bluuebunny/crossref_metadata_2025 huggingface dataset:
Fluorometric Detection of SARS-CoV-2 Single-Nucleotide Variant L452R Using Ligation-Based Isothermal Gene Amplification
Authors: Kyung Kangwuk , Ku Jamin , Cho Eunbin , Ryu Junhyung , Woo Jin , Jung Woong , Kim Dong-Eun
Published: September 2023

Since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant was first discovered, several variants showing different infectivity and immune responses have emerged globally. As the conventional method, whole-genome sequencing following polymerase chain reaction (PCR) is currently used for diagnosis of SARS-CoV-2 mutations. However, these conventional PCR-based direct DNA sequencing methods are time-consuming, complicated, and require expensive DNA sequencing modules. Here, we developed a fluorometric method for the accurate detection of a single missense mutation of U to G in the spike (S) gene that changes leucine to arginine (L452R) in SARS-CoV-2 genomic RNA. Our method for the detection of single-nucleotide mutations (SNM) in the viral RNA genome includes RNA sequence-dependent DNA ligation and tandem isothermal gene amplification methods, such as strand displacement amplification (SDA) and rolling circle amplification (RCA) generating G-quadruplex (GQ). In the presence of SNM in the viral RNA, ligation of both ends of the probe DNAs occurs between 5′-phosphorylated hairpin DNA and linear probe DNA that can discriminate a single base mismatch. The ligated DNAs were then extended to generate long-stem hairpin DNAs that are subjected to the first isothermal gene amplification (SDA). SDA produces multitudes of short ssDNA from the long-stem hairpin DNAs, which then serve as primers by annealing to circular padlock DNA for the second isothermal gene amplification (RCA). RCA produces a long stretch of ssDNA containing GQ structures. Thioflavin T (ThT) is then intercalated into GQ and emits green fluorescence, which allows the fluorometric identification of SARS-CoV-2 variants. This fluorometric analysis sensitively distinguished SNM in the L452R variant of SARS-CoV-2 RNA as low as 10 pM within 2 h. Hence, this fluorometric detection method using ligation-assisted tandem isothermal gene amplification can be applied for the diagnosis of SARS-CoV-2 SNM variants with high accuracy and sensitivity, without the need for cumbersome whole-genome DNA sequencing.
SECP-Net: SE-Connection Pyramid Network for Segmentation of Organs at Risk with Nasopharyngeal Carcinoma
Authors: Huang Zexi , Yang Xin , Huang Sijuan , Guo Lihua
Published: September 2023

Nasopharyngeal carcinoma (NPC) is a kind of malignant tumor. The accurate and automatic segmentation of computed tomography (CT) images of organs at risk (OAR) is clinically significant. In recent years, deep learning models represented by U-Net have been widely applied in medical image segmentation tasks, which can help to reduce doctors’ workload. In the OAR segmentation of NPC, the sizes of the OAR are variable, and some of their volumes are small. Traditional deep neural networks underperform in segmentation due to the insufficient use of global and multi-size information. Therefore, a new SE-Connection Pyramid Network (SECP-Net) is proposed. For extracting global and multi-size information, the SECP-Net designs an SE-connection module and a pyramid structure for improving the segmentation performance, especially that of small organs. SECP-Net also uses an auto-context cascaded structure to further refine the segmentation results. Comparative experiments are conducted between SECP-Net and other recent methods on a private dataset with CT images of the head and neck and a public liver dataset. Five-fold cross-validation is used to evaluate the performance based on two metrics; i.e., Dice and Jaccard similarity. The experimental results show that SECP-Net can achieve SOTA performance in these two challenging tasks.
Application of Deep Learning for Prediction of Alzheimer’s Disease in PET/MR Imaging
Authors: Zhao Yan , Guo Qianrui , Zhang Yukun , Zheng Jia , Yang Yang , Du Xuemei , Feng Hongbo , Zhang Shuo
Published: September 2023

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects millions of people worldwide. Positron emission tomography/magnetic resonance (PET/MR) imaging is a promising technique that combines the advantages of PET and MR to provide both functional and structural information of the brain. Deep learning (DL) is a subfield of machine learning (ML) and artificial intelligence (AI) that focuses on developing algorithms and models inspired by the structure and function of the human brain’s neural networks. DL has been applied to various aspects of PET/MR imaging in AD, such as image segmentation, image reconstruction, diagnosis and prediction, and visualization of pathological features. In this review, we introduce the basic concepts and types of DL algorithms, such as feed forward neural networks, convolutional neural networks, recurrent neural networks, and autoencoders. We then summarize the current applications and challenges of DL in PET/MR imaging in AD, and discuss the future directions and opportunities for automated diagnosis, predictions of models, and personalized medicine. We conclude that DL has great potential to improve the quality and efficiency of PET/MR imaging in AD, and to provide new insights into the pathophysiology and treatment of this devastating disease.
Autophagy in Parkinson’s Disease
Authors: Nechushtai Lior , Frenkel Dan , Pinkas-Kramarski Ronit
Published: September 2023

Parkinson’s disease (PD) is a devastating disease associated with accumulation of α-synuclein (α-Syn) within dopaminergic neurons, leading to neuronal death. PD is characterized by both motor and non-motor clinical symptoms. Several studies indicate that autophagy, an important intracellular degradation pathway, may be involved in different neurodegenerative diseases including PD. The autophagic process mediates the degradation of protein aggregates, damaged and unneeded proteins, and organelles, allowing their clearance, and thereby maintaining cell homeostasis. Impaired autophagy may cause the accumulation of abnormal proteins. Incomplete or impaired autophagy may explain the neurotoxic accumulation of protein aggregates in several neurodegenerative diseases including PD. Indeed, studies have suggested the contribution of impaired autophagy to α-Syn accumulation, the death of dopaminergic neurons, and neuroinflammation. In this review, we summarize the recent literature on the involvement of autophagy in PD pathogenesis.
Retrovirus-Derived RTL/SIRH: Their Diverse Roles in the Current Eutherian Developmental System and Contribution to Eutherian Evolution
Authors: Kaneko-Ishino Tomoko , Ishino Fumitoshi
Published: September 2023

Eutherians have 11 retrotransposon Gag-like (RTL)/sushi-ichi retrotransposon homolog (SIRH) genes presumably derived from a certain retrovirus. Accumulating evidence indicates that the RTL/SIRH genes play a variety of roles in the current mammalian developmental system, such as in the placenta, brain, and innate immune system, in a eutherian-specific manner. It has been shown that the functional role of Paternally Expressed 10 (PEG10) in placental formation is unique to the therian mammals, as are the eutherian-specific roles of PEG10 and PEG11/RTL1 in maintaining the fetal capillary network and the endocrine regulation of RTL7/SIRH7 (aka Leucine Zipper Down-Regulated in Cancer 1 (LDOCK1)) in the placenta. In the brain, PEG11/RTL1 is expressed in the corticospinal tract and hippocampal commissure, mammalian-specific structures, and in the corpus callosum, a eutherian-specific structure. Unexpectedly, at least three RTL/SIRH genes, RTL5/SIRH8, RTL6/SIRH3, and RTL9/SIRH10, play important roles in combating a variety of pathogens, namely viruses, bacteria, and fungi, respectively, suggesting that the innate immunity system of the brain in eutherians has been enhanced by the emergence of these new components. In this review, we will summarize the function of 10 out of the 11 RTL/SIRH genes and discuss their roles in eutherian development and evolution.
The Role of Doxycycline and IL-17 in Regenerative Potential of Periodontal Ligament Stem Cells: Implications in Periodontitis
Authors: Okić Đorđević Ivana , Kukolj Tamara , Živanović Milena , Momčilović Sanja , Obradović Hristina , Petrović Anđelija , Mojsilović Slavko , Trivanović Drenka , Jauković Aleksandra
Published: September 2023

Periodontitis (PD) is a degenerative, bacteria-induced chronic disease of periodontium causing bone resorption and teeth loss. It includes a strong reaction of immune cells through the secretion of proinflammatory factors such as Interleukin-17 (IL-17). PD treatment may consider systemic oral antibiotics application, including doxycycline (Dox), exhibiting antibacterial and anti-inflammatory properties along with supportive activity in wound healing, thus affecting alveolar bone metabolism. In the present study, we aimed to determine whether Dox can affect the regenerative potential of periodontal ligament mesenchymal stem cells (PDLSCs) modulated by IL-17 in terms of cell migration, osteogenic potential, bioenergetics and expression of extracellular matrix metalloproteinase 2 (MMP-2). Our findings indicate that Dox reduces the stimulatory effect of IL-17 on migration and MMP-2 expression in PDLSCs. Furthermore, Dox stimulates osteogenic differentiation of PDLSCs, annulling the inhibitory effect of IL-17 on PDLSCs osteogenesis. In addition, analyses of mitochondrial respiration reveal that Dox decreases oxygen consumption rate in PDLSCs exposed to IL-17, suggesting that changes in metabolic performance can be involved in Dox-mediated effects on PDLSCs. The pro-regenerative properties of Dox in inflammatory microenvironment candidates Dox in terms of regenerative therapy of PD-affected periodontium are observed.
Chemical Composition, In Vitro Antitumor Effect, and Toxicity in Zebrafish of the Essential Oil from Conyza bonariensis (L.) Cronquist (Asteraceae)
Authors: Ferreira Rafael Carlos , do Nascimento Yuri Mangueira , de Araújo Loureiro Paulo Bruno , Martins Rafael Xavier , de Souza Maia Maria Eduarda , Farias Davi Felipe , Tavares Josean Fechine , Gonçalves Juan Carlos Ramos , da Silva Marcelo Sobral , Sobral Marianna Vieira
Published: September 2023

The essential oil from Conyza bonariensis (Asteraceae) aerial parts (CBEO) was extracted by hydrodistillation in a Clevenger-type apparatus and was characterized by gas chromatography–mass spectrometry. The antitumor potential was evaluated against human tumor cell lines (melanoma, cervical, colorectal, and leukemias), as well as non-tumor keratinocyte lines using the MTT assay. The effect of CBEO on the production of Reactive Oxygen Species (ROS) was evaluated by DCFH-DA assay, and a protection assay using the antioxidant N-acetyl-L-cysteine (NAC) was also performed. Moreover, the CBEO toxicity in the zebrafish model was assessed. The majority of the CBEO compound was (Z)-2-lachnophyllum ester (57.24%). The CBEO exhibited selectivity towards SK-MEL-28 melanoma cells (half maximal inhibitory concentration, IC50 = 18.65 ± 1.16 µg/mL), and induced a significant increase in ROS production. In addition, the CBEO’s cytotoxicity against SK-MEL-28 cells was reduced after pretreatment with NAC. Furthermore, after 96 h of exposure, 1.5 µg/mL CBEO induced death of all zebrafish embryos. Non-lethal effects were observed after exposure to 0.50–1.25 µg/mL CBEO. Additionally, significant alterations in the activity of enzymes associated with oxidative stress in zebrafish larvae were observed. These results provide evidence that CBEO has a significant in vitro antimelanoma effect by increasing ROS production and moderate embryotoxicity in zebrafish.
Unraveling the Mechanism of Epichaperome Modulation by Zelavespib: Biochemical Insights on Target Occupancy and Extended Residence Time at the Site of Action
Authors: Sharma Sahil , Joshi Suhasini , Kalidindi Teja , Digwal Chander S. , Panchal Palak , Lee Sang-Gyu , Zanzonico Pat , Pillarsetty Nagavarakishore , Chiosis Gabriela
Published: September 2023

Drugs with a long residence time at their target sites are often more efficacious in disease treatment. The mechanism, however, behind prolonged retention at the site of action is often difficult to understand for non-covalent agents. In this context, we focus on epichaperome agents, such as zelavespib and icapamespib, which maintain target binding for days despite rapid plasma clearance, minimal retention in non-diseased tissues, and rapid metabolism. They have shown significant therapeutic value in cancer and neurodegenerative diseases by disassembling epichaperomes, which are assemblies of tightly bound chaperones and other factors that serve as scaffolding platforms to pathologically rewire protein–protein interactions. To investigate their impact on epichaperomes in vivo, we conducted pharmacokinetic and target occupancy measurements for zelavespib and monitored epichaperome assemblies biochemically in a mouse model. Our findings provide evidence of the intricate mechanism through which zelavespib modulates epichaperomes in vivo. Initially, zelavespib becomes trapped when epichaperomes bound, a mechanism that results in epichaperome disassembly, with no change in the expression level of epichaperome constituents. We propose that the initial trapping stage of epichaperomes is a main contributing factor to the extended on-target residence time observed for this agent in clinical settings. Zelavespib’s residence time in tumors seems to be dictated by target disassembly kinetics rather than by frank drug–target unbinding kinetics. The off-rate of zelavespib from epichaperomes is, therefore, much slower than anticipated from the recorded tumor pharmacokinetic profile or as determined in vitro using diluted systems. This research sheds light on the underlying processes that make epichaperome agents effective in the treatment of certain diseases.
Catecholamine Variations in Pediatric Gastrointestinal Disorders and Their Neuropsychiatric Expression
Authors: Matiș Loredana , Alexandru Bogdana Ariana , Ghitea Timea Claudia
Published: September 2023

The interplay between the central nervous system and the intestinal environment hinges on neural, hormonal, immune, and metabolic reactions. Over decades, significant effort has gone into exploring the link between the digestive system and the brain. The primary objective of this study is to assess catecholamine levels in children with neuropsychiatric disorders. We aim to examine how these levels impact the mental and physical wellbeing of these children, with a specific focus on psychoemotional symptoms and cognitive performance. Our research seeks to identify the significance of modifying neurotransmitter levels in pediatric medical interventions, ultimately striving to reduce mental health risks and enhance children’s future development. A total of 135 individuals were chosen to partake, and they engaged in regular monthly consultations according to established study protocols. Clinical evaluations were conducted in a medical environment, encompassing the observation of constipation, diarrhea, and additional gastrointestinal anomalies not confined to constipation or diarrhea. This entailed the assessment of neurotransmitter imbalances, with a specific focus on dopamine, adrenaline, noradrenaline, and the noradrenaline/adrenaline ratio. Gastrointestinal disorders are indicative of imbalances in catecholamines, with lower gastrointestinal problems being correlated with such imbalances. In subjects with psychiatric disorders, a more pronounced dopamine and noradrenaline/adrenaline ratio was observed, while elevated adrenaline levels were associated with psychoanxiety disorders.
Assessing Stroke-Related Sarcopenia in Chronic Stroke: Identification of Clinical Assessment Tools—A Pilot Study
Authors: Arnal-Gómez Anna , Cortés-Amador Sara , Ruescas-Nicolau Maria-Arantzazu , Carrasco Juan J. , Pérez-Alenda Sofía , Santamaría-Balfagón Ana , Sánchez-Sánchez M. Luz
Published: September 2023

Stroke-related sarcopenia has recently been defined as the muscle atrophy consequent to stroke and assessing it following the guidelines with simple clinical tools is crucial in chronic stroke survivors. The aim of this study was to determine the characteristics of patient-friendly instruments sarcopenia in a chronic stroke sample (SG) compared to non-stroke counterparts (CG). Each participant underwent a single assessment which consisted of: SARC-F questionnaire, assessment of muscle strength (hand grip and five-times sit-to-stand test, 5STS), the calf circumference (CC) of both legs, the short physical performance battery (SPPB), and the 10 m walk test. A total of 68 participants were included (SG, n = 34 and CG, n = 34). All variables showed statistical differences (p < 0.05) between the SG and the CG, except handgrip although it showed lower values for SG. The values of the 5STS (16.26 s) and the SPPB (7 points) were below to the cutoff values for the SG. The five-times sit-to-stand test, SPPB, and gait speed can lead clinicians to detect stroke-related sarcopenia. Maximum handgrip shows a trend of low values for men and women in the SG, however, CC did not detect sarcopenia in our sample.
Comparing Parameters of Motor Potentials Recordings Evoked Transcranially with Neuroimaging Results in Patients with Incomplete Spinal Cord Injury: Assessment and Diagnostic Capabilities
Authors: Leszczyńska Katarzyna , Huber Juliusz
Published: September 2023

This study aimed to investigate the relationships between the different levels and degrees of incomplete spinal cord injury (iSCI) evaluated with magnetic resonance imaging (MRI) and the results of non-invasive electromyography (mcsEMG), motor-evoked potentials (MEP), and electroneurography (ENG). With a focus on patients with injuries at four different levels, C3–C5, C6–Th1, Th3–Th6, and Th7–L1, this research delved into the intricate interplay of spinal circuits and functional recovery. The study uses MEP, EMG, and ENG assessments to unveil the correlations between the MEP amplitudes and the MRI injury scores. We analysed data from 85 iSCI patients (American Spinal Injury Association—ASIA scale; ASIA C = 24, and D = 61). We compared the MRI and diagnostic neurophysiological test results performed within 1–2 months after the injury. A control group of 80 healthy volunteers was examined to establish reference values for the clinical and neurophysiological recordings. To assess the structural integrity of spinal white and grey matter on the transverse plane reconstructed from the sagittal readings, a scoring system ranging from 0 to 4 was established. The spinal cord was divided into two halves (left and right) according to the midline, and each half was further divided into two quadrants. Each quadrant was assessed separately. MEP and EMG were used to assess conduction in the corticospinal tract and the contraction properties of motor units in key muscles: abductor pollicis brevis (APB), rectus abdominis (RA), rectus femoris (RF), and extensor digitorum brevis muscles (EXT). We also used electroneurography (ENG) to assess peripheral nerve conduction and to find out whether the changes in this system significantly affect patients’ scores and their neurophysiological status. The study revealed consistent positive correlations in iSCI patients between the bilateral decrease of the spinal half injury MRI scores and a decrease of the transcranially-evoked MEP amplitudes, highlighting the complex relationship between neural pathways and functional outcomes. Positive correlations are notably pronounced in the C3–C5, C6–Th1, and Th3–Th6 subgroups (mostly rs 0.5 and above with p < 0.05), while Th7–L1 presents distinct patterns (rs less than 0.5 and p being statistically insignificant) potentially influenced by unique structural compensation mechanisms. We also revealed statistically significant relationships between the decrease of the cumulative mcsEMG and MEP amplitudes and the cumulative ENG scores. These insights shed light on the multifaceted interactions between spinal cord injury levels, structural damage, neurophysiological measures, and motor function outcomes. Further research is warranted to unravel the intricate mechanisms driving these correlations and their implications for enhancing functional recovery and the rehabilitation algorithms in patients with iSCI.
Vasopressin as Possible Treatment Option in Autism Spectrum Disorder
Authors: László Kristóf , Vörös Dávid , Correia Pedro , Fazekas Csilla Lea , Török Bibiána , Plangár Imola , Zelena Dóra
Published: September 2023

Autism spectrum disorder (ASD) is rather common, presenting with prevalent early problems in social communication and accompanied by repetitive behavior. As vasopressin was implicated not only in salt-water homeostasis and stress-axis regulation, but also in social behavior, its role in the development of ASD might be suggested. In this review, we summarized a wide range of problems associated with ASD to which vasopressin might contribute, from social skills to communication, motor function problems, autonomous nervous system alterations as well as sleep disturbances, and altered sensory information processing. Beside functional connections between vasopressin and ASD, we draw attention to the anatomical background, highlighting several brain areas, including the paraventricular nucleus of the hypothalamus, medial preoptic area, lateral septum, bed nucleus of stria terminalis, amygdala, hippocampus, olfactory bulb and even the cerebellum, either producing vasopressin or containing vasopressinergic receptors (presumably V1a). Sex differences in the vasopressinergic system might underline the male prevalence of ASD. Moreover, vasopressin might contribute to the effectiveness of available off-label therapies as well as serve as a possible target for intervention. In this sense, vasopressin, but paradoxically also V1a receptor antagonist, were found to be effective in some clinical trials. We concluded that although vasopressin might be an effective candidate for ASD treatment, we might assume that only a subgroup (e.g., with stress-axis disturbances), a certain sex (most probably males) and a certain brain area (targeting by means of virus vectors) would benefit from this therapy.
On the Use of Machine Learning Techniques and Non-Invasive Indicators for Classifying and Predicting Cardiac Disorders
Authors: Ospina Raydonal , Ferreira Adenice G. O. , de Oliveira Hélio M. , Leiva Víctor , Castro Cecilia
Published: September 2023

This research aims to enhance the classification and prediction of ischemic heart diseases using machine learning techniques, with a focus on resource efficiency and clinical applicability. Specifically, we introduce novel non-invasive indicators known as Campello de Souza features, which require only a tensiometer and a clock for data collection. These features were evaluated using a comprehensive dataset of heart disease cases from a machine learning data repository. Our findings highlight the ability of machine learning algorithms to not only streamline diagnostic procedures but also reduce diagnostic errors and the dependency on extensive clinical testing. Three key features—mean arterial pressure, pulsatile blood pressure index, and resistance-compliance indicator—were found to significantly improve the accuracy of machine learning algorithms in binary heart disease classification. Logistic regression achieved the highest average accuracy among the examined classifiers when utilizing these features. While such novel indicators contribute substantially to the classification process, they should be integrated into a broader diagnostic framework that includes comprehensive patient evaluations and medical expertise. Therefore, the present study offers valuable insights for leveraging data science techniques in the diagnosis and management of cardiovascular diseases.
Potential of Selected African Medicinal Plants as Alternative Therapeutics against Multi-Drug-Resistant Bacteria
Authors: Moiketsi Bertha N. , Makale Katlego P. P. , Rantong Gaolathe , Rahube Teddie O. , Makhzoum Abdullah
Published: September 2023

Antimicrobial resistance is considered a “One-Health” problem, impacting humans, animals, and the environment. The problem of the rapid development and spread of bacteria resistant to multiple antibiotics is a rising global health threat affecting both rich and poor nations. Low- and middle-income countries are at highest risk, in part due to the lack of innovative research on the surveillance and discovery of novel therapeutic options. Fast and effective drug discovery is crucial towards combatting antimicrobial resistance and reducing the burden of infectious diseases. African medicinal plants have been used for millennia in folk medicine to cure many diseases and ailments. Over 10% of the Southern African vegetation is applied in traditional medicine, with over 15 species being partially or fully commercialized. These include the genera Euclea, Ficus, Aloe, Lippia. And Artemisia, amongst many others. Bioactive compounds from indigenous medicinal plants, alone or in combination with existing antimicrobials, offer promising solutions towards overcoming multi-drug resistance. Secondary metabolites have different mechanisms and modes of action against bacteria, such as the inhibition and disruption of cell wall synthesis; inhibition of DNA replication and ATP synthesis; inhibition of quorum sensing; inhibition of AHL or oligopeptide signal generation, broadcasting, and reception; inhibition of the formation of biofilm; disruption of pathogenicity activities; and generation of reactive oxygen species. The aim of this review is to highlight some promising traditional medicinal plants found in Africa and provide insights into their secondary metabolites as alternative options in antibiotic therapy against multi-drug-resistant bacteria. Additionally, synergism between plant secondary metabolites and antibiotics has been discussed.
Inflammation-Involved Proteins in Blood Serum of Cataract Patients—A Preliminary Study
Authors: Sutkowy Paweł , Lesiewska Hanna , Woźniak Alina , Malukiewicz Grażyna
Published: September 2023

Approximately 50% of all global blindness is caused by cataract in adults aged ≥50 years. The mechanisms of the disease are most arguably related to a redox imbalance and inflammation; therefore, the aim of the study was to evaluate the processes associated with inflammation in cataract patients. Twenty-four patients aged 22–60 years (62.5% females) participated in the study, with 33 controls aged 28–60 years (66.7% females). Venous blood serum of the subjects was examined for alpha 1-antitrypsin, as well as selected lysosomal enzymes and adipokines. The activities of lysosomal enzymes, as well as the activity of alpha 1-antitrypsin and the concentrations of c-reactive protein and leptin, were similar in the patients versus the controls. The concentrations of interleukin 6 and resistin were lower, in turn, whereas omentin-1 and adiponectin were higher. Moreover, the study revealed the existence of many linear relationships between the parameters, including multiple linear regression, especially gender-wise. No systemic inflammation was probably noted in the cataract patients tested; nevertheless, the deregulation of adiponectin, omentin-1 and resistin secretion was observed.
A History and Atlas of the Human CD4+ T Helper Cell
Authors: Crater Jacqueline M. , Dunn Daniel C. , Nixon Douglas F. , Furler O’Brien Robert L.
Published: September 2023

CD4+ T cells have orchestrated and regulated immunity since the introduction of jawed vertebrates, yet our understanding of CD4+ T cell evolution, development, and cellular physiology has only begun to be unearthed in the past few decades. Discoveries of genetic diseases that ablate this cellular population have provided insight into their critical functions while transcriptomics, proteomics, and high-resolution microscopy have recently revealed new insights into CD4+ T cell anatomy and physiology. This article compiles historical, microscopic, and multi-omics data that can be used as a reference atlas and index to dissect cellular physiology within these influential cells and further understand pathologies like HIV infection that inflict human CD4+ T cells.
Molecular Processes Involved in the Shared Pathways between Cardiovascular Diseases and Diabetes
Authors: Tokarek Julita , Budny Emilian , Saar Maciej , Stańczak Kamila , Wojtanowska Ewa , Młynarska Ewelina , Rysz Jacek , Franczyk Beata
Published: September 2023

Cardiovascular diseases and diabetes mellitus are currently among the diseases with the highest morbidity and mortality. The pathogenesis and development of these diseases remain strongly connected, along with inflammation playing a major role. Therefore, the treatment possibilities showing a positive impact on both of these diseases could be especially beneficial for patients. SGLT-2 inhibitors and GLP-1 receptor agonists present this dual effect. Moreover, the hostile composition of the gut microbiota could influence the progression of these conditions. In this review, the authors present the latest knowledge on and innovations in diabetes mellitus and CVD—with the focus on the molecular mechanisms and the role of the microbiota.
Effects of Prolonged Serum Calcium Suppression during Extracorporeal Cardiopulmonary Resuscitation in Pigs
Authors: Pooth Jan-Steffen , Liu Yechi , Petzold Ralf , Scherer Christian , Benning Leo , Kreibich Maximilian , Czerny Martin , Beyersdorf Friedhelm , Benk Christoph , Trummer Georg , Brixius Sam Joé
Published: September 2023

Controlled reperfusion by monitoring the blood pressure, blood flow, and specific blood parameters during extracorporeal reperfusion after cardiac arrest has the potential to limit ischemia–reperfusion injury. The intracellular calcium overload as part of the ischemia–reperfusion injury provides the possibility for the injury to be counteracted by the early suppression of serum calcium with the aim of improving survival and the neurological outcome. We investigated the effects of prolonged serum calcium suppression via sodium citrate during extracorporeal resuscitation using the CARL protocol (CARL—controlled automated reperfusion of the whole body) compared to a single-dose approach in a porcine model after prolonged cardiac arrest. A control group (N = 10) was resuscitated after a 20 min cardiac arrest, initially lowering the intravascular calcium with the help of a single dose of sodium citrate as part of the priming solution. Animals in the intervention group (N = 13) received additional sodium citrate for the first 15 min of reperfusion. In the control group, 9/10 (90.0%) animals survived until day 7 and 7/13 (53.8%) survived in the intervention group (p = 0.09). A favorable neurological outcome on day 7 after the cardiac arrest was observed in all the surviving animals using a species-specific neurological deficit score. The coronary perfusion pressure was significantly lower with a tendency towards more cardiac arrhythmias in the intervention group. In conclusion, a prolonged reduction in serum calcium levels over the first 15 min of reperfusion after prolonged cardiac arrest tended to be unfavorable regarding survival and hemodynamic variables compared to a single-dose approach in this animal model.
Emerging Insights into Molecular Mechanisms of Inflammation in Myelodysplastic Syndromes
Authors: Vallelonga Veronica , Gandolfi Francesco , Ficara Francesca , Della Porta Matteo Giovanni , Ghisletti Serena
Published: September 2023

Inflammation impacts human hematopoiesis across physiologic and pathologic conditions, as signals derived from the bone marrow microenvironment, such as pro-inflammatory cytokines and chemokines, have been shown to alter hematopoietic stem cell (HSCs) homeostasis. Dysregulated inflammation can skew HSC fate-related decisions, leading to aberrant hematopoiesis and potentially contributing to the pathogenesis of hematological disorders such as myelodysplastic syndromes (MDS). Recently, emerging studies have used single-cell sequencing and muti-omic approaches to investigate HSC cellular heterogeneity and gene expression in normal hematopoiesis as well as in myeloid malignancies. This review summarizes recent reports mechanistically dissecting the role of inflammatory signaling and innate immune response activation due to MDS progression. Furthermore, we highlight the growing importance of using multi-omic techniques, such as single-cell profiling and deconvolution methods, to unravel MDSs’ heterogeneity. These approaches have provided valuable insights into the patterns of clonal evolution that drive MDS progression and have elucidated the impact of inflammation on the composition of the bone marrow immune microenvironment in MDS.
Stain-Free Sperm Analysis and Selection for Intracytoplasmic Sperm Injection Complying with WHO Strict Normal Criteria
Authors: Michailov Yulia , Nemerovsky Luba , Ghetler Yehudith , Finkelstein Maya , Schonberger Oshrat , Wiser Amir , Raziel Arie , Saar-Ryss Bozhena , Ben-Ami Ido , Kaplanski Olga , Miller Netanella , Haikin Herzberger Einat , Mashiach Friedler Yardena , Levitas-Djerbi Tali , Amsalem Eden , Umanski Natalia , Tamadaev Valeria , Ovadia Yaniv S. , Peretz Aharon , Sacks Gilat , Dekel Nava , Zaken Odelya , Levi Mattan
Published: September 2023

This multi-center study evaluated a novel microscope system capable of quantitative phase microscopy (QPM) for label-free sperm-cell selection for intracytoplasmic sperm injection (ICSI). Seventy-three patients were enrolled in four in vitro fertilization (IVF) units, where senior embryologists were asked to select 11 apparently normal and 11 overtly abnormal sperm cells, in accordance with current clinical practice, using a micromanipulator and 60× bright field microscopy. Following sperm selection and imaging via QPM, the individual sperm cell was chemically stained per World Health Organization (WHO) 2021 protocols and imaged via bright field microscopy for subsequent manual measurements by embryologists who were blinded to the QPM measurements. A comparison of the two modalities resulted in mean differences of 0.18 µm (CI −0.442–0.808 µm, 95%, STD—0.32 µm) for head length, −0.26 µm (CI −0.86–0.33 µm, 95%, STD—0.29 µm) for head width, 0.17 (CI −0.12–0.478, 95%, STD—0.15) for length–width ratio and 5.7 for acrosome–head area ratio (CI −12.81–24.33, 95%, STD—9.6). The repeatability of the measurements was significantly higher in the QPM modality. Surprisingly, only 19% of the subjectively pre-selected normal cells were found to be normal according to the WHO2021 criteria. The measurements of cells imaged stain-free through QPM were found to be in good agreement with the measurements performed on the reference method of stained cells imaged through bright field microscopy. QPM is non-toxic and non-invasive and can improve the clinical effectiveness of ICSI by choosing sperm cells that meet the strict criteria of the WHO2021.
MicroRNA Profile, Putative Diagnostic Biomarkers and RNA-Based Therapies in the Inherited Lipid Storage Disease Niemann-Pick Type C
Authors: Encarnação Marisa , David Hugo , Coutinho Maria Francisca , Moreira Luciana , Alves Sandra
Published: September 2023

Lipids are essential for cellular function and are tightly controlled at the transcriptional and post-transcriptional levels. Dysregulation of these pathways is associated with vascular diseases, diabetes, cancer, and several inherited metabolic disorders. MicroRNAs (miRNAs), in particular, are a family of post-transcriptional gene repressors associated with the regulation of many genes that encode proteins involved in multiple lipid metabolism pathways, thereby influencing their homeostasis. Thus, this class of non-coding RNAs (ncRNAs) has emerged as a promising therapeutic target for the treatment of lipid-related metabolic alterations. Most of these miRNAs act at an intracellular level, but in the past few years, a role for miRNAs as intercellular signaling molecules has also been uncovered since they can be transported in bodily fluids and used as potential biomarkers of lipid metabolic alterations. In this review, we point out the current knowledge on the miRNA signature in a lysosomal storage disorder associated with lipid dysfunction, Niemann-Pick type C, and discuss the potential use of miRNAs as biomarkers and therapeutic targets for RNA-based therapies.
The Impact of Clinical and Histopathological Factors on Disease Progression and Survival in Thick Cutaneous Melanomas
Authors: Țăpoi Dana Antonia , Derewicz Diana , Gheorghișan-Gălățeanu Ancuța-Augustina , Dumitru Adrian Vasile , Ciongariu Ana Maria , Costache Mariana
Published: September 2023

Thick cutaneous melanomas (Breslow depth > 4 mm) are locally advanced tumors, generally associated with poor prognosis. Nevertheless, these tumors sometimes display unpredictable behavior. This study aims to analyze clinical and histopathological features that can influence the prognosis of thick melanomas. This is a retrospective study on 94 thick primary cutaneous melanomas diagnosed between 2012 and 2018 that were followed-up for at least five years to assess disease progression and survival. We evaluated the age, gender, tumor location, histological subtype, Breslow depth, Clark level, resection margins, mitotic index, the presence/absence of ulceration, necrosis, regression, microsatellites, neurotropism, lymphovascular invasion, and the pattern of tumor-infiltrating lymphocytes, and their association with disease progression and survival. By conducting univariate analysis, we found that progression-free survival (PFS) was significantly associated with female gender, the superficial spreading melanoma (SSM) subtype, mitotic index, necrosis, microsatellites, and perineural invasion. Overall survival (OS) was significantly associated with female gender, Breslow depth, SSM subtype, necrosis, microsatellites, and perineural invasion. Through multivariate Cox proportional hazards regression, we found that the only factors associated with PFS were Breslow depth, necrosis, microsatellites, and perineural invasion, while the factors associated with OS were Breslow depth, necrosis, microsatellites, and perineural invasion. Certain histopathological features such as Breslow depth, necrosis, microsatellites, and perineural invasion could explain differences in disease evolution. This is one of the first studies to demonstrate an association between necrosis and perineural invasion and outcomes in patients with thick melanomas. By identifying high-risk patients, personalized therapy can be provided for improved prognosis.
Integrative Approaches in Acute Ischemic Stroke: From Symptom Recognition to Future Innovations
Authors: Saceleanu Vicentiu Mircea , Toader Corneliu , Ples Horia , Covache-Busuioc Razvan-Adrian , Costin Horia Petre , Bratu Bogdan-Gabriel , Dumitrascu David-Ioan , Bordeianu Andrei , Corlatescu Antonio Daniel , Ciurea Alexandru Vlad
Published: September 2023

Among the high prevalence of cerebrovascular diseases nowadays, acute ischemic stroke stands out, representing a significant worldwide health issue with important socio-economic implications. Prompt diagnosis and intervention are important milestones for the management of this multifaceted pathology, making understanding the various stroke-onset symptoms crucial. A key role in acute ischemic stroke management is emphasizing the essential role of a multi-disciplinary team, therefore, increasing the efficiency of recognition and treatment. Neuroimaging and neuroradiology have evolved dramatically over the years, with multiple approaches that provide a higher understanding of the morphological aspects as well as timely recognition of cerebral artery occlusions for effective therapy planning. Regarding the treatment matter, the pharmacological approach, particularly fibrinolytic therapy, has its merits and challenges. Endovascular thrombectomy, a game-changer in stroke management, has witnessed significant advances, with technologies like stent retrievers and aspiration catheters playing pivotal roles. For select patients, combining pharmacological and endovascular strategies offers evidence-backed benefits. The aim of our comprehensive study on acute ischemic stroke is to efficiently compare the current therapies, recognize novel possibilities from the literature, and describe the state of the art in the interdisciplinary approach to acute ischemic stroke. As we aspire for holistic patient management, the emphasis is not just on medical intervention but also on physical therapy, mental health, and community engagement. The future holds promising innovations, with artificial intelligence poised to reshape stroke diagnostics and treatments. Bridging the gap between groundbreaking research and clinical practice remains a challenge, urging continuous collaboration and research.
Shorter Anogenital Distance in Women with Ovarian Endometriomas and Adenomyosis, but Not Uterine Leiomyomas
Authors: Liu Xishi , Ding Ding , Shen Minhong , Yan Dingmin , Guo Sun-Wei
Published: September 2023

We investigated whether anogenital distance (AGD) is associated with adenomyosis, endometriosis and uterine leiomyomas (UL, also called uterine fibroids). We recruited 81 women with UL, 105 with ovarian endometrioma (OE), 116 with adenomyosis, 28 with both adenomyosis and UL, and 100 control subjects with other acquired gynecological conditions but not endometriosis, adenomyosis, UL, or polycystic ovarian syndrome. Measurements from the anterior clitoral surface to the center of the anus (AGDAC), from the tip of the clitoris to the center of the anus (AGDACt), and from the posterior fourchette to the center of the anus (AGDAF) were made in all subjects. Multiple regression was performed to estimate the association between AGDs and presence of OE, adenomyosis, and UL while controlling for possible confounding factors. We found that, compared with controls, women with OE and adenomyosis, but not UL, had significantly shorter AGDAF, but not AGDAC. However, the amount of variance that could be explained by the disease status is rather moderate, suggesting that factors other than disease status, bodyweight and height were also responsible for AGD. Thus, prenatal exposure to reduced levels of androgen may increase the risk of developing endometriosis and adenomyosis. However, other factors may also contribute to the pathogenesis of endometriosis and adenomyosis.
Benzoindolizidine Alkaloids Tylophorine and Lycorine and Their Analogues with Antiviral, Anti-Inflammatory, and Anticancer Properties: Promises and Challenges
Authors: Di Sotto Antonella , Valipour Mehdi , Azari Aala , Di Giacomo Silvia , Irannejad Hamid
Published: September 2023

Ongoing viral research, essential for public health due to evolving viruses, gains significance owing to emerging viral infections such as the SARS-CoV-2 pandemic. Marine and plant alkaloids show promise as novel potential pharmacological strategies. In this narrative review, we elucidated the potential of tylophorine and lycorine, two naturally occurring plant-derived alkaloids with a shared benzoindolizidine scaffold, as antiviral agents to be potentially harnessed against respiratory viral infections. Possible structure-activity relationships have also been highlighted. The substances and their derivatives were found to be endowed with powerful and broad-spectrum antiviral properties; moreover, they were able to counteract inflammation, which often underpins the complications of viral diseases. At last, their anticancer properties hold promise not only for advancing cancer research but also for mitigating the oncogenic effects of viruses. This evidence suggests that tylophorine and lycorine could effectively counteract the pathogenesis of respiratory viral disease and its harmful effects. Although common issues about the pharmacologic development of natural substances remain to be addressed, the collected evidence highlights a possible interest in tylophorine and lycorine as antiviral and/or adjuvant strategies and encourages future more in-depth pre-clinical and clinical investigations to overcome their drawbacks and harness their power for therapeutic purposes.
COVID-19 in Infants and Children under 2 Years—Could Lung Ultrasound Score Be Correlated with Biomarkers and Symptoms?
Authors: Stoicescu Emil Robert , Lovrenski Jovan , Iacob Roxana , Cerbu Simona , Iacob Daniela , Iacob Emil Radu , Susa Septimiu Radu , Ciuca Ioana Mihaiela , Bolintineanu (Ghenciu) Laura Andreea , Ciornei-Hoffman Andreea , Oancea Cristian , Manolescu Diana Luminita
Published: September 2023

Introduction: It is already well known that infants and children infected with COVID-19 develop mild to moderate forms of the disease, with fever and oropharyngeal congestion being the most common symptoms. However, there are instances when patients claim to be experiencing respiratory symptoms. Because of the repeated lung examinations required in these situations, non-irradiating imaging techniques are preferred. This study’s objective is to ascertain the value of lung ultrasonography (LUS) in the medical management of these specific cases. Methods: Infants and children under two years old with SARS-CoV-2 infection were evaluated using LUS. Patients with other respiratory pathologies were excluded by using specific tests. The LUS score (LUSS) was correlated with biomarkers and clinical findings using the Mann–Whitney U test and Spearman’s rank correlation rho. Results: The LUSS for each patient varied from 1 to 8 points out of a maximum of 36 points. The arithmetic mean was 4.47 ± 2.36 (S.D), while the 95% CI for the arithmetic mean was 3.33 to 5.61. Sparse B-lines were present in all enrolled infants and children (100%), while only 36.84% developed alveolar syndrome (confluent B-lines). The lung changes were correlated with their biomarkers, specifically inflammatory markers. The correlation between LUSS and LDH, D-dimers, and IL-6 was a strongly positive one with rho = 0.55 (p = 0.001, 95% CI 0.13 to 0.80) between the LUSS and D-dimer levels and rho = 0.60 (p = 0.03, 95% CI 0.04 to 0.87) between LUSS and D-dimer levels at symptomatic infants and children (with respiratory involvement). Conclusions: Infants and children under the age of two are prone to develop mild forms of COVID-19 disease with a B-line pattern on LUS, although inflammatory markers have elevated blood levels. Despite the small sample, D-dimer levels and O2 saturation were correlated with LUSS in patients with respiratory involvement, while similar results were also found in the entire lot.
Small Molecule Targeting Immune Cells: A Novel Approach for Cancer Treatment
Authors: Singh Shilpi , Barik Debashis , Arukha Ananta Prasad , Prasad Sujata , Mohapatra Iteeshree , Singh Amar , Singh Gatikrushna
Published: September 2023

Conventional and cancer immunotherapies encompass diverse strategies to address various cancer types and stages. However, combining these approaches often encounters limitations such as non-specific targeting, resistance development, and high toxicity, leading to suboptimal outcomes in many cancers. The tumor microenvironment (TME) is orchestrated by intricate interactions between immune and non-immune cells dictating tumor progression. An innovative avenue in cancer therapy involves leveraging small molecules to influence a spectrum of resistant cell populations within the TME. Recent discoveries have unveiled a phenotypically diverse cohort of innate-like T (ILT) cells and tumor hybrid cells (HCs) exhibiting novel characteristics, including augmented proliferation, migration, resistance to exhaustion, evasion of immunosurveillance, reduced apoptosis, drug resistance, and heightened metastasis frequency. Leveraging small-molecule immunomodulators to target these immune players presents an exciting frontier in developing novel tumor immunotherapies. Moreover, combining small molecule modulators with immunotherapy can synergistically enhance the inhibitory impact on tumor progression by empowering the immune system to meticulously fine-tune responses within the TME, bolstering its capacity to recognize and eliminate cancer cells. This review outlines strategies involving small molecules that modify immune cells within the TME, potentially revolutionizing therapeutic interventions and enhancing the anti-tumor response.