In addition, improvements to computational speed and memory requirements can be made with image masking. This work demonstrates the flexibility and accuracy of STIR’s support for pinhole-SPECT datasets using measured and simulated single-pinhole SPECT data from which reconstructed images were analysed quantitatively and qualitatively. The extension of the open-source STIR project with advanced pinhole-SPECT modelling will enable the research community to study the impact of pinhole collimators in several SPECT imaging scenarios and with different scanners.
Effects of Niacin on Resistance to Enterotoxigenic Escherichia coli Infection in Weaned Piglets
Authors: Zhen Rui , Feng Junsen , He Dongsheng , Chen Yibo , Chen Tianbao , Cai Weiyou , Xiong Yunxia , Qiu Yueqin , Jiang Zongyong , Wang Li , Yi Hongbo
Published: April 2023

Graphical Abstract

Nicotinic acid could improve intestinal antimicrobial peptides to enhance resistance of weaned piglets to E. coli infection by regulating intestinal microflora and its metabolites, histone deacetylase SIRT1 and HDAC7, modification sites such as acH3K9, acH3K27, and pH3S10 in the promoter region.
An 8-step approach for the systematic development of an evidence-based exercise program for patients undergoing hematopoietic stem cell transplantation
Authors: An Ki-Yong , Yu Mi-Seong , Cho Wonhee , Choi Meeok , Courneya Kerry S. , Cheong June-Won , Jeon Justin Y.
Published: April 2023

Background

A tailored and reliable intervention program developed based on evidence is necessary for patients with serious health conditions.

Objective

We describe the development of an exercise program for HSCT patients based on evidence from a systematic process.

Methods

We developed the exercise program for HSCT patients using eight systematic steps: (1) a literature review, (2) understanding patient characteristics, (3) first expert group discussion, (4) development of the first draft of the exercise program, (5) a pre-test, (6) second expert group discussion, (7) a pilot randomized controlled trial (n=21), and (8) a focus group interview.

Results

The developed exercise program was unsupervised and consisted of different exercises and intensities according to the patients’ hospital room and health condition. Participants were provided with instructions for the exercise program, exercise videos via smartphone, and prior education sessions. In the pilot trial, the adherence to the exercise program was only 44.7%, however, some changes in physical functioning and body composition favored the exercise group despite the small sample size.

Conclusion

Strategies to improve adherence to this exercise program and larger sample sizes are needed to adequately test if the developed exercise program may help patients improve physical and hematologic recovery after HSCT. This study may help researchers develop a safe and effective evidence-based exercise program for their intervention studies. Moreover, the developed program may benefit the physical and hematological recovery in patients undergoing HSCT in larger trials, if exercise adherence is improved.

Clinical trial registration

https://cris.nih.go.kr/cris/search/detailSearch.do?seq=24233&search_page=L, identifier KCT 0008269.
Combined treatment of disulfiram with PARP inhibitors suppresses ovarian cancer
Authors: Tang Bin , Wu Min , Zhang Lin , Jian Shuyi , Lv Shiyi , Lin Tongyuan , Zhu Shuangshuang , Liu Layang , Wang Yixue , Yi Zhengfang , Jiang Feiyun
Published: April 2023

Introduction

Due to the difficulty of early diagnosis, nearly 70% of ovarian cancer patients are first diagnosed at an advanced stage. Thus, improving current treatment strategies is of great significance for ovarian cancer patients. Fast-developing poly (ADP-ribose) polymerases inhibitors (PARPis) have been beneficial in the treatment of ovarian cancer at different stages of the disease, but PARPis have serious side effects and can result in drug resistance. Using PARPis in combination with other drug therapies could improve the efficacy of PRAPis.In this study, we identified Disulfiram as a potential therapeutic candidate through drug screening and tested its use in combination with PARPis.

Methods

Cytotoxicity tests and colony formation experiments showed that the combination of Disulfiram and PARPis decreased the viability of ovarian cancer cells

Results

The combination of PARPis with Disulfiram also significantly increased the expression of DNA damage index gH2AX and induced more PARP cleavage. In addition, Disulfiram inhibited the expression of genes associated with the DNA damage repair pathway, indicating that Disulfiram functions through the DNA repair pathway.

Discussion

Based on these findings, we propose that Disulfiram reinforces PARPis activity in ovarian cancer cells by improving drug sensitivity. The combined use of Disulfiram and PARPis provides a novel treatment strategy for patients with ovarian cancer.