bluuebunny/crossref_metadata_2025 huggingface dataset:
Contrasting apatite geochemistry between ore-bearing and ore-barren intrusions of the giant Kalmakyr gold-rich porphyry Cu deposit, Tien Shan, Uzbekistan
Authors: Liu Yangtao , Zhao Xiaobo , Xue Chunji , Nurtaev Bakhtiar , Chen Jing
Published: March 2023

The Kalmakyr deposit in Uzbekistan is one of the world’s largest gold-rich porphyry Cu deposits, and mineralization was proposed to be closely associated with the emplacement of the latest intrusive phases, that is, granodiorite porphyry. However, it is still unclear which features of these ore-bearing intrusions are crucial for the enormous metal enrichment and how they correlate with magmatic fertility. In this study, we address these questions by comparing the petrological and in situ major and trace element geochemistry of apatite for the ore-bearing and ore-barren intrusions. Magmatic apatite from the ore-bearing granodiorite porphyry has higher Eu/Eu* (0.50–0.58), Sr/Y (1.09–1.64), and La/Yb (36.19–53.42) ratios than the ore-barren quartz porphyry (0.01–0.02, 0.02–0.03, and 2.01–3.75, respectively) and monzonite (0.20–0.11, 0.36–1.12, and 19.71–56.32, respectively). Moreover, the ore-bearing granodioritic magma has higher S (average of 111 ppm) and Cl (average of 8602 ppm) contents than the magma of quartz porphyry (S contents average of 9 ppm; Cl contents average of 2652 ppm) and monzonite (S contents average of 9 ppm; Cl contents average of 8483 ppm). These features collectively suggest that the ore-bearing granodiorite porphyry has relatively high oxygen fugacity, H2O, Cl, and S contents compared to those from the ore-barren intrusions. By comparing our data with the published dataset from porphyry Cu–Mo and Mo-only deposits in the world, we suggest that the high Cl content and low F/Cl ratio in magmatic apatite might be an important indicator to prospect for gold-rich porphyry Cu deposits.
Using feedforward to improve pre-service teachers’ academic writing and critical thinking skills
Authors: Baroudi Sandra , Aoun Serena , Hamam Doaa
Published: March 2023

Introduction

Literature to date indicates that constructive, timely, and personalized instructor feedback to student work boosts their academic performance. Peer feedback has been investigated extensively for the past three decades and has demonstrated its effectiveness where students were trained to give quality feedback. Little, however, is known about the use of feedforward as a strategy that focuses on future assignments and paves the way to improved performance.

Methods

This study followed an action research design using a mixed-method approach to examine the impact of feedforward on developing pre-service teachers’ performance on two main skills: critical thinking and academic writing. The teacher researcher followed the same cohort of 14 Emirati pre-service teachers’ over two semesters and used a pre- and post-test to collect quantitative data and a survey to collect qualitative data. Findings in this research study reveal that when using feedforwarding on the same cohort of 14 pre-service teachers over the period of two academic semesters, their scores on the post-test for the two skills improved.

Results

This new strategy promoted their motivation to improve their performance on the next task and enhanced the quality of their work. Findings also highlight potential reasons that inhibited the participants’ ability to create rich assignments that include content-specific vocabulary and to make connections with the course content.

Discussion

This study implies for curriculum designers at the K-12 level to integrate authentic tasks that engage students with real-world problems and train them on inferring information as a scaffold to the development of their critical thinking skills.
Thyroglobulin levels in COVID-19-positive patients: Correlations with thyroid function tests, inflammatory markers, and glucocorticoid use
Authors: Świątkowska-Stodulska Renata , Berlińska Agata , Puchalska-Reglińska Ewelina
Published: March 2023

COVID-19 often results in generalized inflammation and affects various organs and systems. Endocrine research focused on the possible sequelae of COVID-19, with special interest given to the thyroid gland. Clinical problems such as thyroid function in non-thyroidal illness (NTI), autoimmune thyroiditis, and COVID-19-related subacute thyroiditis (SAT) quickly gained wide coverage. Thyrotoxicosis of various origins leads to the release of peripheral thyroid hormones and thyroglobulin (TG), the main glycoprotein contained within the thyroid follicular lumen. In our study, we evaluated TG levels in COVID-19-positive patients and investigated the possible relationships between TG, thyroid function tests (TFTs), and inflammatory markers. Our approach included separate subanalyses of patients who received and those who did not receive glucocorticoids (GCs). In the entire population studied, the concentration of TG tended to decrease with time (p<0.001; p1,2 = 0.025, p1,3 = 0.001, p2,3 = 0.003), and this pattern was especially clear among patients treated with GCs (p<0.001; p1,2=<0.001; p1,3=<0.001; p 2,3=<0.001). The concentration of TG differed significantly between patients treated and those not treated with GC at the second and third time points of observation (p=0.033 and p=0.001, consecutively). TG concentration did not differ between the patients with normal and abnormal TFTs. The correlations between TG, TFTs, and inflammatory markers were very limited. 19 patients had elevated TG levels, but a TFT pattern suggestive of thyrotoxicosis was not common in this group. There were no statistically significant differences between patients who met and those who did not meet the predefined combined primary endpoint.
Identification of biallelic variations of CEP70 in patients with male infertility
Authors: Ruan Tiechao , Yang Yihong , Jiang Chuan , Shen Gan , Li Dingming , Shen Ying
Published: March 2023

Introduction

Male infertility is a severe health issue caused by complex and multifactorial pathological conditions. Genetic factors are a major cause of male infertility. CEP70, a centrosomal protein, has been reported to play an important role in male reproduction in mice. However, the role of CEP70 in human male infertility is limited.

Methods

Whole exome sequencing and Sanger sequencing were used to identify the genetic cause of the infertile patients. Papanicolaou staining, scanning electron microscopy and transmission electron microscopy were further conducted to explore morphological and ultrastructural defects in spermatozoa from the patient. Immunofluorescence staining was used to detect the pathogenicity of the identified variants and the particular expression of CEP70 in testis.

Results

In this study, we identified biallelic mutations of CEP70 in two unrelated infertile male individuals with oligoasthenoteratozoospermia that followed a recessive inheritance pattern. Papanicolaou staining, scanning electron microscopy and transmission electron microscopy showed that morphological and ultrastructural defects in the acrosome and flagellum of sperm from the patient in a pattern strikingly similar to that in Cep70−/− male mice. The results of immunofluorescence staining suggested that CEP70 was normally expressed in the acrosome and flagellum of control sperm but was hardly detected in the sperm of patient carrying CEP70 variation. We also explored the particular expression pattern of CEP70 during spermatogenesis in humans and mice.

Conclusions

Biallelic mutations of CEP70 might be a novel genetic cause of human male infertility, which could potentially serve as a basis for genetic counseling and diagnosis of male infertility.
Expanding the apelin receptor pharmacological toolbox using novel fluorescent ligands
Authors: Williams Thomas L. , Macrae Robyn G. C. , Kuc Rhoda E. , Brown Alastair J. H. , Maguire Janet J. , Davenport Anthony P.
Published: March 2023

Introduction

The apelin receptor binds two distinct endogenous peptides, apelin and ELA, which act in an autocrine/paracrine manner to regulate the human cardiovascular system. As a class A GPCR, targeting the apelin receptor is an attractive therapeutic strategy. With improvements in imaging techniques, and the stability and brightness of dyes, fluorescent ligands are becoming increasingly useful in studying protein targets. Here, we describe the design and validation of four novel fluorescent ligands; two based on [Pyr1]apelin-13 (apelin488 and apelin647), and two based on ELA-14 (ELA488 and ELA647).

Methods

Fluorescent ligands were pharmacologically assessed using radioligand and functional in vitro assays. Apelin647 was validated in high content imaging and internalisation studies, and in a clinically relevant human embryonic stem cell-derived cardiomyocyte model. Apelin488 and ELA488 were used to visualise apelin receptor binding in human renal tissue.

Results

All four fluorescent ligands retained the ability to bind and activate the apelin receptor and, crucially, triggered receptor internalisation. In high content imaging studies, apelin647 bound specifically to CHO-K1 cells stably expressing apelin receptor, providing proof-of-principle for a platform that could screen novel hits targeting this GPCR. The ligand also bound specifically to endogenous apelin receptor in stem cell-derived cardiomyocytes. Apelin488 and ELA488 bound specifically to apelin receptor, localising to blood vessels and tubules of the renal cortex.

Discussion

Our data indicate that the described novel fluorescent ligands expand the pharmacological toolbox for studying the apelin receptor across multiple platforms to facilitate drug discovery.
Effects of intestinal flora on polycystic ovary syndrome
Authors: Liu Jiayue , Liu Ying , Li Xiaoliang
Published: March 2023

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. Its clinical characteristics are mainly oligo-ovulation or anovulation, hyperandrogenemia (HA) and insulin resistance (IR). PCOS is considered to be one of the main causes of infertility in women of childbearing age, and its pathogenesis is still unclear. Intestinal flora, known as the “second genome” of human beings, is closely related to metabolic diseases, immune diseases and infectious diseases. At the same time, mounting evidence suggests that intestinal flora can regulate insulin synthesis and secretion, affect androgen metabolism and follicular development, and is involved in the occurrence of chronic inflammation and obesity. The imbalance of intestinal flora is caused by the abnormal interaction between intestinal flora and host cells caused by the change of intestinal microbial diversity, which is related to the occurrence and development of PCOS. The adjustment of intestinal flora may be a potential direction for the treatment of PCOS.
Optimal energy portfolio allocation method for regulable hydropower plants considering the impact of new energy generation
Authors: Lu Guanpeng , Yang Yi , Li Zhuangzhuang , Tang Yufeng
Published: March 2023

With the growing penetration of new energy sources, the impact of new energy generation on the income of the energy portfolio is becoming more significant. This paper proposes a risk measurement method based on the Conditional Value-at-Risk (CVaR) approach to measure the income risk from new energy generation on the energy portfolio. The superiority is proved by comparing it with the method only considering spot price fluctuations. Then, we constructed an energy allocation model of the hydropower plant to maximize the combined income-risk utility. In solving the optimal allocation of the energy portfolio, the effects of inflow and water level on the risk aversion parameters of the hydropower plant are considered. The results and comparison show that the proposed risk measurement method increases the income of the energy portfolio by 12%, and the proposed risk aversion parameter’s adjustment strategy can increase the income of the energy portfolio by 5.8% and reduces the CVaR value by 14.5%. Moreover, the method that considers the income risk from new energy generation can provide favorable conditions for improved new energy accommodation and safe operation of the system.
Identifying obstacles encountered at different stages of the disaster management cycle (DMC) and its implications for rural flooding in Pakistan
Authors: Shah Ashfaq Ahmad , Ullah Ayat , Khan Nasir Abbas , Shah Muhammad Haroon , Ahmed Rasheed , Hassan Syed Tauseef , Tariq Muhammad Atiq Ur Rehman , Xu Chong
Published: March 2023

The world has seen a number of natural hazards, but among them, floods are perhaps the most frequent devastating natural hazard, resulting in more human causalities and financial losses. Rural inundation has become an issue of concern in various parts of the world, including Pakistan. Over the past few decades, it has been hard for local institutions and rural populations to recover from the trauma inflicted by these events. The disaster risk management cycle is a well-known tool for coping with disasters and their consequences. Yet, the DRM cycle efficacy has been questioned in various rural settings. Thus, this paper applied a programmatic strategy to understand the challenges disaster management authorities and communities face in managing flood risks through the conventional disaster management cycle in Khyber Pakhtunkhwa province, Pakistan. The study objective was accomplished by using both qualitative and exploratory research designs. Four communities (namely, Peshawar, Charsadda, Nowshera, and Dera Ismail Khan) with a historical record of flooding were chosen for focus group discussion (32 in total) using a purposive sampling method. Additionally, 31 key informant interviews were undertaken from pertinent local disaster risk management institutions. We employed a thematic analysis to classify responses and obstacles into the various stages of the disaster management cycle. The findings of this study from interviews and focus groups provided some new insight into the conventional DRM cycle. The issues and challenges encountered by institutions and the community members were divided into four stages: 1-mitigation, 2-preparedness, 3-rescue and relief (R&R), and 4-rehabilitation and recovery (R&R). Based on the findings, it seems that local disaster management institutions still rely on reactive strategies and deal with flood hazards on an ad hoc basis. Poor governance and a lack of responses for present development trajectories were also highlighted as reasons why flood risk management is still challenging. There is an urgent need to perform susceptibility and risk assessments for multiple hazards and develop specialized plans that follow disaster risk reduction principles and adaptation to climate change. This study recommends incorporating resilience and adaptation to climate change into the current disaster management cycle to prevent or reduce future hazards and risks in rural areas.
Shift of combined ecotoxicity index in petroleum polluted soils during a bacterial remediation
Authors: Chai Xiaoyun , Wang Mutian , Fu Xiaowen , Zhang Wen , Huang Yujie , Germaine Kieran J. , Wang Jianing
Published: March 2023

Introduction: Bioremediation has been shown to be an effective strategy for removing toxic pollutants from the environment, particularly organic chemicals such as petroleum hydrocarbons. This paper investigates the changes in toxicity of petroleum-contaminated soil as a result of microbial remediation processes.

Methods: Changes in the ecotoxicity of the contaminated soil were examined using a plant, earthworm, enzyme activity and luminescent bacteria toxicity tests.

Results: The results showed that bioremediation could effectively degrade petroleum hydrocarbon (C10–C40) pollutants. After 42 days of remediation, the petroleum hydrocarbon (C10–C40) content of Group A (bioaugmented polluted wetland soil) decreased from 1.66 g/kg to 1.00 g/kg, and the degradation rate was 40.6%. The petroleum hydrocarbon (C10–C40) content of Group B (bioaugmented polluted farmland soil decreased from 4.00 g/kg to 1.94 g/kg, and the degradation rate was 51.6%. During the microbial remediation progress, the ecological toxicity of petroleum-contaminated soil first increased and then decreased. The photosynthetic pigment content index in the higher plant toxicity test, the earthworm survival index and the soil catalase activity all showed good agreement with the relative luminescence index of extracted DCM/DMSO in the luminescent bacterial toxicity test. The soil toxicity decreased significantly after remediation. Specifically, the photosynthetic pigment content of wheat were inhibited in the soil during the whole process (remediation for 42 days), and decreased to the minimum on remediation day 21. The 7-day and 14-day survival rate of earthworms in Group A and Group B gradually decreased in the soil remediation process, and then gradually increased, survival rate at the end of remediation was higher than at the beginning. Soil catalase activity was significantly negatively correlated with petroleum hydrocarbon (C10–C40) content (−0.988, −0.989). The ecological toxicity of contaminated soil reached to the maximum on the 21st day of remediation, relative luminosity of luminescent bacteria in dichloromethane/dimethyl sulfoxide extracts from Group A and Group B were 26.3% and 16.3%, respectively.

Conclusion: Bioremediation could effectively degrade petroleum hydrocarbon (C10–C40) pollutants. Wheat photosynthetic pigment content, earthworm survival rate, soil catalase activity and relative luminescence of luminescent bacteria can better indicate the ecological toxicity of petroleum-contaminated soil in bioremediation process.
Role of different organic and inorganic amendments in the biofortification of iodine in Coriandrum sativum crop
Authors: Tianyi Yan , Farooq Ambar , Mohiuddin Muhammad , Farooq Asma , Gonzalez Norela C. T. , Abbasi Asim , Hina Aiman , Irshad Muhammad
Published: March 2023

Iodine deficiency disorder (IDDs) is one of the most prevailing and common health issues in mountainous communities. An effective way to control the prevalence and emergence of IDDs in remote areas is to use iodized salt. However, recent studies indicated that iodized salt is mostly lost during the cooking process. The current study of iodine biofortification differed from the previous studies in two main aspects: it involved exogenous organic iodine (OI), and inorganic iodine such as potassium iodide (KI), added in the amended soils, which previous studies did not consider. Moreover, the translocation, transformation, and distribution of iodine from soil to plants are poorly understood in amended soil. Thus, identifying an effective management option to enhance iodine (I) bioavailability in nutrient-deficient soils is currently a significant challenge. Therefore, a greenhouse study was conducted to investigate the effects of organic and inorganic soil amendments on the uptake of different iodine sources in coriander crops. Results showed that applying an inorganic iodine source significantly enhanced the iodine edible part of the crop compared to the control (p < 0.05). The application of soil amendments relatively improved iodine uptake by the coriander crop compared to the control. The highest iodine was found in crop tissues grown in wood ash-amended soil supplemented with KI (291.97 μg kg−1). The KI uptake was significantly higher than the OI (p < 0.05). Compared to OI, a higher translocation factor (0.96) and distribution coefficient (3.51) were found for plants treated with KI. Thus, this study indicates that a suitable soil amendment can be a better option for iodine biofortification and that it can serve as an alternative to iodized salt in preventing IDDs.
Impact of forest fire on radial growth of tree rings and their element concentrations of Pinus sylvestris and Larix gmelinii in northern China
Authors: Wei Mao , Guo Xinbin , Ma Yuanfan , Tigabu Mulualem , Zheng Wenxia , Liu Mengxia , Guo Futao
Published: March 2023

Aims

Through analyzing the responses of the radial growth and element concentrations (B, Mg, Al, K, Ca, Mn, Fe, Zn, Na, P, Ni, and Cu) of tree rings of two dominant tree species to forest fires, we aimed to investigate the relationship between tree rings and the fires.

Methods

We sampled wood cores of Pinus sylvestris and Larix gmelinii in the northern forest region of China, where forest fires happened in 1990 and 2008. The ring-width growth of P. sylvestris and L. gmelinii from 1986 to 1995 and 2004 to 2013 in two sites of Tahe County were measured. Element concentrations in tree rings were determined using inductively coupled plasma mass spectrometry (ICP-MS).

Results

Our results showed that tree-ring radial growth was largely reduced after the fire, together with the increase in concentrations of B, Al, Mn, and Fe but the decrease in some samples in K. Strong correlations were observed between tree-ring growth and concentrations of Mg and Mn of P. sylvestris and Znof L. gmelinii.

Discussion

The results provide evidence that variations in tree-ring growth and element concentrations, particularly concentrations of B, Al, Mn, and Fe, are potentially useful to monitor forest fires, which add new insights into the study of forest fire history.
Overexpression of CHAF1A is associated with poor prognosis, tumor immunosuppressive microenvironment and treatment resistance
Authors: Sun Xia , Ma Qiushuang , Cheng Yahong , Huang Huangwei , Qin Jing , Zhang Mengchen , Qu Sifeng
Published: March 2023

Background: As distinct marker of proliferating cells, chromatin assembly factor-1 (CAF-1) was critical in DNA replication. However, there is paucity information about the clinical significance, functions and co-expressed gene network of CHAF1A, the major subunit in CAF-1, in cancer.

Methods: Bioinformatic analysis of CHAF1A and its co-expression gene network were performed using various public databases. Functional validation of CHAF1A was applied in breast cancer.

Results: Overexpression of CHAF1A was found in 20 types of cancer tissues. Elevated expression of CHAF1A was positively correlated with breast cancer progression and poor patients’ outcome. The analysis of co-expression gene network demonstrated CHAF1A was associated with not only cell proliferation, DNA repair, apoptosis, but cancer metabolism, immune system, and drug resistance. More importantly, higher expression of CHAF1A was positively correlated with immunosuppressive microenvironment and resistance to endocrine therapy and chemotherapy. Elevated expression of CHAF1A was confirmed in breast cancer tissues. Silencing of CHAF1A can significantly inhibit cell proliferation in MDA-MB-231 cells.

Conclusion: The current work suggested that overexpression of CHAF1A can be used as diagnostic and poor prognostic biomarker of breast cancer. Higher expression of CHAF1A induced fast resistance to endocrine therapy and chemotherapy, it may be a promising therapeutic target and a biomarker to predict the sensitivity of immunotherapy in breast cancer.
Machine learning used for simulation of MitraClip intervention: A proof-of-concept study
Authors: Dabiri Yaghoub , Mahadevan Vaikom S. , Guccione Julius M. , Kassab Ghassan S.
Published: March 2023

Introduction: Severe mitral regurgitation (MR) is a mitral valve disease that can lead to lifethreatening complications. MitraClip (MC) therapy is a percutaneous solution for patients who cannot tolerate surgical solutions. In MC therapy, a clip is implanted in the heart to reduce MR. To achieve optimal MC therapy, the cardiologist needs to foresee the outcomes of different scenarios for MC implantation, including the location of the MC. Although finite element (FE) modeling can simulate the outcomes of different MC scenarios, it is not suitable for clinical usage because it requires several hours to complete.

Methods: In this paper, we used machine learning (ML) to predict the outcomes of MC therapy in less than 1 s. Two ML algorithms were used: XGBoost, which is a decision tree model, and a feed-forward deep learning (DL) model. The MC location, the geometrical attributes of the models and baseline stress and MR were the features of the ML models, and the predictions were performed for MR and maximum von Mises stress in the leaflets. The parameters of the ML models were determined to achieve the minimum errors obtained by applying the ML models on the validation set.

Results: The results for the test set (not used during training) showed relative agreement between ML predictions and ground truth FE predictions. The accuracy of the XGBoost models were better than DL models. Mean absolute percentage error (MAPE) for the XGBoost predictions were 0.115 and 0.231, and the MAPE for DL predictions were 0.154 and 0.310, for MR and stress, respectively.

Discussion: The ML models reduced the FE runtime from 6 hours (on average) to less than 1 s. The accuracy of ML models can be increased by increasing the dataset size. The results of this study have important implications for improving the outcomes of MC therapy by providing information about the outcomes of MC implantation in real-time.
Codon-optimized TDP-43 mediates neurodegeneration in a Drosophila model of ALS/FTLD
Authors: Yusuff Tanzeen , Chang Ya-Chu , Sang Tzu-Kang , Jackson George R. , Chatterjee Shreyasi
Published: March 2023

Transactive response DNA binding protein-43 (TDP-43) is known to mediate neurodegeneration associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The exact mechanism by which TDP-43 exerts toxicity in the brains, spinal cord, and lower motor neurons of affected patients remains unclear. In a novel Drosophila melanogaster model, we report gain-of-function phenotypes due to misexpression of insect codon-optimized version of human wild-type TDP-43 (CO-TDP-43) using both the binary GAL4/UAS system and direct promoter fusion constructs. The CO-TDP-43 model showed robust tissue specific phenotypes in the adult eye, wing, and bristles in the notum. Compared to non-codon optimized transgenic flies, the CO-TDP-43 flies produced increased amount of high molecular weight protein, exhibited pathogenic phenotypes, and showed cytoplasmic aggregation with both nuclear and cytoplasmic expression of TDP-43. Further characterization of the adult retina showed a disruption in the morphology and function of the photoreceptor neurons with the presence of acidic vacuoles that are characteristic of autophagy. Based on our observations, we propose that TDP-43 has the propensity to form toxic protein aggregates via a gain-of-function mechanism, and such toxic overload leads to activation of protein degradation pathways such as autophagy. The novel codon optimized TDP-43 model is an excellent resource that could be used in genetic screens to identify and better understand the exact disease mechanism of TDP-43 proteinopathies and find potential therapeutic targets.
Extracellular vesicles as a new horizon in the diagnosis and treatment of inflammatory eye diseases: A narrative review of the literature
Authors: Habibi Azam , Zarei-Behjani Zeinab , Falamarzi Kimia , Malekpour Mahdi , Ebrahimi Fatemeh , Soleimani Masood , Nejabat Mahmood , Khosravi Amir , Moayedfard Zahra , Pakbaz Sara , Dehdari Ebrahimi Niloofar , Azarpira Negar
Published: March 2023

Extracellular vesicles include exosomes, microvesicles, and apoptotic bodies. Their cargos contain a diverse variety of lipids, proteins, and nucleic acids that are involved in both normal physiology and pathology of the ocular system. Thus, studying extracellular vesicles may lead to a more comprehensive understanding of the pathogenesis, diagnosis, and even potential treatments for various diseases. The roles of extracellular vesicles in inflammatory eye disorders have been widely investigated in recent years. The term “inflammatory eye diseases” refers to a variety of eye conditions such as inflammation-related diseases, degenerative conditions with remarkable inflammatory components, neuropathy, and tumors. This study presents an overview of extracellular vesicles’ and exosomes’ pathogenic, diagnostic, and therapeutic values in inflammatory eye diseases, as well as existing and potential challenges.
Enriched environment remodels the central immune environment and improves the prognosis of acute ischemic stroke in elderly mice with chronic ischemia
Authors: Zhang Shehong , Zhang Yonggang , Liu He , Wu Fengfeng , Wang Zhihong , Li Liqin , Huang Huilian , Qiu Sheng , Li Yuntao
Published: March 2023

With the aging of many populations, cognitive and motor dysfunction caused by ischemic stroke (IS) secondary to long-term chronic cerebral ischemia presents a global problem. Enriched environment (EE), a classic paradigm of environment response and genetic interaction, has shown tremendous influence on the brain. This research aimed to investigate the potential effect of EE on cognitive and motor function in mice with chronic cerebral ischemia and secondary IS. In the chronic cerebral hypoperfusion (CCH) phase, EE treatment improved behavior performance by alleviating neuronal loss and white matter myelin damage, promoting the expression of brain-derived neurotrophic factor (BDNF) and phosphor-cAMP response element binding protein (p-CREB). Furthermore, infiltration of microglia/macrophages and astrocytes was inhibited, and the levels of IL-1β and TNFα were decreased. In the IS phase, EE altered the neuronal outcome on day 21 but not on day one after IS. In addition, EE inhibited IS-induced infiltration of microglia/macrophages and astrocytes, mediated the polarization of microglia/macrophages, and reduced pro-inflammatory factors. Importantly, EE improved IS-induced cognitive and motor deficits on day 21. Collectively, our work demonstrates that EE protects mice from cognitive and motor dysfunction and inhibits neuroinflammation caused by CCH and IS.
Meningoencephalitis associated with GAD65 autoimmunity
Authors: Kuang Zuying , Baizabal-Carvallo José Fidel , Mofatteh Mohammad , Xie Sifen , Pan Mengqiu , Ye Jinlong , Zhou Lihua , Yang Shuiquang , Wang Zhanhang , Chen Yimin , Li Yaqin
Published: March 2023

Background

Encephalitis has been recognized in patients with autoimmunity related to the 65-kDa isoform of glutamic acid decarboxylase (GAD65) antibodies; however, patients with meningoencephalitis associated with those antibodies have been rarely identified in the medical literature. We aimed to define the frequency, clinical features, response to therapy, and functional outcomes of patients with meningoencephalitis associated with GAD antibodies.

Methods

We retrospectively studied consecutive patients attending a tertiary care center for evaluation of an autoimmune neurological disorder from January 2018 to June 2022. The modified Rankin Scale (mRS) was used to assess the functional outcome at the last follow-up.

Results

We evaluated 482 patients with confirmed autoimmune encephalitis during the study period. Four among the 25 patients with encephalitis related to GAD65 antibodies were identified. One patient was excluded owing to the coexistence of NMDAR antibodies. Three male patients aged 36, 24, and 16 years had an acute (n = 1) or subacute (n = 2) onset of confusion, psychosis, cognitive symptoms, seizures, or tremor. No patient had fever or clinical signs of meningeal irritation. Mild pleocytosis (<100 leukocytes/106) was identified in two patients, whereas one patient had normal CSF. Following immunotherapy with corticosteroids (n = 3) or intravenous immunoglobulin (n = 1), significant improvement was observed in all three cases, achieving a good outcome (mRS 1) in all cases.

Conclusion

Meningoencephalitis is an uncommon presentation of GAD65 autoimmunity. Patients present with signs of encephalitis but with meningeal enhancement and have good outcomes.
Lacticaseibacilli attenuated fecal dysbiosis and metabolome changes in Candida-administered bilateral nephrectomy mice
Authors: Chancharoenthana Wiwat , Kamolratanakul Supitcha , Visitchanakun Peerapat , Sontidejkul Supistha , Cheibchalard Thanya , Somboonna Naraporn , Settachaimongkon Sarn , Leelahavanichkul Asada
Published: March 2023

The impacts of metabolomic changes (reduced short-chain-fatty acids; SCFAs) in uremic condition is not fully understood. Once dailyCandidagavage with or without probiotics (different times of administration) for 1 week prior to bilateral nephrectomy (Bil Nep) in 8-week-old C57BL6 mice as the possible models more resemble human conditions were performed.Candida-administered Bil Nep mice demonstrated more severe conditions than Bil Nep alone as indicated by mortality (n = 10/group) and other 48 h parameters (n = 6-8/group), including serum cytokines, leaky gut (FITC-dextran assay, endotoxemia, serum beta-glucan, and loss of Zona-occludens-1), and dysbiosis (increasedEnterobacteriaceaewith decreased diversity in microbiome analysis) (n = 3/group for fecal microbiome) without the difference in uremia (serum creatinine). With nuclear magnetic resonance metabolome analysis (n = 3-5/group), Bil Nep reduced fecal butyric (and propionic) acid and blood 3-hydroxy butyrate compared with sham andCandida-Bil Nep altered metabolomic patterns compared with Bil Nep alone. Then,Lacticaseibacillus rhamnosusdfa1 (SCFA-producingLacticaseibacilli) (n = 8/group) attenuated the model severity (mortality, leaky gut, serum cytokines, and increased fecal butyrate) of Bil Nep mice (n = 6/group) (regardless ofCandida). In enterocytes (Caco-2 cells), butyrate attenuated injury induced by indoxyl sulfate (a gut-derived uremic toxin) as indicated by transepithelial electrical resistance, supernatant IL-8,NFκBexpression, and cell energy status (mitochondria and glycolysis activities by extracellular flux analysis). In conclusion, the reduced butyrate by uremia was not enhanced byCandidaadministration; however, the presence ofCandidain the gut induced a leaky gut that was attenuated by SCFA-producing probiotics. Our data support the use of probiotics in uremia.
A pan-variant mRNA-LNP T cell vaccine protects HLA transgenic mice from mortality after infection with SARS-CoV-2 Beta
Authors: Carter Brandon , Huang Pinghan , Liu Ge , Liang Yuejin , Lin Paulo J. C. , Peng Bi-Hung , McKay Lindsay G. A. , Dimitrakakis Alexander , Hsu Jason , Tat Vivian , Saenkham-Huntsinger Panatda , Chen Jinjin , Kaseke Clarety , Gaiha Gaurav D. , Xu Qiaobing , Griffiths Anthony , Tam Ying K. , Tseng Chien-Te K. , Gifford David K.
Published: March 2023

Licensed COVID-19 vaccines ameliorate viral infection by inducing production of neutralizing antibodies that bind the SARS-CoV-2 Spike protein and inhibit viral cellular entry. However, the clinical effectiveness of these vaccines is transitory as viral variants escape antibody neutralization. Effective vaccines that solely rely upon a T cell response to combat SARS-CoV-2 infection could be transformational because they can utilize highly conserved short pan-variant peptide epitopes, but a mRNA-LNP T cell vaccine has not been shown to provide effective anti-SARS-CoV-2 prophylaxis. Here we show a mRNA-LNP vaccine (MIT-T-COVID) based on highly conserved short peptide epitopes activates CD8+ and CD4+ T cell responses that attenuate morbidity and prevent mortality in HLA-A*02:01 transgenic mice infected with SARS-CoV-2 Beta (B.1.351). We found CD8+ T cells in mice immunized with MIT-T-COVID vaccine significantly increased from 1.1% to 24.0% of total pulmonary nucleated cells prior to and at 7 days post infection (dpi), respectively, indicating dynamic recruitment of circulating specific T cells into the infected lungs. Mice immunized with MIT-T-COVID had 2.8 (2 dpi) and 3.3 (7 dpi) times more lung infiltrating CD8+ T cells than unimmunized mice. Mice immunized with MIT-T-COVID had 17.4 times more lung infiltrating CD4+ T cells than unimmunized mice (7 dpi). The undetectable specific antibody response in MIT-T-COVID-immunized mice demonstrates specific T cell responses alone can effectively attenuate the pathogenesis of SARS-CoV-2 infection. Our results suggest further study is merited for pan-variant T cell vaccines, including for individuals that cannot produce neutralizing antibodies or to help mitigate Long COVID.
Model-interpreted outcomes of artificial neural networks classifying immune biomarkers associated with severe infections in ICU
Authors: Martinez Gustavo Sganzerla , Ostadgavahi Ali Toloue , Al-Rafat Abdullah Mahmud , Garduno Alexis , Cusack Rachael , Bermejo-Martin Jesus Francisco , Martin-Loeches Ignacio , Kelvin David
Published: March 2023

Introduction

Millions of deaths worldwide are a result of sepsis (viral and bacterial) and septic shock syndromes which originate from microbial infections and cause a dysregulated host immune response. These diseases share both clinical and immunological patterns that involve a plethora of biomarkers that can be quantified and used to explain the severity level of the disease. Therefore, we hypothesize that the severity of sepsis and septic shock in patients is a function of the concentration of biomarkers of patients.

Methods

In our work, we quantified data from 30 biomarkers with direct immune function. We used distinct Feature Selection algorithms to isolate biomarkers to be fed into machine learning algorithms, whose mapping of the decision process would allow us to propose an early diagnostic tool.

Results

We isolated two biomarkers, i.e., Programmed Death Ligand-1 and Myeloperoxidase, that were flagged by the interpretation of an Artificial Neural Network. The upregulation of both biomarkers was indicated as contributing to increase the severity level in sepsis (viral and bacterial induced) and septic shock patients.

Discussion

In conclusion, we built a function considering biomarker concentrations to explain severity among sepsis, sepsis COVID, and septic shock patients. The rules of this function include biomarkers with known medical, biological, and immunological activity, favoring the development of an early diagnosis system based in knowledge extracted from artificial intelligence.
Immunomodulatory function and anti-tumor mechanism of natural polysaccharides: A review
Authors: Ying Yang , Hao Wu
Published: March 2023

Polysaccharides extracted from natural resources have attracted extensive attention in biomedical research and pharmaceutical fields, due to their medical values in anti-tumor, immunomodulation, drug delivery, and many other aspects. At present, a variety of natural polysaccharides have been developed as adjuvant drugs in clinical application. Benefit from their structural variability, polysaccharides have great potential in regulating cellular signals. Some polysaccharides exert direct anti-tumor effects by inducing cell cycle arrest and apoptosis, while the majority of polysaccharides can regulate the host immune system and indirectly inhibit tumors by activating either non-specific or specific immune responses. As the essential of microenvironment in the process of tumor development has been gradually revealed, some polysaccharides were found to inhibit the proliferation and metastasis of tumor cellsviatumoral niche modulation. Here, we focused on natural polysaccharides with biomedical application potential, reviewed the recent advancement in their immunomodulation function and highlighted the importance of their signaling transduction feature for the antitumor drug development.
Exploring the urban renewal strategy based on transit-oriented development concept--A case study of Japan and Hong Kong
Authors: Dai Peng , Fu Hui , Yang Xuxu , Han Song , Fu Guannan , Wang Yanjun
Published: March 2023

In the wake of decreasing urban development space in China, urban regeneration has gradually changed from incremental renewal to stock renewal. Looking back on the past development process of urban renewal, we can find that “Transit-oriented Development” (TOD) plays an essential role in modern urban renewal. Therefore, in this study, we explain the concept and principles of TOD and discuss the logic of TOD and urban renewal. In addition, we summarize the basic features of urban renewal strategy based on the TOD concept through the analysis of TOD cases to provide some ideas for future urban renewal work.
Retinal vein changes after treatment with aflibercept and PRP in high-risk proliferative diabetic retinopathy
Authors: Zhao Hui , Wang Jundong , Li Shuting , Bao Ying , Zheng Xiaoxia , Tao Yuan , Wang Hong
Published: March 2023

Objective

The objective of the study was to investigate the effectiveness of aflibercept and panretinal photocoagulation (PRP) in the treatment of proliferative diabetic retinopathy (PDR).

Methods

A retrospective analysis was performed on 59 patients (59 eyes) with high-risk PDR who were treated with aflibercept and PRP between January 2018 and December 2019. The best corrected visual acuity (BCVA), central foveal thickness (CFT), and retinal vein diameter post-treatment were compared to those before the treatment.

Results

The best corrected visual acuity (BCVA) at 6 months (0.49 ± 0.14 logMAR), 12 months (0.54 ± 0.15 logMAR), 18 months (0.48 ± 0.15 logMAR), and 24 months (0.51 ± 0.15 logMAR) post-treatment were superior to the pre-treatment measurement (0.65 ± 0.18 logMAR). The central foveal thickness (CFT) at 6 months (310.67 ± 52.53 μm), 12 months (295.98 ± 45.65 μm), 18 months (282.56 ± 43.57 μm), and 24 months (281.53 ± 51.16 μm) post-treatment were lower than the pre-treatment measurement (456.53 ± 51.49 μm); the retinal vein diameter at 12 months (310.13 ± 24.60 μm), 18 months (309.50 ± 31.58 μm), and 24 months (317.00 ± 27.54 μm) post-treatment were lower than the pre-treatment measurement (361.81 ± 30.26 μm).

Conclusion

Aflibercept intravitreal injection and panretinal photocoagulation may morphologically reverse retinal vein diameter and venous beading in high-risk proliferative diabetic retinopathy.
MAE-TransRNet: An improved transformer-ConvNet architecture with masked autoencoder for cardiac MRI registration
Authors: Xiao Xin , Dong Suyu , Yu Yang , Li Yan , Yang Guangyuan , Qiu Zhaowen
Published: March 2023

The heart is a relatively complex non-rigid motion organ in the human body. Quantitative motion analysis of the heart takes on a critical significance to help doctors with accurate diagnosis and treatment. Moreover, cardiovascular magnetic resonance imaging (CMRI) can be used to perform a more detailed quantitative analysis evaluation for cardiac diagnosis. Deformable image registration (DIR) has become a vital task in biomedical image analysis since tissue structures have variability in medical images. Recently, the model based on masked autoencoder (MAE) has recently been shown to be effective in computer vision tasks. Vision Transformer has the context aggregation ability to restore the semantic information in the original image regions by using a low proportion of visible image patches to predict the masked image patches. A novel Transformer-ConvNet architecture is proposed in this study based on MAE for medical image registration. The core of the Transformer is designed as a masked autoencoder (MAE) and a lightweight decoder structure, and feature extraction before the downstream registration task is transformed into the self-supervised learning task. This study also rethinks the calculation method of the multi-head self-attention mechanism in the Transformer encoder. We improve the query-key-value-based dot product attention by introducing both depthwise separable convolution (DWSC) and squeeze and excitation (SE) modules into the self-attention module to reduce the amount of parameter computation to highlight image details and maintain high spatial resolution image features. In addition, concurrent spatial and channel squeeze and excitation (scSE) module is embedded into the CNN structure, which also proves to be effective for extracting robust feature representations. The proposed method, called MAE-TransRNet, has better generalization. The proposed model is evaluated on the cardiac short-axis public dataset (with images and labels) at the 2017 Automated Cardiac Diagnosis Challenge (ACDC). The relevant qualitative and quantitative results (e.g., dice performance and Hausdorff distance) suggest that the proposed model can achieve superior results over those achieved by the state-of-the-art methods, thus proving that MAE and improved self-attention are more effective and promising for medical image registration tasks. Codes and models are available at https://github.com/XinXiao101/MAE-TransRNet.
Enabling technologies driving drug research and development
Authors: Vass Panna , Akdag Dara Sevkan , Broholm Gabriel Enemark , Kjaer Jesper , Humphreys Anthony J. , Ehmann Falk
Published: March 2023

One of the strategic goals of the European Medicines Agency (EMA) and the European Medicines Regulatory Network is to support the research and uptake of innovative methods and technologies in the development of medicines. To promote this goal, EMA drew up a list of enabling technologies (ETs), which are novel and fast-growing technologies that have the potential to enable innovation and therefore exert considerable impact on drug development. In this work, enabling technologies identified by the EMA are analysed to measure their impact on drug development by following their journey from publications through early regulatory interactions to clinical trials between 2019 and 2022. This work also reviews the current list of EMA-identified ETs by scrutinising previously unseen innovative technologies identified in EMA submissions data. The analysis shows large variations in the appearance of the various innovative technologies in the different studied data sources, which provided valuable insights into the “Journey of Innovation” that innovative technologies undergo. Several emerging technologies were identified and endorsed for inclusion in the enabling technologies list, whereas some others already on the list were proposed to be excluded due to their low appearance in regulatory interactions as well as clinical trials and publications. Overall, this analysis highlights the relevance and value of continuously scanning and monitoring enabling technologies, supporting Europe’s goal to remain a leader in research and development of innovative technologies, methods, and methodologies relevant to drug development.
Isolation and characterization of Priestia megaterium KD7 for the biological control of pear fire blight
Authors: Cui Zeling , Hu Lina , Zeng Linglu , Meng Wanqiu , Guo Dong , Sun Li
Published: March 2023

Erwinia amylovora is a plant pathogen that causes fire blight disease in Rosaceous plants, such as pear and apple. To develop an effective biocontrol method to suppress E. amylovora, a total of 16 bacteria were isolated from pear orchard soil in China and screened for antagonistic activity in vitro. Among them, 9 isolates that exhibited antagonistic activity against E. amylovora were identified, including Bacillus atrophaeus, Priestia megaterium (previously known as Bacillus megaterium) and Serratia marcescens based on the partial 16S rDNA sequence analysis and similarity search. The plate confrontation experiments showed that strain 8 (P. megaterium strain KD7) had strong antagonistic activity against E. amylovora. The methanolic extract from cell-free supernatant of strain KD7 displayed high antibacterial activities against E. amylovora. Furthermore, the active compounds of strain KD7 were separated by thin layer chromatography (TLC) and the amino acids were detected by the presence of a spot with retention factor (Rf) of 0.71. Next, three lipopeptides were identified with high-resolution mass spectrometry (HRMS), including C13-surfactin [M+H]+ at m/z 1008.14, C15-surfactin [M+H]+ at m/z 1036.50, and C14-iturin A [M+H]+ at m/z 1043.17. Strain KD7 showed multiple antibiotic resistance, such as ampicillin, erythromycin, penicillin and tetracycline. The detached pear leaves, twigs and fruits assay showed that both protective and curative action with strain KD7 had the ability to decrease the development of fire blight. Taken together, P. megaterium strain KD7 is a potential effective biocontrol agent against fire blight.