Enzyme structure correlates with variant effect predictability.

Protein engineering increasingly relies on machine learning models to computationally pre-screen promising novel candidates. Although machine learning approaches have proven effective, their performance on prospective screening data leaves room for improvement; prediction accuracy can vary greatly from one protein variant to the next. So far, it is unclear what characterizes variants that are associated with large prediction error.

Perseveration and Shifting in Obsessive-Compulsive Disorder as a Function of Uncertainty, Punishment, and Serotonergic Medication.

Background: The nature of cognitive flexibility deficits in obsessive-compulsive disorder (OCD), which historically have been tested with probabilistic reversal learning tasks, remains elusive. Here, a novel deterministic reversal task and inclusion of unmedicated patients in the study sample illuminated the role of fixed versus uncertain rules/contingencies and of serotonergic medication. Additionally, our understanding of probabilistic reversal was enhanced through theoretical computational modeling of cognitive flexibility in OCD.

Effects of cannabidiol on fear conditioning in anxiety disorders: decreased threat expectation during retention, but no enhanced fear re-extinction.

Rationale: Preclinical research suggests that pharmacologically elevating cannabinoid levels may attenuate fear memory expression and enhance fear extinction.

Objectives: We studied the effects of cannabidiol (CBD) on fear memory expression and fear re-extinction in 69 patients with panic disorder with agoraphobia or with social anxiety disorder. Moderation by sex, diagnosis, and serotonergic antidepressant (AD) use was explored.

Cannabidiol enhancement of exposure therapy in treatment refractory patients with social anxiety disorder and panic disorder with agoraphobia: A randomised controlled trial.

Preclinical research suggests that enhancing CB1 receptor agonism may improve fear extinction. In order to translate this knowledge into a clinical application we examined whether cannabidiol (CBD), a hydrolysis inhibitor of the endogenous CB1 receptor agonist anandamide (AEA), would enhance the effects of exposure therapy in treatment refractory patients with anxiety disorders. Patients with panic disorder with agoraphobia or social anxiety disorder were recruited for a double-blind parallel randomised controlled trial at three mental health care centres in the Netherlands.

The lung microbiome regulates brain autoimmunity.

Lung infections and smoking are risk factors for multiple sclerosis, a T-cell-mediated autoimmune disease of the central nervous system. In addition, the lung serves as a niche for the disease-inducing T cells for long-term survival and for maturation into migration-competent effector T cells. Why the lung tissue in particular has such an important role in an autoimmune disease of the brain is not yet known.

Serotonin depletion impairs both Pavlovian and instrumental reversal learning in healthy humans.

Serotonin is involved in updating responses to changing environmental circumstances. Optimising behaviour to maximise reward and minimise punishment may require shifting strategies upon encountering new situations. Likewise, autonomic responses to threats are critical for survival yet must be modified as danger shifts from one source to another.

Genetically induced brain inflammation by deletion transiently benefits from microglia depletion.

Reduced expression of 2'-3'-cyclic nucleotide 3'-phosphodiesterase () in humans and mice causes white matter inflammation and catatonic signs. These consequences are experimentally alleviated by microglia ablation colony-stimulating factor 1 receptor (CSF1R) inhibition using PLX5622. Here we address for the first time preclinical topics crucial for translation, most importantly ) the comparison of 2 long-term PLX5622 applications (prevention and treatment) 1 treatment alone, ) the correlation of catatonic signs and executive dysfunction, ) the phenotype of leftover microglia evading depletion, and ) the role of intercellular interactions for efficient CSF1R inhibition.

Cannabidiol enhancement of exposure therapy in treatment refractory patients with phobias: study protocol of a randomized controlled trial.

Background: Phobic anxiety disorders are among the most prevalent psychiatric disorders and are burdensome in terms of loss of quality of life and work productivity. Evidence-based treatments are relatively successful in the majority of patients, especially exposure therapy. However, a substantial subset of patients fails to achieve or stay in remission.

Specific Frontostriatal Circuits for Impaired Cognitive Flexibility and Goal-Directed Planning in Obsessive-Compulsive Disorder: Evidence From Resting-State Functional Connectivity.

Background: A recent hypothesis has suggested that core deficits in goal-directed behavior in obsessive-compulsive disorder (OCD) are caused by impaired frontostriatal function. We tested this hypothesis in OCD patients and control subjects by relating measures of goal-directed planning and cognitive flexibility to underlying resting-state functional connectivity.

Methods: Multiecho resting-state acquisition, combined with micromovement correction by blood oxygen level-dependent sensitive independent component analysis, was used to obtain in vivo measures of functional connectivity in 44 OCD patients and 43 healthy comparison subjects.

Nosology and causal necessity; the relation between defining a disease and discovering its necessary cause.

The problem of disease definition is related to the problem of proving that a certain agent is the necessary cause of a certain disease. Natural kind terms like 'rheumatoid arthritis' and 'AIDS' refer to essences which are discoverable rather than predeterminate. No statement about such diseases is a priori necessarily true.

Three types of IS-A statement in diagnostic classifications: three types of knowledge needed for development and maintenance.

Update mechanisms for diagnostic classifications should capture changes in medical knowledge but also allow for comparability across versions. This paper provides a basis for such a mechanism by describing types of IS-A statement and types of knowledge used in the construction of diagnostic classifications. Three types of IS-A statement are used: 'A is by definition a B', 'A is probably a B' and 'A is in theory necessarily a B'.

Using the GRAIL language for classification management.

This paper describes a novel approach in classification management where a formal model of medical semantics is being used for manipulations on existing classification systems. The paper addresses the issue of semi-automatically making specialist classifications that are compatible with the source classification. The examples in this paper are from a limited domain.

The challenge of an international classification of procedures in medicine.

This paper reviews the international developments with respect to the classification of medical procedures in light of recent work by CEN/TC251 and the situation in the Netherlands. The historical background is outlined, some advantages and disadvantages of ICPM are discussed, and some new initiatives are reported. Recent initiatives all tend towards the same sort of structure for the classification of medical procedures.

[Postanesthetic recall ability, anxiety and dreams in surgical patients. A clinical study].

The recall of stimuli registered during general anaesthesia is described. Patients were interviewed 2 days after surgery, concerning their experiences during anaesthesia. In a second series of observations, the interview was preceded by a short inquiry, which took place in the recovery room as soon as the patient awoke.