bluuebunny/crossref_metadata_2025 huggingface dataset:
A remark on the Riemann zeta function
Authors: Abe Yukitaka
Published: July 2024

We prove that if the number of nontrivial zeros of the Riemann zeta function which are not on the critical line is finite, then every nontrivial zero is on the critical line.
Infinite-parameter Large Language Model
Authors: Ding Fei
Published: July 2024

In the standard transformer architecture, in creasing model parameters leads to linear growth in computational cost and activation memory. To address this issue, we propose a novel Infinite Parameter Large Language Model (IP-LLM) architecture that decouples model size from computational cost and de vice memory. Existing large language models Figure 1: Parameters A, B, C, and D store knowledge are all fixed-parameter models, while human knowledge is infinite and expands daily. Finite parameters are inherently limited in their capac ity to accommodate this boundless knowledge. Our IP-LLM architecture can potentially ac commodate infinite knowledge, resolving this issue and laying the foundation for realizing a truly omniscient and omnipotent artificial gen eral intelligence in the future.Our architecture surpasses MOE in performance while requiring significantly less memory.
Let’s Do It Differently: Exploring the Effectiveness of 5E-Supported EFL Grammar Instruction
Authors: Bataineh Ruba Fahmi , Al-Dolat Hussein
Published: July 2024

The teaching of and research on grammar have long been central to language education, with an ongoing quest for more effective models for fostering student understanding and application. The 5E (viz., Engagement, Exploration, Explanation, Elaboration, and Evaluation) instructional model, recognized for its effectiveness in promoting engagement and active learning, may not only constitute an innovative approach to grammar instruction but also leverage an interactive inquiry-based environment which improves student comprehension and retention of grammatical concepts. This study examines the potential effectiveness of the 5E Model in EFL grammar instruction. The participants, 70 students in two intact tenth-grade sections from a public school in Irbid, Jordan, were randomly assigned into an experimental group (n=35), taught using the 5E Model, and a control group (n=35), taught per the guidelines of the prescribed teacher’s book. A pre-/post- test targeting five grammatical structures (viz., state and dynamic verbs, second conditional, making suggestions, defining relative clauses, and non-defining relative clauses) was used. The findings showed statistically significant differences (at α= 0.05) between the experimental and control group students’ performance in both overall grammar and each of the five structures in favor of the former. The study concludes with several pedagogical implications and recommendations for further research.
ANÁLISE DO PROCESSO DE REGENERAÇÃO E DESMATAMENTO DA MATA ATL NTICA NO MUNICÍPIO DE CAMPO MOURÃO – PR
Authors: De Araujo Agnes , Lourenço da Silva Ítalo Roberto
Published: July 2024

Compreender a dinâmica do ganho e perda de Mata Atlântica é imprescindível para o desenvolvimento de políticas públicas que visem preservar e conservar os ecossistemas e a biodiversidade. Para analisar as dinâmicas florestais mais recentes, os efeitos das ferramentas legais de proteção da Mata Atlântica e das transformações políticas recentes, dados primários sobre a vegetação nativa e cobertura da terra são essenciais. O objetivo deste artigo é analisar de forma quantitativa se o processo de desmatamento se mantém progressivo ou se há a incidência de regeneração do bioma Mata Atlântica entre 2018 e 2021 no município de Campo Mourão - PR. Para tanto, dados de Sensoriamento Remoto do Sentinel 2A foram utilizados e classificados utilizando o algoritmo Random Forest no Google Earth Engine. Os resultados da classificação foram avaliados a partir do índice kappa. Os resultados demonstram que a região de Campo Mourão está passando por uma transição florestal de perda líquida para ganho líquido na cobertura arbórea nativa (aumento de 18,64 km²). No entanto, a vegetação encontra-se mais fragmentada e isolada. Ademais, apontamos que o rejuvenescimento da cobertura vegetal nativa pode não significar ganhos qualitativos em termos de biodiversidade.
The hybrid nanosystem for the identification and magnetic hyperthermia immunotherapy of metastatic sentinel lymph nodes as a multifunctional theranostic agent
Authors: Qin Qiaoxi , Zhang Qin , Li Pan , Wang Ronghui , Liu Ying , Deng Ruxi , Zhang Juanmin , Nie Quanyu , Zhou Hong , Zhou Yang
Published: July 2024

Lymphatic metastasis is the main cause of early-stage tumor spread, making the identification and therapy of metastatic sentinel lymph nodes (SLNs) are highly desirable in clinic. Currently, suspected malignant SLNs typically undergo a series of independent operations in clinical practice, including imaging, staining, sentinel lymph node biopsy (SLNB) and lymph node dissection (LND), which brings inconvenience to diagnosis and treatment, and may cause postoperative complications for patients. Moreover, the ordinary removal of tumor-draining lymph nodes (TDLNs) may do harm to systemic immunity required for tumor eradication. Hence, we utilized the hybrid nanosystem (SPIOs + RPPs) we constructed before for the integrated staining, ultrasound imaging, and therapy of metastatic SLNs. In this study, SPIOs + RPPs could migrate into SLNs successfully to stain them black for easy visual identification. Beyond staining, the hybrid nanosystem could realize contrast enhanced ultrasound (CEUS) imaging in SLNs. Meanwhile, it could inhibit cancer cells to lower the tumor burden and reverse immune-suppressive microenvironment of metastatic SLNs effectively via magnetic hyperthermia immunotherapy in VX2 tumor-bearing rabbits with popliteal fossa lymph node metastasis. These findings indicate that SPIOs + RPPs is a potential multifunctional theranostic agent for detection and therapy of lymphatic metastasis.
Gastroesophageal reflux disease and risk for arrhythmias: a Mendelian randomization analysis
Authors: Liang JunHao , Tang LuYi , Yang JinHui , Li Yi , Yang XiQiao , Hou ChiJun
Published: July 2024

Background

Clinical observations and epidemiological studies suggest a potential linkage between gastroesophageal reflux disease (GERD) and arrhythmias, yet the underlying mechanism remains elusive. This study investigates the causal relationship between GERD and four types of arrhythmia through a genetic lens, employing Mendelian randomization analysis to elucidate the directionality of these associations.

Methods

Selected single nucleotide polymorphisms (SNPs) from genome-wide association study (GWAS) data were utilized as instrumental variables. The inverse variance weighting (IVW) method, MR-Egger regression analysis, and the weighted median method were employed in two-sample Mendelian randomization analysis. Horizontal pleiotropy was detected and corrected using the MR-PRESSO test and MR-Egger regression. The stability and reliability of the Mendelian randomization results were assessed using the leave-one-out method, Cochran's Q test, and funnel plots. The causal relationship between GERD and four types of arrhythmias was evaluated using the odds ratio (OR).

Results

IVW results indicated that GERD could increase the risk of arrhythmias. A one standard deviation increases in the logarithmically transformed GERD score resulted in a 34% increase in the risk of arrhythmia (OR = 1.34; 95% CI 1.19–1.51; p = 1.66E-06). No significant correlation was found between GERD and other arrhythmias.

Conclusion

A causal relationship exists between GERD and arrhythmias, suggesting that GERD increases the risk of developing these arrhythmias.
Ocean component of the first operational version of Hurricane Analysis and Forecast System: Evaluation of HYbrid Coordinate Ocean Model and hurricane feedback forecasts
Authors: Kim Hyun-Sook , Liu Bin , Thomas Biju , Rosen Daniel , Wang Weiguo , Hazelton Andrew , Zhang Zhan , Zhang Xueijin , Mehra Avichal
Published: July 2024

The first operational version of the coupled Hurricane Analysis and Forecast System (HAFSv1) launched in 2023 consists of the HYbrid Coordinate Ocean Model (HYCOM) and finite-volume cubed-sphere (FV3) dynamic atmosphere model. This system is a product of efforts involving improvements and updates over a 4-year period (2019–2022) through extensive collaborations between the Environmental Modeling Center at the US National Centers for Environmental Prediction (NCEP) and NOAA Atlantic Oceanography and Meteorology Laboratory. To provide two sets of numerical guidance, the initial operational capability of HAFSv1 was configured to two systems—HFSA and HFSB. In this study, we present in-depth analysis of the forecast skills of the upper ocean that was co-evolved by the HFSA and HFSB. We chose hurricane Laura (2020) as an example to demonstrate the interactions between the storm and oceanic mesoscale features. Comparisons performed with the available in situ observations from gliders as well as Argos and National Data Buoy Center moorings show that the HYCOM simulations have better agreement for weak winds than high winds (greater than Category 2). The skill metrics indicate that the model sea-surface temperature (SST) and mixed layer depth (MLD) have a relatively low correlation. The SST, MLD, mixed layer temperature (MLT), and ocean heat content (OHC) are negatively biased. For high winds, SST and MLT are more negative, while MLD is closer to the observations with improvements of about 8%–19%. The OHC discrepancy is proportional to predicted wind intensity. Contrarily, the mixed layer salinity (MLS) uncertainties are smaller and positive for higher winds, probably owing to the higher MLD. The less-negative bias of MLD for high winds implies that the wind-force mixing is less effective owing to the higher MLD and high buoyancy stability (approx. 1.5–1.7 times) than the observations. The heat budget analysis suggests that the maximum heat loss by hurricane Laura was O(< 3°C per day). The main contributor here is advection, followed by entrainment, which act against or with each other depending on the storm quadrant. We also found relatively large unaccountable heat residuals for the in-storm period, and the residuals notably led the heat tendency, meaning that further improvements of the subscale simulations are warranted. In summary, HYCOM simulations showed no systematic differences forced by either HFSA or HFSB.
Impacts of the digital economy on urban low-carbon sustainable development
Authors: Song Yaqing , Sun Xin , Cai Xiaowei , Liu Xi
Published: July 2024

As a novel economic form, the digital economy plays an important role in promoting urban low-carbon sustainable development (LCSD). Based on panel data from 270 cities in China from 2011 to 2021, this study used principal component analysis and the global entropy weight method to calculate the level of digital economy development and LCSD as well as to empirically discuss any correlated effects and mechanisms. The research showed that the digital economy has significantly promoted urban LCSD and has become an important source for promoting green low-carbon development. The digital economy can indirectly promote LCSD by accelerating industrial structure upgrading and promoting technological innovation; Moreover, this promotion can show significant threshold characteristics with these factors. When industrial structure upgrading and technological innovation reach a certain threshold, the digital economy can further enhance urban LCSD. The promotion of the digital economy is positively influenced by marketization level and environmental regulation, and it exhibits distinct regional characteristics. During the critical period of economic development and transformation, the government must continuously promote the development of the digital economy, fully release its dividends on LCSD, and implement a differentiated digital development strategy to promote low-carbon economic development according to local conditions.
Fluvoxamine maleate alleviates amyloid-beta load and neuroinflammation in 5XFAD mice to ameliorate Alzheimer disease pathology
Authors: Kaur Sukhleen , Sharma Kuhu , Sharma Ankita , Sandha Kamalpreet Kaur , Ali Syed Mudassir , Ahmed Riyaz , Ramajayan P. , Singh Parvinder Pal , Ahmed Zabeer , Kumar Ajay
Published: July 2024

Introduction

Alzheimer pathology (AD) is characterized by the deposition of amyloid beta (Aβ) and chronic neuroinflammation, with the NLRP3 inflammasome playing a significant role. This study demonstrated that the OCD drug fluvoxamine maleate (FXN) can potently ameliorate AD pathology in 5XFAD mice by promoting autophagy-mediated clearance of Aβ and inhibiting the NLRP3 inflammasome.

Methods

We used mice primary astrocytes to establish the mechanism of action of FXN against NLRP3 inflammasome by using various techniques like ELISA, Western blotting, confocal microscopy, Immunofluorescence, etc. The anti-AD activity of FXN was validated in transgenic 5XFAD mice following two months of treatment. This was followed by behavior analysis, examination of inflammatory and autophagy proteins and immunohistochemistry analysis for Aβ load in the hippocampi.

Results

Our data showed that FXN, at a low concentration of 78 nM, induces autophagy to inhibit NF-κB and the NLRP3 inflammasome, apart from directly inhibiting NLRP3 inflammasome in primary astrocytes. FXN activated the PRKAA2 pathway through CAMKK2 signaling, leading to autophagy induction. It inhibited the ATP-mediated NLRP3 inflammasome activation by promoting the autophagic degradation of NF-κB, resulting in the downregulation of pro-IL-1β and NLRP3. The anti-NLRP3 inflammasome effect of FXN was reversed when autophagy was inhibited by either genetic knockdown of the PRKAA2 pathway or pharmacological inhibition with bafilomycin A1. Furthermore, FXN treatment led to improved AD pathology in 5XFAD mice, resulting in significant improvements in various behavioral parameters such as working memory and neuromuscular coordination, making their behavior more similar to that of wild-type animals. FXN improved behavior in 5XFAD mice by clearing the Aβ deposits from the hippocampi and significantly reducing multiple inflammatory proteins, including NF-κB, GFAP, IBA1, IL-1β, TNF-α, and IL-6, which are associated with NF-κB and NLRP3 inflammasome in the brain. Moreover, these changes were accompanied by increased expression of autophagic proteins.

Discussion

Our data suggest that FXN ameliorates AD pathology, by simultaneously targeting two key pathological features: Aβ deposits and neuroinflammation. As an already approved drug, FXN holds potential as a candidate for human studies against AD.
Efficacy and safety of a proposed omalizumab biosimilar compared to the reference product in the management of uncontrolled moderate-to-severe allergic asthma: a multicenter, phase III, randomized, double-blind, equivalency clinical trial
Authors: Ghanei Mostafa , Ghalebaghi Babak , Sami Ramin , Torabizadeh Mehdi , Mirsadraee Majid , Amra Babak , Tavakol Marzieh , Raji Hanieh , Fallahpour Morteza , Kiani Arda , Abedini Atefeh , Jabbari Azad Farahzad , Mahdaviani Seyed Alireza , Attaran Davood , Samet Mohammad , Tavana Sasan , Haddadzadeh shoushtari Maryam , Nazari Javad , AghaeiMeybodi FatemehAlsadat , Fazlollahi Mohammad Reza , Ghasemi Ramin , Sabzvari Araz , Kafi Hamidreza , Idani Esmaeil
Published: July 2024

Background and aims

Allergic asthma has a considerable burden on the quality of life. A significant portion of moderate-to-severe allergic asthma patients need omalizumab, an anti-immunoglobulin-E monoclonal antibody, as an add-on therapy. In this phase III clinical trial P043 (Zerafil®, CinnaGen, Iran) efficacy, safety, and immunogenicity were compared with Xolair® (the originator omalizumab). The primary outcome was the rate of protocol-defined asthma exacerbations.

Methods

Exacerbation rates, Asthma Control Test (ACT) results, spirometry measurements, immunogenicity, and safety were evaluated. Each subject received either medication with a dose ranging from 150 to 375 mg based on pre-treatment serum total IgE level (IU/mL) and body weight (kg) every two or four weeks for a duration of 28 weeks.

Results

Exacerbation rates were 0.150 (CI: 0.079-0.220) in the P043 group, and 0.190 (CI: 0.110-0.270) in the omalizumab group (per-protocol). The least squares mean differences of predicted Forced Expiratory Volume in the First second (FEV1) were -2.51% (CI: -7.17-2.15, P=0.29) and -3.87% (CI: -8.79-1.04, P=0.12), pre- and post-bronchodilator use. The mean ± SD of ACT scores at the screening and the last visit were 10.62 ± 2.93 and 20.93 ± 4.26 in P043 and 11.09 ± 2.75 and 20.46 ± 5.11 in the omalizumab group. A total of 288 adverse events were reported for the 256 enrolled participants. Among all, “dyspnea” and “headache” were the most reported ones. The overall incidence of adverse events (P=0.62) and serious adverse events (P=0.07) had no significant differences between the two groups. None of the samples were positive for anti-drug antibodies.

Conclusion

P043 was equivalent to omalizumab in the management of asthma in reduction of exacerbations. There was no significant difference in other efficacy and safety parameters.

Clinical trial registration

www.clinicaltrials.gov (NCT05813470) and www.IRCT.ir (IRCT20150303021315N20).
Detection of autoantibodies to heat shock protein 70 in the saliva and urine of normal individuals
Authors: Sitko Krzysztof , Mantej Jagoda , Bednarek Marta , Tukaj Stefan
Published: July 2024

Cells exposed to stressors of various origin activate protective mechanisms that include the expression of heat shock proteins (Hsps)/molecular chaperones belonging to several families. Well-characterized inducible Hsp70 is present in all human cell-types and biological fluids, including blood, urine, and saliva. The presence of anti-Hsp70 autoantibodies in the serum of healthy individuals has already been confirmed, and their elevated titers positively correlated with the severity of several pathological conditions, including coeliac disease and dermatitis herpetiformis – a cutaneous manifestation of coeliac disease. Here, using an indirect enzyme-linked immunosorbent assay, we demonstrate, for the first time, that anti-Hsp70 autoantibodies are present in the saliva and urine of healthy individuals. Although the occurrence of anti-Hsp70 autoantibodies in the biological fluids of healthy individuals is intriguing, their physiological role is currently unknown. It is believed that antibodies reacting with self-molecules present in the serum of healthy individuals are part of natural autoantibody pool with multiple regulatory functions. On the other hand, some autoantibodies (e.g., typical of autoimmune bullous skin diseases or systemic lupus erythematosus) may be present before the onset of the disease and serve as specific predictive biomarkers. Therefore, we would like to initiate a discussion or future research direction on the use of anti-Hsp70 autoantibodies as a potential “biomarker” in the diagnosis or prediction of autoimmune diseases. Our findings can be considered in biomedical research to develop noninvasive, inexpensive and easy-to-use tests. Nevertheless, large-scale comparative studies should be initiated, involving the collection and analysis of biological samples such as saliva or urine from patients suffering from autoimmune diseases or other inflammatory or neoplastic diseases, to determine whether the levels of anti-Hsp70 autoantibodies are indeed elevated and whether they correlate with the clinical picture of any disease or established biomarkers.
An assessment of a GMP schistosomiasis vaccine (SchistoShield®)
Authors: Kim Jiho , Davis Jenn , Lee Jinhee , Cho Sang-Nae , Yang Kiyoung , Yang Jaekyoon , Bae Sungmin , Son Joohee , Kim Boyoung , Whittington Dale , Siddiqui Afzal A. , Carter Darrick , Gray Sean A.
Published: July 2024

Introduction

Schistosomiasis is a neglected tropical disease that puts over 200 million people at risk, and prevention options are sparse with no approved vaccine. Our vaccine candidate, SchistoShield®, is based on an approximately 87 kDa large subunit of calcium activated neutral protease - termed Sm-p80 - combined with a potent TLR4 agonist-based adjuvant. SchistoShield® has been shown to prevent disease throughout the parasitic life cycle - including egg, juvenile, and adult worm stages - in numerous animal models up to and including baboons. SchistoShield® has been shown safe in both preclinical toxicology studies in rabbits and in a Phase 1 clinical trial in the USA. A Phase 1b trial was initiated in 2023 in endemic regions of Africa, and to date no serious safety signals have been reported.

Methods

In preparation for large-scale Phase 2 clinical trials and eventual vaccine deployment, the Sm-p80 antigen production process has been transferred to a manufacturing organization, Quratis Corporation in South Korea, which specializes in preparation of vaccines for large-scale European and African trials. The process of scaling from our current production level of ~ 2000 vaccine doses, to a process that will generate more than 100 million doses has required multiple improvement steps in the process including fermentation, downstream purification of the protein antigen, lyophilization, and fill and finish.

Results

In this study, we detail the large-scale production process of the SchistoShield® protein product by Quratis. In addition, an effort was made to analyze and compare the Quratis-made lot of Sm-p80, referred to as QTP-105, to the cGMP lot of Sm-p80 which is in use in human trials in the USA and Africa, referred to as Sm-p80 DP (made in USA). We show that QTP-105 demonstrates excellent potency, purity, identity, and endotoxin levels compared to our Phase 1 Sm-p80 DP and is suitable for use in Phase 2 studies and beyond.
Comparison of annual biosynthetic calorie productions by phytoplankton in different southern Korean bays
Authors: Jang Hyo Keun , Kang Jae Joong , Lee Jae Hyung , Lee Dabin , Jo Naeun , Kim Yejin , Kim Kwanwoo , Kim Myung-Joon , Park Sanghoon , Kim Jaehong , Kim Jaesoon , Ahn So Hyun , Lee Sang Heon
Published: July 2024

We investigated assessments of calorie production and energy efficiencies of phytoplankton in Gwangyang, Jaran, and Geoje-Hansan bays in southern Korea, based on seasonal field measurements data for particulate organic carbon (POC), macromolecular compositions, calorie contents, and primary production. Our findings revealed that Geoje-Hansan Bay consistently exhibits higher POC concentrations compared to Gwangyang and Jaran bays, except during the summer season. The observed seasonal variations in POC concentrations and primary productions indicated distinct factors influencing POC distribution among the bays, which varies with the seasons. Macromolecular compositions displayed notable patterns, with Gwangyang Bay exhibiting pronounced seasonal variations, Jaran and Geoje-Hansan bays showing stable carbohydrate (CHO) dominance, and Gwangyang Bay displaying protein (PRT) dominance influenced by river-borne nutrients. Analysis of calorie content revealed that Geoje-Hansan Bay exhibited the highest calorie content, suggesting a more favorable physiological state of phytoplankton compared to Gwangyang and Jaran bays. Estimations of annual primary production and calorie production demonstrated regional variations, with Geoje-Hansan Bay having the highest values followed by Jaran Bay and Gwangyang Bay. These differences in primary production and calorie production reflect the diverse ecological conditions and nutrient availability specific to each bay. Interestingly, Gwangyang Bay demonstrated the highest energy efficiency, producing more calories per unit of carbon compared to the other two bays, potentially due to the influence of different dominant phytoplankton communities. This study enhances our understanding of ecosystem dynamics and ecological characteristics among the three bays, emphasizing the importance of considering seasonal variations and specific bay characteristics in investigating biogeochemical processes, energy flow, and ecosystem functioning. The findings contribute valuable insights for the sustainable management of coastal ecosystems and aquaculture practices.
Chronic neuropathic pain components in whiplash-associated disorders correlate with metabolite concentrations in the anterior cingulate and dorsolateral prefrontal cortex: a consensus-driven MRS re-examination
Authors: Pinilla-Fernández Irene , Ríos-León Marta , Deelchand Dinesh Kumar , Garrido Leoncio , Torres-Llacsa Mabel , García-García Fernando , Vidorreta Marta , Ip I. Betina , Bridge Holly , Taylor Julian , Barriga-Martín Andrés
Published: July 2024

Introduction

Whiplash injury (WHI) is characterised by a forced neck flexion/extension, which frequently occurs after motor vehicle collisions. Previous studies characterising differences in brain metabolite concentrations and correlations with neuropathic pain (NP) components with chronic whiplash-associated disorders (WAD) have been demonstrated in affective pain-processing areas such as the anterior cingulate cortex (ACC). However, the detection of a difference in metabolite concentrations within these cortical areas with chronic WAD pain has been elusive. In this study, single-voxel magnetic resonance spectroscopy (MRS), following the latest MRSinMRS consensus group guidelines, was performed in the anterior cingulate cortex (ACC), left dorsolateral prefrontal cortex (DLPFC), and occipital cortex (OCC) to quantify differences in metabolite concentrations in individuals with chronic WAD with or without neuropathic pain (NP) components.

Materials and methods

Healthy individuals (n = 29) and participants with chronic WAD (n = 29) were screened with the Douleur Neuropathique 4 Questionnaire (DN4) and divided into groups without (WAD-noNP, n = 15) or with NP components (WAD-NP, n = 14). Metabolites were quantified with LCModel following a single session in a 3 T MRI scanner within the ACC, DLPFC, and OCC.

Results

Participants with WAD-NP presented moderate pain intensity and interference compared with the WAD-noNP group. Single-voxel MRS analysis demonstrated a higher glutamate concentration in the ACC and lower total choline (tCho) in the DLPFC in the WAD-NP versus WAD-noNP group, with no intergroup metabolite difference detected in the OCC. Best fit and stepwise multiple regression revealed that the normalised ACC glutamate/total creatine (tCr) (p = 0.01), DLPFC n-acetyl-aspartate (NAA)/tCr (p = 0.001), and DLPFC tCho/tCr levels (p = 0.02) predicted NP components in the WAD-NP group (ACC r2 = 0.26, α = 0.81; DLPFC r2 = 0.62, α = 0.98). The normalised Glu/tCr concentration was higher in the healthy than the WAD-noNP group within the ACC (p < 0.05), but not in the DLPFC or OCC. Neither sex nor age affected key normalised metabolite concentrations related to WAD-NP components when compared to the WAD-noNP group.

Discussion

This study demonstrates that elevated glutamate concentrations within the ACC are related to chronic WAD-NP components, while higher NAA and lower tCho metabolite levels suggest a role for increased neuronal–glial signalling and cell membrane dysfunction in individuals with chronic WAD-NP components.
Biocontrol of plant parasitic nematodes by bacteria and fungi: a multi-omics approach for the exploration of novel nematicides in sustainable agriculture
Authors: Ayaz Muhammad , Zhao Jing-Tian , Zhao Wei , Chi Yuan-Kai , Ali Qurban , Ali Farman , Khan Abdur Rashid , Yu Qing , Yu Jing-Wen , Wu Wen-Cui , Qi Ren-De , Huang Wen-Kun
Published: July 2024

Plant parasitic nematodes (PPNs) pose a significant threat to global crop productivity, causing an estimated annual loss of US $157 billion in the agriculture industry. While synthetic chemical nematicides can effectively control PPNs, their overuse has detrimental effects on human health and the environment. Biocontrol agents (BCAs), such as bacteria and fungi in the rhizosphere, are safe and promising alternatives for PPNs control. These BCAs interact with plant roots and produce extracellular enzymes, secondary metabolites, toxins, and volatile organic compounds (VOCs) to suppress nematodes. Plant root exudates also play a crucial role in attracting beneficial microbes toward infested roots. The complex interaction between plants and microbes in the rhizosphere against PPNs is mostly untapped which opens new avenues for discovering novel nematicides through multi-omics techniques. Advanced omics approaches, including metagenomics, transcriptomics, proteomics, and metabolomics, have led to the discovery of nematicidal compounds. This review summarizes the status of bacterial and fungal biocontrol strategies and their mechanisms for PPNs control. The importance of omics-based approaches for the exploration of novel nematicides and future directions in the biocontrol of PPNs are also addressed. The review highlighted the potential significance of multi-omics techniques in biocontrol of PPNs to ensure sustainable agriculture.
Association study of brain structure–function coupling and glymphatic system function in patients with mild cognitive impairment due to Alzheimer’s disease
Authors: Sun Yong-Wen , Lyu Xin-Yue , Lei Xiao-Yang , Huang Ming-Ming , Wang Zhen-Min , Gao Bo
Published: July 2024

Background

Mild cognitive impairment (MCI) is a critical transitional phase from healthy cognitive aging to dementia, offering a unique opportunity for early intervention. However, few studies focus on the correlation of brain structure and functional activity in patients with MCI due to Alzheimer’s disease (AD). Elucidating the complex interactions between structural-functional (SC-FC) brain connectivity and glymphatic system function is crucial for understanding this condition.

Method

The aims of this study were to explore the relationship among SC-FC coupling values, glymphatic system function and cognitive function. 23 MCI patients and 18 healthy controls (HC) underwent diffusion tensor imaging (DTI) and resting-state functional MRI (fMRI). DTI analysis along the perivascular space (DTI-ALPS) index and SC-FC coupling values were calculated using DTI and fMRI. Correlation analysis was conducted to assess the relationship between Mini-Mental State Examination (MMSE) scores, DTI-ALPS index, and coupling values. Receiver operating characteristic (ROC) curves was conducted on the SC-FC coupling between the whole brain and subnetworks. The correlation of coupling values with MMSE scores was also analyzed.

Result

MCI patients (67.74 ± 6.99 years of age) exhibited significantly lower coupling in the whole-brain network and subnetworks, such as the somatomotor network (SMN) and ventral attention network (VAN), than HCs (63.44 ± 6.92 years of age). Whole-brain network coupling was positively correlated with dorsal attention network (DAN), SMN, and visual network (VN) coupling. MMSE scores were significantly positively correlated with whole-brain coupling and SMN coupling. In MCI, whole-brain network demonstrated the highest performance, followed by the SMN and VAN, with the VN, DAN, limbic network (LN), frontoparietal network (FPN), and default mode network (DMN). Compared to HCs, lower DTI-ALPS index was observed in individuals with MCI. Additionally, the left DTI-ALPS index showed a significant positive correlation with MMSE scores and coupling values in the whole-brain network and SMN.

Conclusion

These findings reveal the critical role of SC-FC coupling values and the ALPS index in cognitive function of MCI. The positive correlations observed in the left DTI-ALPS and whole-brain and SMN coupling values provide a new insight for investigating the asymmetrical nature of cognitive impairments.
Interaction of the intestinal cytokines-JAKs-STAT3 and 5 axes with RNA N6-methyladenosine to promote chronic inflammation-induced colorectal cancer
Authors: Esmaeili Nardana , Bakheet Ahmed , Tse William , Liu Shujun , Han Xiaonan
Published: July 2024

Colorectal cancer (CRC) is one of the most common cancers, with a high mortality rate worldwide. Mounting evidence indicates that mRNA modifications are crucial in RNA metabolism, transcription, processing, splicing, degradation, and translation. Studies show that N6-methyladenosine (m6A) is mammalians’ most common epi-transcriptomic modification. It has been demonstrated that m6A is involved in cancer formation, progression, invasion, and metastasis, suggesting it could be a potential biomarker for CRC diagnosis and developing therapeutics. Cytokines, growth factors, and hormones function in JAK/STAT3/5 signaling pathway, and they could regulate the intestinal response to infection, inflammation, and tumorigenesis. Reports show that the JAK/STAT3/5 pathway is involved in CRC development. However, the underlying mechanism is still unclear. Signal Transducer and Activator of Transcription 3/5 (STAT3, STAT5) can act as oncogenes or tumor suppressors in the context of tissue types. Also, epigenetic modifications and mutations could alter the balance between pro-oncogenic and tumor suppressor activities of the STAT3/5 signaling pathway. Thus, exploring the interaction of cytokines-JAKs-STAT3 and/or STAT5 with mRNA m6A is of great interest. This review provides a comprehensive overview of the characteristics and functions of m6A and JAKs-STAT3/5 and their relationship with gastrointestinal (GI) cancers.
Treatment satisfaction and medication adherence and predictors among patients with heart failure in Ethiopia: a hospital-based cross-sectional study
Authors: Tsige Abate Wondesen , Endalifer Bedilu Linger , Habteweld Habtemariam Alekaw , Wondmkun Yehualashet Teshome , Ayele Siraye Genzeb , Kefale Belayneh
Published: July 2024

Background

Globally, about 18 million people died from cardiovascular diseases (CVDs) in 2019, over three-quarters in developing countries. Non-adherence to medication in CVD patients causes hospitalization, worsened symptoms, higher healthcare costs, and more emergency visits. Hence, this study aimed to assess treatment satisfaction and medication adherence and predictors in heart failure (HF) patients attending Debre Berhan Comprehensive Specialized Hospital (DBCSH), Ethiopia.

Methods

A hospital-based cross-sectional study was undertaken at the medical referral clinic of DBCSH. A total of 344 ambulatory HF patients who visited the medical care of the DBCSH medical referral clinic during the study period were included. Treatment satisfaction was assessed using a self-administered Medicine Questionnaire (SATMED-Q). Relationships between predictor variables and treatment satisfaction were determined using one-way analysis of variance (ANOVA) and an independent t-test. Medication adherence was determined using the Morisky Green Levin Medication Adherence Scale (MGLS).

Results

Participants with drug-drug interactions (DDIs) were approximately 38% less likely to adhere to medication compared to their counterparts (AOR = 0.62, 95% CI: 0.54–0.71). Additionally, participants who had taken five or more drugs were approximately 68% less likely to adhere to medication compared to those who had taken only one drug (AOR = 0.32, 95% CI: 0.2–0.51). The correlation between medication adherence and drug-drug interactions remains a possible pseudo-correlation via the number of medications taken. There was a noteworthy positive correlation (rs = 0.34, p = 0.027) between participants’ treatment adherence and treatment satisfaction.

Conclusion

The rate of treatment satisfaction and treatment adherence among HF patients was 67.6% and 60.9%, respectively. The presence of DDI and the number of drugs were identified as predictors to medication adherence.
Protective effect of andrographolide against ulcerative colitis by activating Nrf2/HO-1 mediated antioxidant response
Authors: Shu Long , Fu Hangjie , Pi Aiwen , Feng Yuliang , Dong Hui , Si Caijuan , Li Songtao , Zhu Feiye , Zheng Peifen , Zhu Qin
Published: July 2024

Ulcerative colitis (UC) is a recurring inflammatory bowel disease, in which oxidative stress plays a role in its progression, and regulation of the oxidative/antioxidative balance has been suggested as a potential target for the treatment of UC. The aim of this study was to evaluate the protective effect of andrographolide against UC and its potential antioxidant properties by modulating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. Dextran sulfate sodium (DSS) -induced UC mice and the LPS-induced HT29 inflammatory cell model were established to uncover the potential mechanisms of andrographolide. ML385, a Nrf2 inhibitor, was used in both models to assess whether andrographolide exerts a protective effect against UC through the Nrf2/HO-1 pathway. The in vivo experiment showed that andrographolide ameliorated the symptoms and histopathology of DSS-induced mice and restored the expressions of ZO-1, Occludin-1 and Claudin-1. Meanwhile, DSS-induced oxidative stress and inflammation were suppressed by andrographolide treatment, along with the upregulation of key proteins in the Nrf2/HO-1 pathway. In vitro experiments showed that andrographolide attenuated LPS-induced excessive generation of ROS in HT29 cells, reduced inflammatory factors, and upregulated the expression of proteins related to tight junctions and Nrf2/HO-1 pathway. In addition, ML385 abolished the beneficial effect of andrographolide. In conclusion, the protective effect of andrographolide against UC may involve the suppression of oxidative stress and inflammation via the Nrf2/HO-1 pathway.
Association between medication complexity and follow-up care attendance: insights from a retrospective multicenter cohort study across 1,223 Chinese hospitals
Authors: Ma Xuedi , Wang Yang , Chen Yongwu , Lian Yufei , Zhao Xiaoyu , He Xuan , Qiu Yue , Han Sheng , Liu Lihong , Wang Chen
Published: July 2024

Background

Patients with Chronic Obstructive Pulmonary Disease (COPD) frequently face substantial medication burdens. Follow-up care on medication management is critical in achieving disease control. This study aimed to analyze the complexity of COPD-specific medication and determine how it impacted patients’ attendance on follow-up care.

Methods

This multicenter study includes patients with COPD from 1,223 hospitals across 29 provinces in China from January 2021 to November 2022. The medication Regimen Complexity Index (MRCI) score was used to measure COPD-specific medication complexity. The association between medication complexity and follow-up care attendance was evaluated using the Cox Proportional Hazard Model.

Results

Among 16,684 patients, only 2,306 (13.8%) returned for follow-up medication management. 20.3% of the patients had high complex medication regimen (MRCI score >15.0). The analysis revealed that compared to those with less complex regimens, patients with more complex medication regimens were significantly less likely to attend the follow-up medication care, with a Hazard Ratio (HR) of 0.82 (95% Confidence Interval [CI], 0.74–0.91). Specifically, patients with more complex dosage forms were 51% less likely to attend the follow-up care (95% CI, 0.43–0.57). This pattern was especially marked among male patients, patients younger than 65 years, and those without comorbid conditions.

Conclusion

Higher medication complexity was associated with a decreased likelihood of attending follow-up care. To promote care continuity in chronic disease management, individuals with complex medication regimens should be prioritized for enhanced education. Furthermore, pharmacists collaborating with respiratory physicians to deprescribe and simplify dosage forms should be considered in the disease management process.
Enhanced sensing response of the three dimensional MoS2 microstructure for NO2 gas detection at room temperature
Authors: Cheng Hongdao , Huang Sihuan , Xing Zengshan , Yang Lu , Yu Jianhui , Zhong Yongchun
Published: July 2024

As a promising sensing material, Molybdenum disulfide (MoS2) nanosheets is being increasingly studied for Nitrogen dioxide (NO2) gas sensing. However, the MoS2 nanosheets is prone to the stacking effect that compromises the sensing performances. Here, the stacking effect is mitigated by engineering MoS2 nanosheets into a three dimensional (3D) network microstructure, which was fabricated by method of electrostatically self-assembling of MoS2/SiO2 microspheres. The fabricated sensor based on 3D MoS2 network observed a significantly improved response of 15% to 12.3 ppm NO2, which is a 75-fold increase compared to the control sensor with pure MoS2 nanosheets. In addition, the sensitivity of the sensor with 3D MoS2 network was 6.15 times larger than that of the control sensor with pure MoS2 nanosheets. The detection limit of our sensor was 0.297 ppm, lower than most of reported MoS2-based NO2 sensors. The enhanced sensitivity and dynamic response stem from the improved interaction between NO2 molecules and MoS2 network, thanks to its increased surface area per footprint of MoS2 nanosheets compared to pure 2D MoS2 film (single- or few-layer). This work presents a new approach to enhancing the performance of gas sensors based on 2D materials.
CT image-based 3D inflorescence estimation of Chrysanthemum seticuspe
Authors: Matsumoto Soushi , Utsumi Yuzuko , Kozuka Toshiaki , Iwamura Masakazu , Nakai Tomonori , Yamauchi Daisuke , Karahara Ichirou , Mineyuki Yoshinobu , Hoshino Masato , Uesugi Kentaro , Kise Koichi
Published: July 2024

To study plant organs, it is necessary to investigate the three-dimensional (3D) structures of plants. In recent years, non-destructive measurements through computed tomography (CT) have been used to understand the 3D structures of plants. In this study, we use the Chrysanthemum seticuspe capitulum inflorescence as an example and focus on contact points between the receptacles and florets within the 3D capitulum inflorescence bud structure to investigate the 3D arrangement of the florets on the receptacle. To determine the 3D order of the contact points, we constructed slice images from the CT volume data and detected the receptacles and florets in the image. However, because each CT sample comprises hundreds of slice images to be processed and each C. seticuspe capitulum inflorescence comprises several florets, manually detecting the receptacles and florets is labor-intensive. Therefore, we propose an automatic contact point detection method based on CT slice images using image recognition techniques. The proposed method improves the accuracy of contact point detection using prior knowledge that contact points exist only around the receptacle. In addition, the integration of the detection results enables the estimation of the 3D position of the contact points. According to the experimental results, we confirmed that the proposed method can detect contacts on slice images with high accuracy and estimate their 3D positions through clustering. Additionally, the sample-independent experiments showed that the proposed method achieved the same detection accuracy as sample-dependent experiments.
Leaf carbon, nitrogen, and phosphorus ecological stoichiometry of grassland ecosystems along 2,600-m altitude gradients at the Northern slope of the Tianshan Mountains
Authors: Wang Yao , Xu Zhonglin
Published: July 2024

Ecological stoichiometry of terrestrial ecosystems has been a hot issue in current research, with intense focus on the proportional relationships of nutritional elements within plants and between plants and their environment. To clarify these relationships along continuous environmental gradients is essential for a more comprehensive understanding how plants adapt to a changing environment. In arid regions, the varying plant and soil types along altitude gradients offer a unique opportunity to examine the vertical spectrum of plant and soil ecological stoichiometry. In this study, the northern slope of the Tianshan Mountains was selected as the study area to explore the carbon (C), nitrogen (N), and phosphorus (P) ecological stoichiometric characteristics of herbaceous plants along 900-m–3,500-m altitude gradients. We also investigated the variation of ecological stoichiometric characteristics among different grassland types. The results indicated that the mean C, N, and P in leaf of grassland were 342.95 g·kg−1–557.73 g·kg−1, 6.02 g·kg−1–20.97 g·kg−1, and 0.71 g·kg−1–3.14 g·kg−1, respectively. There was no significant change in leaf carbon content along the elevation gradient, and the highest and lowest leaf C concentrations were in the upland meadow and the semidesert grasslands. Both N and P concentrations obtained their highest value in the meadow steppe. The P concentration gradually increased in desert and semidesert grasslands and reached the highest value in the meadow steppe, and then decreased to the lowest value in the upland meadow and subsequently increased in the alpine meadow. The ranges of the C:N ratio, C:P ratio, and N:P ratio were 16.36–155.53, 109.36–786.52, and 2.58–17.34, respectively. Due to fluctuations in the P concentration, the C:P ratio and N:P ratio reached the lowest value in the meadow steppe and obtained their highest value in the upland meadow. Redundancy analysis showed that temperature was the dominant factor affecting the C, N, and P ecological stoichiometry of herbaceous plants, followed by soil organic carbon, mean annual precipitation, soil pH, and soil electrical conductivity. Corresponding results could enhance predictive models of nutrient cycling and ecosystem responses to climate change, particularly in arid and semiarid regions.
Using QSAR to predict polymer-drug interactions for drug delivery
Authors: Xin Alison W. , Rivera-Delgado Edgardo , von Recum Horst A.
Published: July 2024

Affinity-mediated drug delivery utilizes electrostatic, hydrophobic, or other non-covalent interactions between molecules and a polymer to extend the timeframe of drug release. Cyclodextrin polymers exhibit affinity interaction, however, experimentally testing drug candidates for affinity is time-consuming, making computational predictions more effective. One option, docking programs, provide predictions of affinity, but lack reliability, as their accuracy with cyclodextrin remains unverified experimentally. Alternatively, quantitative structure-activity relationship models (QSARs), which analyze statistical relationships between molecular properties, appear more promising. Previously constructed QSARs for cyclodextrin are not publicly available, necessitating an openly accessible model. Around 600 experimental affinities between cyclodextrin and guest molecules were cleaned and imported from published research. The software PaDEL-Descriptor calculated over 1,000 chemical descriptors for each molecule, which were then analyzed with R to create several QSARs with different statistical methods. These QSARs proved highly time efficient, calculating in minutes what docking programs could accomplish in hours. Additionally, on test sets, QSARs reached R2 values of around 0.7–0.8. The speed, accuracy, and accessibility of these QSARs improve evaluation of individual drugs and facilitate screening of large datasets for potential candidates in cyclodextrin affinity-based delivery systems. An app was built to rapidly access model predictions for end users using the Shiny library. To demonstrate the usability for drug release planning, the QSAR predictions were coupled with a mechanistic model of diffusion within the app. Integrating new modules should provide an accessible approach to use other cheminformatic tools in the field of drug delivery.