Functional gonadotroph pituitary adenoma: A case report.

Most clinically non-functioning pituitary tumour arise from gonadotroph cells. However, clinically functional pituitary gonadotroph adenoma is rare. Here we report a female case who presented with menstrual disturbances, however further workup demonstrated a pituitary microadenoma with elevated FSH and oestradiol level. Transsphenoidal resection was performed and the surgical histopathology confirmed pituitary gonadotroph adenoma. Postoperatively, improvement in both symptoms and hormonal profile were observed. Interestingly, the initially enlarged and polycystic ovaries became within normal range around eight months after the surgery. We suggest functional gonadotroph adenoma should be considered in the presence of gynaecological disorder with persistently elevated oestradiol and FSH levels.

RIPK1 inhibitors: A key to unlocking the potential of necroptosis in drug development.

Within the field of medical science, there is a great deal of interest in investigating cell death pathways in the hopes of discovering new drugs. Over the past two decades, pharmacological research has focused on necroptosis, a cell death process that has just been discovered. Receptor-interacting protein kinase 1 (RIPK1), an essential regulator in the cell death receptor signalling pathway, has been shown to be involved in the regulation of important events, including necrosis, inflammation, and apoptosis. Therefore, researching necroptosis inhibitors offers novel ways to treat a variety of disorders that are not well-treated by the therapeutic medications now on the market. The research and medicinal potential of RIPK1 inhibitors, a promising class of drugs, are thoroughly examined in this study. The journey from the discovery of Necrostatin-1 (Nec-1) to the recent advancements in RIPK1 inhibitors is marked by significant progress, highlighting the integration of traditional medicinal chemistry approaches with modern technologies like high-throughput screening and DNA-encoded library technology. This review presents a thorough exploration of the development and therapeutic potential of RIPK1 inhibitors, a promising class of compounds. Simultaneously, this review highlights the complex roles of RIPK1 in various pathological conditions and discusses potential inhibitors discovered through diverse pathways, emphasizing their efficacy against multiple disease models, providing significant guidance for the expansion of knowledge about RIPK1 and its inhibitors to develop more selective, potent, and safe therapeutic agents.

Single cell multi-omics reveal intra-cell-line heterogeneity across human cancer cell lines.

Human cancer cell lines have long served as tools for cancer research and drug discovery, but the presence and the source of intra-cell-line heterogeneity remain elusive. Here, we perform single-cell RNA-sequencing and ATAC-sequencing on 42 and 39 human cell lines, respectively, to illustrate both transcriptomic and epigenetic heterogeneity within individual cell lines. Our data reveal that transcriptomic heterogeneity is frequently observed in cancer cell lines of different tissue origins, often driven by multiple common transcriptional programs. Copy number variation, as well as epigenetic variation and extrachromosomal DNA distribution all contribute to the detected intra-cell-line heterogeneity. Using hypoxia treatment as an example, we demonstrate that transcriptomic heterogeneity could be reshaped by environmental stress. Overall, our study performs single-cell multi-omics of commonly used human cancer cell lines and offers mechanistic insights into the intra-cell-line heterogeneity and its dynamics, which would serve as an important resource for future cancer cell line-based studies.

How Merkel cells transduce mechanical stimuli: A biophysical model of Merkel cells.

Merkel cells combine with Aß afferents, producing slowly adapting type 1(SA1) responses to mechanical stimuli. However, how Merkel cells transduce mechanical stimuli into neural signals to Aß afferents is still unclear. Here we develop a biophysical model of Merkel cells for mechanical transduction by incorporating main ingredients such as Ca2+ and K+ voltage-gated channels, Piezo2 channels, internal Ca2+ stores, neurotransmitters release, and cell deformation. We first validate our model with several experiments. Then we reveal that Ca2+ and K+ channels on the plasma membrane shape the depolarization of membrane potentials, further regulating the Ca2+ transients in the cells. We also show that Ca2+ channels on the plasma membrane mainly inspire the Ca2+ transients, while internal Ca2+ stores mainly maintain the Ca2+ transients. Moreover, we show that though Piezo2 channels are rapidly adapting mechanical-sensitive channels, they are sufficient to inspire sustained Ca2+ transients in Merkel cells, which further induce the release of neurotransmitters for tens of seconds. Thus our work provides a model that captures the membrane potentials and Ca2+ transients features of Merkel cells and partly explains how Merkel cells transduce the mechanical stimuli by Piezo2 channels.

Discovery and Optimization of the First ATP Competitive Type-III c-MET Inhibitor.

Recent clinical reports have highlighted the need for wild-type (WT) and mutant dual inhibitors of c-MET kinase for the treatment of cancer. We report herein a novel chemical series of ATP competitive type-III inhibitors of WT and D1228V mutant c-MET. Using a combination of structure-based drug design and computational analyses, ligand 2 was optimized to a highly selective chemical series with nanomolar activities in biochemical and cellular settings. Representatives of the series demonstrate excellent pharmacokinetic profiles in rat in vivo studies with promising free-brain exposures, paving the way for the design of brain permeable drugs for the treatment of c-MET driven cancers.

Novel Refreshable Braille Display Based on the Layered Electromagnetic Driving Mechanism of Braille Dots.

In the digital era, Braille displays enable visually impaired people to easily access information. Different from traditional piezoelectric Braille displays, a novel electromagnetic Braille display is realized in this study. The novel display has the advantages of a stable performance, a long service life and a low cost and is based on an innovative layered electromagnetic driving mechanism of Braille dots, which can achieve a dense arrangement of Braille dots and provide a sufficient support force for them. The T-shaped screw compression spring, which causes the Braille dots to fall back instantaneously, is optimized to achieve a high refresh frequency and to enable visually impaired people to read Braille quickly. The experimental results show that under an input voltage of 6 V, the Braille display can work stably and reliably and provide a good fingertip touch; the Braille dot support force is greater than 150 mN, the maximum refresh frequency can reach 50 Hz, and the operating temperature is lower than 32 °C. Therefore, this cost-effective Braille display is expected to benefit a vast number of low-income visually impaired people in developing countries and improve their learning, working and living conditions.

Bas-relief modeling from RGB monocular images with regional division characteristics.

Traditional Bas-relief modeling methods are often limited to inefficient and difficult to be altered after the product is formed. This paper presents a novel method for bas-relief modeling from RGB monocular images with regional division characteristics. The problem discussed in this paper involves edge detection, region division, height value recovery and three-dimensional reconstruction of image. In our framework, we can automatically obtain the pixel height of each area in the image and can adjust the concave-convex relationship of each image area to obtain a bas-relief modeling which can be printed directly in 3D. The edge detection algorithm used Gaussian difference pyramid to combine the luminance information and chrominance information of digital image; the regions of the RGB monocular image are divided by the improved connected-component labeling algorithm;and the 3D pixel point cloud of each region is calculated by the shape-from-shading algorithm. Different from previous work, our method can fully obtain the image height field data and completely restored the depth information,which makes it possible to use any RGB monocular image for bas-relief modeling. Experiments with groups of images show that our method can effectively generate bas-relief modeling.

Optical fibre taper-enabled waveguide photoactuators.

Photoactuators have attracted significant interest for soft robot and gripper applications, yet most of them rely on free-space illumination, which requires a line-of-site low-loss optical path. While waveguide photoactuators can overcome this limitation, their actuating performances are fundamentally restricted by the nature of standard optical fibres. Herein, we demonstrated miniature photoactuators by embedding optical fibre taper in a polydimethylsiloxane/Au nanorod-graphene oxide photothermal film. The special geometric features of the taper endow the designed photoactuator with microscale active layer thickness, high energy density and optical coupling efficiency. Hence, our photoactuator show large bending angles (>270°), fast response (1.8 s for 180° bending), and low energy consumption (<0.55 mW/°), significantly exceeding the performance of state-of-the-art waveguide photoactuators. As a proof-of-concept study, one-arm and two-arm photoactuator-based soft grippers are demonstrated for capturing/moving small objects, which is challenging for free-space light-driven photoactuators.

Effects of pre-pregnancy body mass index on pregnancy and perinatal outcomes in women based on a retrospective cohort.

To investigate the prevalence of underweight, overweight and obesity as defined by pre-pregnancy body mass index (BMI) and the relationship between pre-pregnancy BMI and pregnancy and perinatal outcomes in women based on a retrospective cohort. Women registered via the Free Pre-pregnancy Health Check (FPHC) program from 2017 to 2019 in Hunan Province, China, were included to the study cohort. The data regarding maternal characteristics, pregnancy outcomes, and infant characteristics were retrieved from the surveillance system of the FPHC program. Logistic regressions were performed to calculate odds ratios (ORs) and adjusted odds ratios (AORs) with 95% confidence intervals (95% CIs) to assess the associations between pre-pregnancy BMIs and the outcomes. Among a total of 398,368 women, 54,238 (13.62%) were underweight (BMI < 18.5 kg/m2), 51,251 (12.87%) were overweight (24.0 kg/m2 ≤ BMI < 28.0 kg/m2), and 10,399 (2.61%) were obese (BMI ≥ 28.0 kg/m2). Underweight occurred more commonly in the 20-24 years old (17.98%), Han Chinese (13.89), college-educated (16.09%), rural (13.74%), and teacher/public servant/office clerk (16.09%) groups. Obesity occurred more often in the older than 35-year-old (4.48%), minority (3.64%), primary school or below (4.98%), urban (3.06%), and housewife (3.14%) groups (P < 0.001). Compared with the normal BMI group, underweight was associated with increased risk of low birth weight (LBW) (AOR = 1.25) and small-for-gestational age (SGA) (AOR = 1.11), but protected against gestational hypertensive disorder (GHD) (AOR = 0.85), gestational diabetes mellitus (GDM) (AOR = 0.69), macrosomia (AOR = 0.67), post-term pregnancy (AOR = 0.76), and cesarean-section (AOR = 0.81). Overweight and obesity were associated with increased risk of GHD (AOR = 1.28, 2.47), GDM (AOR = 1.63, 3.02), preterm birth (AOR = 1.18, 1.47), macrosomia (AOR = 1.51, 2.11), large-for-gestational age (LGA) (AOR = 1.19, 1.35), post-term pregnancy (AOR = 1.39, 1.66), and cesarean- section (AOR = 1.60, 2.05). Pre-pregnancy underweight is relatively common in Hunan Province, China. Pre-pregnancy underweight to some extent is associated with better maternal outcomes, but it has certain adverse effects on neonatal outcomes. Pre-pregnancy overweight, especially obesity, has a substantial adverse effect on pregnancy and perinatal outcomes.

Discovery of AZD8154, a Dual PI3Kγδ Inhibitor for the Treatment of Asthma.

Starting from our previously described PI3Kγ inhibitors, we describe the exploration of structure-activity relationships that led to the discovery of highly potent dual PI3Kγδ inhibitors. We explored changes in two positions of the molecules, including macrocyclization, but ultimately identified a simpler series with the desired potency profile that had suitable physicochemical properties for inhalation. We were able to demonstrate efficacy in a rat ovalbumin challenge model of allergic asthma and in cells derived from asthmatic patients. The optimized compound, AZD8154, has a long duration of action in the lung and low systemic exposure coupled with high selectivity against off-targets.

A Survey on Tactile Displays For Visually Impaired People.

Traditional paper documents with Braille characters and tangible graphics have obvious defects to disseminate knowledge in the information age. Information accessibility is an urgent challenge for blind individuals. Although many types of tactile displays were created for different applications, we especially focus on the tactile display for visually impaired people, which can dynamically generate tangible graphics and Braille characters, to help the blind obtain information conveniently. In this article, we present the state-of-the-art of graphic tactile displays (GTDs) and refreshable Braille displays (RBDs), then discuss their common kernel technologies about actuators and latch structures. This article summarizes the performance of typical actuators of tactile displays and analyzes the working principles of some latch structures. This article systematically summarizes latch structures of GTDs and RBDs, for the first time. Several comments in this paper will be useful to develop high-performance tactile displays for visually impaired people.

Chromosomal abnormality: Prevalence, prenatal diagnosis and associated anomalies based on a provincial-wide birth defects monitoring system.

AIM: To investigate the epidemiology of chromosomal abnormalities (CA) in fetuses of all pregnancies based on a provincial-wide birth defects-monitoring system, which could provide scientific basis for making relatively policy and research. METHODS: Chromosomal abnormalities cases were collected from all hospitals in Hunan Province, China, between 2016 and 2019. The prevalence of CAs was calculated to examine associations among infant sex, maternal age and region. The rates of prenatal diagnosis and termination of pregnancy (TOP) involving CA or associated anomalies were calculated as rates or proportions. RESULTS: From 2016 to 2019, a total of 2 883 890 perinatal infants (28 weeks of gestation to postpartum 7 days) underwent prenatal screening and diagnostic tests, and 3181 fetuses were diagnosed as CA, with the prevalence of 11.03/10 000. The average prevalence of CAs was higher for male than female fetuses (11.33/10 000 vs 10.06/10 000) (OR = 1.13, 95% CI: 1.05-1.21), which was higher in urban areas than rural areas (23.03/10 000 vs 7.13/10 000) (OR = 3.23, 95% CI: 3.02-3.47), and the prevalence increased linearly with maternal age ( X trend 2 = 1821.844, P = 0.000). Among the fetuses with CAs, 3097 (97.36%) were diagnosed prenatally, and 3046 (98.35%) underwent TOP. The majority of CA were numerical abnormalities (90.18%). The main types of numerical autosomal abnormalities were trisomy 21 (6.69/10 000, 59.57%), trisomy 18 (1.13/10 000, 10.04%) and trisomy 13 (0.21/10 000, 1.88%). The main types of numerical gonosomal abnormalities were Klinefelter syndrome (0.68/10 000, 6.02%), Turner syndrome (0.49/10 000, 4.39%), Triple X syndrome (0.26/10 000, 2.29%) and 47,XYY syndrome (0.21/10 000, 1.91%). The three associated anomalies with the highest proportions were congenital heart defects (CHD) (41.06%), cleft palate or/and cleft lip (10.89%) and congenital talipes equinovarus (8.94%). CONCLUSION: The prevalence of CA was lower than that reported. Chromosome detection should be further promoted including test contest and coverage, especially for urban areas, older mothers and fetuses with CHD, cleft palate or/and cleft lip or congenital talipes equinovarus.

Hub gene identification and prognostic model construction for isocitrate dehydrogenase mutation in glioma.

Our study attempted to identify hub genes related to isocitrate dehydrogenase (IDH) mutation in glioma and develop a prognostic model for IDH-mutant glioma patients. In a first step, ten hub genes significantly associated with the IDH status were identified by weighted gene coexpression analysis (WGCNA). The functional enrichment analysis demonstrated that the most enriched terms of these hub genes were cadherin binding and glutathione metabolism. Three of these hub genes were significantly linked with the survival of glioma patients. 328 samples of IDH-mutant glioma were separated into two datasets: a training set (N = 228) and a test set (N = 100). Based on the training set, we identified two IDH-mutant subtypes with significantly different pathological features by using consensus clustering. A 31 gene-signature was identified by the least absolute shrinkage and selection operator (LASSO) algorithm and used for establishing a differential prognostic model for IDH-mutant patients. In addition, the test set was employed for validating the prognostic model, and the model was proven to be of high value in classifying prognostic information of samples. The functional annotation revealed that the genes related to the model were mainly enriched in nuclear division, DNA replication, and cell cycle. Collectively, this study provided novel insights into the molecular mechanism of IDH mutation in glioma, and constructed a prognostic model which can be effective for predicting prognosis of glioma patients with IDH-mutation, which might promote the development of IDH target agents in glioma therapies and contribute to accurate prognostication and management in IDH-mutant glioma patients.

Protease-activated receptor-2 ligands reveal orthosteric and allosteric mechanisms of receptor inhibition.

Protease-activated receptor-2 (PAR2) has been implicated in multiple pathophysiologies but drug discovery is challenging due to low small molecule tractability and a complex activation mechanism. Here we report the pharmacological profiling of a potent new agonist, suggested by molecular modelling to bind in the putative orthosteric site, and two novel PAR2 antagonists with distinctly different mechanisms of inhibition. We identify coupling between different PAR2 binding sites. One antagonist is a competitive inhibitor that binds to the orthosteric site, while a second antagonist is a negative allosteric modulator that binds at a remote site. The allosteric modulator shows probe dependence, more effectively inhibiting peptide than protease activation of PAR2 signalling. Importantly, both antagonists are active in vivo, inhibiting PAR2 agonist-induced acute paw inflammation in rats and preventing activation of mast cells and neutrophils. These results highlight two distinct mechanisms of inhibition that potentially could be targeted for future development of drugs that modulate PAR2.

[Short-term memory characteristics of vibro-tactile perception in human fingertips].

This paper discusses the short-term memory of vibro-tactile perception of human fingertips. By using a self-developed vibro-tactile expression device, a recall experiment was firstly carried out among 20 subjects aged 20-30 (10 males and 10 females) to discover the memory span about the vibro-tactile perception of human fingertips. Within this memory span, a cognitive experiment analyzing the recognition accuracy and the reaction time was carried out. The results showed: (1) The vibro-tactile memory span of human fingertip is 4 ± 1; (2) The vibro-tactile memory span increases as the discrete intensity between vibration stimuli increases; (3) Too long or too short vibration duration will reduce the vibro-tactile memory span, and the optimal vibration duration for men is 400 ms, for women is 300 ms; (4) The more the number of vibration stimuli is perceived by the human fingertip, the lower the recognition accuracy and the longer the reaction time it needs; (5) Compared with the vibration stimuli in disorder, people are more likely to remember the vibration stimuli in increasing/decreasing order; (6) The information extraction mechanism of the short-term memory about fingertip vibro-tactile perception bases a point to point scanning process among these stimuli. These results help to understand the human fingertip tactile characteristics and provide a physiological basis for the study of tactile feedback technologies.

Design, Synthesis, and Biological Evaluation of MEK PROTACs.

PROteolysis TArgeting Chimeras (PROTACs) targeting the degradation of MEK have been designed based on allosteric MEK inhibitors. Inhibition of the phosphorylation of ERK1/2 was less effective with the PROTACs than a small-molecule inhibitor; the best PROTACs, however, were more effective in inhibiting proliferation of A375 cells than an inhibitor.

Combined hyperactive dysfunction syndrome of the cranial nerves complicated by essential hypertension: A case report.

RATIONALE: Combined hyperactive dysfunction syndrome (HDS) refers to a special type of HDS characterized by a combination of trigeminal neuralgia (TN), hemi facial spasm (HFS), and/or gloss pharyngeal neuralgia (GPN). Rostra ventrolateral medulla (RVLM) plays a crucial role in central cardiovascular regulation, and neurovascular compression of the RVLM has been identified as a contributor to essential hypertension. PATIENT CONCERNS: A 65-year-old female with a facial tic and pain located in the root of the tongue and throat on the same side; the systolic and diastolic blood pressure was approximately 170 and 100 mmHg. DIAGNOSIS: The patient was diagnosed with combined HDS (HFS-GPN) and essential hypertension. Brain magnetic resonance 3-dimensional time-of-flight imaging and digital subtraction angiography revealed vertebrobasilar artery compressed the left RVLM and contacted with the root entry zones of multiple cranial nerves. INTERVENTIONS: The patient was treated with microvascular decompression surgery OUTCOMES:: The symptoms were completely relieved, and blood pressure was well-controlled. LESSONS: The pathological association of hypertension and HDS should be highlighted, and microvascular decompression is an effective approach for relieving the hypertension.

A review of pretreatment and analytical methods of biogenic amines in food and biological samples since 2010.

Biogenic amines (BAs), mainly produced by amino acid decarboxylation, are widespread in foods and human organisms. Appropriate intake of BAs is beneficial to the human body, while excessive consumption may cause discomfort. Meanwhile, BAs are a kind of chemical marker for evaluating meat freshness. For these reasons, simple, rapid and efficient methods have been developed for the determination of BAs in food and biological products. This review introduces the provenance, classification and physiological activity of eight essential BAs and summarizes the dominant pretreatment and analysis methods since 2010. Pretreatment technologies mainly include the "dilute and shoot" method, ultrasonic assisted extraction, solid-phase extraction, matrix solid-phase dispersion, dispersive liquid-liquid microextraction, etc. Determination methods include liquid chromatography coupled to ultraviolet or fluorescence detectors, liquid chromatography tandem mass spectrometry, capillary electrophoresis, biosensors and so on.

Traumatic bifrontoparietal extradural hematomas with detachment of superior sagittal sinus: a case report and review of the literature.

A 45-year-old man suffered bifrontoparietal extradural hematoma resulting from head injury, which cause superior sagittal sinus detachment from its subperiosteal loggia. We present the patient who was treated by early surgical evacuation of the hematoma with an excellent outcome and we also perform a review of the current literature.

Multiple myeloma with pathologically proven skull plasmacytoma after a mild head injury: Case report.

RATIONALE: MM is a malignant tumor originating from the plasma cells of the bone marrow. Central nervous system myelomatosis is very rare and may be a complication of MM. PATIENT CONCERNS: A 60-year-old man presented with a slowly growing soft mass at his right frontal scalp after a mild head injury 6 months ago. DIAGNOSES: Neuroradiological examinations revealed a solid intracranial-extracranial mass with an osteolytic lesion in the skull. Histopathological examination showed skull plasmacytoma, and postoperative examinations revealed multiple myeloma. INTERVENTIONS: The tumor was completely removed and the skull defect repaired with the titanium mesh. Then, chemotherapy was initiated after surgery with bortezomib and dexamethasone. OUTCOMES: The patient received eight chemotherapies within one year after surgery. LESSONS: Despite a history of head injury, a differential diagnosis should be kept in mind during the diagnosis of solid intracranial-extracranial masses, especially in the presence of osteolytic skull at the lesioned site.