bluuebunny/crossref_metadata_2025 huggingface dataset:
Distribution of Indolic Glucosinolates in Different Developmental Stages and Tissues of 13 Varieties of Cabbage (Brassica oleracea L. var. capitata)
Authors: Pan Qiming , Zhang Jiahao , Yan Chengtai , Khan Abid , Fei Siming , Lei Ting , Xu Zhongming , Li Baohua , Zhang Ruixing , Hui Maixia
Published: July 2023

Cabbage (Brassica oleracea L. var. capitata) is an excellent source of glucosinolates (GLS) that could reduce the risk of chronic diseases. The purpose of this study was to investigate the biological traits, pigment contents, color, and GLS content of 13 cabbage varieties. This study found that there were significant differences in the GLS content for various developmental stages of cabbage varieties, and the accumulation of GLS in young leaves was higher than that in mature stages. In most of the samples, the GLS content accumulated in different parts and changed as inner leaf > middle leaf > condensed stem > root. Double haploids of the M18-15 variety may be good candidates for future breeding programs and consumers, due to their high GLS content (ranging from 201.10 to 396.25 nmol mg−1 FW). GLS also act as a defense substance, and the data related to GLS accumulation patterns in different leaf locations and root parts may be useful for understanding leaf defense mechanisms and potential source–sink relationships. In addition, the observed interspecific variability is beneficial for breeders to develop Brassica varieties with high GLS content, as well as for the development of new functional food additives.
COVID-19 and Access to Medical Professional Careers: Does Gender Matter?
Authors: Díaz-Fernández Montserrat , Llorente-Marrón Mar , Cocina-Díaz Virginia , Asensi Victor
Published: July 2023

Objective: To know to what extent home confinement resulting from the COVID-19 pandemic has affected the results of the Medical Intern Resident Program (MIR) exam and whether or not a gender gap has occurred as a consequence. Method: Econometric modeling of the final result obtained in the MIR exam and identification of the explanatory factors that determine it and its relevance, effect and meaning. Results: From the results obtained in the MIR test of the 2019, 2020 and 2021 calls, it can be seen that examinations and academic records together with demographic and calendar factors are determinants to explain the observed behavior of the final result. In relation to the gender factor, the existence of a differential fixed effect in favor of women is shown, although the interaction with the exam shows the opposite result. The nationality variable allows us to visualize a scenario of academic homogeneity. The effect of the calendar directly linked to the COVID-19 pandemic makes it possible to quantify the negative impact exerted on the final result. Conclusions: (1) The work reflects the impact of factors such as sex, nationality or the COVID-19 pandemic on access to specialized health training in Spain. (2) In contrast to previous studies, we found a significant difference in behavior between men and women, favorably linked to the female sex. However, the so-called sprint effect associated with the male sex was detected. (3) The negative effects of the COVID-19 pandemic on the final score are visualized. The existing differential with respect to the control category is quantified and the dominance of the hierarchical position of the temporal component within the set of explanatory factors is visualized.
Informal Caregiving in Adolescents from 10 to 16 Years Old: A Longitudinal Study Using Data from the Tokyo Teen Cohort
Authors: Nakanishi Miharu , Stanyon Daniel , Richards Marcus , Yamasaki Syudo , Ando Shuntaro , Endo Kaori , Hosozawa Mariko , Miyashita Mitsuhiro , Hiraiwa-Hasegawa Mariko , Kasai Kiyoto , Nishida Atsushi
Published: July 2023

There is growing evidence of the impact of informal caregiving on adolescent mental health, and its role is often hidden unintentionally or intentionally, which may hamper early identification and support for young informal caregivers. However, the quantitative evidence regarding household factors relating to informal caregiving has mostly been based on cross-sectional findings. This study examines the longitudinal associations between household characteristics and the duration of informal caregiving in adolescents from 10 to 16 years of age. Child–household respondent pairs (n = 2331) from the Tokyo Teen Cohort in Japan were followed every 2 years from 10 to 16 years of age. Informal caregiving was assessed repeatedly based on the household respondent’s survey responses. Persistent caregiving was defined as daily caregiving at two or more waves. There were 2.2% of children who gave daily care at two or more waves. Cross-sectional associations with daily informal caregiving at each wave were found with girls, low household income, and cohabiting with grandparents. A significant association with persistent caregiving was found only in cohabiting with grandparents at 10 years of age after adjusting for sex, number of siblings, single parent, and household income. Our longitudinal examination highlighted cohabiting with grandparents as a preceding factor for persistent caregiving. Identification and support for young informal caregivers should be integrated into social care service systems for older adults. The mechanism of persistent caregiving requires clarification.
Nursing Care for Metastatic Bone Cancer: Trends for the Future
Authors: Penrod Debra , Hirsch Brandon
Published: July 2023

To effectively treat patients and minimize viral exposure, oncology nurses and radiology departments during COVID-19 had to re-examine the ability to offer palliative radiation treatments to people with metastatic bone cancer. Decreasing potential exposure to the virus resulted in extra measures to keep patients and personnel safe. Limiting radiotherapy treatments, social distancing, and limiting caregivers were a few of the ways that oncology patients were impacted by the pandemic. Hypofractionated radiation therapy (HFRT), or the delivery of fewer higher-dose treatments, was a method of providing care but also limiting exposure to infection for immunocompromised patients as well as healthcare staff. As oncology radiation centers measure the impact of patient care during the pandemic, a trend toward HFRT may occur in treating the painful symptoms of bone cancer. In anticipation that HFRT may be increasingly used in patient treatment plans, oncology nurses should consider patient perspectives and outcomes from the pandemic to further determine how to manage future trends in giving personalized care, and supportive care.
Interpersonal and Intimate Violence in Mexican Youth: Drug Use, Depression, Anxiety, and Stress during the COVID-19 Pandemic
Authors: Chainé Silvia Morales , Bacigalupe Gonzalo , García Rebeca Robles , Montoya Alejandra López , Romero Violeta Félix , Gispert Mireya Atzala Imaz
Published: July 2023

The COVID-19 pandemic may have increased interpersonal and intimate violence, harmful use of alcohol and other drugs (AODs), and mental health problems. This study uses a valid path model to describe relationships between these conditions of young Mexicans during the second year of the pandemic. A sample of 7420 Mexicans ages 18 to 24—two-thirds of whom are women—completed the Life Events Checklist, the Alcohol, Smoking, and Substance Involvement Screening Test, the Major Depressive Episode Checklist, the Generalized Anxiety Scale, and the Post-traumatic Stress Disorder (PTSD) Checklist. Young Mexicans reported higher rates of victimization and perpetration of interpersonal and intimate violence and mental health symptomatology than those noted pre- and in the first year of the pandemic. The harmful use of AOD rates were similar to those reported by adolescents before. The findings suggest asymmetric victimization and perpetration of intimate violence by gender (with women at a higher risk). More men than women have engaged in the harmful use of AODs (except for sedatives, which more women abuse). More women than men were at risk of all mental health conditions. The path model indicates that being a victim of intimate violence predicts the harmful use of tobacco, alcohol, cocaine, and sedatives, depression, anxiety, and specific PTSD symptoms (such as re-experimentation and avoidance symptoms). Being a victim of interpersonal violence resulted in severe PTSD symptoms (including avoidance, negative alterations in cognition-mood, and hyperarousal signs). The harmful use of sedatives predicted depressive symptoms. Men’s victimizing intimate violence model contrasted with that of women, which included being the victim of interpersonal violence and severe PTSD symptoms. The high school youth model had three paths: victimizing intimate violence, victimizing interpersonal abuse, and sedative use, which predicted depression. Our findings could serve as the basis for future studies exploring the mechanisms that predict violence to develop cost-effective preventive programs and public policies and to address mental health conditions during community emergencies.
Levels and Predictors of Proactive Practical Experience to Solve COVID-19 among Public Health Officers in Primary Care Units in the Upper Southern Region, Thailand: An Explanatory Mixed Methods Approach
Authors: Sangpoom Suttida , Adesina Femi , Kaewchandee Chuthamat , Sikanna Kannika , Noppapak Natchima , Maneerattanasak Sarunya , Shohaimi Shamarina , Suwanbamrung Charuai
Published: July 2023

Public Health Officers (PHOs)’ experiences in reaction to the COVID-19 pandemic can be based on whether the PHO is active or passive regarding five experience aspects, including knowledge, understanding, opinion, participation, and practice. Therefore, this study’s objectives are to identify the types of experiences and analyse the predictors of proactive practical experiences in addressing the COVID-19 pandemic among PHOs in the southern region of Thailand. Methods: An explanatory mixed methods approach was used to collect data, through questionnaires and online in-depth interviews. This study was conducted from 4 August 2020 to 3 August 2021. Results: The results include 60 PHOs from 60 Primary Care Units in six provinces, with 41 (68.3%) females and an average age of 35.57 years (SD = 11.61). The PHOs’ knowledge, understanding, and participation experience aspects were mostly proactive rather than passive. The factors that significantly predicted proactive practical experiences included sex (ORadj = 1.52, 95% CI = 1.04–2.21), age (ORadj = 1.69, 95% CI = 1.16–2.48), married status (ORadj = 1.69, 95% CI = 1.16–2.48), education level (ORadj = 1.50, 95% CI = 1.02–2.20), and position for work (ORadj = 1.69, 95% CI = 1.16–2.48). The results of quantitative method were confirmed by 12 sub-themes of 8 PHOs’ experiences from qualitative method. Conclusions: The PHOs’ knowledge, understanding, opinion, and participation experiences were significant predictors of practical experience. Primary health care systems should promote proactive experiences in all four aspects to increase proactive practical experiences.
The Effects of a Low Linoleic Acid/α-Linolenic Acid Ratio on Lipid Metabolism and Endogenous Fatty Acid Distribution in Obese Mice
Authors: Wang Qiong , Wang Xingguo
Published: July 2023

A reduced risk of obesity and metabolic syndrome has been observed in individuals with a low intake ratio of linoleic acid/α-linolenic acid (LA/ALA). However, the influence of a low ratio of LA/ALA intake on lipid metabolism and endogenous fatty acid distribution in obese patients remains elusive. In this investigation, 8-week-old C57BL/6J mice were randomly assigned to four groups: low-fat diet (LFD) as a control, high-fat diet (HFD), high-fat diet with a low LA/ALA ratio (HFD+H3L6), and high-fat diet with a high LA/ALA ratio (HFD+L3H6) for 16 weeks. Our results show that the HFD+H3L6 diet significantly decreased the liver index of HFD mice by 3.51%, as well as the levels of triacylglycerols (TGs) and low-density lipoprotein cholesterol (LDL-C) by 15.67% and 10.02%, respectively. Moreover, the HFD+H3L6 diet reduced the pro-inflammatory cytokines interleukin-6 (IL-6) level and aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio and elevated the level of superoxide dismutase (SOD) in the liver. The HFD+H3L6 diet also resulted in the downregulation of fatty acid synthetase (FAS) and sterol regulatory element binding proteins-1c (SREBP-1c) expression and the upregulation of peroxisome proliferator-activated receptor-α (PPAR-α) and acyl-CoA oxidase 1 (ACOX1) gene expression in the liver. The low LA/ALA ratio diet led to a notable increase in the levels of ALA and its downstream derivative docosahexaenoic acid (DHA) in the erythrocyte, liver, perienteric fat, epididymal fat, perirenal fat, spleen, brain, heart, and gastrocnemius, with a strong positive correlation. Conversely, the accumulation of LA in abdominal fat was more prominent, and a high LA/ALA ratio diet exacerbated the deposition effect of LA. In conclusion, the low LA/ALA ratio not only regulated endogenous fatty acid levels but also upregulated PPAR-α and ACOX1 and downregulated SREBP-1c and FAS gene expression levels, thus maintaining lipid homeostasis. Optimizing dietary fat intake is important in studying lipid nutrition. These research findings emphasize the significance of understanding and optimizing dietary fat intake.
Challenges of Diagnosing Mendelian Susceptibility to Mycobacterial Diseases in South Africa
Authors: Scholtz Denise , Jooste Tracey , Möller Marlo , van Coller Ansia , Kinnear Craig , Glanzmann Brigitte
Published: July 2023

Inborn errors of immunity (IEI) are genetic disorders with extensive clinical presentations. They can range from increased susceptibility to infections to significant immune dysregulation that results in immune impairment. While IEI cases are individually rare, they collectively represent a significant burden of disease, especially in developing countries such as South Africa, where infectious diseases like tuberculosis (TB) are endemic. This is particularly alarming considering that certain high penetrance mutations that cause IEI, such as Mendelian Susceptibility to Mycobacterial Disease (MSMD), put individuals at higher risk for developing TB and other mycobacterial diseases. MSMD patients in South Africa often present with different clinical phenotypes than those from the developed world, therefore complicating the identification of disease-associated variants in this setting with a high burden of infectious diseases. The lack of available data, limited resources, as well as variability in clinical phenotype are the reasons many MSMD cases remain undetected or misdiagnosed. This article highlights the challenges in diagnosing MSMD in South Africa and proposes the use of transcriptomic analysis as a means of potentially identifying dysregulated pathways in affected African populations.
Transgenic East African Highland Banana Plants Are Protected against Radopholus similis through Host-Delivered RNAi
Authors: Mwaka Henry Shaykins , Bauters Lander , Namaganda Josephine , Marcou Shirley , Bwesigye Priver Namanya , Kubiriba Jerome , Smagghe Guy , Tushemereirwe Wilberforce Kateera , Gheysen Godelieve
Published: July 2023

The burrowing nematode Radopholus similis is considered a major problem of intensive banana cultivation. It can cause extensive root damage resulting in the toppling disease of banana, which means that plants fall to the ground. Soaking R. similis in double-stranded (ds) RNA of the nematode genes Rps13, chitin synthase (Chs-2), Unc-87, Pat-10 or beta-1,4-endoglucanase (Eng1a) suppressed reproduction on carrot discs, from 2.8-fold (Chs-2) to 7-fold (Rps13). The East African Highland Banana cultivar Nakitembe was then transformed with constructs for expression of dsRNA against the same genes, and for each construct, 30 independent transformants were tested with nematode infection. Four months after transfer from in vitro culture to the greenhouse, the banana plants were transferred to a screenhouse and inoculated with 2000 nematodes per plant, and thirteen weeks later, they were analyzed for several parameters including plant growth, root necrosis and final nematode population. Plants with dsRNA constructs against the nematode genes were on average showing lower nematode multiplication and root damage than the nontransformed controls or the banana plants expressing dsRNA against the nonendogenous gene. In conclusion, RNAi seems to efficiently protect banana against damage caused by R. similis, opening perspectives to control this pest.
α-Synuclein Strains and Their Relevance to Parkinson’s Disease, Multiple System Atrophy, and Dementia with Lewy Bodies
Authors: Graves Noah J. , Gambin Yann , Sierecki Emma
Published: July 2023

Like many neurodegenerative diseases, Parkinson’s disease (PD) is characterized by the formation of proteinaceous aggregates in brain cells. In PD, those proteinaceous aggregates are formed by the α-synuclein (αSyn) and are considered the trademark of this neurodegenerative disease. In addition to PD, αSyn pathological aggregation is also detected in atypical Parkinsonism, including Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA), as well as neurodegeneration with brain iron accumulation, some cases of traumatic brain injuries, and variants of Alzheimer’s disease. Collectively, these (and other) disorders are referred to as synucleinopathies, highlighting the relation between disease type and protein misfolding/aggregation. Despite these pathological relationships, however, synucleinopathies cover a wide range of pathologies, present with a multiplicity of symptoms, and arise from dysfunctions in different neuroanatomical regions and cell populations. Strikingly, αSyn deposition occurs in different types of cells, with oligodendrocytes being mainly affected in MSA, while aggregates are found in neurons in PD. If multiple factors contribute to the development of a pathology, especially in the cases of slow-developing neurodegenerative disorders, the common presence of αSyn aggregation, as both a marker and potential driver of disease, is puzzling. In this review, we will focus on comparing PD, DLB, and MSA, from symptomatology to molecular description, highlighting the role and contribution of αSyn aggregates in each disorder. We will particularly present recent evidence for the involvement of conformational strains of αSyn aggregates and discuss the reciprocal relationship between αSyn strains and the cellular milieu. Moreover, we will highlight the need for effective methodologies for the strainotyping of aggregates to ameliorate diagnosing capabilities and therapeutic treatments.
Adipose-Derived Stem Cells Spontaneously Express Neural Markers When Grown in a PEG-Based 3D Matrix
Authors: Gomila Pelegri Neus , Stanczak Aleksandra M. , Bottomley Amy L. , Milthorpe Bruce K. , Gorrie Catherine A. , Padula Matthew P. , Santos Jerran
Published: July 2023

Neurological diseases are among the leading causes of disability and death worldwide and remain difficult to treat. Tissue engineering offers avenues to test potential treatments; however, the development of biologically accurate models of brain tissues remains challenging. Given their neurogenic potential and availability, adipose-derived stem cells (ADSCs) are of interest for creating neural models. While progress has been made in differentiating ADSCs into neural cells, their differentiation in 3D environments, which are more representative of the in vivo physiological conditions of the nervous system, is crucial. This can be achieved by modulating the 3D matrix composition and stiffness. Human ADSCs were cultured for 14 days in a 1.1 kPa polyethylene glycol-based 3D hydrogel matrix to assess effects on cell morphology, cell viability, proteome changes and spontaneous neural differentiation. Results showed that cells continued to proliferate over the 14-day period and presented a different morphology to 2D cultures, with the cells elongating and aligning with one another. The proteome analysis revealed 439 proteins changed in abundance by >1.5 fold. Cyclic nucleotide 3′-phosphodiesterase (CNPase) markers were identified using immunocytochemistry and confirmed with proteomics. Findings indicate that ADSCs spontaneously increase neural marker expression when grown in an environment with similar mechanical properties to the central nervous system.
The Biostimulant, Potassium Humate Ameliorates Abiotic Stress in Arabidopsis thaliana by Increasing Starch Availability
Authors: Benito Patricia , Bellón Javier , Porcel Rosa , Yenush Lynne , Mulet José M.
Published: July 2023

Potassium humate is a widely used biostimulant known for its ability to enhance growth and improve tolerance to abiotic stress. However, the molecular mechanisms explaining its effects remain poorly understood. In this study, we investigated the mechanism of action of potassium humate using the model plant Arabidopsis thaliana. We demonstrated that a formulation of potassium humate effectively increased the fresh weight accumulation of Arabidopsis plants under normal conditions, salt stress (sodium or lithium chloride), and particularly under osmotic stress (mannitol). Interestingly, plants treated with potassium humate exhibited a reduced antioxidant response and lower proline accumulation, while maintaining photosynthetic activity under stress conditions. The observed sodium and osmotic tolerance induced by humate was not accompanied by increased potassium accumulation. Additionally, metabolomic analysis revealed that potassium humate increased maltose levels under control conditions but decreased levels of fructose. However, under stress, both maltose and glucose levels decreased, suggesting changes in starch utilization and an increase in glycolysis. Starch concentration measurements in leaves showed that plants treated with potassium humate accumulated less starch under control conditions, while under stress, they accumulated starch to levels similar to or higher than control plants. Taken together, our findings suggest that the molecular mechanism underlying the abiotic stress tolerance conferred by potassium humate involves its ability to alter starch content under normal growth conditions and under salt or osmotic stress.
Fate of Entosis: From the Beginning to the End in Untreated Advanced Breast Cancer
Authors: Dziuba Ireneusz , Gawel Agata M. , Tyrna Paweł , Rybczynska Jolanta , Bialy Lukasz P. , Mlynarczuk-Bialy Izabela
Published: July 2023

Homotypic entosis is a phenomenon in which one cancer cell invades a neighboring cancer cell and is closed entirely within its entotic vacuole. The fate of entosis can lead to inner cell death or survival. Recent evidence draws attention to entosis as a novel prognostic marker in breast cancer. Nevertheless, little is known about the quantity and quality of the process of entosis in human cancer specimens. Here, for the first time, we analyze the frequency of entotic figures in a case of NOS (Non-Other Specified) breast cancer with regard to location: the primary tumor, regional lymph node, and distant metastasis. For the identification of entotic figures, cells were stained using hematoxylin/eosin and assessed using criteria proposed by Mackay. The majority of entotic figures (65%) were found in the lymph node, 27% were found in the primary tumor, and 8% were found in the far metastasis. In the far metastases, entotic figures demonstrated an altered, atypic morphology. Interestingly, in all locations, entosis did not show any signs of cell death. Moreover, the slides were stained for E-cadherin or Ki67, and we identified proliferating (Ki67-positive) inner and outer entotic cells. Therefore, we propose additional criteria for the identification of pro-survival entotic structures in diagnostic histopathology.
Axitinib Rechallenge Restores the Anticancer Effect after Nivolumab: A Case Report
Authors: Chang Yueh-Shih , Chang Pei-Hung , Wang Deng-Huang , Chen Chun-Bing , Huang Chi-Ying F.
Published: July 2023

The immune checkpoint inhibitor/tyrosine kinase inhibitor (ICI/TKI) combination treatment is currently the first-line treatment for metastatic renal cell carcinoma (mRCC). However, its efficacy beyond the third-line setting is expected to be relatively poor, and high-grade toxicities can develop by prior exposure to multiple drugs, resulting in a relatively poor performance in patients. Determining the best treatment regimen and sequence remains difficult and requires further investigation in patients with mRCC. In this study, two cases of mRCC, who failed several lines of TKI and nivolumab but exhibited a good anticancer effect after rechallenging with axitinib, are described. Both patients had a faster time to best response and better progression-free survival (PFS) than during previous treatments. Moreover, the axitinib dose could be reduced to 2.5 mg daily when used in combination with nivolumab while continuing to exert an impressive anticancer effect. To determine the cytotoxic effect, we performed a lymphocyte activation test and found that the level of granzyme B released by cytotoxic T lymphocytes and natural killer cells was higher when axitinib was combined with nivolumab. To evaluate this result, a bioinformatics approach was used to analyze the PRISM database. In conclusion, based on the results of a lymphocyte activation test and PD-1 expression, our findings indicate that sequential therapy with axitinib rechallenge after nivolumab resistance is reasonable for the treatment of mRCC.
A Novel Mechanism for Bone Loss: Platelet Count Negatively Correlates with Bone Mineral Density via Megakaryocyte-Derived RANKL
Authors: Kikuchi Shohei , Wada Akinori , Kamihara Yusuke , Yamamoto Imari , Kirigaya Daiki , Kunimoto Kohei , Horaguchi Ryusuke , Fujihira Takuma , Nabe Yoshimi , Minemura Tomoki , Dang Nam H. , Sato Tsutomu
Published: July 2023

A potential association between hematopoietic stem cell status in bone marrow and surrounding bone tissue has been hypothesized, and some studies have investigated the link between blood count and bone mineral density (BMD), although their exact relationship remains controversial. Moreover, biological factors linking the two are largely unknown. In our present study, we found no clear association between platelet count and BMD in the female group, with aging having a very strong effect on BMD. On the other hand, a significant negative correlation was found between platelet count and BMD in the male group. As a potential mechanism, we examined whether megakaryocytes, the source of platelet production, secrete cytokines that regulate BMD, namely OPG, M-CSF, and RANKL. We detected the production of these cytokines by megakaryocytes derived from bone marrow mononuclear cells, and found that RANKL was negatively correlated with BMD. This finding suggests that RANKL production by megakaryocytes may mediate the negative correlation between platelet count and BMD. To our knowledge, this is the first report to analyze bone marrow cells as a mechanism for the association between blood count and BMD. Our study may provide new insights into the development and potential treatment of osteoporosis.
Blood–Brain Barrier Dysfunction and Aβ42/40 Ratio Dose-Dependent Modulation with the ApoE Genotype within the ATN Framework
Authors: Toniolo Sofia , Di Lorenzo Francesco , Bernardini Sergio , Mercuri Nicola Biagio , Sancesario Giulia Maria
Published: July 2023

The definition of Alzheimer’s disease (AD) now considers the presence of the markers of amyloid (A), tau deposition (T), and neurodegeneration (N) essential for diagnosis. AD patients have been reported to have increased blood–brain barrier (BBB) dysfunction, but that has not been tested within the ATN framework so far. As the field is moving towards the use of blood-based biomarkers, the relationship between BBB disruption and AD-specific biomarkers requires considerable attention. Moreover, other factors have been previously implicated in modulating BBB permeability, including age, gender, and ApoE status. A total of 172 cognitively impaired individuals underwent cerebrospinal fluid (CSF) analysis for AD biomarkers, and data on BBB dysfunction, demographics, and ApoE status were collected. Our data showed that there was no difference in BBB dysfunction across different ATN subtypes, and that BBB damage was not correlated with cognitive impairment. However, patients with BBB disruption, if measured with a high Qalb, had low Aβ40 levels. ApoE status did not affect BBB function but had a dose-dependent effect on the Aβ42/40 ratio. These results might highlight the importance of understanding dynamic changes across the BBB in future studies in patients with AD.
Total Neoadjuvant Treatment for Locally Advanced Rectal Cancer Patients: Where Do We Stand?
Authors: Daprà Valentina , Airoldi Marco , Bartolini Michela , Fazio Roberta , Mondello Giuseppe , Tronconi Maria Chiara , Prete Maria Giuseppina , D’Agostino Giuseppe , Foppa Caterina , Spinelli Antonino , Puccini Alberto , Santoro Armando
Published: July 2023

The therapeutic landscape in locally advanced rectal cancer (LARC) has undergone a significant paradigm shift in recent years with the rising adoption of total neoadjuvant treatment (TNT). This comprehensive approach entails administering chemotherapy and radiation therapy before surgery, followed by optional adjuvant chemotherapy. To establish and deliver the optimal tailored treatment regimen to the patient, it is crucial to foster collaboration among a multidisciplinary team comprising healthcare professionals from various specialties, including medical oncology, radiation oncology, surgical oncology, radiology, and pathology. This review aims to provide insights into the current state of TNT for LARC and new emerging strategies to identify potential directions for future research and clinical practice, such as circulating tumor-DNA, immunotherapy in mismatch-repair-deficient tumors, and nonoperative management.
CXCL5 Promotes Acetaminophen-Induced Hepatotoxicity by Activating Kupffer Cells
Authors: Qiu Kexin , Pan Yan , Huang Weizhi , Li Mengyuan , Yan Xueqing , Zhou Zixiong , Qi Jing
Published: July 2023

Kupffer cells (KCs) play a key part in the pathological process of acetaminophen (APAP)-induced acute liver injury (ALI), the leading cause of acute liver failure in the world. CXC motif chemokine ligand 5 (CXCL5) exerts proinflammatory effects in acute respiratory distress syndrome and arthritis. In the current study, we aim to reveal the effects of CXCL5 on the activation of KCs and the role of CXCL5 in the pathogenesis of APAP-induced hepatotoxicity. The in vivo study, conducted on mice intraperitoneally injected with APAP (300 mg/kg) to establish the ALI model and then treated with Anti-CXCL5 mAb at 30 min and 12 h after the APAP challenge, showed that CXCL5 expression significantly increased in injured livers, and Anti-CXCL5 mAb mitigated the degree of APAP-evoked ALI in mice which was proven through biochemicals and histological examination. Also, neutralization of CXCL5 had no significant effect on APAP metabolism in the liver but exhibited anti-inflammatory effects and ameliorated hepatocellular death in the injured liver. The in vitro data displayed that recombinant mouse CXCL5 treatment promoted APAP-induced cellular toxicity in primary hepatocytes co-cultured with KCs, compared with single-cultured hepatocytes. Consistent with the result, we found that the Anti-CXCL5 mAb gradient decreased LPS-induced expression of inflammatory cytokines in single-cultured KCs. Therefore, CXCL5 could stimulate KCs to produce inflammatory mediators, therefore damaging hepatocytes from APAP toxicity.
FaMYB5 Interacts with FaBBX24 to Regulate Anthocyanin and Proanthocyanidin Biosynthesis in Strawberry (Fragaria × ananassa)
Authors: Zhang Lianxi , Wang Yiping , Yue Maolan , Jiang Leiyu , Zhang Nating , Luo Ya , Chen Qing , Zhang Yong , Wang Yan , Li Mengyao , Zhang Yunting , Lin Yuanxiu , Tang Haoru
Published: July 2023

MYB and BBX transcription factors play important roles in flavonoid biosynthesis. Here, we obtained transgenic woodland strawberry with stable overexpression of FaMYB5, demonstrating that FaMYB5 can increase anthocyanin and proanthocyanidin content in roots, stems and leaves of woodland strawberry. In addition, bimolecular fluorescence complementation assays and yeast two-hybridization demonstrated that the N-terminal (1-99aa) of FaBBX24 interacts with FaMYB5. Transient co-expression of FaBBX24 and FaMYB5 in cultivated strawberry ‘Xiaobai’ showed that co-expression strongly promoted the expression of F3′H, 4CL-2, TT12, AHA10 and ANR and then increased the content of anthocyanin and proanthocyanidin in strawberry fruits. We also determined that FaBBX24 is also a positive regulator of anthocyanin and proanthocyanidin biosynthesis in strawberry. The results reveal a novel mechanism by which the FaMYB5–FaBBX24 module collaboratively regulates anthocyanin and proanthocyanidin in strawberry fruit.
Lipopolysaccharide Tolerance in Human Primary Monocytes and Polarized Macrophages
Authors: Li Hui , Breedijk Annette , Dietrich Nadine , Nitschke Katja , Jarczyk Jonas , Nuhn Philipp , Krämer Bernhard K. , Yard Benito A. , Leipe Jan , Hauske Sibylle
Published: July 2023

Innate immune memory allows macrophages to adequately respond to pathogens to which they have been pre-exposed. To what extent different pattern recognition receptors, cytokines and resolution signals influence innate immune memory needs further elucidation. The present study assessed whether lipopolysaccharide (LPS) tolerance in monocytes and macrophages is affected by these factors. Human CD14+ cells were isolated from peripheral blood, stimulated by LPS and re-stimulated after 3 days of resting. Hereafter, immune-responsive gene 1 (IRG-1), heme oxygenase 1 (HO-1), tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) expression were assessed. Our study revealed the following findings: (1) While pre-stimulation with the Toll-like receptor 4 ligand LPS inhibits the induction of IRG-1, TNF-α and IL-6 expression, pre-stimulation with TLR 1/2 ligands only affects cytokine production but not IRG-1 expression upon subsequent TLR4 engagement. (2) Prior TNF-α stimulation does not affect LPS tolerance but rather increases LPS-mediated cytokine expression. (3) Dimethyl itaconate (DMI) inhibits the expression of IRG-1 in a dose-dependent manner but does not affect TNF-α or IL-6 expression. (4) Docosahexaenoic acid (DHA) partly inhibits IRG-1 expression in monocytes but not in M(IFNγ) and M(IL-4) polarized macrophages. LPS tolerance is not affected in these cells by DHA. The data presented in this study partly corroborate and extend previous findings on innate immune memory and warrant further studies on LPS tolerance to gain a better understanding of innate immune memory at the molecular level.
Parkinson’s Disease and the Heart: Studying Cardiac Metabolism in the 6-Hydroxydopamine Model
Authors: Silva da Fonsêca Victor , Goncalves Valeria de Cassia , Augusto Izidoro Mario , Guimarães de Almeida Antônio-Carlos , Luiz Affonso Fonseca Fernando , Alexandre Scorza Fulvio , Finsterer Josef , Scorza Carla Alessandra
Published: July 2023

Parkinson’s-disease (PD) is an incurable, age-related neurodegenerative disease, and its global prevalence of disability and death has increased exponentially. Although motor symptoms are the characteristic manifestations of PD, the clinical spectrum also contains a wide variety of non-motor symptoms, which are the main cause of disability and determinants of the decrease in a patient’s quality of life. Noteworthy in this regard is the stress on the cardiac system that is often observed in the course of PD; however, its effects have not yet been adequately researched. Here, an untargeted metabolomics approach was used to assess changes in cardiac metabolism in the 6-hydroxydopamine model of PD. Beta-sitosterol, campesterol, cholesterol, monoacylglycerol, α-tocopherol, stearic acid, beta-glycerophosphoric acid, o-phosphoethanolamine, myo-inositol-1-phosphate, alanine, valine and allothreonine are the metabolites that significantly discriminate parkinsonian rats from sham counterparts. Upon analysis of the metabolic pathways with the aim of uncovering the main biological pathways involved in concentration patterns of cardiac metabolites, the biosynthesis of both phosphatidylethanolamine and phosphatidylcholine, the glucose-alanine cycle, glutathione metabolism and plasmalogen synthesis most adequately differentiated sham and parkinsonian rats. Our results reveal that both lipid and energy metabolism are particularly involved in changes in cardiac metabolism in PD. These results provide insight into cardiac metabolic signatures in PD and indicate potential targets for further investigation.
Synthesis, 123I-Radiolabeling Optimization, and Initial Preclinical Evaluation of Novel Urea-Based PSMA Inhibitors with a Tributylstannyl Prosthetic Group in Their Structures
Authors: Hasnowo Lutfi A. , Larkina Maria S. , Plotnikov Evgenii , Bodenko Vitalina , Yuldasheva Feruza , Stasyuk Elena , Petrov Stanislav A. , Zyk Nikolai Y. , Machulkin Aleksei E. , Vorozhtsov Nikolai I. , Beloglazkina Elena K. , Nenajdenko Valentine G. , Tolmachev Vladimir , Orlova Anna , Majouga Alexander G. , Yusubov Mekhman S.
Published: July 2023

Prostate-specific membrane antigen (PSMA) has been identified as a target for the development of theranostic agents. In our current work, we describe the design and synthesis of novel N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-(S)-L-lysine (DCL) urea-based PSMA inhibitors with a chlorine-substituted aromatic fragment at the lysine ε-nitrogen atom, a dipeptide including two phenylalanine residues in the L-configuration as the peptide fragment of the linker, and 3- or 4-(tributylstannyl)benzoic acid as a prosthetic group in their structures for radiolabeling. The standard compounds [127I]PSMA-m-IB and [127I]PSMA-p-IB for comparative and characterization studies were first synthesized using two alternative synthetic approaches. An important advantage of the alternative synthetic approach, in which the prosthetic group (NHS-activated esters of compounds) is first conjugated with the polypeptide sequence followed by replacement of the Sn(Bu)3 group with radioiodine, is that the radionuclide is introduced in the final step of synthesis, thereby minimizing operating time with iodine-123 during the radiolabeling process. The obtained DCL urea-based PSMA inhibitors were radiolabeled with iodine-123. The radiolabeling optimization results showed that the radiochemical yield of [123I]PSMA-p-IB was higher than that of [123I]PSMA-m-IB, which were 74.9 ± 1.0% and 49.4 ± 1.2%, respectively. The radiochemical purity of [123I]PSMA-p-IB after purification was greater than 99.50%. The initial preclinical evaluation of [123I]PSMA-p-IB demonstrated a considerable affinity and specific binding to PC-3 PIP (PSMA-expressing cells) in vitro. The in vivo biodistribution of this new radioligand [123I]PSMA-p-IB showed less accumulation than [177Lu]Lu-PSMA-617 in several normal organs (liver, kidney, and bone). These results warrant further preclinical development, including toxicology evaluation and experiments in tumor-bearing mice.
Marginal Zone B (MZB) Cells: Comparison of the Initial Identification of Immune Activity Leading to Dacryoadenitis and Sialadenitis in Experimental Sjögren’s Syndrome
Authors: Peck Ammon B. , Ambrus Julian L.
Published: July 2023

Although multiple mouse strains have been advanced as models for Sjögren’s syndrome (SS), which is a human systemic autoimmune disease characterized primarily as the loss of lacrimal and salivary gland functions, the C57BL/6.NOD-Aec1Aec2 recombinant inbred (RI) mouse derived from the NOD/ShiLtJ line is considered one of the more appropriate models exhibiting virtually all the characteristics of the human disease. This mouse model, as well as other mouse models of SS, have shown that B lymphocytes are essential for the onset and development of observed clinical manifestations. Recently, studies carried out in the C57BL/6.IL14α transgenic mouse have provided clear evidence that the marginal zone B (MZB) cell population is directly involved in the early pathological events initiating the development of the clinical SS disease, as well as late-stage lymphomagenesis resulting in B-cell lymphomas. Since MZB cells are difficult to study in vivo and in vitro, we carried out a series of ex vivo investigations that utilize temporal global RNA transcriptomic analyses to profile differentially expressed genes exhibiting temporal upregulation during the initial onset and subsequent development of pathophysiological events within the lacrimal and salivary gland tissues per se or associated with the leukocyte cell migrations into these glands. The initial transcriptomic analyses revealed that while the upregulated gene expression profiles obtained from lacrimal and salivary glands overlap, multiple genetic differences exist between the defined activated pathways. In the current study, we present a concept suggesting that the initial pathological events differ between the two glands, yet the subsequent upregulated TLR4/TLR3 signal transduction pathway that activates the type-1 interferon signature appears to be identical in the two glands and indicates an autoimmune response against dsRNA, possibly a virus. Here, we attempt to put these findings into perspective and determine how they can impact the design of future therapeutic protocols.
Ga···C Triel Bonds—Why They Are Not Strong Enough to Change Trigonal Configuration into Tetrahedral One: DFT Calculations on Dimers That Occur in Crystal Structures
Authors: Grabowski Sławomir J.
Published: July 2023

Structures characterized by the trigonal coordination of the gallium center that interacts with electron rich carbon sites are described. These interactions may be classified as Ga···C triel bonds. Their properties are analyzed in this study since these interactions may be important in numerous chemical processes including catalytical activities; additionally, geometrical parameters of corresponding species are described. The Ga···C triel bonds discussed here, categorized also as the π-hole bonds, do not change the trigonal configuration of the gallium center into the tetrahedral one despite total interactions in dimers being strong; however, the main contribution to the stabilization of corresponding structures comes from the electrostatic forces. The systems analyzed theoretically here come from crystal structures since the Cambridge Structural Database, CSD, search was performed to find structures where the gallium center linked to CC bonds of Lewis base units occurs. The majority structures found in CSD are characterized by parallel, stacking-like arrangements of species containing the Ga-centers. The theoretical results show that interactions within dimers are not classified as the three-centers links as in a case of typical hydrogen bonds and numerous other interactions. The total interactions in dimers analyzed here consist of several local intermolecular atom–atom interactions; these are mainly the Ga···C links. The DFT results are supported in this study by calculations with the use of the quantum theory of atoms in molecules, QTAIM, the natural bond orbital, NBO, and the energy decomposition analysis, EDA, approaches.
Hepatocellular Carcinoma: Latest Research in Pathogenesis, Detection and Treatment
Authors: Foglia Beatrice , Turato Cristian , Cannito Stefania
Published: July 2023

The most common form of primary liver malignancy is hepatocellular carcinoma (HCC) [...]
Plasmalogen Improves Memory Function by Regulating Neurogenesis in a Mouse Model of Alzheimer’s Diseases
Authors: Li Rongzi , Xiong Wei , Li Boying , Li Yixuan , Fang Bing , Wang Xifan , Ren Fazheng
Published: July 2023

Adult hippocampal neurogenesis (AHN) is associated with hippocampus-dependent cognitive function, and its initiation is attributed to neural stem cells (NSCs). Dysregulated AHN has been identified in Alzheimer’s disease (AD) and may underlie impaired cognitive function in AD. Modulating the function of NSCs and stimulating AHN are potential ways to manipulate AD. Plasmalogen (PLA) are a class of cell membrane glycerophospholipids which exhibit neuroprotective properties. However, the effect of PLA on altered AHN in AD has not been investigated. In our study, PLA(10μg/mL) -attenuated Aβ (1-42) (5μM) induced a decrease in NSC viability and neuronal differentiation of NSCs, partially through regulating the Wnt/β-catenin pathway. Additionally, AD mice were supplemented with PLA (67mg/kg/day) for 6 weeks. PLA treatment improved the impaired AHN in AD mice, including increasing the number of neural stem cells (NSCs) and newly generated neurons. The memory function of AD mice was also enhanced after PLA administration. Therefore, it was summarized that PLA could regulate NSC differentiation by activating the Wnt/β-catenin pathway and ameliorate AD-related memory impairment through up-regulating AHN.
ZnO-Doped Metal-Organic Frameworks Nanoparticles: Antibacterial Activity and Mechanisms
Authors: Zheng Huiying , Zhong Biying , Wang Qiaowen , Li Xi , Chen Jiehan , Liu Li , Liu Tiantian
Published: July 2023

Metal-Organic Frameworks (MOFs) offer new ideas for the design of antibacterial materials because of their antibacterial properties, high porosity and specific surface area, low toxicity and good biocompatibility compared with other nanomaterials. Herein, a novel antimicrobial nanomaterial, MIL-101(Fe)@ZnO, has been synthesized by hydrothermal synthesis and characterized by FTIR, UV-vis, ICP-OES, XRD, SEM, EDS and BET to show that the zinc ions are doped into the crystal lattice of MIL-101(Fe) to form a Fe-Zn bimetallic structure. MIL-101(Fe)@ZnO was found to be effective against a wide range of antibacterial materials including Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, Acinetobacter junii and Staphylococcus epidermidis. It has a significant antibacterial effect, weak cytotoxicity, high safety performance and good biocompatibility. Meanwhile, MIL-101(Fe)@ZnO was able to achieve antibacterial effects by causing cells to produce ROS, disrupting the cell membrane structure, and causing protein leakage and lipid preoxidation mechanisms. In conclusion, MIL-101(Fe)@ZnO is an easy-to-prepare antimicrobial nanomaterial with broad-spectrum bactericidal activity and low toxicity.
G Protein-Coupled Receptor 40 Agonist LY2922470 Alleviates Ischemic-Stroke-Induced Acute Brain Injury and Functional Alterations in Mice
Authors: Lu Yingyu , Zhou Wanlu , Cui Qinghua , Cui Chunmei
Published: July 2023

Stroke is a major cause of fatalities and disabilities around the world, yet the available treatments for it are still limited. The quest for more efficacious drugs and therapies is still an arduous task. LY2922470 is currently used as a G protein-coupled receptor 40 (GPR40) agonist for the treatment of type 2 diabetes. Previous studies have reported protective effects of other GPR40 activators on the brain; however, it remains unclear whether LY2922470 could be a new stroke therapy and improve the stroke-induced brain damage. Here, we first reveal that the transcriptomic gene signature induced by LY2922470 is highly similar to those induced by some agents being involved in defending from cerebrovascular accidents and transient ischemic attacks, including acetylsalicylic acid, progesterone, estradiol, dipyridamole, and dihydroergotamine. This result thus suggests that LY2922470 could have protective effects against ischemic stroke. As a result, further experiments show that giving the small molecule LY2922470 via oral administration or intraperitoneal injection was seen to have a positive effect on neuroprotection with a reduction in infarct size and an improvement in motor skills in mice. Finally, it was demonstrated that LY2922470 could successfully mitigate the harm to the brain caused by ischemic stroke.