Enabled Discovery of KAI-11101, a Preclinical DLK Inhibitor for the Treatment of Neurodegenerative Disease and Neuronal Injury.

Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of neuronal degeneration in response to cellular stress from chronic disease or neuronal injury. This makes it an attractive target for the treatment of neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, and neuronal injury, such as chemotherapy-induced peripheral neuropathy. Here, we describe the discovery of a potent, selective, brain-penetrant DLK inhibitor, KAI-11101 ().

Discovery of a Novel Mutant-Selective Epidermal Growth Factor Receptor Inhibitor Using an Enabled Drug Discovery Platform.

Despite the success of first, second, and third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for non-small cell lung cancer with classical EGFR mutations (L858R or Exon 19 deletions), disease progression occurs due to the acquisition of T790M and C797S resistance. Herein, we report a physics-based computationally driven lead identification approach that identified structurally unique imidazo[3.2-]pyrazoles as reversible and wild-type-sparing EGFR TKIs of classical mutations bearing both T790M and C797S.

Group 2 innate lymphoid cells promote inhibitory synapse development and social behavior.

The innate immune system shapes brain development and is implicated in neurodevelopmental diseases. It is critical to define the relevant immune cells and signals and their impact on brain circuits. In this work, we found that group 2 innate lymphoid cells (ILC2s) and their cytokine interleukin-13 (IL-13) signaled directly to inhibitory interneurons to increase inhibitory synapse density in the developing mouse brain.

A National Survey Study of Cannabis Use During Menopause: Identifying Variables Associated With Recreational, Medical, and Hybrid Use.

Objective: Previous research has demonstrated different cannabis-related outcomes depending on the goal of cannabis use (i.e., recreational, medical, a hybrid of both), underscoring the need to identify variables associated with specific goals of use, particularly in understudied populations.

"Everyone who wants to can practice on me"- a qualitative study of patients' view on health profession students' learning in an interprofessional clinical placement.

Introduction: Healthcare services face significant challenges due to the aging population, increasing complexity of health issues, and a global shortage of health professionals. Health professions education needs to adapt and develop with healthcare services' needs. Interprofessional education and patient partnership are two trends that are increasingly being reinforced.

Identifying Variables Associated with Menopause-Related Shame and Stigma: Results from a National Survey Study.

Despite the significance of menopause as a natural biological milestone experienced by approximately half the population, few studies have evaluated factors associated with menopause-related shame and stigma. Given previous research indicating increased shame and stigma are associated with negative outcomes that directly impact health ( reduced access to health care), it is critical to identify variables associated with menopause-related shame and stigma. As part of a larger, national survey, 214 perimenopausal ( = 111) and postmenopausal ( = 103) individuals completed self-report questionnaires assessing demographics and menopause-related symptoms, shame, and stigma.

CITED1 as a marker of favourable outcome in anti-endocrine treated, estrogen-receptor positive, lymph-node negative breast cancer.

Objective: To investigate CITED1 as a potential biomarker of anti-endocrine response and breast cancer recurrence, given its previously determined role in mediating estrogen-dependant transcription. The study is a continuation of earlier work establishing the role of CITED1 in mammary gland development.

Results: CITED1 mRNA is associated with estrogen-receptor positivity and selectively expressed in the GOBO dataset of cell lines and tumours representing the luminal-molecular subtype.

Group 2 innate lymphoid cells constrain type 3/17 lymphocytes in shared stromal niches to restrict liver fibrosis.

Group 2 innate lymphoid cells (ILC2s) cooperate with adaptive Th2 cells as key organizers of tissue type 2 immune responses, while a spectrum of innate and adaptive lymphocytes coordinate early type 3/17 immunity. Both type 2 and type 3/17 lymphocyte associated cytokines are linked to tissue fibrosis, but how their dynamic and spatial topographies may direct beneficial or pathologic organ remodelling is unclear. Here we used volumetric imaging in models of liver fibrosis, finding accumulation of periportal and fibrotic tract IL-5 lymphocytes, predominantly ILC2s, in close proximity to expanded type 3/17 lymphocytes and IL-33 niche fibroblasts.

CannaCount: an improved metric for quantifying estimates of maximum possible cannabinoid exposure.

Increasing numbers of individuals have access to cannabinoid-based products containing various amounts of delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), and other cannabinoids. Exposure to specific cannabinoids likely influences outcomes; however, current methods for quantifying cannabis exposure do not account for the cannabinoid concentrations of the products used. We developed CannaCount, an examiner-driven metric that quantifies estimated maximum possible cannabinoid exposure by accounting for variables related to cannabinoid concentration, duration, frequency, and quantity of use.

Student-led clinic cervical cancer screening-medical students' views on progression of learning, quality of Pap smears and women´s experiences of the visit - a mixed methods study.

Background: Student-led clinics (SLC) have been described, but not in gynecology. Gynecology is a subject typically covered in the last terms of medical training, however it includes few opportunities for students to tackle all phases of a consultation and a shortage of opportunities to perform gynecological examinations. Therefore, we started a student-led clinic for cervical cancer screening (SLC-CCS) in Linköping, Sweden and aimed to evaluate students' views on the progression of learning, the quality of the Papanicolaou (Pap) smear, and women´s experiences of the visit, using mixed methodology.

Group 2 innate lymphoid cells promote inhibitory synapse development and social behavior.

The innate immune system plays essential roles in brain synaptic development, and immune dysregulation is implicated in neurodevelopmental diseases. Here we show that a subset of innate lymphocytes (group 2 innate lymphoid cells, ILC2s) is required for cortical inhibitory synapse maturation and adult social behavior. ILC2s expanded in the developing meninges and produced a surge of their canonical cytokine Interleukin-13 (IL-13) between postnatal days 5-15.

Dysregulated lung stroma drives emphysema exacerbation by potentiating resident lymphocytes to suppress an epithelial stem cell reservoir.

Aberrant tissue-immune interactions are the hallmark of diverse chronic lung diseases. Here, we sought to define these interactions in emphysema, a progressive disease characterized by infectious exacerbations and loss of alveolar epithelium. Single-cell analysis of human emphysema lungs revealed the expansion of tissue-resident lymphocytes (TRLs).

Increased White Matter Coherence Following Three and Six Months of Medical Cannabis Treatment.

Previous studies have demonstrated abnormal white matter (WM) microstructure in recreational cannabis consumers; however, the long-term impact of medical cannabis (MC) use on WM coherence is unknown. Accordingly, this study assessed the longitudinal impact of MC treatment on WM coherence. Given results from preclinical studies, we hypothesized that MC treatment would be associated with increased fractional anisotropy (FA) and reduced mean diffusivity (MD).

Clinical and cognitive improvement following full-spectrum, high-cannabidiol treatment for anxiety: open-label data from a two-stage, phase 2 clinical trial.

Background: Evidence suggests cannabidiol (CBD) has anxiolytic properties, indicating potential for novel treatment strategies. However, few clinical trials of CBD-based products have been conducted, and none thus far have examined the impact of these products on cognition.

Methods: For the open-label stage of clinical trial NCT02548559, autoregressive linear modeling assessed efficacy and tolerability of four-weeks of 1 mL t.

Getting real in interprofessional clinical placements: patient-centeredness in student teams' collaborative learning.

Collaboration between healthcare providers helps tackle the increasing complexity of healthcare. When learning teamwork, interprofessional students are expected to work patient-centered; recognizing the patient's expertise and partnering with them. Research on interprofessional education (IPE) for undergraduates has illuminated learning outcomes, organization of learning activities, change in attitudes, etc.

A survey of medical cannabis use during perimenopause and postmenopause.

Objective: Expanding access to legal cannabis has dovetailed with increased interest in medical cannabis (MC) use; however, there is a paucity of research examining MC use to alleviate menopause-related symptoms. This survey study assessed patterns of MC use in perimenopausal and postmenopausal individuals.

Methods: Participants (perimenopausal, n = 131; postmenopausal, n = 127) completed assessments of menopause-related symptomatology and cannabis use, including modes of use, type of use, and menopause-related symptoms addressed by MC use.

Type I Interferons Promote Germinal Centers Through B Cell Intrinsic Signaling and Dendritic Cell Dependent Th1 and Tfh Cell Lineages.

Type I interferons (IFNs) are essential for antiviral immunity, appear to represent a key component of mRNA vaccine-adjuvanticity, and correlate with severity of systemic autoimmune disease. Relevant to all, type I IFNs can enhance germinal center (GC) B cell responses but underlying signaling pathways are incompletely understood. Here, we demonstrate that a succinct type I IFN response promotes GC formation and associated IgG subclass distribution primarily through signaling in cDCs and B cells.

Potent and selective TYK2-JH1 inhibitors highly efficacious in rodent model of psoriasis.

TYK2 is a member of the JAK family of kinases and a key mediator of IL-12, IL-23, and type I interferon signaling. These cytokines have been implicated in the pathogenesis of multiple inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, lupus, and inflammatory bowel diseases. Supported by compelling data from human genetic association studies, TYK2 inhibition is an attractive therapeutic strategy for these diseases.

Discovery of a Novel Class of d-Amino Acid Oxidase Inhibitors Using the Schrödinger Computational Platform.

d-Serine is a coagonist of the -methyl d-aspartate (NMDA) receptor, a key excitatory neurotransmitter receptor. In the brain, d-serine is synthesized from its l-isomer by serine racemase and is metabolized by the D-amino acid oxidase (DAO, DAAO). Many studies have linked decreased d-serine concentration and/or increased DAO expression and enzyme activity to NMDA dysfunction and schizophrenia.

Clinical associations of ESR2 (estrogen receptor beta) expression across thousands of primary breast tumors.

Estrogen receptor alpha (ERα, encoded by ESR1) is a well-characterized transcription factor expressed in more than 75% of breast tumors and is the key biomarker to direct endocrine therapies. On the other hand, much less is known about estrogen receptor beta (ERβ, encoded by ESR2) and its importance in cancer. Previous studies had some disagreement, however most reports suggested a more favorable prognosis for patients with high ESR2 expression.

Interferon gamma constrains type 2 lymphocyte niche boundaries during mixed inflammation.

Allergic immunity is orchestrated by group 2 innate lymphoid cells (ILC2s) and type 2 helper T (Th2) cells prominently arrayed at epithelial- and microbial-rich barriers. However, ILC2s and Th2 cells are also present in fibroblast-rich niches within the adventitial layer of larger vessels and similar boundary structures in sterile deep tissues, and it remains unclear whether they undergo dynamic repositioning during immune perturbations. Here, we used thick-section quantitative imaging to show that allergic inflammation drives invasion of lung and liver non-adventitial parenchyma by ILC2s and Th2 cells.

Elevated striatal glutamate + glutamine in recreational cannabis users during abstinence.

Cannabis withdrawal symptoms contribute to relapse, but the underlying mechanism remains unclear. We hypothesize that cannabis withdrawal may be associated with a reset of regional γ-amino butyric acid (GABA) and glutamate concentrations secondary to changes in the endocannabinoid system during abstinence and conducted a study on this issue. We used magnetic resonance spectroscopy (MRS) to detect the associated changes of these neurochemicals in twenty-six frequent, recreational cannabis users and eleven age-matched non-using controls.

Color Biophysics and the Human Color Perception in Relation to Pigments and Tattooed Skin.

Perception of skin color in the natural state, or with tattoo pigment installed in the dermis is highly complex and includes both optical requisites and eye and brain functions connected to advanced cognitive and psychological functions. Permanent makeup (PMU) is miniaturized tattooing on critical anatomical location aiming at fulfilment of a person's esthetic ideal. It is a special challenge since a satisfactory outcome depends on perfectionated technique and very critical selection of pigments.

Regulatory T-cells inhibit microglia-induced pain hypersensitivity in female mice.

Peripheral nerve injury-induced neuropathic pain is a chronic and debilitating condition characterized by mechanical hypersensitivity. We previously identified microglial activation via release of colony-stimulating factor 1 (CSF1) from injured sensory neurons as a mechanism contributing to nerve injury-induced pain. Here, we show that intrathecal administration of CSF1, even in the absence of injury, is sufficient to induce pain behavior, but only in male mice.