Orbital reconstruction: titanium mesh implant after excision of orbitozygomaticomaxillary tumors.

Pathologic lesions of the orbitozygomaticomaxillary complex (OZMC) and caudal oral cavity can be a challenge in veterinary oromaxillofacial surgery. Neoplastic lesions that are in close proximity to or invading the orbit may result in significant loss of structural integrity after curative intent surgery. This in turn may alter the topography of the bulbous oculi (globe) with resultant enophthalmos, diplopia, and entropion.

Cell-based high-content approach for SARS-CoV-2 neutralization identifies unique monoclonal antibodies and PI3K pathway inhibitors.

The sudden rise of the SARS-CoV-2 virus and the delay in the development of effective therapeutics to mitigate it made evident a need for ways to screen for compounds that can block infection and prevent further pathogenesis and spread. Yet, identifying effective drugs efficacious against viral infection and replication with minimal toxicity for the patient can be difficult. Monoclonal antibodies were shown to be effective, yet as the SARS-CoV-2 mutated, these antibodies became ineffective.

The "Doorstop Pocket" In Thioredoxin Reductases─An Unexpected Druggable Regulator of the Catalytic Machinery.

Pyridine nucleotide-disulfide oxidoreductases are underexplored as drug targets, and thioredoxin reductases (TrxRs) stand out as compelling pharmacological targets. Selective TrxR inhibition is challenging primarily due to the reliance on covalent inhibition strategies. Recent studies identified a regulatory and druggable pocket in thioredoxin glutathione reductase (TGR), a TrxR-like enzyme, and an established drug target for schistosomiasis.

Surgical reconstruction of a composite nasomaxillary and superior labial defect in a dog with a fascia lata graft, titanium mesh implant and angularis oris axial pattern flap.

Objective: To document the successful surgical reconstruction of a composite nasomaxillary and superior labial defect using a fascia lata graft, titanium mesh and angularis oris axial pattern flap in a dog.

Case Summary: An estimated 2-year-old female intact mixed-breed dog was presented with a composite (hard and soft tissue) nasomaxillary defect, suspected to be caused by a chemical burn. Physical examination revealed nasal discharge, exposed bilateral maxilla and nasal bone, nasomaxillary fistula with air movement, and intrinsic discoloration of the left maxillary canine tooth.

Estradiol improves behavior in FAD transgenic mice that express but not after ovariectomy.

Increasing evidence suggests that female individuals have a higher Alzheimer's disease (AD) risk associated with post-menopausal loss of circulating estradiol (E). However, clinical data are conflicting on whether E lowers AD risk. One potential contributing factor is .

Channeling Nicotinamide Phosphoribosyltransferase (NAMPT) to Address Life and Death.

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step in NAD biosynthesis via salvage of NAM formed from catabolism of NAD by proteins with NADase activity (e.g., PARPs, SIRTs, CD38).

Structure-Guided Design and Synthesis of Pyridinone-Based Selective Bromodomain and Extra-Terminal Domain (BET)-First Bromodomain (BD1) Inhibitors.

The bromodomain and extra-terminal domain (BET) proteins are epigenetic readers, regulating transcription via two highly homologous tandem bromodomains, BD1 and BD2. Clinical development of nonselective pan-BD BET inhibitors has been challenging, partly due to dose-limiting side effects such as thrombocytopenia. This has prompted the push for domain-selective BET inhibitors to achieve a more favorable therapeutic window.

Application of a maxillary transfacial approach to the caudal oral cavity and orbitozygomaticomaxillary complex in dogs.

Surgical access and visualization for excision of large pathologic lesions of the orbitozygomaticomaxillary complex (OZMC) and caudal oral cavity can be a challenge in veterinary oromaxillofacial surgery and may limit one's ability to perform such procedures. Combined intra- and extra-oral approaches as well as commissurotomy have been advocated in the past. However, each of these approaches present unique limitations specific to each approach.

Synthesis, Optimization, and Structure-Activity Relationships of Nicotinamide Phosphoribosyltransferase (NAMPT) Positive Allosteric Modulators (N-PAMs).

Depletion of nicotinamide adenine dinucleotide (NAD) is associated with aging and disease, spurring the study of dietary supplements to replenish NAD. The catabolism of NAD to nicotinamide (NAM) requires the salvage of NAM to replenish cellular NAD, which relies on the rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT). Pharmacological activation of NAMPT provides an alternative to dietary supplements.

Non-covalent inhibitors of thioredoxin glutathione reductase with schistosomicidal activity in vivo.

Only praziquantel is available for treating schistosomiasis, a disease affecting more than 200 million people. Praziquantel-resistant worms have been selected for in the lab and low cure rates from mass drug administration programs suggest that resistance is evolving in the field. Thioredoxin glutathione reductase (TGR) is essential for schistosome survival and a validated drug target.

Inhibition of ACAT as a Therapeutic Target for Alzheimer's Disease Is Independent of ApoE4 Lipidation.

APOE4, encoding apolipoprotein E4 (apoE4), is the greatest genetic risk factor for Alzheimer's disease (AD), compared to the common APOE3. While the mechanism(s) underlying APOE4-induced AD risk remains unclear, increasing the lipidation of apoE4 is an important therapeutic target as apoE4-lipoproteins are poorly lipidated compared to apoE3-lipoproteins. ACAT (acyl-CoA: cholesterol-acyltransferase) catalyzes the formation of intracellular cholesteryl-ester droplets, reducing the intracellular free cholesterol (FC) pool.

Temporomandibular Joint Gape Angles in Normal and Painful Domestic Felines.

The purpose of this study was to determine and compare the gape angles (temporomandibular joint range of motion with mouth opening) of conscious and anesthetized domestic felines and to compare gape angles with and without evidence of oral pain. This prospective study evaluated the gape angle of 58 domestic felines. The cats were grouped into painful ( = 33) and nonpainful cohorts ( = 25) and gape angles were compared during conscious and anesthetized conditions.

TrkA expression directs the anti-neoplastic activity of MLK3 inhibitors in triple-negative breast cancer.

Mixed Lineage Kinase 3 (MLK3) is a viable target for neoplastic diseases; however, it is unclear whether its activators or inhibitors can act as anti-neoplastic agents. We reported that the MLK3 kinase activity was higher in triple-negative (TNBC) than in hormone receptor-positive human breast tumors, where estrogen inhibited MLK3 kinase activity and provided a survival advantage to ER breast cancer cells. Herein, we show that in TNBC, the higher MLK3 kinase activity paradoxically promotes cancer cell survival.

Mechanism of Allosteric Modulation of Nicotinamide Phosphoribosyltransferase to Elevate Cellular NAD.

In aging and disease, cellular nicotinamide adenine dinucleotide (NAD) is depleted by catabolism to nicotinamide (NAM). NAD supplementation is being pursued to enhance human healthspan and lifespan. Activation of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting step in NAD biosynthesis, has the potential to increase the salvage of NAM.

Virtual surgical planning and 3D printing: Methodology and applications in veterinary oromaxillofacial surgery.

Virtual surgical planning is the process of planning and rehearsing a surgical procedure completely within the virtual environment on computer models. Virtual surgical planning and 3D printing is gaining popularity in veterinary oromaxillofacial surgery and are viable tools for the most basic to the most complex cases. These techniques can provide the surgeon with improved visualization and, thus, understanding of the patients' 3D anatomy.

Synthesis, Optimization, and Structure-Activity Relationships of Imidazo[1,2-]pyrimidines as Inhibitors of Group 2 Influenza A Viruses.

The influenza A virus (IAV) is a highly contagious virus that causes pandemics and seasonal epidemics, which are major public health issues. Current anti-influenza therapeutics are limited partly due to the continuous emergence of drug-resistant IAV strains; thus, there is an unmet need to develop novel anti-influenza therapies. Here, we present a novel imidazo[1,2-]pyrimidine scaffold that targets group 2 IAV entry.

Combined Gap and Interpositional Arthroplasty Utilizing Three-Dimensional Printed Model in a Dog with Temporomandibular Joint Ankylosis and Pseudoankylosis.

To report the surgical treatment of a canine with both ankylosis and pseudoankylosis of temporomandibular joint (TMJ). The patient presented for inability to open his mouth. Facial asymmetry with normal dental occlusion was appreciated and computed tomography (CT) was performed.

Remembering your A, B, C's: Alzheimer's disease and ABCA1.

The function of ATP binding cassette protein A1 (ABCA1) is central to cholesterol mobilization. Reduced ABCA1 expression or activity is implicated in Alzheimer's disease (AD) and other disorders. Therapeutic approaches to boost ABCA1 activity have yet to be translated successfully to the clinic.

CT characterisation and classification of feline temporomandibular joint trauma: a case series of 79 cats.

Objectives: The aim of this study was to characterise and describe patterns of temporomandibular joint (TMJ) injuries occurring in cats using CT.

Methods: A cross-sectional study was carried out in adherence with the STROBE guidelines. Among the medical and CT records of 79 cats, 158 TMJs were reviewed in a collaborative study between six institutions.

XP-524 is a dual-BET/EP300 inhibitor that represses oncogenic KRAS and potentiates immune checkpoint inhibition in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is associated with extensive dysregulation of the epigenome and epigenetic regulators, such as bromodomain and extraterminal motif (BET) proteins, have been suggested as potential targets for therapy. However, single-agent BET inhibition has shown poor efficacy in clinical trials, and no epigenetic approaches are currently used in PDAC. To circumvent the limitations of the current generation of BET inhibitors, we developed the compound XP-524 as an inhibitor of the BET protein BRD4 and the histone acetyltransferase EP300/CBP, both of which are ubiquitously expressed in PDAC tissues and cooperate to enhance tumorigenesis.

Virtual Surgical Planning and 3D Printing in Veterinary Dentistry and Oromaxillofacial Surgery.

Virtual surgical planning and three-dimensional (3D) printing are preoperative processes requiring the acquisition of high-quality imaging data. A surgical treatment plan is created and rehearsed virtually as the operator manipulates the 3D images of the patient within the software. When the operator is satisfied with the plan, including anticipated osteotomies, tumor excision margins, and reconstruction options, physical 3D prints can be produced.

Design of SARS-CoV-2 PLpro Inhibitors for COVID-19 Antiviral Therapy Leveraging Binding Cooperativity.

Antiviral agents that complement vaccination are urgently needed to end the COVID-19 pandemic. The SARS-CoV-2 papain-like protease (PLpro), one of only two essential cysteine proteases that regulate viral replication, also dysregulates host immune sensing by binding and deubiquitination of host protein substrates. PLpro is a promising therapeutic target, albeit challenging owing to featureless P1 and P2 sites recognizing glycine.