Abnormal c-Fos expression in TetTag mice containing fos-EGFP.

Molecular and genetic techniques now allow selective tagging and manipulation of the population of neurons, often referred to as "engram cells," that were active during a specific experience. One common approach to labeling these cells is to use the transgenic mouse (TetTag). In addition to tagging cells active during learning, it is common to examine the reactivation of these cells using immediate early gene (IEG) expression as an index of neural activity.

Phasic locus coeruleus activity enhances trace fear conditioning by increasing dopamine release in the hippocampus.

Locus coeruleus (LC) projections to the hippocampus play a critical role in learning and memory. However, the precise timing of LC-hippocampus communication during learning and which LC-derived neurotransmitters are important for memory formation in the hippocampus are currently unknown. Although the LC is typically thought to modulate neural activity via the release of norepinephrine, several recent studies have suggested that it may also release dopamine into the hippocampus and other cortical regions.

Cheminformatics and artificial intelligence for accelerating agrochemical discovery.

The global cost-benefit analysis of pesticide use during the last 30 years has been characterized by a significant increase during the period from 1990 to 2007 followed by a decline. This observation can be attributed to several factors including, but not limited to, pest resistance, lack of novelty with respect to modes of action or classes of chemistry, and regulatory action. Due to current and projected increases of the global population, it is evident that the demand for food, and consequently, the usage of pesticides to improve yields will increase.

The US Hereditary Angioedema Association Scientific Registry: hereditary angioedema demographics, disease severity, and comorbidities.

Background: Hereditary angioedema (HAE) and idiopathic nonhistaminergic angioedema (INHA) are ultra-rare diseases whose natural histories and comorbidities are incompletely understood.

Objective: To develop a national patient-centric registry to address these deficiencies in our knowledge and improve our ability to assess the real-world impact of therapeutic interventions.

Methods: Data from members of the US HAE Association were collected into an online registry between 2009 and April 7, 2021.

Septo-hippocampal dynamics and the encoding of space and time.

Encoding an event in memory requires neural activity to represent multiple dimensions of behavioral experience in space and time. Recent experiments have explored the influence of neural dynamics regulated by the medial septum on the functional encoding of space and time by neurons in the hippocampus and associated structures. This review addresses these dynamics, focusing on the role of theta rhythm, the differential effects of septal inactivation and activation on the functional coding of space and time by individual neurons, and the influence on phase coding that appears as phase precession.

An Online Teaching Resource to Support UK Medical Student Education During the COVID-19 Pandemic: A Descriptive Account.

This paper describes the development and use of the bespoke digital learning resource CAPSULE (Clinical and Professional Studies Unique Learning Environment) which was launched UK wide in May 2020 to facilitate the delivery of core learning content for UK medical students during the COVID-19 pandemic. CAPSULE is a digital learning resource comprising case-based scenarios and multiple-choice questions, encompassing all undergraduate medical specialities and supported by a pan-speciality editorial board. Following the COVID-19 pandemic lockdown and loss of face-to-face learning opportunities, CAPSULE was made available to all UK medical schools in May 2020.

Discovery of florylpicoxamid, a mimic of a macrocyclic natural product.

Natural products have routinely been used both as sources of and inspiration for new crop protection active ingredients. The natural product UK-2A has potent anti-fungal activity but lacks key attributes for field translation. Post-fermentation conversion of UK-2A to fenpicoxamid resulted in an active ingredient with a new target site of action for cereal and banana pathogens.

Amnesia for context fear is caused by widespread disruption of hippocampal activity.

The hippocampus plays an essential role in the formation and retrieval of episodic memories in humans and contextual memories in animals. However, amnesia is not always observed when this structure is compromised. To determine why this is the case, we compared the effects of several different circuit manipulations on memory retrieval and hippocampal activity.

Preclinical studies on the toxicology, pharmacokinetics and safety of K1-70 a human monoclonal autoantibody to the TSH receptor with TSH antagonist activity.

Background: The human monoclonal autoantibody K1-70™ binds to the TSH receptor (TSHR) with high affinity and blocks TSHR cyclic AMP stimulation by TSH and thyroid stimulating autoantibodies.

Methods: The preclinical toxicology assessment following weekly intravenous (IV) or intramuscular (IM) administration of K1-70™ in rats and cynomolgus monkeys for 29 days was carried out. An assessment of delayed onset toxicity and/or reversibility of toxicity was made during a further 4 week treatment free period.

Acute Disruption of the Dorsal Hippocampus Impairs the Encoding and Retrieval of Trace Fear Memories.

A major function of the hippocampus is to link discontiguous events in memory. This process can be studied in animals using Pavlovian trace conditioning, a procedure where the conditional stimulus (CS) and unconditional stimulus (US) are separated in time. While the majority of studies have found that trace conditioning requires the dorsal segment of the hippocampus, others have not.

Crystal structure of a ligand-free stable TSH receptor leucine-rich repeat domain.

The crystal structures of the thyroid-stimulating hormone receptor (TSHR) leucine-rich repeat domain (amino acids 22-260; TSHR260) in complex with a stimulating human monoclonal autoantibody (M22TM) and in complex with a blocking human autoantibody (K1-70™) have been solved. However, attempts to purify and crystallise free TSHR260, that is not bound to an autoantibody, have been unsuccessful due to the poor stability of free TSHR260. We now describe a TSHR260 mutant that has been stabilised by the introduction of six mutations (H63C, R112P, D143P, D151E, V169R and I253R) to form TSHR260-JMG55TM, which is approximately 900 times more thermostable than wild-type TSHR260.

Comparison of drug delivery with autoinjector versus manual prefilled syringe and between three different autoinjector devices administered in pig thigh.

Parenteral routes of drug administration are often selected to optimize actual dose of drug delivered, assure high bioavailability, bypass first-pass metabolism or harsh gastrointestinal environments, as well as maximize the speed of onset. Intramuscular (IM) delivery can be preferred to intravenous delivery when initiating intravenous access is difficult or impossible. Drugs can be injected intramuscularly using a syringe or an automated delivery device (autoinjector).

Primary Follicular Lymphoma of the Gastrointestinal Tract: Case Report and Review.

Purpose: Primary gastrointestinal follicular lymphoma (GI-FL) is considered a rare disease with fewer than 400 cases reported in the literature. It accounts for roughly 1-3 % of GI non-Hodgkins lymphomas (NHL). It originates in the GI tract and typically affects small bowel.

Helicobacter pylori treatment: Still a work in progress.

Helicobacter pylori is a common worldwide bacterium, possessing adaptability that has created difficulty achieving eradication. While the standard treatment was thought to be triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin, growing rates of treatment failure and antibiotic resistance have stimulated research into novel regimens. Quadruple therapy with bismuth has been compared for both first- and second-line treatments, but eradication still has not reached expected goals.

A cross-sectional questionnaire assessing patient and physician use of short-term prophylaxis for hereditary angioedema.

Background: Current guidelines recommend short-term prophylaxis (STP) before invasive procedures to prevent hereditary angioedema (HAE) attacks; however, adherence to these guidelines may be variable because this indication lacks Food and Drug Administration approval in the United States.

Objective: To ascertain the STP experiences of patients with HAE and HAE-treating physicians.

Methods: Online questionnaires focusing on STP experiences were distributed by the US Hereditary Angioedema Association to the first 250 patients with HAE and to registered HAE-treating physicians.

Total synthesis, relay synthesis, and structural confirmation of the C18-norditerpenoid alkaloid neofinaconitine.

The first total synthesis of the C18-norditerpenoid aconitine alkaloid neofinaconitine and relay syntheses of neofinaconitine and 9-deoxylappaconitine from condelphine are reported. A modular, convergent synthetic approach involves initial Diels-Alder cycloaddition between two unstable components, cyclopropene 10 and cyclopentadiene 11. A second Diels-Alder reaction features the first use of an azepinone dienophile (8), with high diastereofacial selectivity achieved via rational design of siloxydiene component 36 with a sterically demanding bromine substituent.

Similarities and differences in interactions of thyroid stimulating and blocking autoantibodies with the TSH receptor.

Binding of a new thyroid-stimulating human monoclonal autoantibody (MAb) K1-18 to the TSH receptor (TSHR) leucine-rich domain (LRD) was predicted using charge-charge interaction mapping based on unique complementarities between the TSHR in interactions with the thyroid-stimulating human MAb M22 or the thyroid-blocking human MAb K1-70. The interactions of K1-18 with the TSHR LRD were compared with the interactions in the crystal structures of the M22-TSHR LRD and K1-70-TSHR LRD complexes. Furthermore, the predicted position of K1-18 on the TSHR was validated by the effects of TSHR mutations on the stimulating activity of K1-18.

In vivo effects of a human thyroid-stimulating monoclonal autoantibody (M22) and a human thyroid-blocking autoantibody (K1-70).

Purpose: To study in vivo effects of the human monoclonal TSH receptor (TSHR) autoantibodies M22 (stimulating type) and K1-70 (blocking type) on thyroid hormone levels in rats.

Methods: Serum levels of total T4, free T4, M22 and K1-70 were measured following intramuscular injection of M22 IgG (2-4 μg/animal), K1-70 IgG (10-200 μg/animal) or both into rats. Thyroid pathology was assessed in M22-injected rats.

Crystal structure of the TSH receptor (TSHR) bound to a blocking-type TSHR autoantibody.

A complex of the TSH receptor extracellular domain (amino acids 22-260; TSHR260) bound to a blocking-type human monoclonal autoantibody (K1-70) was purified, crystallised and the structure solved at 1.9 Å resolution. K1-70 Fab binds to the concave surface of the TSHR leucine-rich domain (LRD) forming a large interface (2565 Å(2)) with an extensive network of ionic, polar and hydrophobic interactions.

Monoclonal autoantibodies to the TSH receptor, one with stimulating activity and one with blocking activity, obtained from the same blood sample.

Objective: Patients who appear to have both stimulating and blocking TSHR autoantibodies in their sera have been described, but the two activities have not been separated and analysed. We now describe the isolation and detailed characterization of a blocking type TSHR monoclonal autoantibody and a stimulating type TSHR monoclonal autoantibody from a single sample of peripheral blood lymphocytes.

Design, Patients And Measurements: Two heterohybridoma cell lines secreting TSHR autoantibodies were isolated using standard techniques from the lymphocytes of a patient with hypothyroidism and high levels of TSHR autoantibodies (160 units/l by inhibition of TSH binding).

Religious Practice and Spirituality in the Psychological Adjustment of Survivors of Breast Cancer.

Religion and spirituality are resources regularly used by patients with cancer coping with diagnosis and treatment, yet there is little research that examines these factors separately. This study investigated the relationships between religious practice and spirituality and quality of life (QoL) and stress in survivors of breast cancer. The sample included 130 women assessed 2 years following diagnosis.

A human monoclonal autoantibody to the thyrotropin receptor with thyroid-stimulating blocking activity.

Background: Human monoclonal autoantibodies (MAbs) are valuable tools to study autoimmune responses. To date only one human MAb to the thyrotropin (TSH) receptor (TSHR) with stimulating activity has been available. We now describe the detailed characterization of a blocking type human MAb to the TSHR.

Synthesis of antiproliferative Cephalotaxus esters and their evaluation against several human hematopoietic and solid tumor cell lines: uncovering differential susceptibilities to multidrug resistance.

Deoxyharringtonine (2), homoharringtonine (3), homodeoxyharringtonine (4), and anhydroharringtonine (5) are reported to be among the most potent members of the antileukemia alkaloids isolated from the Cephalotaxus genus. Convergent syntheses of these four natural products are described, each involving novel synthetic methods and strategies. These syntheses enabled evaluation of several advanced natural and non-natural compounds against an array of human hematopoietic and solid tumor cells.