Corrigendum: An orally available small molecule that targets soluble TNF to deliver anti-TNF biologic-like efficacy in rheumatoid arthritis.

[This corrects the article DOI: 10.3389/fphar.2022.

Understanding non-response in psychotherapy: A meta-synthesis.

Introduction: There is considerable research focusing on the negative outcomes of psychotherapy, however, there remains an overlooked population: those who appear to show no response after treatment. This qualitative evidence synthesis aimed to review the available literature exploring client and therapist experiences of psychotherapy nonresponse.

Method: Seven databases were searched for studies using qualitative approaches to explore nonresponse.

Pre-treatment magnetic resonance imaging in anal cancer: large-scale evaluation of mrT, mrN and novel staging parameters.

Background: In patients with squamous cell carcinoma of the anus (SCCA), magnetic resonance (MR) imaging is recommended for pre-treatment staging prior to chemo-radiotherapy (CRT), but large-scale evaluation of its staging performance is lacking.

Methods: We re-characterised pre-treatment MRs from 228 patients with non-metastatic SCCA treated consecutively by CRT (2006-2015) at one UK cancer centre. We derived TN staging from tumour size (mrTr) and nodal involvement (mrN), and additionally characterised novel beyond TN features such as extramural vascular invasion (mrEMVI) and tumour signal heterogeneity (mrTSH).

Correction: Using Conversational AI to Facilitate Mental Health Assessments and Improve Clinical Efficiency Within Psychotherapy Services: Real-World Observational Study.

[This corrects the article DOI: 10.2196/44358.].

Using Conversational AI to Facilitate Mental Health Assessments and Improve Clinical Efficiency Within Psychotherapy Services: Real-World Observational Study.

Background: Most mental health care providers face the challenge of increased demand for psychotherapy in the absence of increased funding or staffing. To overcome this supply-demand imbalance, care providers must increase the efficiency of service delivery.

Objective: In this study, we examined whether artificial intelligence (AI)-enabled digital solutions can help mental health care practitioners to use their time more efficiently, and thus reduce strain on services and improve patient outcomes.

Closing the accessibility gap to mental health treatment with a personalized self-referral chatbot.

Inequality in treatment access is a pressing issue in most healthcare systems across many medical disciplines. In mental healthcare, reduced treatment access for minorities is ubiquitous but remedies are sparse. Here we demonstrate that digital tools can reduce the accessibility gap by addressing several key barriers.

Transcriptomic profiling of tissue environments critical for post-embryonic patterning and morphogenesis of zebrafish skin.

Pigment patterns and skin appendages are prominent features of vertebrate skin. In zebrafish, regularly patterned pigment stripes and an array of calcified scales form simultaneously in the skin during post-embryonic development. Understanding the mechanisms that regulate stripe patterning and scale morphogenesis may lead to the discovery of fundamental mechanisms that govern the development of animal form.

Zebrafish Injectable Plastic for Identification Tagging (ZIP IT) for larvae to adults using a fluorescent Visible Implant Elastomer.

Distinguishing individuals or small groups is essential for many experiments. The regenerative properties of zebrafish make traditional marking methods for rodent models (e.g.

Fluorescent PCR-based Screening Methods for Precise Knock-in of Small DNA Fragments and Point Mutations in Zebrafish.

Generation of zebrafish () models with targeted insertion of epitope tags and point mutations is highly desirable for functional genomics and disease modeling studies. Currently, CRISPR/Cas9-mediated knock-in is the method of choice for insertion of exogeneous sequences by providing a repair template for homology-directed repair (HDR). A major hurdle in generating knock-in models is the labor and cost involved in screening of injected fish to identify the precise knock-in events due to low efficiency of the HDR pathway in zebrafish.

A novel de novo TP63 mutation in whole-exome sequencing of a Syrian family with Oral cleft and ectrodactyly.

Background: Oral clefts and ectrodactyly are common, heterogeneous birth defects. We performed whole-exome sequencing (WES) analysis in a Syrian family. The proband presented with both orofacial clefting and ectrodactyly but not ectodermal dysplasia as typically seen in ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome-3.

A robust pipeline for efficient knock-in of point mutations and epitope tags in zebrafish using fluorescent PCR based screening.

Background: Genome editing using CRISPR/Cas9 has become a powerful tool in zebrafish to generate targeted gene knockouts models. However, its use for targeted knock-in remains challenging due to inefficient homology directed repair (HDR) pathway in zebrafish, highlighting the need for efficient and cost-effective screening methods.  RESULTS: Here, we present our fluorescent PCR and capillary electrophoresis based screening approach for knock-in using a single-stranded oligodeoxynucleotide donor (ssODN) as a repair template for the targeted insertion of epitope tags, or single nucleotide changes to recapitulate pathogenic human alleles.

An orally available small molecule that targets soluble TNF to deliver anti-TNF biologic-like efficacy in rheumatoid arthritis.

Tumor necrosis factor (TNF) is a pleiotropic cytokine belonging to a family of trimeric proteins with both proinflammatory and immunoregulatory functions. TNF is a key mediator in autoimmune diseases and during the last couple of decades several biologic drugs have delivered new therapeutic options for patients suffering from chronic autoimmune diseases such as rheumatoid arthritis and chronic inflammatory bowel disease. Attempts to design small molecule therapies directed to this cytokine have not led to approved products yet.

A RUNX1-FPDMM rhesus macaque model reproduces the human phenotype and predicts challenges to curative gene therapies.

Germ line loss-of-function heterozygous mutations in the RUNX1 gene cause familial platelet disorder with associated myeloid malignancies (FPDMM) characterized by thrombocytopenia and a life-long risk of hematological malignancies. Although gene therapies are being considered as promising therapeutic options, current preclinical models do not recapitulate the human phenotype and are unable to elucidate the relative fitness of mutation-corrected and RUNX1-heterozygous mutant hematopoietic stem and progenitor cells (HSPCs) in vivo long term. We generated a rhesus macaque with an FPDMM competitive repopulation model using CRISPR/Cas9 nonhomologous end joining editing in the RUNX1 gene and the AAVS1 safe-harbor control locus.

Zrsr2 Is Essential for the Embryonic Development and Splicing of Minor Introns in RNA and Protein Processing Genes in Zebrafish.

ZRSR2 (zinc finger CCCH-type, RNA binding motif and serine/arginine rich 2) is an essential splicing factor involved in 3' splice-site recognition as a component of both the major and minor spliceosomes that mediate the splicing of U2-type (major) and U12-type (minor) introns, respectively. Studies of -depleted cell lines and -mutated patient samples revealed its essential role in the U12-dependent minor spliceosome. However, the role of during embryonic development is not clear, as its function is compensated for by in mice.

A Comprehensive Review of Indel Detection Methods for Identification of Zebrafish Knockout Mutants Generated by Genome-Editing Nucleases.

The use of zebrafish in functional genomics and disease modeling has become popular due to the ease of targeted mutagenesis with genome editing nucleases, i.e., zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeats/Cas9 (CRISPR/Cas9).

Pancytopenia and thrombosis defects in zebrafish mutants of Fanconi anemia genes.

Progressive pancytopenia is a common feature observed in DNA crosslink repair deficiency disorder, Fanconi anemia (FA). However, this phenotype has not been recapitulated in single FA gene knockout animal models. In this study, we analyzed hematological characteristics in zebrafish null mutants for two FA genes, fanca and fanco.

Compound heterozygous variants in progressive myoclonus epilepsy.

KCTD7 is a member of the potassium channel tetramerization domain-containing protein family and has been associated with progressive myoclonic epilepsy (PME), characterized by myoclonus, epilepsy, and neurological deterioration. Here we report four affected individuals from two unrelated families in which we identified compound heterozygous single nucleotide variants through exome sequencing. RNAseq was used to detect a non-annotated splicing junction created by a synonymous variant in the second family.

Clinical and genomic analysis of a large Chinese family with familial cortical myoclonic tremor with epilepsy and intronic repeat expansion.

Objective: Our goal was to perform detailed clinical and genomic analysis of a large multigenerational Chinese family with 21 individuals showing symptoms of Familial Cortical Myoclonic Tremor with Epilepsy (FCMTE) that we have followed for over 20 years.

Methods: Patients were subjected to clinical evaluation, routine EEG, and structural magnetic resonance imaging. Whole exome sequencing, repeat-primed PCR, long-range PCR, and PacBio sequencing were performed to characterize the disease-causing mutation in this family.

A conformation-selective monoclonal antibody against a small molecule-stabilised signalling-deficient form of TNF.

We have recently described the development of a series of small-molecule inhibitors of human tumour necrosis factor (TNF) that stabilise an open, asymmetric, signalling-deficient form of the soluble TNF trimer. Here, we describe the generation, characterisation, and utility of a monoclonal antibody that selectively binds with high affinity to the asymmetric TNF trimer-small molecule complex. The antibody helps to define the molecular dynamics of the apo TNF trimer, reveals the mode of action and specificity of the small molecule inhibitors, acts as a chaperone in solving the human TNF-TNFR1 complex crystal structure, and facilitates the measurement of small molecule target occupancy in complex biological samples.

Structural insights into the disruption of TNF-TNFR1 signalling by small molecules stabilising a distorted TNF.

Tumour necrosis factor (TNF) is a trimeric protein which signals through two membrane receptors, TNFR1 and TNFR2. Previously, we identified small molecules that inhibit human TNF by stabilising a distorted trimer and reduce the number of receptors bound to TNF from three to two. Here we present a biochemical and structural characterisation of the small molecule-stabilised TNF-TNFR1 complex, providing insights into how a distorted TNF trimer can alter signalling function.

Three-dimensional (3D) magnetic resonance volume assessment and loco-regional failure in anal cancer: early evaluation case-control study.

Background: The primary aim was to test the hypothesis that deriving pre-treatment 3D magnetic resonance tumour volume (mrTV) quantification improves performance characteristics for the prediction of loco-regional failure compared with standard maximal tumour diameter (1D) assessment in patients with squamous cell carcinoma of the anus undergoing chemoradiotherapy.

Methods: We performed an early evaluation case-control study at two UK centres (2007-2014) in 39 patients with loco-regional failure (cases), and 41 patients disease-free at 3 years (controls). mrTV was determined using the summation of areas method (Vol).

Functional analysis of Sonic Hedgehog variants associated with holoprosencephaly in humans using a CRISPR/Cas9 zebrafish model.

Genetic variation in the highly conserved Sonic Hedgehog (SHH) gene is one of the most common genetic causes for the malformations of the brain and face in humans described as the holoprosencephaly clinical spectrum. However, only a minor fraction of known SHH variants have been experimentally proven to lead to abnormal function. Employing a phenotypic rescue assay with synthetic human messenger RNA variant constructs in shha knockout zebrafish, we evaluated 104 clinically reported in-frame and missense SHH variants.

Rare hypomorphic human variation in the heptahelical domain of SMO contributes to holoprosencephaly phenotypes.

Holoprosencephaly (HPE) is the most common congenital anomaly affecting the forebrain and face in humans and occurs as frequently as 1:250 conceptions or 1:10,000 livebirths. Sonic Hedgehog signaling molecule is one of the best characterized HPE genes that plays crucial roles in numerous developmental processes including midline neural patterning and craniofacial development. The Frizzled class G-protein coupled receptor Smoothened (SMO), whose signaling activity is tightly regulated, is the sole obligate transducer of Hedgehog-related signals.