Risk analysis of disinformation weaponized against critical networks.

The vulnerability of critical networks to disinformation creates significant risks of disruption with potentially severe societal consequences. Maintaining secure and resilient networks, including infrastructure and supply chain networks, is important for ensuring economic productivity along with securing the health and well-being of society. An over-the-horizon threat to critical networks deals with adversaries who attack such networks indirectly by altering the consumption behavior of unwitting users influenced by weaponized disinformation.

Targeting transcription factors through an IMiD independent zinc finger domain.

Immunomodulatory imide drugs (IMiDs) degrade specific C2H2 zinc finger degrons in transcription factors, making them effective against certain cancers. SALL4, a cancer driver, contains seven C2H2 zinc fingers in three clusters, including an IMiD degron in zinc finger cluster one (ZFC1). Surprisingly, IMiDs do not inhibit the growth of SALL4-expressing cancer cells.

Targeting transcription factors through an IMiD independent zinc finger domain.

Immunomodulatory imide drugs (IMiDs) degrade specific C2H2 zinc finger degrons in transcription factors, making them effective against certain cancers. SALL4, a cancer driver, contains seven C2H2 zinc fingers in four clusters, including an IMiD degron in zinc finger cluster two (ZFC2). Surprisingly, IMiDs do not inhibit growth of SALL4 expressing cancer cells.

Advances in Animal Models and Cutting-Edge Research in Alternatives: Proceedings of the Third International Conference on 3Rs Research and Progress, Vishakhapatnam, 2022.

Animal experimentation has been integral to drug discovery and development and safety assessment for many years, since it provides insights into the mechanisms of drug efficacy and toxicity (e.g. pharmacology, pharmacokinetics and pharmacodynamics).

Current Challenges in Small Molecule Proximity-Inducing Compound Development for Targeted Protein Degradation Using the Ubiquitin Proteasomal System.

Bivalent proximity-inducing compounds represent a novel class of small molecule therapeutics with exciting potential and new challenges. The most prominent examples of such compounds are utilized in targeted protein degradation where E3 ligases are hijacked to recruit a substrate protein to the proteasome via ubiquitination. In this review we provide an overview of the current state of E3 ligases used in targeted protein degradation, their respective ligands as well as challenges and opportunities that present themselves with these compounds.

Reply to Chan et al.

We agree that smoking might be a risk factor for the severity of COVID-19, but in our previous study, smoking was not so robust compared with our conclusion. Also, we strongly agreed that COVID-19 patients with diabetes or other chronic diseases might worsen the situation of the disease. But these factors were out of the scope of our study and we had published other research on this topic related to diabetes.

A novel allosteric site employs a conserved inhibition mechanism in human kidney-type glutaminase.

Glutaminase catalyses the metabolic process called glutaminolysis. Cancer cells harness glutaminolysis to increase energy reserves under stressful conditions for rapid proliferation. Glutaminases are upregulated in many tumours.

Addition of Soluble Fiber in Low-Fat Purified Diets Maintains Cecal and Colonic Morphology, Modulates Bacterial Populations and Predicted Functions, and Improves Glucose Tolerance Compared with Traditional AIN Diets in Male Mice.

Background: Purified diets (PDs) contain refined ingredients with one main nutrient, allowing for greater control relative to grain-based diets (GBDs), which contain unrefined grains and animal byproducts. Traditional PDs like the American Institute of Nutrition (AIN)-76A (76A) and AIN-93G (93G) can negatively impact metabolic and gut health when fed long term, in part due to lower total fiber, no soluble fiber, and higher sucrose content.

Objective: Two studies were conducted to determine how PDs with reduced sucrose and increased fiber (soluble and insoluble) influence metabolic and gut health in mice compared with traditional AIN PDs or GBDs.

Protecting infrastructure performance from disinformation attacks.

Disinformation campaigns are prevalent, affecting vaccination coverage, creating uncertainty in election results, and causing supply chain disruptions, among others. Unfortunately, the problems of misinformation and disinformation are exacerbated due to the wide availability of online platforms and social networks. Naturally, these emerging disinformation networks could lead users to engage with critical infrastructure systems in harmful ways, leading to broader adverse impacts.

The clinical and bioinformatics analysis for the role of antihypertension drugs on mortality among patients with hypertension hospitalized with COVID-19.

Comorbidities such as hypertension could exacerbate symptoms of coronaviral disease 2019 (COVID)-19 infection. Patients with hypertension may receive both anti-COVID-19 and antihypertension therapies when infected with COVID-19. However, it is not clear how different classes of anti-hypertension drugs impact the outcome of COVID-19 treatment.

Targeted Protein Degradation: An Important Tool for Drug Discovery for "Undruggable" Tumor Transcription Factors.

Conventional small-molecule drugs (SMDs) are compounds characterized by low molecular weight, high cell permeability, and high selectivity. In clinical translation, SMDs are regarded as good candidates for oral drug formulation. SMD inhibitors play an important role in cancer treatment; however, resistance and low effectiveness have been major bottlenecks in clinical application.

Considerations When Choosing High-Fat, High-Fructose, and High-Cholesterol Diets to Induce Experimental Nonalcoholic Fatty Liver Disease in Laboratory Animal Models.

Nonalcoholic fatty liver disease (NAFLD) is intricately linked to metabolic disease (including obesity, glucose intolerance, and insulin resistance) and encompasses a spectrum of disorders including steatosis, nonalcoholic steatohepatitis (NASH), and fibrosis. Rodents consuming high-fat (HF; ∼40 kcal% fat including fats containing higher concentrations of saturated and fats), high-fructose (HFr), and high-cholesterol (HC) diets display many clinically relevant characteristics of NASH, along with other metabolic disorders. C57BL/6 mice are the most commonly used animal model because they can develop significant metabolic disorders including severe NASH with fibrosis after months of feeding, but other models also are susceptible.

A Translational Mouse Model for NASH with Advanced Fibrosis and Atherosclerosis Expressing Key Pathways of Human Pathology.

Non-alcoholic steatohepatitis (NASH) is a fast-growing liver disorder that is associated with an increased incidence of cardiovascular disease and type 2 diabetes. Animal models adequately mimicking this condition are scarce. We herein investigate whether Ldlr-/-.

Targeted Nutrient Modifications in Purified Diets Differentially Affect Nonalcoholic Fatty Liver Disease and Metabolic Disease Development in Rodent Models.

Nonalcoholic fatty liver disease (NAFLD) is a complex spectrum of disorders ranging from simple benign steatosis to more aggressive forms of nonalcoholic steatohepatitis (NASH) and fibrosis. Although not every patient with NAFLD/NASH develops liver complications, if left untreated it may eventually lead to cirrhosis and hepatocellular carcinoma. Purified diets formulated with specific nutritional components can drive the entire spectrum of NAFLD in rodent models.

Targeting hallmarks of cancer with a food-system-based approach.

Although extensive resources are dedicated to the development and study of cancer drugs, the cancer burden is expected to rise by about 70% over the next 2 decade. This highlights a critical need to develop effective, evidence-based strategies for countering the global rise in cancer incidence. Except in high-risk populations, cancer drugs are not generally suitable for use in cancer prevention owing to potential side effects and substantial monetary costs (Sporn, 2011).

Styryl quinazolinones and its ethynyl derivatives induce myeloid differentiation.

The tumor suppressor transcription factor CCAAT enhancer-binding protein α (C/EBPα) expression is downregulated in myeloid leukemias and enhancement of C/EBPα expression induces granulocytic differentiation in leukemic cells. Previously we reported that Styryl quinazolinones induce myeloid differentiation in HL-60 cells by upregulating C/EBPα expression. To identify more potent molecule that can induce leukemic cell differentiation we synthesized and evaluated new series of styryl quinazolinones, ethynyl styryl quinazolinones, styryl quinolinones and thienopyrimidinones.

Neurophysiology of spontaneous facial expressions: II. Motor control of the right and left face is partially independent in adults.

Facial expressions are described traditionally as monolithic or unitary entities. However, humans have the capacity to produce facial blends of emotion in which the upper and lower face simultaneously display different expressions. Recent neuroanatomical studies in monkeys have demonstrated that there are separate cortical motor areas for controlling the upper and lower face in each hemisphere that, presumably, also occur in humans.

Styryl Quinazolinones as Potential Inducers of Myeloid Differentiation via Upregulation of C/EBPα.

The CCAAT enhancer-binding protein α (C/EBPα) plays an important role in myeloid cell differentiation and in the enhancement of C/EBPα expression/activity, which can lead to granulocytic differentiation in acute myeloid leukemia (AML) cells. We found that styryl quinazolinones induce upregulation of C/EBPα expression, and thereby induce myeloid differentiation in human myeloid leukemia cell lines. We screened a series of active styryl quinazolinones and evaluated the structure⁻activity relationship (SAR) of these small molecules in inducing C/EBPα expression-thereby prompting the leukemic cells to differentiate.

A Metabolite-Triggered Tuft Cell-ILC2 Circuit Drives Small Intestinal Remodeling.

The small intestinal tuft cell-ILC2 circuit mediates epithelial responses to intestinal helminths and protists by tuft cell chemosensory-like sensing and IL-25-mediated activation of lamina propria ILC2s. Small intestine ILC2s constitutively express the IL-25 receptor, which is negatively regulated by A20 (Tnfaip3). A20 deficiency in ILC2s spontaneously triggers the circuit and, unexpectedly, promotes adaptive small-intestinal lengthening and remodeling.

Pigs, Unlike Mice, Have Two Distinct Colonic Stem Cell Populations Similar to Humans That Respond to High-Calorie Diet prior to Insulin Resistance.

Basal colonic crypt stem cells are long lived and play a role in colon homeostasis. Previous evidence has shown that high-calorie diet (HCD) enhances colonic stem cell numbers and expansion of the proliferative zone, an important biomarker for colon cancer. However, it is not clear how HCD drives dysregulation of colon stem cell/colonocyte proliferative kinetics.

A food-based approach that targets interleukin-6, a key regulator of chronic intestinal inflammation and colon carcinogenesis.

Studies have shown a causal link between high-calorie diet (HCD) and colon cancer. However, molecular mechanisms are not fully elucidated. To understand etiology of HCD-induced colon carcinogenesis, we screened 10 pathways linked to elevated colonic cell proliferation and chronic inflammation in an HCD-consuming human-relevant pig model.

Grape compounds suppress colon cancer stem cells in vitro and in a rodent model of colon carcinogenesis.

Background: We have previously shown that the grape bioactive compound resveratrol (RSV) potentiates grape seed extract (GSE)-induced colon cancer cell apoptosis at physiologically relevant concentrations. However, RSV-GSE combination efficacy against colon cancer stem cells (CSCs), which play a key role in chemotherapy and radiation resistance, is not known.

Methods: We tested the anti-cancer efficacy of the RSV-GSE against colon CSCs using isolated human colon CSCs in vitro and an azoxymethane-induced mouse model of colon carcinogenesis in vivo.

Eugenia jambolana (Java Plum) Fruit Extract Exhibits Anti-Cancer Activity against Early Stage Human HCT-116 Colon Cancer Cells and Colon Cancer Stem Cells.

The World Health Organization predicts over a 70% increase in cancer incidents in developing nations over the next decade. Although these nations have limited access to novel therapeutics, they do have access to foods that contain chemopreventive bioactive compounds such as anthocyanins, and as such, consumption of these foods can be encouraged to combat cancer. We and others have previously characterized the anti-colon cancer properties of dietary anthocyanins from different sources.

Neurophysiology of spontaneous facial expressions: I. Motor control of the upper and lower face is behaviorally independent in adults.

Facial expressions are described traditionally as monolithic entities. However, humans have the capacity to produce facial blends, in which the upper and lower face simultaneously display different emotional expressions. This, in turn, has led to the Component Theory of facial expressions.

Medical devices regulatory aspects: a special focus on polymeric material based devices.

Medical devices form a broad range of appliances from a basic nanoparticle coating or surgical gloves to a complicated laser therapy device. These devices are designed to support patients, surgeons and healthcare personnel in meeting patients' healthcare needs. Regulatory authorities of each country regulate the process of approval, manufacturing and sales of these medical devices so as to ensure safety and quality to patients or users.