The effect of localized disturbance on the acoustic behavior of the common tern (Sterna hirundo).

In this study, passive acoustic monitoring was used to assess the impact of investigator disturbance on the acoustic behavior of a colony of common terns. A graded antipredator response in the colony was hypothesized, which would result in an increase in acoustic energy with increased proximity to investigator disturbance. Human disturbance was found to result in a significant increase in acoustic energy within 20 meters of recorders, though not from farther distances.

Assessing tissue mechanical properties: Development of a custom-made tensile device and application on rodents sciatic nerves.

The development of biomaterials such as synthetic scaffolds for peripheral nerve regeneration requires a precise knowledge of the mechanical properties of the nerve in physiological-like conditions. Mechanical properties (Young's modulus, maximum stress and strain at break) for peripheral nerves are scarce and large discrepancies are observed in between reports. This is due in part to the absence of a robust testing device for nerves.

Revisiting the NPcis mouse model: A new tool to model plexiform neurofibroma.

Neurofibromatosis Type I (NF1) is a rare genetic disorder. NF1 patients frequently develop a benign tumor in peripheral nerve plexuses called plexiform neurofibroma. In the past two decades, tissue-specific Nf1 knockout mouse models were developed using commercially available tissue-specific Cre recombinase and the Nf1 flox mice to mimic neurofibroma development.

ITPRIPL1 binds CD3ε to impede T cell activation and enable tumor immune evasion.

Cancer immunotherapy has transformed treatment possibilities, but its effectiveness differs significantly among patients, indicating the presence of alternative pathways for immune evasion. Here, we show that ITPRIPL1 functions as an inhibitory ligand of CD3ε, and its expression inhibits T cells in the tumor microenvironment. The binding of ITPRIPL1 extracellular domain to CD3ε on T cells significantly decreased calcium influx and ZAP70 phosphorylation, impeding initial T cell activation.

Whole Central and Peripheral Nervous System Mice Dissection.

Animal models represent the workhorse of the neuroscience field. Despite this, today, there is still no step-by-step protocol to dissect a complete rodent nervous system, nor is there a complete schematic representing it that is freely available. Only methods to harvest the brain, the spinal cord, a specific dorsal root ganglion, and the sciatic nerve (separately) are available.

A peptidic inhibitor for PD-1 palmitoylation targets its expression and functions.

Programmed cell death protein 1 (PD-1) is a crucial anticancer target, but the relatively low response rate and acquired resistance to existing antibody drugs highlight an urgent need to develop alternative targeting strategies. Here, we report the palmitoylation of PD-1, discover the main DHHC enzyme for this modification, reveal the mechanism of its effect on PD-1 protein stability, and rationally develop a peptide for targeting PD-1 expression. Palmitoylation promoted the trafficking of PD-1 to the recycling endosome, thus preventing its lysosome-dependent degradation.

Toward Understanding the Mechanisms of Malignant Peripheral Nerve Sheath Tumor Development.

Malignant peripheral nerve sheath tumors (MPNSTs) originate from the neural crest lineage and are associated with the neurofibromatosis type I syndrome. MPNST is an unmet clinical need. In this review article, we summarize the knowledge and discuss research perspectives related to (1) the natural history of MPNST development; (2) the mouse models recapitulating the progression from precursor lesions to MPNST; (3) the role of the tumor microenvironment in MPNST development, and (4) the signaling pathways linked to MPNST development.

Human cutaneous neurofibroma matrisome revealed by single-cell RNA sequencing.

Neurofibromatosis Type I (NF1) is a neurocutaneous genetic syndrome characterized by a wide spectrum of clinical presentations, including benign peripheral nerve sheath tumor called neurofibroma. These tumors originate from the Schwann cell lineage but other cell types as well as extracellular matrix (ECM) in the neurofibroma microenvironment constitute the majority of the tumor mass. In fact, collagen accounts for up to 50% of the neurofibroma's dry weight.

Targeted degradation of immune checkpoint proteins: emerging strategies for cancer immunotherapy.

Cancer immunotherapy using immune-checkpoint blockade has displayed promising clinical effects, but prevalent antibody-based inhibitors face multiple challenges such as low response rate, acquired resistance, and adverse effects. The intracellular expression of PD-1/PD-L1 in recycling endosomes and their active trafficking to membrane highlight the importance of depleting rather than interfering with checkpoint proteins. Preclinical investigations on the therapeutic effects of lead compounds that function by degrading immune checkpoint ligands and receptors have reported highly promising results.

Schwannoma development is mediated by Hippo pathway dysregulation and modified by RAS/MAPK signaling.

Schwannomas are tumors of the Schwann cells that cause chronic pain, numbness, and potentially life-threatening impairment of vital organs. Despite the identification of causative genes, including NF2 (Merlin), INI1/SMARCB1, and LZTR1, the exact molecular mechanism of schwannoma development is still poorly understood. Several studies have identified Merlin as a key regulator of the Hippo, MAPK, and PI3K signaling pathways; however, definitive evidence demonstrating the importance of these pathways in schwannoma pathogenesis is absent.

Translating current basic research into future therapies for neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a hereditary tumour syndrome that predisposes to benign and malignant tumours originating from neural crest cells. Biallelic inactivation of the tumour-suppressor gene NF1 in glial cells in the skin, along a nerve plexus or in the brain results in the development of benign tumours: cutaneous neurofibroma, plexiform neurofibroma and glioma, respectively. Despite more than 40 years of research, only one medication was recently approved for treatment of plexiform neurofibroma and no drugs have been specifically approved for the management of other tumours.

Regulations on Messenger RNA: Wires and Nodes.

Somatic cells of an organism virtually share the same DNA but it is the timely expression of specific genes that determine their phenotype and cellular identity. A series of complex molecular machinery allows for the regulated process of RNA transcription, splicing, and translation. In addition, microRNAs and specialized RNA binding proteins can trigger the degradation of mRNAs.

Heterozygous Tumor Suppressor Microenvironment in Cancer Development.

Hereditary cancer syndromes are typically caused by mutations of a tumor suppressor gene that lead to the early development of multifocal benign neoplasms followed by their malignant progression. However, the term 'hereditary cancer syndrome' may be misleading, as a large subgroup of syndromes are characterized by highly penetrant benign tumors. The reason why these cardinal tumors rarely progress to malignancy has been an elusive question in cancer biology.

Author Correction: Inhibiting PD-L1 palmitoylation enhances T-cell immune responses against tumours.

In the version of this Article originally published, 'palmitoyltransferase ZDHHC3 (DHHC3)' was incorrectly referred to as an 'acetyltransferase' rather than an as an 'acyltransferase'; this has now been corrected in five instances. In Fig. 3a, the label for the bottom row of the blots was mistakenly written as 'GAPHD'; it should have read 'GAPDH'.

Inhibiting PD-L1 palmitoylation enhances T-cell immune responses against tumours.

Checkpoint blockade therapy targeting the programmed-death ligand 1 (PD-L1) and its receptor programmed cell death 1 promotes T-cell-mediated immunosurveillance against tumours, and has been associated with marked clinical benefit in cancer patients. Antibodies against PD-L1 function by blocking PD-L1 on the cell surface, but intracellular storage of PD-L1 and its active redistribution to the cell membrane can minimize the therapeutic benefits, which highlights the importance of targeting PD-L1 throughout the whole cell. Here, we show that PD-L1 is palmitoylated in its cytoplasmic domain, and that this lipid modification stabilizes PD-L1 by blocking its ubiquitination, consequently suppressing PD-L1 degradation by lysosomes.

NF1 heterozygosity fosters de novo tumorigenesis but impairs malignant transformation.

Neurofibromatosis type 1 (NF1) is an autosomal genetic disorder. Patients with NF1 are associated with mono-allelic loss of the tumor suppressor gene NF1 in their germline, which predisposes them to develop a wide array of benign lesions. Intriguingly, recent sequencing efforts revealed that the NF1 gene is frequently mutated in multiple malignant tumors not typically associated with NF1 patients, suggesting that NF1 heterozygosity is refractory to at least some cancer types.

Spatiotemporal Loss of in Schwann Cell Lineage Leads to Different Types of Cutaneous Neurofibroma Susceptible to Modification by the Hippo Pathway.

Neurofibromatosis type 1 (NF1) is a cancer predisposition disorder that results from inactivation of the tumor suppressor neurofibromin, a negative regulator of RAS signaling. Patients with NF1 present with a wide range of clinical manifestations, and the tumor with highest prevalence is cutaneous neurofibroma (cNF). Most patients harboring cNF suffer greatly from the burden of those tumors, which have no effective medical treatment.

Contributions of inflammation and tumor microenvironment to neurofibroma tumorigenesis.

Neurofibromatosis type 1 associates with multiple neoplasms, and the Schwann cell tumor neurofibroma is the most prevalent. A hallmark feature of neurofibroma is mast cell infiltration, which is recruited by chemoattractant stem cell factor (SCF) and has been suggested to sustain neurofibroma tumorigenesis. In the present study, we use new, genetically engineered Scf mice to decipher the contributions of tumor-derived SCF and mast cells to neurofibroma development.

Impact of Statins on Influenza Vaccine Effectiveness Against Medically Attended Acute Respiratory Illness.

Background: Statins have antiinflammatory effects that may impact vaccine-induced immune responses. We investigated the impact of statin therapy on influenza vaccine effectiveness (VE) against medically attended acute respiratory illness (MAARI).

Methods: We conducted a retrospective cohort study over nine influenza seasons using research databases of a large managed care organization in the United States.

Board certification in internal medicine and cardiology: Historical success and future challenges.

Board certification is at a critical juncture. As physicians face increased regulation and pressures from both inside and outside the profession, board certification and Maintenance of Certification (MOC) are coming under increased scrutiny from the public and the medical community. At this challenging time, it is important to remind ourselves what board certification is (and what it is not) and revisit the origins of this tangible expression of professional self-regulation, even as we contemplate how it needs to improve.

Electronic versus paper-based assessment of health-related quality of life specific to HIV disease: reliability study of the PROQOL-HIV questionnaire.

Background: Electronic patient-reported outcomes (PRO) provide quick and usually reliable assessments of patients' health-related quality of life (HRQL).

Objective: An electronic version of the Patient-Reported Outcomes Quality of Life-human immunodeficiency virus (PROQOL-HIV) questionnaire was developed, and its face validity and reliability were assessed using standard psychometric methods.

Methods: A sample of 80 French outpatients (66% male, 52/79; mean age 46.

Redirecting splicing with bifunctional oligonucleotides.

Ectopic modulators of alternative splicing are important tools to study the function of splice variants and for correcting mis-splicing events that cause human diseases. Such modulators can be bifunctional oligonucleotides made of an antisense portion that determines target specificity, and a non-hybridizing tail that recruits proteins or RNA/protein complexes that affect splice site selection (TOSS and TOES, respectively, for targeted oligonucleotide silencer of splicing and targeted oligonucleotide enhancer of splicing). The use of TOSS and TOES has been restricted to a handful of targets.

Tumor microenvironment-associated modifications of alternative splicing.

Pre-mRNA alternative splicing is modified in cancer, but the origin and specificity of these changes remain unclear. Here, we probed ovarian tumors to identify cancer-associated splicing isoforms and define the mechanism by which splicing is modified in cancer cells. Using high-throughput quantitative PCR, we monitored the expression of splice variants in laser-dissected tissues from ovarian tumors.

8-BuS-ATP derivatives as specific NTPDase1 inhibitors.

Background And Purpose: Ectonucleotidases control extracellular nucleotide levels and consequently, their (patho)physiological responses. Among these enzymes, nucleoside triphosphate diphosphohydrolase-1 (NTPDase1), -2, -3 and -8 are the major ectonucleotidases responsible for nucleotide hydrolysis at the cell surface under physiological conditions, and NTPDase1 is predominantly located at the surface of vascular endothelial cells and leukocytes. Efficacious inhibitors of NTPDase1 are required to modulate responses induced by nucleotides in a number of pathological situations such as thrombosis, inflammation and cancer.