bluuebunny/crossref_metadata_2025 huggingface dataset:
Differences in recent and future trends in the Arabian Sea oxygen minimum zone: processes and uncertainties
Authors: Lachkar Zouhair , Lévy Marina , Hailegeorgis Derara , Vallivattathillam Parvathi
Published: April 2023

The Arabian Sea is an exceptionally complex system that hosts a highly productive marine ecosystem. This intense productivity leads to high oxygen consumption at depth that maintains, together with the sluggish circulation, the world’s thickest oxygen minimum zone (OMZ). While observations have been scarce in the region, evidence for a recent (1960-2020) decline in oxygen is emerging in the northern Arabian Sea. However, in the longer term (2050 to 2100) the future evolution of the OMZ is more uncertain, as the model projections that have been carried out are not consistent with each other. On the one hand, this reflects the limitations of current generation models that do not adequately represent key physical and biogeochemical processes, resulting in large O2biases in the region under present-day conditions. On the other hand, the inherent difficulty of predicting future O2conditions in the Arabian Sea is a consequence of the sensitivity of O2supply and consumption to local and remote changes that evolve on different timescales. Here we aim to synthesize current knowledge of the Arabian Sea OMZ in relation to important factors controlling its intensity and review its recent change and potential future evolution. In particular, we explore potential causes of the differences in recent and future O2trends in the region and identify key challenges to our ability to project future OMZ changes and discuss ideas for the way forward.
The linkages between stomatal physiological traits and rapid expansion of exotic mangrove species (Laguncularia racemosa) in new territories
Authors: Bai Jiankun , Meng Yuchen , Gou Ruikun , Dai Zheng , Zhu Xiaoshan , Lin Guanghui
Published: April 2023

The fast-growing exotic mangrove species (Laguncularia racemosa) has been widely introduced in new territories such as China to restore mangrove ecosystems. However, the invasiveness, as well as the mechanisms for the rapid expansion after the introduction are still not well studied. Here, we try to reveal possible micro-mechanisms for the fast expansion of L. racemosa, using the data on leaf stomata straits, gas-exchange parameters, stable isotope ratios, carbon-nitrogen allocation from L. racemosa and the adjacent native mangroves (Avicennia marina, Aegiceras corniculatum, Bruguiera gymnorhiza, Kandelia obovata) in Hainan Island, China. We found that the higher density but smaller size stoma of L. racemosa enhanced stomatal conductance and shorten the diffusion path of carbon dioxide, thereby increasing the photosynthetic rate. Moreover, the higher stomatal density of L. racemosa exerts a significant positive effect on transpiration, which thus accelerated the water transport and nutrient uptake to meet the advanced need for nutrients and water for fast-growing. The evidence from leaf δ13C and carbon-nitrogen allocation further proved that L. racemosa has a lower intrinsic water use efficiency but a higher rate of photosynthesis than native mangrove species. Our results suggest that stomatal morphological and physiological traits could strongly influence the growth of L. racemosa compared to the adjacent native mangroves, which provides a new perspective for the fast expansion of exotic mangrove species in China. These findings also suggest that L. racemosa has an invasive potential in native mangrove habitats, thereby the mangrove reforestation projects by introducing L. racemosa should be treated with caution.
A new species of the genus Catillopecten (Bivalvia: Pectinoidea: Propeamussiidae): morphology, mitochondrial genome, and phylogenetic relationship
Authors: Lin Yi-Tao , Li Yi-Xuan , Sun Yanan , Tao Jun , Qiu Jian-Wen
Published: April 2023

Catillopectenis a small genus of deep-sea glass scallops, but its diversity is poorly known in many parts of the world ocean. We describedC. margaritatusn. sp. (Pectinoidea: Propeamussiidae), and performed morphological analyses and DNA sequencing, and estimated the divergence time of scallops based on samples collected from Haima cold seep in the South China Sea. Morphologically, the new species can be distinguished from congeneric species by its large shell size, relatively small auricle length, absence of monocrystal aerials, presence of longitudinal radial ridges on the left valve, and the alternated rounded striae and distal and proximal growth lines of prisms on the right valve. Anatomically, this new species can be distinguished fromC. vulcaniby its anteriorly located auriculate gills, compared to the centrally located lamellar gills of the latter, and the different locations of the pericardium. Sequence comparison and phylogenetic analysis based on the18S rRNAfragments supported the placement of the new species inCatillopecten. We also report the mitogenome ofC. margaritatusn. sp. as the only reported mitogenome of the family Propeamussiidae, which differs from those of other scallops substantially in gene order arrangement. Divergence time estimation revealed that Propeamussiidae and Pectinidae diverged in the early Carboniferous, whileCatillopectenandParvamussiumdiverged during the late Cretaceous to early Eocene. Finally, we presented a key to the species ofCatillopecten.
A risk prediction model for type 2 diabetes mellitus complicated with retinopathy based on machine learning and its application in health management
Authors: Pan Hong , Sun Jijia , Luo Xin , Ai Heling , Zeng Jing , Shi Rong , Zhang An
Published: April 2023

Objective

This study aimed to establish a risk prediction model for diabetic retinopathy (DR) in the Chinese type 2 diabetes mellitus (T2DM) population using few inspection indicators and to propose suggestions for chronic disease management.

Methods

This multi-centered retrospective cross-sectional study was conducted among 2,385 patients with T2DM. The predictors of the training set were, respectively, screened by extreme gradient boosting (XGBoost), a random forest recursive feature elimination (RF-RFE) algorithm, a backpropagation neural network (BPNN), and a least absolute shrinkage selection operator (LASSO) model. Model I, a prediction model, was established through multivariable logistic regression analysis based on the predictors repeated ≥3 times in the four screening methods. Logistic regression Model II built on the predictive factors in the previously released DR risk study was introduced into our current study to evaluate the model’s effectiveness. Nine evaluation indicators were used to compare the performance of the two prediction models, including the area under the receiver operating characteristic curve (AUROC), accuracy, precision, recall, F1 score, balanced accuracy, calibration curve, Hosmer-Lemeshow test, and Net Reclassification Index (NRI).

Results

When including predictors, such as glycosylated hemoglobin A1c, disease course, postprandial blood glucose, age, systolic blood pressure, and albumin/urine creatinine ratio, multivariable logistic regression Model I demonstrated a better prediction ability than Model II. Model I revealed the highest AUROC (0.703), accuracy (0.796), precision (0.571), recall (0.035), F1 score (0.066), Hosmer-Lemeshow test (0.887), NRI (0.004), and balanced accuracy (0.514).

Conclusion

We have built an accurate DR risk prediction model with fewer indicators for patients with T2DM. It can be used to predict the individualized risk of DR in China effectively. In addition, the model can provide powerful auxiliary technical support for the clinical and health management of patients with diabetes comorbidities.
Activation of the integrated stress response (ISR) pathways in response to Ref-1 inhibition in human pancreatic cancer and its tumor microenvironment
Authors: Mijit Mahmut , Boner Megan , Cordova Ricardo A. , Gampala Silpa , Kpenu Eyram , Klunk Angela J. , Zhang Chi , Kelley MarK R. , Staschke Kirk A. , Fishel Melissa L.
Published: April 2023

Pancreatic cancer or pancreatic ductal adenocarcinoma (PDAC) is characterized by a profound inflammatory tumor microenvironment (TME) with high heterogeneity, metastatic propensity, and extreme hypoxia. The integrated stress response (ISR) pathway features a family of protein kinases that phosphorylate eukaryotic initiation factor 2 (eIF2) and regulate translation in response to diverse stress conditions, including hypoxia. We previously demonstrated that eIF2 signaling pathways were profoundly affected in response to Redox factor-1 (Ref-1) knockdown in human PDAC cells. Ref-1 is a dual function enzyme with activities of DNA repair and redox signaling, responds to cellular stress, and regulates survival pathways. The redox function of Ref-1 directly regulates multiple transcription factors including HIF-1α, STAT3, and NF-κB, which are highly active in the PDAC TME. However, the mechanistic details of the crosstalk between Ref-1 redox signaling and activation of ISR pathways are unclear. Following Ref-1 knockdown, induction of ISR was observed under normoxic conditions, while hypoxic conditions were sufficient to activate ISR irrespective of Ref-1 levels. Inhibition of Ref-1 redox activity increased expression of p-eIF2 and ATF4 transcriptional activity in a concentration-dependent manner in multiple human PDAC cell lines, and the effect on eIF2 phosphorylation was PERK-dependent. Treatment with PERK inhibitor, AMG-44 at high concentrations resulted in activation of the alternative ISR kinase, GCN2 and induced levels of p-eIF2 and ATF4 in both tumor cells and cancer-associated fibroblasts (CAFs). Combination treatment with inhibitors of Ref-1 and PERK enhanced cell killing effects in both human pancreatic cancer lines and CAFs in 3D co-culture, but only at high doses of PERK inhibitors. This effect was completely abrogated when Ref-1 inhibitors were used in combination with GCN2 inhibitor, GCN2iB. We demonstrate that targeting of Ref-1 redox signaling activates the ISR in multiple PDAC lines and that this activation of ISR is critical for inhibition of the growth of co-culture spheroids. Combination effects were only observed in physiologically relevant 3D co-cultures, suggesting that the model system utilized can greatly affect the outcome of these targeted agents. Inhibition of Ref-1 signaling induces cell death through ISR signaling pathways, and combination of Ref-1 redox signaling blockade with ISR activation could be a novel therapeutic strategy for PDAC treatment.
Gastric microbiota: an emerging player in gastric cancer
Authors: Zhou Shizhen , Li Chenxi , Liu Lixiang , Yuan Qinggang , Miao Ji , Wang Hao , Ding Chao , Guan Wenxian
Published: April 2023

Gastric cancer (GC) is a common cancer worldwide with a high mortality rate. Many microbial factors influence GC, of which the most widely accepted one is Helicobacter pylori (H. pylori) infection. H. pylori causes inflammation, immune reactions and activation of multiple signaling pathways, leading to acid deficiency, epithelial atrophy, dysplasia and ultimately GC. It has been proved that complex microbial populations exist in the human stomach. H. pylori can affect the abundance and diversity of other bacteria. The interactions among gastric microbiota are collectively implicated in the onset of GC. Certain intervention strategies may regulate gastric homeostasis and mitigate gastric disorders. Probiotics, dietary fiber, and microbiota transplantation can potentially restore healthy microbiota. In this review, we elucidate the specific role of the gastric microbiota in GC and hope these data can facilitate the development of effective prevention and therapeutic approaches for GC.
Plasmid-mediated colistin resistance among human clinical Enterobacterales isolates: national surveillance in the Czech Republic
Authors: Zelendova Marketa , Papagiannitsis Costas C. , Sismova Petra , Medvecky Matej , Pomorska Katarina , Palkovicova Jana , Nesporova Kristina , Jakubu Vladislav , Jamborova Ivana , Zemlickova Helena , Dolejska Monika ,   Working Group for Monitoring of Antibiotic Resistance
Published: April 2023

The occurrence of colistin resistance has increased rapidly among Enterobacterales around the world. We performed a national survey of plasmid-mediated colistin resistance in human clinical isolates through a retrospective analysis of samples from 2009 to 2017 and a prospective sampling in 2018–2020. The aim of this study was to identify and characterize isolates with mcr genes from various regions of the Czech Republic using whole genome sequencing (WGS). Of all 1932 colistin-resistant isolates analyzed, 73 (3.8%) were positive for mcr genes. Most isolates carried mcr-1 (48/73) and were identified as Escherichia coli (n = 44) and Klebsiella pneumoniae (n = 4) of various sequence types (ST). Twenty-five isolates, including Enterobacter spp. (n = 24) and Citrobacter freundii (n = 1) carrying the mcr-9 gene were detected; three of them (Enterobacter kobei ST54) co-harbored the mcr-4 and mcr-9 genes. Multi-drug resistance phenotype was a common feature of mcr isolates and 14% (10/73) isolates also co-harbored clinically important beta-lactamases, including two isolates with carbapenemases KPC-2 and OXA-48. Phylogenetic analysis of E. coli ST744, the dominant genotype in this study, with the global collection showed Czech isolates belonged to two major clades, one containing isolates from Europe, while the second composed of isolates from diverse geographical areas. The mcr-1 gene was carried by IncX4 (34/73, 47%), IncHI2/ST4 (6/73, 8%) and IncI2 (8/73, 11%) plasmid groups. Small plasmids belonging to the ColE10 group were associated with mcr-4 in three isolates, while mcr-9 was carried by IncHI2/ST1 plasmids (4/73, 5%) or the chromosome (18/73, 25%). We showed an overall low level of occurrence of mcr genes in colistin-resistant bacteria from human clinical samples in the Czech Republic.
Pathogen genomics and phage-based solutions for accurately identifying and controlling Salmonella pathogens
Authors: Lopez-Garcia Angela V. , AbuOun Manal , Nunez-Garcia Javier , Nale Janet Y. , Gaylov Edouard E. , Phothaworn Preeda , Sukjoi Chutikarn , Thiennimitr Parameth , Malik Danish J. , Korbsrisate Sunee , Clokie Martha R. J. , Anjum Muna F.
Published: April 2023

Salmonella is a food-borne pathogen often linked to poultry sources, causing gastrointestinal infections in humans, with the numbers of multidrug resistant (MDR) isolates increasing globally. To gain insight into the genomic diversity of common serovars and their potential contribution to disease, we characterized antimicrobial resistance genes, and virulence factors encoded in 88 UK and 55 Thai isolates from poultry; the presence of virulence genes was detected through an extensive virulence determinants database compiled in this study. Long-read sequencing of three MDR isolates, each from a different serovar, was used to explore the links between virulence and resistance. To augment current control methods, we determined the sensitivity of isolates to 22 previously characterized Salmonella bacteriophages. Of the 17 serovars included, Salmonella Typhimurium and its monophasic variants were the most common, followed by S. Enteritidis, S. Mbandaka, and S. Virchow. Phylogenetic analysis of Typhumurium and monophasic variants showed poultry isolates were generally distinct from pigs. Resistance to sulfamethoxazole and ciprofloxacin was highest in isolates from the UK and Thailand, respectively, with 14–15% of all isolates being MDR. We noted that >90% of MDR isolates were likely to carry virulence genes as diverse as the srjF, lpfD, fhuA, and stc operons. Long-read sequencing revealed the presence of global epidemic MDR clones in our dataset, indicating they are possibly widespread in poultry. The clones included MDR ST198 S. Kentucky, harboring a Salmonella Genomic Island-1 (SGI)-K, European ST34 S. 1,4,[5],12:i:-, harboring SGI-4 and mercury-resistance genes, and a S. 1,4,12:i:- isolate from the Spanish clone harboring an MDR-plasmid. Testing of all isolates against a panel of bacteriophages showed variable sensitivity to phages, with STW-77 found to be the most effective. STW-77 lysed 37.76% of the isolates, including serovars important for human clinical infections: S. Enteritidis (80.95%), S. Typhimurium (66.67%), S. 1,4,[5],12:i:- (83.3%), and S. 1,4,12: i:- (71.43%). Therefore, our study revealed that combining genomics and phage sensitivity assays is promising for accurately identifying and providing biocontrols for Salmonella to prevent its dissemination in poultry flocks and through the food chain to cause infections in humans.
Analysis of the current status of rehabilitation motivation and its influencing factors in older adults with stroke: a cross-sectional study
Authors: Tan Mingyang , Li Hongyu , Wang Xiuli
Published: April 2023

Objective

Among stroke patients, exercise adherence is an important factor in reducing the rate of physical disability and mortality. Rehabilitation exercise after stroke is a safe and effective measure to restore normal body functions, but the analysis of factors influencing patients’ motivation for rehabilitation is not well established. Therefore, this study will explore the influencing factors of rehabilitation motivation in older adults with stroke so as to reduce the disability rate of stroke.

Method

A convenience sampling method was used to study 350 patients in a stroke ward of a tertiary care hospital in Jinzhou, Liaoning Province. Patients’ general demographic data, Multidimensional Scale of Perceived Social Support (PSSS), Questionnaire of Exercise Adherence (EAQ), Tampa scale of kinesiophobia (TSK-11), and Motivation in stroke patients for rehabilitation scale (MORE) were assessed. ANOVA or t-test analysis, correlation analysis, and linear regression analysis were used to explore the factors influencing the motivation for rehabilitation in older adults with stroke.

Results

The results showed that stroke patients’ motivation for rehabilitation was at a moderate level. Perceived social support, exercise adherence, and stroke motivation were positively correlated (r = 0.619, p < 0.01; r = 0.569, p < 0.01), and kinesiophobia was negatively correlated with stroke motivation (r = −0.677, p < 0.01). Time of stroke, location of the lesion, perceived social support, exercise adherence, and kinesiophobia are influential factors affecting patients’ motivation to recover.

Conclusion

In the rehabilitation program for older adult patients with stroke, healthcare providers should specify targeted rehabilitation measures according to the different degrees of the patient’s condition, so as to improve the effectiveness of rehabilitation medical implementation.
Anterior basolateral amygdala neurons comprise a remote fear memory engram
Authors: Hammack Robert J. , Fischer Victoria E. , Andrade Mary Ann , Toney Glenn M.
Published: April 2023

Introduction

Threatening environmental cues often generate enduring fear memories, but how these are formed and stored remains actively investigated. Recall of a recent fear memory is thought to reflect reactivation of neurons, in multiple brain regions, activated during memory formation, indicating that anatomically distributed and interconnected neuronal ensembles comprise fear memory engrams. The extent to which anatomically specific activation-reactivation engrams persist during long-term fear memory recall, however, remains largely unexplored. We hypothesized that principal neurons in the anterior basolateral amygdala (aBLA), which encode negative valence, acutely reactivate during remote fear memory recall to drive fear behavior.

Methods

Using adult offspring of TRAP2 and Ai14 mice, persistent tdTomato expression was used to “TRAP” aBLA neurons that underwent Fos-activation during contextual fear conditioning (electric shocks) or context only conditioning (no shocks) (n = 5/group). Three weeks later, mice were re-exposed to the same context cues for remote memory recall, then sacrificed for Fos immunohistochemistry.

Results

TRAPed (tdTomato +), Fos +, and reactivated (double-labeled) neuronal ensembles were larger in fear- than context-conditioned mice, with the middle sub-region and middle/caudal dorsomedial quadrants of aBLA displaying the greatest densities of all three ensemble populations. Whereas tdTomato + ensembles were dominantly glutamatergic in context and fear groups, freezing behavior during remote memory recall was not correlated with ensemble sizes in either group.

Discussion

We conclude that although an aBLA-inclusive fear memory engram forms and persists at a remote time point, plasticity impacting electrophysiological responses of engram neurons, not their population size, encodes fear memory and drives behavioral manifestations of long-term fear memory recall.
Safety and efficacy of endovascular recanalization for symptomatic non-acute atherosclerotic intracranial large artery occlusion
Authors: Chu Xi , Meng Yao , Zhang Jun , Sun Lili , Yin Hao , Dong Kaiyue , Chen Yingkun , Song Yun , Zheng Meimei , Wang Wei , Zhao Wei , Han Ju
Published: April 2023

Background and objective

The optimal treatment for patients with symptomatic non-acute atherosclerotic intracranial large artery occlusion (ILAO) despite medical treatment is not well established. We aimed to assess the safety, efficacy, and feasibility of angioplasty and stenting for these patients.

Methods

A total of 251 consecutive patients with symptomatic non-acute atherosclerotic ILAO treated with interventional recanalization were retrospectively collected in our center from March 2015 to August 2021. The rate of successful recanalization, perioperative complications, and follow-up outcomes were evaluated.

Results

Successful recanalization was achieved in 88.4% (222/251) of the patients. A total of 24 (24/251, 9.6%) symptomatic complications occurred among 251 procedures. In the 193 patients with clinical follow-up during 19.0 ± 14.7 months, 11 (11/193, 5.7%) patients developed ischemic stroke and four (4/193, 2.1%) patients developed transient ischemic attack (TIA). In the 106 patients with vascular imaging follow-up during 6.8 ± 6.6 months, seven (7/106, 6.6%) patients had restenosis and 10 (10/106, 9.4%) patients had reocclusion.

Conclusion

This study suggests that interventional recanalization may be a feasible, basically safe, and an effective alternative in carefully selected patients with symptomatic non-acute atherosclerotic ILAO who have failed medical management.
The role of neurophysiological tools in the evaluation of ischemic stroke evolution: a narrative review
Authors: Motolese Francesco , Lanzone Jacopo , Todisco Antonio , Rossi Mariagrazia , Santoro Francesca , Cruciani Alessandro , Capone Fioravante , Di Lazzaro Vincenzo , Pilato Fabio
Published: April 2023

Ischemic stroke is characterized by a complex cascade of events starting from vessel occlusion. The term “penumbra” denotes the area of severely hypo-perfused brain tissue surrounding the ischemic core that can be potentially recovered if blood flow is reestablished. From the neurophysiological perspective, there are local alterations—reflecting the loss of function of the core and the penumbra—and widespread changes in neural networks functioning, since structural and functional connectivity is disrupted. These dynamic changes are closely related to blood flow in the affected area. However, the pathological process of stroke does not end after the acute phase, but it determines a long-term cascade of events, including changes of cortical excitability, that are quite precocious and might precede clinical evolution. Neurophysiological tools—such as Transcranial Magnetic Stimulation (TMS) or Electroencephalography (EEG)—have enough time resolution to efficiently reflect the pathological changes occurring after stroke. Even if they do not have a role in acute stroke management, EEG and TMS might be helpful for monitoring ischemia evolution—also in the sub-acute and chronic stages. The present review aims to describe the changes occurring in the infarcted area after stroke from the neurophysiological perspective, starting from the acute to the chronic phase.
A method for capturing dynamic spectral coupling in resting fMRI reveals domain-specific patterns in schizophrenia
Authors: Alaçam Deniz , Miller Robyn , Agcaoglu Oktay , Preda Adrian , Ford Judith , Calhoun Vince
Published: April 2023

Introduction

Resting-state functional magnetic resonance imaging (rs-fMRI) is a powerful tool for assessing functional brain connectivity. Recent studies have focused on shorter-term connectivity and dynamics in the resting state. However, most of the prior work evaluates changes in time-series correlations. In this study, we propose a framework that focuses on time-resolved spectral coupling (assessed via the correlation between power spectra of the windowed time courses) among different brain circuits determined via independent component analysis (ICA).

Methods

Motivated by earlier work suggesting significant spectral differences in people with schizophrenia, we developed an approach to evaluate time-resolved spectral coupling (trSC). To do this, we first calculated the correlation between the power spectra of windowed time-courses pairs of brain components. Then, we subgrouped each correlation map into four subgroups based on the connectivity strength utilizing quartiles and clustering techniques. Lastly, we examined clinical group differences by regression analysis for each averaged count and average cluster size matrices in each quartile. We evaluated the method by applying it to resting-state data collected from 151 (114 males, 37 females) people with schizophrenia (SZ) and 163 (117 males, 46 females) healthy controls (HC).

Results

Our proposed approach enables us to observe the change of connectivity strength within each quartile for different subgroups. People with schizophrenia showed highly modularized and significant differences in multiple network domains, whereas males and females showed less modular differences. Both cell count and average cluster size analysis for subgroups indicate a higher connectivity rate in the fourth quartile for the visual network in the control group. This indicates increased trSC in visual networks in the controls. In other words, this shows that the visual networks in people with schizophrenia have less mutually consistent spectra. It is also the case that the visual networks are less spectrally correlated on short timescales with networks of all other functional domains.

Conclusions

The results of this study reveal significant differences in the degree to which spectral power profiles are coupled over time. Importantly, there are significant but distinct differences both between males and females and between people with schizophrenia and controls. We observed a more significant coupling rate in the visual network for the healthy controls and males in the upper quartile. Fluctuations over time are complex, and focusing on only time-resolved coupling among time-courses is likely to miss important information. Also, people with schizophrenia are known to have impairments in visual processing but the underlying reasons for the impairment are still unknown. Therefore, the trSC approach can be a useful tool to explore the reasons for the impairments.
The potential of the gut microbiome for identifying Alzheimer’s disease diagnostic biomarkers and future therapies
Authors: Zhan Yu , Al-Nusaif Murad , Ding Cong , Zhao Li , Dong Chunbo
Published: April 2023

Being isolated from the peripheral system by the blood–brain barrier, the brain has long been considered a completely impervious tissue. However, recent findings show that the gut microbiome (GM) influences gastrointestinal and brain disorders such as Alzheimer’s disease (AD). Despite several hypotheses, such as neuroinflammation, tau hyperphosphorylation, amyloid plaques, neurofibrillary tangles, and oxidative stress, being proposed to explain the origin and progression of AD, the pathogenesis remains incompletely understood. Epigenetic, molecular, and pathological studies suggest that GM influences AD development and have endeavored to find predictive, sensitive, non-invasive, and accurate biomarkers for early disease diagnosis and monitoring of progression. Given the growing interest in the involvement of GM in AD, current research endeavors to identify prospective gut biomarkers for both preclinical and clinical diagnoses, as well as targeted therapy techniques. Here, we discuss the most recent findings on gut changes in AD, microbiome-based biomarkers, prospective clinical diagnostic uses, and targeted therapy approaches. Furthermore, we addressed herbal components, which could provide a new venue for AD diagnostic and therapy research.
Mouse all-cone retina models of Cav1.4 synaptopathy
Authors: Laird Joseph G. , Kopel Ariel , Lankford Colten K. , Baker Sheila A.
Published: April 2023

The voltage-gated calcium channel, Cav1.4 is localized to photoreceptor ribbon synapses and functions both in molecular organization of the synapse and in regulating release of synaptic vesicles. Mutations in Cav1.4 subunits typically present as either incomplete congenital stationary night blindness or a progressive cone-rod dystrophy in humans. We developed a cone-rich mammalian model system to further study how different Cav1.4 mutations affect cones. RPE65 R91W KI; Nrl KO “Conefull” mice were crossed to Cav1.4 α1F or α2δ4 KO mice to generate the “Conefull:α1F KO” and “Conefull:α2δ4 KO” lines. Animals were assessed using a visually guided water maze, electroretinogram (ERG), optical coherence tomography (OCT), and histology. Mice of both sexes and up to six-months of age were used. Conefull: α1F KO mice could not navigate the visually guided water maze, had no b-wave in the ERG, and the developing all-cone outer nuclear layer reorganized into rosettes at the time of eye opening with degeneration progressing to 30% loss by 2-months of age. In comparison, the Conefull: α2δ4 KO mice successfully navigated the visually guided water maze, had a reduced amplitude b-wave ERG, and the development of the all-cone outer nuclear layer appeared normal although progressive degeneration with 10% loss by 2-months of age was observed. In summary, new disease models for studying congenital synaptic diseases due to loss of Cav1.4 function have been created.
Functional regionalization of the differentiating cerebellar Purkinje cell population occurs in an activity-dependent manner
Authors: Dorigo Alessandro , Valishetti Komali , Hetsch Florian , Matsui Hideaki , Meier Jochen C. , Namikawa Kazuhiko , Köster Reinhard W.
Published: April 2023

Introduction

The cerebellum is organized into functional regions each dedicated to process different motor or sensory inputs for controlling different locomotor behaviors. This functional regionalization is prominent in the evolutionary conserved single-cell layered Purkinje cell (PC) population. Fragmented gene expression domains suggest a genetic organization of PC layer regionalization during cerebellum development. However, the establishment of such functionally specific domains during PC differentiation remained elusive.

Methods and results

We show the progressive emergence of functional regionalization of PCs from broad responses to spatially restricted regions in zebrafish by means of in vivo Ca2+-imaging during stereotypic locomotive behavior. Moreover, we reveal that formation of new dendritic spines during cerebellar development using in vivo imaging parallels the time course of functional domain development. Pharmacological as well as cell-type specific optogenetic inhibition of PC neuronal activity results in reduced PC dendritic spine density and an altered stagnant pattern of functional domain formation in the PC layer.

Discussion

Hence, our study suggests that functional regionalization of the PC layer is driven by physiological activity of maturing PCs themselves.
18F-labeled FGFR1 peptide: a new PET probe for subtype FGFR1 receptor imaging
Authors: Chen Yang , Han Jingya , Zhao Yan , Zhao Xinming , Zhao Mengmeng , Zhang Jingmian , Wang Jianfang
Published: April 2023

Introduction

The fibroblast growth factor receptor (FGFR) family is highly expressed in a variety of tumor types and represents a new target for cancer therapy. Different FGFR subtype aberrations have been found to exhibit highly variable sensitivity and efficacy to FGFR inhibitors.

Methods

The present study is the first to suggest an imaging method for assessing FGFR1 expression. The FGFR1-targeting peptide NOTA-PEG2-KAEWKSLGEEAWHSK was synthesized by manual solid-phase peptide synthesis and high-pressure liquid chromatography (HPLC) purification and then labeled with fluorine-18 using NOTA as a chelator. In vitro and in vivo experiments were conducted to evaluate the stability, affinity and specificity of the probe. Tumor targeting efficacy and biodistribution were evaluated by micro-PET/CT imaging in RT-112, A549, SNU-16 and Calu-3 xenografts.

Results

The radiochemical purity of [18F]F-FGFR1 was 98.66% ± 0.30% (n = 3) with excellent stability. The cellular uptake rate of [18F]F-FGFR1 in the RT-112 cell line (FGFR1 overexpression) was higher than that in the other cell lines and could be blocked by the presence of excess unlabeled FGFR1 peptide. Micro-PET/CT imaging revealed a significant concentration of [18F]F-FGFR1 in RT-112 xenografts with no or very low uptake in nontargeted organs and tissues, which demonstrated that [18F]F-FGFR1 was selectively taken up by FGFR1-positive tumors.

Conclusion

[18F]F-FGFR1 showed high stability, affinity, specificity and good imaging capacity for FGFR1-overexpressing tumors in vivo, which provides new application potential in the visualization of FGFR1 expression in solid tumors.
CD146+ mural cells from infantile hemangioma display proangiogenic ability and adipogenesis potential in vitro and in xenograft models
Authors: Chen Jialin , Chen Qianyi , Qiu Yajing , Chang Lei , Yu Zhang , Li Yuanbo , Chang Shih-jen , Chen Zongan , Lin Xiaoxi
Published: April 2023

Objective

Infantile hemangioma (IH), the most common infantile vascular neoplasm, is uniquely characterized by rapid proliferation followed by slow spontaneous involution lasting for years. In IH lesions, perivascular cells are the most dynamic cell subset during the transition from the proliferation phase to the involution phase, and we aimed to systematically study this kind of cell.

Methods and results

CD146-selective microbeads were used to isolate IH-derived mural-like cells (HemMCs). Mesenchymal markers of HemMCs were detected by flow cytometry, and the multilineage differentiation potential of HemMCs was detected by specific staining after conditioned culture. CD146-selected nonendothelial cells from IH samples showed characteristics of mesenchymal stem cells with distinct angiogenesis-promoting effects detected by transcriptome sequencing. HemMCs spontaneously differentiated into adipocytes 2 weeks after implantation into immunodeficient mice, and almost all HemMCs had differentiated into adipocytes within 4 weeks. HemMCs could not be induced to differentiate into endothelial cells in vitro. However, 2 weeks after implantation in vivo, HemMCs in combination with human umbilical vein endothelial cells (HUVECs) formed GLUT1+ IH-like blood vessels, which spontaneously involuted into adipose tissue 4 weeks after implantation.

Conclusions

In conclusion, we identified a specific cell subset that not only showed behavior consistent with the evolution of IH but also recapitulated the unique course of IH. Thus, we speculate that proangiogenic HemMCs may be a potential target for the construction of hemangioma animal models and the study of IH pathogenesis.
Predictive value of intratumoral-metabolic heterogeneity derived from 18F-FDG PET/CT in distinguishing microsatellite instability status of colorectal carcinoma
Authors: Zhang Li , Liu Yu , Ding Ying , Deng Yinqian , Chen Huanyu , Hu Fan , Fan Jun , Lan Xiaoli , Cao Wei
Published: April 2023

Purpose/background

Microsatellite instability (MSI) status is a significant biomarker for the response to immune checkpoint inhibitors, response to 5-fluorouracil-based adjuvant chemotherapy, and prognosis in colorectal carcinoma (CRC). This study investigated the predictive value of intratumoral-metabolic heterogeneity (IMH) and conventional metabolic parameters derived from 18F-FDG PET/CT for MSI in patients with stage I–III CRC.

Methods

This study was a retrospective analysis of 152 CRC patients with pathologically proven MSI who underwent 18F-FDG PET/CT examination from January 2016 to May 2022. Intratumoral-metabolic heterogeneity (including heterogeneity index [HI] and heterogeneity factor [HF]) and conventional metabolic parameters (standardized uptake value [SUV], metabolic tumor volume [MTV], and total lesion glycolysis [TLG]) of the primary lesions were determined. MTV and SUVmean were calculated on the basis of the percentage threshold of SUVs at 30%–70%. TLG, HI, and HF were obtained on the basis of the above corresponding thresholds. MSI was determined by immunohistochemical evaluation. Differences in clinicopathologic and various metabolic parameters between MSI-High (MSI-H) and microsatellite stability (MSS) groups were assessed. Potential risk factors for MSI were assessed by logistic regression analyses and used for construction of the mathematical model. Area under the curve (AUC) were used to evaluate the predictive ability of factors for MSI.

Results

This study included 88 patients with CRC in stages I–III, including 19 (21.6%) patients with MSI-H and 69 (78.4%) patients with MSS. Poor differentiation, mucinous component, and various metabolic parameters including MTV30%, MTV40%, MTV50%, and MTV60%, as well as HI50%, HI60%, HI70%, and HF in the MSI-H group were significantly higher than those in the MSS group (all P < 0.05). In multivariate logistic regression analyses, post-standardized HI60% by Z-score (P = 0.037, OR: 2.107) and mucinous component (P < 0.001, OR:11.394) were independently correlated with MSI. AUC of HI60% and our model of the HI60% + mucinous component was 0.685 and 0.850, respectively (P = 0.019), and the AUC of HI30% in predicting the mucinous component was 0.663.

Conclusions

Intratumoral-metabolic heterogeneity derived from 18F-FDG PET/CT was higher in MSI-H CRC and predicted MSI in stage I–III CRC patients preoperatively. HI60% and mucinous component were independent risk factors for MSI. These findings provide new methods to predict the MSI and mucinous component for patients with CRC.
Radiotherapy or chemotherapy: a real-world study of the first-time relapsed and refractory primary central nervous system lymphoma
Authors: Yang Yu , Li Qing , Ma Jingjing , Kang Hui , Lin Zhiguang , Wang Yang , Ma Yan , Chen Bobin
Published: April 2023

Background

Primary central nervous system lymphoma (PCNSL) is an uncommon variant of non-Hodgkin lymphoma (NHL) with high aggressiveness and poor prognosis. Although complete remission (CR) could be achieved with therapy, some patients remain refractory or recurrently with a worse response to salvage treatment and poor prognosis. No consensus on rescue therapy has been established currently. This study is aimed to evaluate the efficacy of radiotherapy or chemotherapy in first-time relapsed or refractory progressed PCNSL (R/R PCNSL) and analysis the prognostic factors, to explore differences between relapsed and refractory PCNSL.

Methods

Totally 105 R/R PCNSL patients from Huashan Hospital between 1 January 2016 and 31 December 2020 were enrolled, underwent salvage radiotherapy or chemotherapy and received response assessments after each course. PFS1 was defined as the time from diagnosis to the first time of recurrence or refractory progression. Statistical analysis was performed with SPSS version 26.0.

Results

Response and survival were analyzed over a 17.5months (median) follow-up. Compared to relapsed PCNSL (n = 42), refractory PCNSL (n = 63) had a shorter median PFS1 related to deep lesions. 82.4% of cases were discovered as the second relapse or progression. ORR and PFS were both higher in relapsed PCNSL than those in refractory PCNSL. ORR of radiotherapy in both relapsed and refractory PCNSL was higher than that of chemotherapy. Elevated CSF protein and ocular involvement were related to PFS and OS after recurrence respectively in relapsed PCNSL. Age ≥ 60y was unfavorable to OS-R (OS after recurrence or progression) in refractory PCNSL.

Conclusions

Our results indicate that relapsed PCNSL responds well to inducing and salvage therapy and has a better prognosis compared to refractory PCNSL. Radiotherapy is effective for PCNSL after the first relapse or progression. Age, CSF protein level, and ocular involvement could be potential factors to predict prognosis.
125I Radiotherapy combined with metronomic chemotherapy may boost the abscopal effect, leading to complete regression of liver metastasis in an SCLC patient with a 58.5-month OS: a case report
Authors: Lu Linlin , Wang Yu , Li Lei , Yu Lan , Liu Li , Qu Baozhen , Zhang Xiaotao
Published: April 2023

The liver is the most common and lethal metastatic site in patients with extensive-stage small-cell lung cancer (ES-SCLC), and median survival with current standard treatment is only 9–10 months from diagnosis. Clinical observations show that a complete response (CR) is extremely rare in ES-SCLC patients with liver metastasis. Moreover, to the best of our knowledge, complete regression of liver metastasis induced by the abscopal effect, boosted primarily by permanent radioactive iodine-125 seeds implantation (PRISI), combined with a low-dose metronomic temozolomide (TMZ) regimen, has not been recorded. Here, we present the case of a 54-year-old male patient who developed multiple liver metastases from ES-SCLC after multiple lines of chemotherapy. The patient was given partial PRISI therapy (two out of six tumor lesions; 38 iodine-125 seeds in one dorsal lesion and 26 seeds in one ventral lesion), which was combined with TMZ metronomic chemotherapy (50 mg/m2/day, days 1–21, every 28 days). The abscopal effect was observed for 1 month after PRISI treatment. After about 1 year, all the liver metastases had completely disappeared, and the patient experienced no relapse. The patient eventually died of malnutrition caused by a non-tumor intestinal obstruction and had an overall survival of 58.5 months after diagnosis. PRISI combined with TMZ metronomic chemotherapy might be considered a potential therapy to trigger the abscopal effect in patients with liver metastases.
The molecular mechanism for inhibiting the growth of nasopharyngeal carcinoma cells using polymethoxyflavonoids purified from pericarp of Citrus reticulata ‘Chachi’ via HSCCC
Authors: Yang Wanling , Liang Yiyao , Liu Yujie , Chen Baizhong , Wang Kanghui , Chen Xiaojing , Yu Zhiqian , Yang Depo , Cai Yi , Zheng Guodong
Published: April 2023

Polymethoxyflavonoids (PMFs), the main bioactive compounds naturally occurring in the pericarp of Citrus reticulata ‘Chachi’ (CRCP), possess significant antitumor action. However, the action of PMFs in nasopharyngeal carcinoma (NPC) is currently unknown. The present research study was conducted to investigate the inhibitory mechanisms of PMFs from CRCP on NPC growth in vivo and in vitro. In our research, we used high-speed counter-current chromatography (HSCCC) to separate four PMFs (nobiletin (NOB), 3,5,6,7,8,3′,4′-heptamethoxyflavone (HMF), tangeretin (TGN), and 5-hydroxy-6,7,8,3′,4′-pentamethoxyflavone (5-HPMF)) from CRCP. CCK-8 assay was used to preliminarily screen cell viability following exposure to the four PMFs. Colony formation, Hoechst-33258 staining, transwell, and wound scratch assays were performed to assess the anti-proliferation, invasion, migration, and apoptosis-inducing effects of HMF on NPC cells. NPC tumors in xenograft tumor transplantation experiments were also established to explore the effect of HMF (100 and 150 mg/kg/day) on NPC. The histopathological changes in the treated rats were observed by H&E staining and Ki-67 detection by immunohistochemical techniques. The expressions of P70S6K, p-P70S6K, S6, p-S6, COX-2, p53, and p-p53 were measured by Western blot. The four PMFs were obtained with high purity (>95.0%). The results of the preliminary screening by CCK-8 assay suggested that HMF had the strongest inhibitory effect on NPC cell growth. The results of the colony formation, Hoechst-33258 staining, transwell, and wound scratch assays indicated that HMF had significant anti-proliferation, invasion, migration, and apoptosis-inducing ability in NPC cells. Moreover, HMF suppressed NPC tumor growth in xenograft tumor transplantation experiments. Further investigation suggested that HMF regulated NPC cells proliferation, apoptosis, migration, and invasion by activating AMPK-dependent signaling pathways. In conclusion, HMF-induced AMPK activation inhibited NPC cell growth, invasion, and metastatic potency by downregulating the activation of the mTOR signaling pathway and COX-2 protein levels, as well as enhancing the p53 phosphorylation level. Our study provides a crucial experimental basis for the clinical treatment of NPC, as well as the development and utilization of PMFs from CRCP.
Heparanase-2 protein and peptides have a protective effect on experimental glomerulonephritis and diabetic nephropathy
Authors: Buijsers Baranca , Garsen Marjolein , de Graaf Mark , Bakker-van Bebber Marinka , Guo Chunming , Li Xue , van der Vlag Johan
Published: April 2023

Introduction: The endothelial glycocalyx degrading enzyme heparanase-1 (HPSE1) is a major contributor to kidney diseases, such as glomerulonephritis and diabetic nephropathy. Therefore, inhibition of HPSE1 could be an interesting therapeutic strategy to treat glomerular diseases. A possible HPSE1 inhibitor is heparanase-2 (HPSE2) because HPSE2 is a structural homolog of HPSE1 without enzymatic activity. The importance of HPSE2 has been recently demonstrated in HPSE2-deficient mice, since these mice developed albuminuria and died within a few months after birth. We postulate that inhibition of HPSE1 activity by HPSE2 is a promising therapeutic strategy to target albuminuria and resulting renal failure.

Methods: First, we evaluated the regulation of HPSE2 expression in anti-GBM and LPS-induced glomerulonephritis, streptozotocin-induced diabetic nephropathy, and adriamycin nephropathy by qPCR and ELISA. Second, we measured the HPSE1 inhibiting capacity of HPSE2 protein and 30 different HPSE2 peptides and assessed their therapeutic potential in both experimental glomerulonephritis and diabetic nephropathy using kidney function and cortical mRNA expression of HPSE1 and cytokines as outcome parameters.

Results: HPSE2 expression was downregulated under inflammatory and diabetic conditions, whereas this effect on HPSE2 expression was absent with HPSE1 inhibition and in HPSE1-deficient mice. Both HPSE2 protein and a mixture of the three most potent HPSE1 inhibitory HPSE2 peptides could prevent LPS and streptozotocin induced kidney injury.

Discussion: Taken together, our data suggest a protective effect of HPSE2 in (experimental) glomerular diseases and support the therapeutic potential of HPSE2 as HPSE1 inhibitor in glomerular diseases.