Miracle-dz/UniFAR-FTUs huggingface dataset:
Heterogeneity of tumor lymphangiogenesis: Progress and prospects

Lymphangiogenesis and increased expression of lymphangiogenic growth factors are associated with high rates of lymph node (LN) metastasis and with poor prognosis in some, but not all, solid tumors. In addition to its involvement in metastasis, lymphangiogenesis has been shown to have other roles in tumor pathogenesis, such as the niche function of tumor stem cells and regulatory functions of antitumor immune responses. In contrast, evidence has accumulated that tumor‐induced lymphangiogenesis displays the heterogeneity in gene signature, structure, cellular origins and functional plasticity. This review summarizes the advances in the research on the heterogeneity of tumor lymphangiogenesis and discusses how it may contribute to functional complexity and multiplicity of lymphangiogenesis in tumor progression.
Commit, hide and escape: the story of Plasmodium gametocytes

Abstract Malaria is the major cause of mortality and morbidity in tropical countries. The causative agent, Plasmodium sp. , has a complex life cycle and is armed with various mechanisms which ensure its continuous transmission. Gametocytes represent the sexual stage of the parasite and are indispensable for the transmission of the parasite from the human host to the mosquito. Despite its vital role in the parasite's success, it is the least understood stage in the parasite's life cycle. The presence of gametocytes in asymptomatic populations and induction of gametocytogenesis by most antimalarial drugs warrants further investigation into its biology. With a renewed focus on malaria elimination and advent of modern technology available to biologists today, the field of gametocyte biology has developed swiftly, providing crucial insights into the molecular mechanisms driving sexual commitment. This review will summarise key current findings in the field of gametocyte biology and address the associated challenges faced in malaria detection, control and elimination.
Toward Intra-Operative Prostate Photoacoustic Imaging: Configuration Evaluation and Implementation Using the da Vinci Research Kit

We compare different possible scanning geometries for prostate photoacoustic tomography (PAT) while considering a realistic reconstruction scenario in which the limited view of the prostate and the directivity effect of the transducer are considered. Simulations and experiments confirm that an intra-operative configuration in which the photoacoustic signal is received by a pickup transducer from the anterior surface of the prostate provides the best approach. We propose a PAT acquisition system that includes a da Vinci system controlled by the da Vinci Research Kit, an illumination laser, and an ultrasound machine with parallel data acquisition. The robot maneuvers the pickup transducer to form a cylindrical detection surface around the prostate. The robot is programmed to acquire trajectories in which the transducer face is parallel to and oriented toward a rotational tomography axis, while the laser is fired and PAT data are collected at regular intervals. We present our initial images acquired with this novel system.
Organization of the Orexin/Hypocretin System in the Brain of Holostean Fishes: Assessment of Possible Relationships with Monoamines and Neuropeptide Y

Holosteans form a small group of actinopterygian fishes considered the sister group of teleosts. Despite this proximity to the biggest group of vertebrates, relatively few studies have been conducted to investigate the organization of the central nervous system of this group of fishes. In this study, the neuroanatomical distribution of orexin/hypocretin-like immunoreactive (OX-ir) cell bodies and fibers was analyzed in the brain of 3 representative species of the 2 orders of extant holosteans, the spotted gar Lepisosteus oculatus, the Florida gar Lepisosteus platyrhincus, and the bowfin Amia calva. Antibodies against orexin-A (OXA) and orexin-B (OXB) were used, which labeled the same cells and fibers throughout the brain. In addition, double immunohistofluorescence was performed for the simultaneous detection of OXA and OXB with tyrosine hydroxylase, serotonin, and neuropeptide Y (NPY), in an attempt to localize the orexinergic structures precisely and study the possible interactions between these neuroactive substances. The pattern of distribution of OX-ir cells in the 3 species was largely similar, showing labeled cells in the preoptic area (POA), and the tuberal and retrotuberal hypothalamic regions, with only subtle differences between species in the density of labeled cells. OX-ir fibers were found in all main brain subdivisions of the 3 species, mostly in the ventral subpallial areas, POA, hypothalamus, posterior tubercle, thalamus, and mesencephalic tectum. Different densities of orexinergic fibers were observed in relation to catecholaminergic and serotoninergic cell groups, as well as an absence of colocalization between orexins and NPY in the same hypothalamic neurons. The comparison of these results with those obtained in other vertebrates highlights a constant pattern of distribution of this system of neurotransmission among different groups of actinopterygian fishes, especially in teleosts. Conserved features shared by all vertebrates studied were also observed, such as the presence of OX-ir cells in the basal hypothalamus, reflecting the preserved functions of these neuropeptides over the course of evolution.
Assessment of nasal and oral flow of amniotic fluid in 46 non-anomalous fetuses with sonographic and echocardiographic examination.

OBJECTIVES The aim of the paper was to assess nasal and oral amniotic fluid flows, with the use of color ultrasound and spectral Doppler, in normal fetuses. MATERIAL AND METHODS Forty-six fetuses of singleton gestations were studied prospectively. Spectrum imaging and maximal nasal fluid flow velocities were described. Episodes of regurgitation (external flow from the mouth), swallowing (internal flow at the level of oropharynx and then entrance to the esophagus) were evaluated in two groups: Fetuses < 27 weeks of gestation and 27 weeks of gestation and older. Statistical analysis was done using Fischer exact test and t-test at p = 0.05. RESULTS Twenty-one fetuses were < 27 weeks of gestational age and presented mean maximal both inspiratory and expiratory nasal fluid flow velocities significantly lower than twenty-five fetuses who were ≥ 27 weeks of gestational age (p = 0.035 and p = 0.031 respectively, t-test). Episodes of regurgitation were observed more frequently in group of "younger" fetuses (p = 0.006, Fischer exact test). There was no statistically significant relationship between irregular nasal flow spectrum by color Doppler and gestational age group (p = 0.264, Fischer exact test). CONCLUSIONS Episodes of regurgitation occurred in normal fetuses < 27th week of gestation. Fast amniotic nasal fluid flows without episodes of regurgitation were observed more frequently in fetuses ≥ 27 weeks and it could be interpreted as an additional sonographic feature of prenatal maturation.
Cerebral Amyloid Angiopathy and Cerebral Amyloid Angiopathy-Related Inflammation: Comparison of Hemorrhagic and DWI MRI Features.

BACKGROUND Cerebral amyloid angiopathy (CAA) can be associated with primary vasculitis of small/medium-sized leptomeningeal and cortical arteries, called CAA-related inflammation (CAA-ri). OBJECTIVE To compare hemorrhagic and diffusion-weighted imaging (DWI) MRI features in CAA and CAA-ri. METHODS We prospectively scored in a consecutive CAA and CAA-ri cohort: presence/number of chronic intracerebral hemorrhage (ICH), cerebral microbleeds (CMB), and cortical superficial siderosis (CSS) on initial T2*-weighted imaging, and DWI lesions on both initial and follow-up imaging. In a subgroup, ApoE, CSF, and 18F-florbetaben-positron emission tomography (FBB-PET) were also analyzed. RESULTS In CAA-ri, CMB presence was more frequent (100% versus 40%, p < 0.001) and CMB numbers higher (mean 137 versus 8, p < 0.001). No difference was observed for chronic ICH or CSS. DWI lesions were more frequent in acute compared to chronic CAA-ri (p = 0.025), whereas no such difference was observed between acute and chronic CAA (p = 0.18). Both ApoE4 (genotyping available in 22 CAA-ri and 48 CAA patients) carriers and homozygosity were more frequent in CAA-ri (48% versus 19% [p = 0.014] and 32% versus 2% [p < 0.001] respectively). CSF biomarker analyses (performed in 20 CAA-ri and 45 CAA patients) showed lower Aβ42 levels in CAA-ri compared to CAA (median 312 versus 422 pg/mL, p = 0.0032). FBB-PET (performed in 11 CAA-ri and 20 CAA patients) showed higher standardized uptake value ratios in CAA-ri compared with CAA, only significant when the pons was used as reference (p = 0.037). CONCLUSION Compared to CAA, CAA-ri was associated with higher CMB numbers, more frequent ApoE4 carriers and homozygotes, lower CSF Aβ42 levels, and more severe amyloid load on FBB-PET.
Pharmacologic and immunologic management of cytomegalovirus infection after solid organ and hematopoietic stem cell transplantation

ABSTRACT Introduction: Cytomegalovirus (CMV) is a common opportunistic infection that causes significant morbidity and preventable mortality after solid-organ and allogeneic hematopoietic stem cell transplantation. Areas covered: Current strategies of pharmacological treatment of CMV in solid-organ and hematologic stem cell transplantation are reviewed. The role of the newly approved drug, letermovir, and other novel investigational compounds is discussed. The complementary role of viral and immunologic monitoring in guiding the optimal role of pharmacologic agents on the management of CMV after transplantation is highlighted. Advances in immunotherapeutics are highlighted. Expert commentary: With advances in therapeutic and diagnostic modalities, the management of CMV infection and disease after transplantation continues to evolve. The authors provide a succinct yet comprehensive review of the current prevention and treatment for CMV infection and disease in transplant recipients. The role of the newly approved drug, letermovir, for CMV prevention is highlighted in the context of current prevention strategies after allogeneic hematopoietic stem cell transplantation. The emerging role of cell-mediated immunologic monitoring, which complements the established function of viral load testing, is emphasized. Finally, the integration of novel antiviral therapies, standardized molecular tests, immunologic assays, and immunotherapeutics are discussed.
Drug Repositioning for Schizophrenia and Depression/Anxiety Disorders: A Machine Learning Approach Leveraging Expression Data

Development of new medications is a lengthy and costly process, and drug repositioning might help to shorten the development cycle. We present a machine learning (ML) workflow to drug discovery or repositioning by predicting indication for a particular disease based on drug expression profiles, with a focus on applications in psychiatry. Drugs that are not originally indicated for the disease but with high predicted probabilities serve as candidates for repurposing. This approach is widely applicable to any chemicals or drugs with expression profiles measured, even if drug targets are unknown. It is also highly flexible as virtually any supervised learning algorithms can be used. We employed the ML approach to identify repositioning opportunities for schizophrenia as well as depression and anxiety disorders. We applied various state-of-the-art ML approaches, including deep neural networks (DNNs), support vector machines (SVMs), elastic net regression, random forest, and gradient boosted trees. The predictive performance of the five approaches in cross validation did not differ substantially, with SVM slightly outperforming the others. However, other methods also reveal literature-supported repositioning candidates of different mechanisms of actions. As a further validation, we showed that the repositioning hits are enriched for psychiatric medications considered in clinical trials. We also examined the correlation between predicted probabilities of treatment potential and the number of related research articles, and found significant correlations for all methods, especially DNN. Finally, we propose that ML may provide a new avenue to exploring drug mechanisms via examining the variable importance of gene features.
The ribosomal stalk protein is crucial for the action of the conserved ATPase ABCE1

Abstract The ATP-binding cassette (ABC) protein ABCE1 is an essential factor in ribosome recycling during translation. However, the detailed mechanochemistry of its recruitment to the ribosome, ATPase activation and subunit dissociation remain to be elucidated. Here, we show that the ribosomal stalk protein, which is known to participate in the actions of translational GTPase factors, plays an important role in these events. Biochemical and crystal structural data indicate that the conserved hydrophobic amino acid residues at the C-terminus of the archaeal stalk protein aP1 binds to the nucleotide-binding domain 1 (NBD1) of aABCE1, and that this binding is crucial for ATPase activation of aABCE1 on the ribosome. The functional role of the stalk•ABCE1 interaction in ATPase activation and the subunit dissociation is also investigated using mutagenesis in a yeast system. The data demonstrate that the ribosomal stalk protein likely participates in efficient actions of both archaeal and eukaryotic ABCE1 in ribosome recycling. The results also show that the stalk protein has a role in the function of ATPase as well as GTPase factors in translation.
Increasing methamphetamine doses inhibit glycogen synthase kinase 3β activity by stimulating the insulin signaling pathway in substantia nigra

Methamphetamine (MA), a highly abused psychostimulant, exerts neurotoxic effects on the dopaminergic system via several neurotoxicity mechanisms in the long‐term administration. Since the effect of MA on the signaling insulin pathway is less studied, the current study was designed to evaluate the effect of escalating an MA regimen on different insulin signaling elements in substantia nigra (SN) and striatum of a rat. Increasing MA doses (1‐14 mg/kg) were administrated intraperitoneally twice a day for 14 days in rats. In the control group, normal saline was injected in the same volume. On days 1, 14, 28, and 60 after MA discontinuation, molecular assessments were performed. Insulin receptor (IR) and insulin receptor substrate (IRS) 1 and 2 gene expression were evaluated using real‐time polymerase chain reaction, and protein levels of phosphatidylinositol‐4,5‐bisphosphate 3‐kinase (PI3K), phospho‐PI3K, Akt, phospho‐Akt, glycogen synthase kinase 3β (GSK3β), and phospho‐GSK3β were measured by the Western blot analysis in SN and striatum. Messenger RNA levels of IR and insulin receptor substrate 2 were increased in SN, 1 day after the last injection. Although no changes were observed in PI3K, phospho‐PI3K, Akt, phospho‐Akt, and GSK3β levels, increase in the level of inactive form of GSK3β (phosphorylated on serine 9) was indicated in SN on day 28. In striatum, decreases in IR and phospho‐Akt were demonstrated, without any change in other elements. Repeated escalating regimen of MA activated the insulin signaling pathway and inhibited GSK3β activity in SN. This response, which did not occur in striatum, may act as an adaptive mechanism to prevent MA‐induced neurotoxicity in dopaminergic cell bodies.
ATR-mediated proteome remodeling is a major determinant of homologous recombination capacity in cancer cells

Abstract The ATR kinase is crucial for genome maintenance, but the mechanisms by which ATR controls the DNA repair machinery are not fully understood. Here, we find that long-term chronic inhibition of ATR signaling severely impairs the ability of cells to utilize homologous recombination (HR)-mediated DNA repair. Proteomic analysis shows that chronic ATR inhibition depletes the abundance of key HR factors, suggesting that spontaneous ATR signaling enhances the capacity of cells to use HR-mediated repair by controlling the abundance of the HR machinery. Notably, ATR controls the abundance of HR factors largely via CHK1-dependent transcription, and can also promote stabilization of specific HR proteins. Cancer cells exhibit a strong dependency on ATR signaling for maintaining elevated levels of HR factors, and we propose that increased constitutive ATR signaling caused by augmented replication stress in cancer cells drives the enhanced HR capacity observed in certain tumor types. Overall, these findings define a major pro-HR function for ATR and have important implications for therapy by providing rationale for sensitizing HR-proficient cancer cells to PARP inhibitors.
AuTom-dualx: a toolkit for fully automatic fiducial marker-based alignment of dual-axis tilt series with simultaneous reconstruction

Motivation: Dual‐axis electron tomography is an important 3 D macro‐molecular structure reconstruction technology, which can reduce artifacts and suppress the effect of missing wedge. However, the fully automatic data process for dual‐axis electron tomography still remains a challenge due to three difficulties: (i) how to track the mass of fiducial markers automatically; (ii) how to integrate the information from the two different tilt series; and (iii) how to cope with the inconsistency between the two different tilt series. Results: Here we develop a toolkit for fully automatic alignment of dual‐axis electron tomography, with a simultaneous reconstruction procedure. The proposed toolkit and its workflow carries out the following solutions: (i) fully automatic detection and tracking of fiducial markers under large‐field datasets; (ii) automatic combination of two different tilt series and global calibration of projection parameters; and (iii) inconsistency correction based on distortion correction parameters and the consequently simultaneous reconstruction. With all of these features, the presented toolkit can achieve accurate alignment and reconstruction simultaneously and conveniently under a single global coordinate system. Availability and implementation: The toolkit AuTom‐dualx (alignment module dualxmauto and reconstruction module volrec_mltm) are accessible for general application at http://ear.ict. ac.cn, and the key source code is freely available under request. Supplementary information: Supplementary data are available at Bioinformatics online.
Evolutionary insights into Trm112-methyltransferase holoenzymes involved in translation between archaea and eukaryotes

Abstract Protein synthesis is a complex and highly coordinated process requiring many different protein factors as well as various types of nucleic acids. All translation machinery components require multiple maturation events to be functional. These include post-transcriptional and post-translational modification steps and methylations are the most frequent among these events. In eukaryotes, Trm112, a small protein (COG2835) conserved in all three domains of life, interacts and activates four methyltransferases (Bud23, Trm9, Trm11 and Mtq2) that target different components of the translation machinery (rRNA, tRNAs, release factors). To clarify the function of Trm112 in archaea, we have characterized functionally and structurally its interaction network using Haloferax volcanii as model system. This led us to unravel that methyltransferases are also privileged Trm112 partners in archaea and that this Trm112 network is much more complex than anticipated from eukaryotic studies. Interestingly, among the identified enzymes, some are functionally orthologous to eukaryotic Trm112 partners, emphasizing again the similarity between eukaryotic and archaeal translation machineries. Other partners display some similarities with bacterial methyltransferases, suggesting that Trm112 is a general partner for methyltransferases in all living organisms.
The imperative of integrating empirical and theoretical considerations when developing policy responses to Internet-gaming disorder

This commentary proposes an integrative approach of theoretical and empirical considerations when developing policy responses to Internet-gaming disorder and when evaluating their efficacy. It complements the overview by Király et al. (2018) about preventive and treatment programs by referring to a lack of inclusion of internal factors, such as individual aspects and cognitions, and missing empirical evidence. This commentary claims the integration of current research addressing individual predisposing and maintaining factors in order to evaluate existing programs and to enhance the exchange between actors including policy. This integrative approach has the potential to develop successful preventive strategies, which could be implemented realistically and socially responsible.
CpG Island Methylation in Sessile Serrated Adenomas Increases With Age, Indicating Lower Risk of Malignancy in Young Patients.

Among sessile serrated adenomas (SSAs) with identical histologic features, some never progress, whereas others become dysplastic and develop into invasive cancers. Development of the CpG island methylator phenotype is a feature of SSA progression; we examined the CIMP status of 448 SSAs and examined the association with patient clinical data. Overall, 190 SSAs were CpG island methylator phenotype-positive. CpG island methylator phenotype positivity was associated with older patient age (P < .001) and proximal polyp site (P < .001), but not with patient sex (P = .94) or polyp size (P = .34). These results might be used to improve SSA surveillance guidelines.
Embryonic estrogen exposure recapitulates persistent ovarian transcriptional programs in a model of environmental endocrine disruption†

Abstract Estrogens regulate key aspects of sexual determination and differentiation, and exposure to exogenous estrogens can alter ovarian development. Alligators inhabiting Lake Apopka, FL, are historically exposed to estrogenic endocrine disrupting contaminants and are characterized by a suite of reproductive abnormalities, including altered ovarian gene expression and abated transcriptional responses to follicle stimulating hormone. Here, we test the hypothesis that disrupting estrogen signaling during gonadal differentiation results in persistent alterations to ovarian gene expression that mirror alterations observed in alligators from Lake Apopka. Alligator embryos collected from a reference site lacking environmental contamination were exposed to estradiol-17 beta or a nonaromatizable androgen in ovo and raised to the juvenile stage. Changes in basal and gonadotropin-challenged ovarian gene expression were then compared to Apopka juveniles raised under identical conditions. Assessing basal transcription in untreated reference and Apopka animals revealed a consistent pattern of differential expression of key ovarian genes. For each gene where basal expression differed across sites, in ovo estradiol treatment in reference individuals recapitulated patterns observed in Apopka alligators. Among those genes affected by site and estradiol treatment were three aryl hydrocarbon receptor (AHR) isoforms, suggesting that developmental estrogen signaling might program sensitivity to AHR ligands later in life. Treatment with gonadotropins stimulated strong ovarian transcriptional responses; however, the magnitude of responses was not strongly affected by steroid hormone treatment. Collectively, these findings demonstrate that precocious estrogen signaling in the developing ovary likely underlies altered transcriptional profiles observed in a natural population exposed to endocrine disrupting contaminants. Summary Sentence Precocious estrogen signaling in the developing alligator embryo induces persistent shifts in ovarian transcriptional profiles that recapitulate effects observed in animals naturally exposed to environmental endocrine disruptors.