Competitive Inhibition of Okanin against Plasmodium falciparum Tyrosyl-tRNA Synthetase.

Malaria is a severe disease that presents a significant threat to human health. As resistance to current drugs continues to increase, there is an urgent need for new antimalarial medications. Aminoacyl-tRNA synthetases (aaRSs) represent promising targets for drug development. In this study, we identified Plasmodium falciparum tyrosyl-tRNA synthetase (PfTyrRS) as a potential target for antimalarial drug development through a comparative analysis of the amino acid sequences and three-dimensional structures of human and plasmodium TyrRS, with particular emphasis on differences in key amino acids at the aminoacylation site. A total of 2141 bioactive compounds were screened using a high-throughput thermal shift assay (TSA). Okanin, known as an inhibitor of LPS-induced TLR4 expression, exhibited potent inhibitory activity against PfTyrRS, while showing limited inhibition of human TyrRS. Furthermore, bio-layer interferometry (BLI) confirmed the high affinity of okanin for PfTyrRS. Molecular dynamics (MD) simulations highlighted the stable conformation of okanin within PfTyrRS and its sustained binding to the enzyme. A molecular docking analysis revealed that okanin binds to both the tyrosine and partial ATP binding sites of the enzyme, preventing substrate binding. In addition, the compound inhibited the production of Plasmodium falciparum in the blood stage and had little cytotoxicity. Thus, okanin is a promising lead compound for the treatment of malaria caused by P. falciparum.

Biointerfaces with ultrathin patterns for directional control of cell migration.

In the context of wound healing and tissue regeneration, precise control of cell migration direction is deemed crucial. To address this challenge, polydimethylsiloxane (PDMS) platforms with patterned 10 nm thick TiOx in arrowhead shape were designed and fabricated. Remarkably, without tall sidewall constraints, MC3T3-E1 cells seeded on these platforms were constrained to migrate along the tips of the arrowheads, as the cells were guided by the asymmetrical arrowhead tips which provided large contact areas. To the best of our knowledge, this is the first study demonstrating the use of thin TiOx arrowhead pattern in combination with a cell-repellent PDMS surface to provide guided cell migration unidirectionally without tall sidewall constraints. Additionally, high-resolution fluorescence imaging revealed that the asymmetrical distribution of focal adhesions, triggered by the patterned TiOx arrowheads with arm lengths of 10, 20, and 35 µm, promoted cell adhesion and protrusion along the arrowhead tip direction, resulting in unidirectional cell migration. These findings have important implications for the design of biointerfaces with ultrathin patterns to precisely control cell migration. Furthermore, microelectrodes were integrated with the patterned TiOx arrowheads to enable dynamic monitoring of cell migration using impedance measurement. This microfluidic device integrated with thin layer of guiding pattern and microelectrodes allows simultaneous control of directional cell migration and characterization of the cell movement of individual MC3T3-E1 cells, offering great potential for the development of biosensors for single-cell monitoring.

Single-cell transcriptomics reveal distinct immune-infiltrating phenotypes and macrophage-tumor interaction axes among different lineages of pituitary neuroendocrine tumors.

BACKGROUND: Pituitary neuroendocrine tumors (PitNETs) are common gland neoplasms demonstrating distinctive transcription factors. Although the role of immune cells in PitNETs has been widely recognized, the precise immunological environment and its control over tumor cells are poorly understood. METHODS: The heterogeneity, spatial distribution, and clinical significance of macrophages in PitNETs were analyzed using single-cell RNA sequencing (scRNA-seq), bulk RNA-seq, spatial transcriptomics, immunohistochemistry, and multiplexed quantitative immunofluorescence (QIF). Cell viability, cell apoptosis assays, and in vivo subcutaneous xenograft experiments have confirmed that INHBA-ACVR1B influences the process of tumor cell apoptosis. RESULTS: The present study evaluated scRNA-seq data from 23 PitNET samples categorized into 3 primary lineages. The objective was to explore the diversity of tumors and the composition of immune cells across these lineages. Analyzed data from scRNA-seq and 365 bulk RNA sequencing samples conducted in-house revealed the presence of three unique subtypes of tumor immune microenvironment (TIME) in PitNETs. These subtypes were characterized by varying levels of immune infiltration, ranging from low to intermediate to high. In addition, the NR5A1 lineage is primarily associated with the subtype characterized by limited infiltration of immune cells. Tumor-associated macrophages (TAMs) expressing CX3CR1+, C1Q+, and GPNMB+ showed enhanced contact with tumor cells expressing NR5A1 + , TBX19+, and POU1F1+, respectively. This emphasizes the distinct interaction axes between TAMs and tumor cells based on their lineage. Moreover, the connection between CX3CR1+ macrophages and tumor cells via INHBA-ACVR1B regulates tumor cell apoptosis. CONCLUSIONS: In summary, the different subtypes of TIME and the interaction between TAM and tumor cells offer valuable insights into the control of TIME that affects the development of PitNET. These findings can be utilized as prospective targets for therapeutic interventions.

Therapeutic potential of targeting Nrf2 by panobinostat in pituitary neuroendocrine tumors.

We aimed to identify the druggable cell-intrinsic vulnerabilities and target-based drug therapies for PitNETs using the high-throughput drug screening (HTS) and genomic sequencing methods. We examined 9 patient-derived PitNET primary cells in HTS. Based on the screening results, the potential target genes were analyzed with genomic sequencing from a total of 180 PitNETs. We identified and verified one of the most potentially effective drugs, which targeted the Histone deacetylases (HDACs) both in in vitro and in vivo PitNET models. Further RNA sequencing revealed underlying molecular mechanisms following treatment with the representative HDACs inhibitor, Panobinostat. The HTS generated a total of 20,736 single-agent dose responses which were enriched among multiple inhibitors for various oncogenic targets, including HDACs, PI3K, mTOR, and proteasome. Among these drugs, HDAC inhibitors (HDACIs) were, on average, the most potent drug class. Further studies using in vitro, in vivo, and isolated PitNET primary cell models validated HDACIs, especially Panobinostat, as a promising therapeutic agent. Transcriptional surveys revealed substantial alterations to the Nrf2 signaling following Panobinostat treatment. Moreover, Nrf2 is highly expressed in PitNETs. The combination of Panobinostat and Nrf2 inhibitor ML385 had a synergistic effect on PitNET suppression. The current study revealed a class of effective anti-PitNET drugs, HDACIs, based on the HTS and genomic sequencing. One of the representative compounds, Panobinostat, may be a potential drug for PitNET treatment via Nrf2-mediated redox modulation. Combination of Panobinostat and ML385 further enhance the effectiveness for PitNET treatment.

Broadband Photodetection of Centimeter-Scale T-Phase Gallium Telluride Grown by Molecular Beam Epitaxy.

Two-dimensional (2D) semiconductors have recently attracted considerable attention due to their promising applications in future integrated electronic and optoelectronic devices. Large-scale synthesis of high-quality 2D semiconductors is an increasingly essential requirement for practical applications, such as sensing, imaging, and communications. In this work, homogeneous 2D GaTe films on a centimeter scale are epitaxially grown on fluorphlogopite mica substrates by molecular beam epitaxy (MBE). The epitaxial GaTe thin films showed an atomically 2D layered lattice structure with a T phase, which has not been discovered in the GaTe geometric isomer. Furthermore, semiconducting behavior and high mobility above room temperature were found in T-GaTe epitaxial films, which are essential for application in semiconducting devices. The T-GaTe-based photodetectors demonstrated respectable photodetection performance with a responsivity of 13 mA/W and a fast response speed. By introducing monolayer graphene as the substrate, we successfully realized high-quality GaTe/graphene heterostructures. The performance has been significantly improved, such as the responsivity was enhanced more than 20 times. These results highlight a feasible scheme for exploring the crystal phase of 2D GaTe and realizing the controlled growth of GaTe films on large substrates, which could promote the development of broadband, high-performance, and large-scale photodetection applications.

Alternations of Blood Pressure Following Surgical or Drug Therapy for Prolactinomas.

Several subtypes of pituitary neuroendocrine tumors (PitNETs), such as acromegaly and Cushing's disease, can result in hypertension. However, whether prolactinoma is associated with this complication remains unknown. Moreover, the effect of treatment with surgery or drugs on blood pressure (BP) is unknown. Herein, a retrospective study reviewed 162 patients with prolactinoma who underwent transsphenoidal surgery between January 2005 and December 2022. BP measurements were performed 1 day before and 5 days after surgery. Accordingly, patients' medical characteristics were recorded. In addition, in situ rat and xenograft nude-mice prolactinoma models have been used to mimic prolactinoma. In vivo BP and serum prolactin (PRL) levels were measured after cabergoline (CAB) administration in both rats and mice. Our data suggest that surgery can effectively decrease BP in prolactinoma patients with or without hypertension. The BP-lowering effect was significantly associated with several variables, including age, sex, disease duration, tumor size, invasion, dopamine agonists (DAs)-resistance, recurrence, and preoperative PRL levels. Moreover, in situ and xenograft prolactinomas induced BP elevation, which was alleviated by CAB treatment without and with a statistical difference in rats and mice, respectively. Thus, surgery or CAB can decrease BP in prolactinoma, indicating that pre- and postoperative BP management becomes essential.

Fully endoscopic far-lateral supracerebellar infratentorial approach for trigeminal neuralgia: illustrative case reports.

BACKGROUND: Trigeminal neuralgia (TN) is a common cause of craniofacial pain. The retrosigmoid approach is usually used to treat TN, but no cases of endoscopic far-lateral supracerebellar infratentorial approach (EF-SCITA) were used to undergo operation for TN. CASE PRESENTATION: Two patients were presented with severe facial pain and preliminary diagnosis was TN. Preoperative magnetic resonance imaging revealed that a superior cerebellar artery (SCA) compressed the trigeminal nerve in case 1, and a tumor located in the petrous apex extending into the Meckel's cave compressed the trigeminal nerve in case 2. Operations were achieved through the EF-SCITA. The pain was totally relieved with no postsurgical complications in both cases. CONCLUSIONS: We present the first two case reports of EF-SCITA to relieve classical and secondary TN successfully. The EF-SCITA can be a promising approach for treating TN.

Upper tract urothelial carcinoma accompanied by hyperthermia: A case report.

Upper tract urothelial carcinoma (UTUC) is a relatively rare malignant neoplasm of the urinary system. Due to its highly aggressiveness, the tumor has already undergone invasive growth when most UTUC patients are diagnosed. In addition, the most common cause of fever in cancer patients is infection, and cancer patients with neoplastic fever are relatively rare. We reported a 58-year-old man with invasive high-grade UTUC accompanied by hyperthermia.

Mitochondrial Inhibitor Rotenone Triggers and Enhances Neuronal Ferroptosis Following Intracerebral Hemorrhage.

Ferroptosis, a form of regulatory non-apoptotic cell death driven by iron-dependent lipid peroxidation, accounts for more than 80% of the total types of neuronal death in the acute phase of intracerebral hemorrhage (ICH). Mitochondria have essential roles in energy production, macromolecule synthesis, cellular metabolism, and cell death regulation. However, its role in ferroptosis remains unclear and somewhat controversial, especially in ICH. This study aimed to investigate whether damaged mitochondria could trigger and enhance neuronal ferroptosis in ICH. The isobaric tag for relative and absolute quantitation proteomics on human ICH samples suggested that ICH caused significant damage to the mitochondria, which presented ferroptosis-like morphology under electron microscopy. Subsequently, use of the mitochondrial special inhibitor Rotenone (Rot) to induce mitochondrial damage showed that it has significant dose-dependent toxicity on primary neurons. Single Rot administration markedly inhibited neuronal viability, promoted iron accumulation, increased malondialdehyde (MDA) contents, decreased total superoxide dismutase (SOD) activity, and downregulated ferroptosis-related proteins RPL8, COX-2, xCT, ASCL4, and GPX4 in primary neurons. Moreover, Rot enhanced these changes via hemin and autologous blood administration in primary neurons and mice, mimicking the in vitro and in vivo ICH models, respectively. Furthermore, Rot exacerbated the ICH-induced hemorrhagic volumes, brain edema, and neurological deficits in mice. Together, our data revealed that ICH induced significant mitochondrial dysfunction and that mitochondrial inhibitor Rot can trigger and enhance neuronal ferroptosis.

Effects of nanopillars and surface coating on dynamic traction force.

The extracellular matrix serves as structural support for cells and provides biophysical and biochemical cues for cell migration. Topography, material, and surface energy can regulate cell migration behaviors. Here, the responses of MC3T3-E1 cells, including migration speed, morphology, and spreading on various platform surfaces, were investigated. Polydimethylsiloxane (PDMS) micropost sensing platforms with nanopillars, silicon oxide, and titanium oxide on top of the microposts were fabricated, and the dynamic cell traction force during migration was monitored. The relationships between various platform surfaces, migration behaviors, and cell traction forces were studied. Compared with the flat PDMS surface, cells on silicon oxide and titanium oxide surfaces showed reduced mobility and less elongation. On the other hand, cells on the nanopillar surface showed more elongation and a higher migration speed than cells on silicon oxide and titanium oxide surfaces. MC3T3-E1 cells on microposts with nanopillars exerted a larger traction force than those on flat PDMS microposts and had more filopodia and long protrusions. Understanding the relationships between platform surface condition, migration behavior, and cell traction force can potentially lead to better control of cell migration in biomaterials capable of promoting tissue repair and regeneration.

DRD2 expression based on 18F-fallypride PET/MR predicts the dopamine agonist resistance of prolactinomas: a pilot study.

PURPOSE: The dopamine agonists (DA) have been used widely to treat prolactinomas. However, it is difficult to predict whether the patient will be responsive to DA treatment. METHODS: We aimed to investigate whether the in vivo expression of DRD2 based on 18F-fallypride PET/MR could predict the therapeutic effect of DA on prolactinomas. Seven patients with prolactinomas completed 18F-fallypride PET/MR. Among them, three patients underwent surgery and further tumor immunohistochemistry. Imaging findings and immunohistochemical staining were compared with treatment outcomes. RESULTS: 18F-fallypride PET/MR was visually positive in 7 of 7 patients, and DRD2 target specificity could be confirmed by immunohistochemical staining. A significantly lower tracer standard uptake value (SUV) could be detected in the resistant patients (n = 3) than in the sensitive patients (n = 4; SUVmean, 4.67 ± 1.32 vs. 13.57 ± 2.42, p < 0.05). DRD2 expression determined by 18F-fallypride PET/MR corresponded with the DA treatment response. CONCLUSION: 18F-fallypride PET/MR may be a promising technique for predicting DA response in patients with prolactinoma.

Nonlinear SNR estimation based on the data augmentation-assisted DNN with a small-scale dataset.

Fiber nonlinearity is one of the major impairments for long-haul transmission systems. Therefore, estimating the nonlinear signal-to-noise ratio (SNRNL) is indispensable to guarantee the quality of transmission and manage the operation of optical networks. The deep neural network (DNN) has been successfully applied for the SNRNL estimation. However, the performance substantially degrades, when the mega dataset is inaccessible. Here, we demonstrate an accurate SNRNL estimation based on the data augmentation (DA)-assisted DNN with a small-scale dataset in the frequency domain. When the 95-GBaud dual-polarization 16 quadrature amplitude modulation (DP-16QAM) signal with variable optical launch powers from -2 to 4-dBm is numerically transmitted from 80-km to 1520-km standard single-mode fiber (SSMF), we identify that, in comparison with traditional DNN scheme, the DA allows the reduction of the training dataset size by about 60% while keeping the same mean absolute error (MAE) as 0.2-dB of SNRNL estimation. Meanwhile, the DA-assisted DNN scheme can reduce the MAE by about 0.14-dB compared with the traditional DNN scheme, when both SNRNL estimation schemes use 100 raw datasets which contain 700 symbols. Due to these observations, the DA-assisted DNN scheme is promising for field-trial nonlinear SNR estimation, especially when the collection of mega datasets is inconvenient.

Sellar Glomus Tumor Misdiagnosed as Pituitary Adenoma: A Case Report and Review of the Literature.

Glomus tumor is a rare mesenchymal tumor with an organ-like structure. Sellar glomus tumors are extremely rare with only six reported cases in the literature. Because of the lack of special clinical manifestations and imaging features, the disorder may be easily misdiagnosed as other sellar tumors, especially pituitary adenomas. Here, the present study showed a case of a 69-year-old male with hypopituitarism who was preliminarily misdiagnosed as non-functional pituitary adenoma.

Meta-learning-enabled accurate OSNR monitoring of directly detected QAM signals with one-shot training.

We experimentally demonstrate meta-learning-enabled accurate optical signal-to-noise ratio (OSNR) monitoring of directly detected 16QAM signals with extremely few training data. When one-shot training, where one amplitude histogram (AH) for each OSNR value includes only 2000 data samples, is implemented for a 16QAM signal within a variable OSNR range of 15-24 dB, the experimental root mean squared error (RMSE) of the retraining technique is 1.53 dB. For transfer learning from the 16QAM simulation to the experimentally generated AH, the RMSE can be reduced to 1.11 dB. In comparison with both the retraining and transfer learning techniques, the RMSE of meta-learning-enabled OSNR monitoring can be further reduced by 42.8% and 22.3%, respectively. In order to reach the optimal accuracy with an RMSE of 0.66 dB, the meta-learning technique requires only 15 AHs for each OSNR value to be monitored, while the retraining and the transfer learning techniques need 20 and 25 AHs, respectively.

TRIM65 determines the fate of a novel subtype of pituitary neuroendocrine tumors via ubiquitination and degradation of TPIT.

BACKGROUND: Pituitary neuroendocrine tumors (PitNETs) are common intracranial tumors that are classified into seven histological subtypes, including lactotroph, somatotroph, corticotroph, thyrotroph, gonadotroph, null cell, and plurihormonal PitNETs. However, the molecular characteristics of these types of PitNETs are not completely clear. METHODS: A total of 180 consecutive cases of PitNETs were collected to perform RNA sequencing. All subtypes of PitNETs were distinguished by unsupervised clustering analysis. We investigated the regulation of TPIT by TRIM65 and its effects on ACTH production and secretion in ACTH-secreting pituitary cell lines, as well as in murine models using biochemical analyses, confocal microscopy, and luciferase reporter assays. RESULTS: A novel subtype of PitNETs derived from TPIT lineage cells was identified as with normal TPIT transcription but with lowered protein expression. Furthermore, for the first time, TRIM65 was identified as the E3 ubiquitin ligase of TPIT. Depending on the RING domain, TRIM65 ubiquitinated and degraded the TPIT protein at multiple Lys sites. In addition, TRIM65-mediated ubiquitination of TPIT inhibited POMC transcription and ACTH production to determine the fate of the novel subtype of PitNETs in vitro and in vivo. CONCLUSION: Our studies provided a novel classification of PitNETs and revealed that the TRIM65-TPIT complex controlled the fate of the novel subtype of PitNETs, which provides a potential therapy target for Cushing's disease.

Combining ultrasound with bio-indicators reveals progression of carotid stenosis.

BACKGROUND: Carotid artery stenosis (CAS) is one of the leading causes of ischemic stroke. However, knowledge of the changes in the plaque itself is lacking. Information about the ultrasound and clinical features of CAS will help elucidate the changes in prognostic and risk factors. METHODS: We evaluated 736 patients with carotid stenosis for an average 18-month follow-up. According to their degree of CAS stenosis, patients were allocated to one of three groups: regression (n=125), stable (n=443), or progression (n=168). An ordinal regression analysis was used to determine the risk factors for atherosclerosis progression. A logistic regression was subsequently applied to investigate the effects of CAS stenosis on cerebrovascular events after adjusting for various factors. RESULTS: The progression group had more male patients (P=0.02), hypoechoic plaque (P<0.01), high-risk high sensitivity C-reactive protein (hs-CRP) (P=0.02), ulcerative plaque (P=0.05), and hyperlipidemia (P=0.05) than the other two groups. There were no significant differences in residual ultrasound and clinical features among the three groups, including age, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), intima-media thickness (IMT), body mass index (BMI), diabetes mellitus (DM), hypertension (HTN), coronary heart disease (CHD), statin use, ulcerative plaque. The ordinal regression analysis identified hypoechoic plaque (OR, 1.53; 95% CI: 1.14-2.05; P<0.01) and high-risk hs-CRP (OR, 1.75; 95% CI: 1.17-2.61; P<0.01) as independent risk factors for CAS progression. Logistic regression analysis revealed that the stroke/transient ischemic attack adjusted odds ratio was 1.80 (95% CI: 1.03-3.13) in the progression group. CONCLUSIONS: High-risk hs-CRP and hypoechoic plaque are independently associated with CAS progression. The progression of carotid stenosis is associated with a high risk of cerebrovascular events.

The Family Check-Up Online: A Telehealth Model for Delivery of Parenting Skills to High-Risk Families With Opioid Use Histories.

Growing opioid misuse in the United States has resulted in more children living with an adult with an opioid use history. Although an abundance of research has demonstrated a link between opioid misuse and negative parenting behaviors, few intervention efforts have been made to target this underserved population. The Family Check-Up (FCU) has been tested in more than 25 years of research, across multiple settings, and is an evidence-based program for reducing risk behavior, enhancing parenting skills, and preventing the onset of substance use. It is designed to motivate parents to engage in positive parenting practices and to change problematic parenting and has been tested across a variety of ages including early childhood and adolescence. It is highlighted in NIDA's Principles of Substance Use Prevention for Early Childhood: A research-based guide as one of only three effective selective prevention programs for substance abuse among families with young children. Recently, we developed an online version of the FCU that has now been adapted for early childhood and families with opioid use histories. The online platform and telehealth model allow for wide-scale dissemination, ease of training with community providers, and increased public health reach for families in remote, rural areas. This is particularly important when targeting families with opioid misuse and addiction because there are high rates of addiction in remote areas, yet few services available. In this article, we describe the FCU Online and review new content in the model that targets a population of young adult parents with substance abuse histories, including opioid use. New modules include content focused on harm reduction for this high-risk population of parents, such as safety in the home, substance use while parenting, and managing conflict with partners and friends.

Reduced Oligodendrocyte Precursor Cell Impairs Astrocytic Development in Early Life Stress.

Astrocyte maldevelopment is implicated in various neuropsychiatric diseases associated with early life stress. However, the underlying astrocytopathy mechanism, which can result in the psychiatric symptoms, remains unclear. In this study, it is shown that a reduced oligodendrocyte precursor cell (OPC) population accompanies hindered hippocampal astrocytic development in an improved parental isolation mouse model, and that the loss of OPCs suppresses astrocytic network formation and activity. It is further demonstrated that OPC-derived Wnt ligands, in particular Wnt7b, are required for Wnt/ß-catenin pathway-mediated astrocytic development and subsequent effects related to neuronal function. In addition, focal replenishment of Wnt7a/b is sufficient to rescue astrocytic maldevelopment. These results elucidate a Wnt-paracrine-dependent but myelin-independent role of OPCs in regulating astrocytic development, which provides a unique insight into the astrocytopathy mechanism in early life stress, and can be implicated in the pathogenesis of human early life stress-related neuropsychiatric disorders.