Arrayed CRISPR libraries for the genome-wide activation, deletion and silencing of human protein-coding genes.

Arrayed CRISPR libraries extend the scope of gene-perturbation screens to non-selectable cell phenotypes. However, library generation requires assembling thousands of vectors expressing single-guide RNAs (sgRNAs). Here, by leveraging massively parallel plasmid-cloning methodology, we show that arrayed libraries can be constructed for the genome-wide ablation (19,936 plasmids) of human protein-coding genes and for their activation and epigenetic silencing (22,442 plasmids), with each plasmid encoding an array of four non-overlapping sgRNAs designed to tolerate most human DNA polymorphisms.

Clinical and biological underpinnings of longitudinal atrophy pattern progression in Alzheimer's disease.

Background: Magnetic resonance imaging (MRI) has recently enabled to identify four distinct Alzheimer's disease (AD) subtypes: hippocampal sparing (HpSp), typical AD (tAD), limbic predominant (Lp), and minimal atrophy (MinAtr). To date, however, the natural history of these subtypes, especially regarding the presence of subjects switching to other MRI patterns and their clinical and biological differences, remains poorly understood.

Objective: To investigate the clinical and biological underpinnings of longitudinal atrophy pattern progression in AD.

Novel approach to bone comorbidity in resistant acromegaly.

Active acromegaly may lead to irreversible complications. Among them, acromegaly osteopathy and fragility (vertebral and hip) fractures have emerged as frequent and precocious events in the natural history of the disease, being correlated with longer disease duration and higher growth hormone (GH) levels, accounting for patients' reported poor quality of life, physical performance and other life-impacting complications. Differently from primary osteoporosis, bone mineral density is not a reliable tool to predict fracture risk in this clinical setting, as patients with active disease frequently have normal or slightly reduced bone mass; whereas bone quality is particularly compromised, as determined by low trabecular bone score (TBS) in patients with active disease as compared to healthy controls or patients with cured/controlled disease.

TSH-secreting pituitary adenomas and bone.

TSH-secreting pituitary adenoma (TSHoma) is the rarest functioning pituitary tumor, with an increasing incidence over the last decades. Diagnosis is often delayed, exposing patients to a high risk of developing chronic complications of long-standing hyperthyroidism. Although thyroid hormone excess is a recognized cause of secondary osteoporosis, very few studies have investigated skeletal damage in patients with TSHoma, with data limited to bone turnover markers (BTM) and a study on the prevalence of radiological vertebral fractures (VFs) incidentally detected on chest X-ray, whereas data on bone mineral density (BMD) are anecdotal.

The ASC inflammasome adapter governs SAA-derived protein aggregation in inflammatory amyloidosis.

Extracellularly released molecular inflammasome assemblies -ASC specks- cross-seed Aβ amyloid in Alzheimer's disease. Here we show that ASC governs the extent of inflammation-induced amyloid A (AA) amyloidosis, a systemic disease caused by the aggregation and peripheral deposition of the acute-phase reactant serum amyloid A (SAA) in chronic inflammatory conditions. Using super-resolution microscopy, we found that ASC colocalized tightly with SAA in human AA amyloidosis.

Longitudinal microbiome investigation throughout prion disease course reveals pre- and symptomatic compositional perturbations linked to short-chain fatty acid metabolism and cognitive impairment in mice.

Commensal intestinal bacteria shape our microbiome and have decisive roles in preserving host metabolic and immune homeostasis. They conspicuously impact disease development and progression, including amyloid-beta (Aβ) and alpha (α)-synuclein pathology in neurodegenerative diseases, conveying the importance of the brain-gut-microbiome axis in such conditions. However, little is known about the longitudinal microbiome landscape and its potential clinical implications in other protein misfolding disorders, such as prion disease.

PBX1 and PBX3 transcription factors regulate expression in the Frontonasal Ectodermal Zone through complementary mechanisms.

Sonic hedgehog (SHH) signaling from the frontonasal ectodermal zone (FEZ) is a key regulator of craniofacial morphogenesis. Along with SHH, pre-B-cell leukemia homeobox (PBX) transcription factors regulate midfacial development. PBXs act in the epithelium during fusion of facial primordia, but their specific interactions with have not been fully investigated.

High prevalence of morphometric vertebral fractures opportunistically detected on thoracic radiograms in patients with non-functioning pituitary adenoma.

Purpose: Vertebral fractures (VFs), the hallmark of skeletal fragility, have been reported as an emerging complication in patients with pituitary diseases associated with hormonal excess and/or deficiency, independently from bone mineral density. Non-functioning pituitary adenoma (NFPA) is amongst the most frequent pituitary adenomas; however, skeletal health in this context has never been investigated. We aimed at assessing the prevalence and the determinants of morphometric VFs in patients with NFPA.

Study on the Long-Term Salt Release Characteristics of Self-Melting Ice Asphalt Mixtures and Their Impact on Pavement Performance.

Self-melting ice asphalt pavement materials inhibit pavement freezing and improve driving safety. This paper aims to study the long-term salt release characteristics of self-melting ice asphalt mixtures and the impact on pavement after complete salt release. Firstly, a method to accelerate the rapid release of salt based on the Los Angeles abrasion tester.

Targeted therapy in BRAF mutated aggressive papillary craniopharyngioma: a case report and overview of the literature.

Background: Papillary craniopharyngiomas harbor the BRAF V600E mutation, which paves the way for using BRAF inhibitor molecules to treat tumors refractory to standard therapies. Single case reports confirmed the efficacy of targeted therapy. However, most reports were limited by the short follow-up.

Single Versus Fractionated Gamma Knife Radiosurgery for Nonfunctioning Pituitary Adenomas Close to the Optic Pathway: A Multicenter Propensity Score Matched Study.

Background And Objectives: Gamma Knife radiosurgery (GKRS), typically administered in a single session (S-GKRS), is an effective treatment for nonfunctioning pituitary adenoma (NFPA). For lesions close to the optic pathway, the use of hypofractionated radiosurgery is growing. This study seeks to compare the results of S-GKRS vs fractionated-GKRS (F-GKRS) for NFPAs adjacent to the optic pathway.

Gamma knife radiosurgery is effective in patients with thyrotropin-secreting pituitary adenomas.

Purpose: Thyrotropin (TSH)-secreting pituitary adenoma (TSHoma) is a rare cause of TSH-dependent hyperthyroidism. The first therapeutic option is surgery. Medical treatment with somatostatin analogs is also effective.

Incident anti-LGI1 autoimmune encephalitis during dementia with Lewy bodies: when Occam razor is a double-edged sword.

In Dementia with Lewy bodies (DLB), rapid cognitive decline and seizures seldom complicate the typical clinical course. Nevertheless, concurrent, treatable conditions may be responsible. We report a case of DLB with superimposed anti-LGI1 encephalitis, emphasizing the importance of thorough diagnostic reasoning beyond the simplest explanation amid distinct clinical cues.

A novel somatostatin receptor ligand for human ACTH - and GH -secreting pituitary adenomas.

Objective: Somatostatin receptor ligands have come to play a pivotal role in the treatment of both ACTH- and GH-secreting pituitary adenomas. Clinical efficacy averages 30-50%, thus a considerable number of patients with Cushing's disease or acromegaly remain unresponsive to this therapeutic approach. HTL0030310 is a new somatostatin receptor ligand selective for subtype 5 over subtype 2, thus with a different receptor profile compared to clinical somatostatin receptor ligands.

The role of surgical management for prolactin-secreting tumors in the era of dopaminergic agonists: An international multicenter report.

Objective: First-line prolactin-secreting tumor (PST) management typically involves treatment with dopamine agonists and the role of surgery remains to be further explored. We examined the international experience of 12 neurosurgical centers to assess the patient characteristics, safety profile, and effectiveness of surgery for PST management.

Methods: Patients surgically treated for PST from January 2017 through December 2020 were evaluated for surgical characteristics, outcomes, and safety.

Crooke Cell Adenoma Confers Poorer Endocrinological Outcomes Compared with Corticotroph Adenoma: Results of a Multicenter, International Analysis.

Background: Crooke cell adenomas (CCAs) are a rare, aggressive subset of secretory pituitary corticotroph adenomas (sCTAs) found in 5%-10% of patients with Cushing disease. Multiple studies support worse outcomes in CCAs but are limited by small sample size and single-institution databases. We compared outcomes in CCA and sCTA using a multicenter, international retrospective database of high-volume skull base centers.

Defining benchmark outcomes for transsphenoidal surgery of pituitary adenomas: a multicenter analysis.

Importance: Benchmarks aid in improve outcomes for surgical procedures. However, best achievable results that have been validated internationally for transsphenoidal surgery (TS) are not available.

Objective: We aimed to establish standardized outcome benchmarks for TS of pituitary adenomas.

ESCRT-dependent control of craniofacial morphogenesis with concomitant perturbation of NOTCH signaling.

Craniofacial development is orchestrated by transcription factor-driven regulatory networks, epigenetic modifications, and signaling pathways. Signaling molecules and their receptors rely on endo-lysosomal trafficking to prevent accumulation on the plasma membrane. ESCRT (Endosomal Sorting Complexes Required for Transport) machinery is recruited to endosomal membranes enabling degradation of such endosomal cargoes.

Craniopharyngioma in Pediatrics and Adults.

Craniopharyngiomas are rare malignancies of dysembryogenic origin, involving the sellar and parasellar areas. These low-grade, epithelial tumors account for two main histological patterns (adamantinomatous craniopharyngioma and papillary craniopharyngioma), which differ in epidemiology, pathogenesis, and histomorphological appearance. Adamantinomatous craniopharyngiomas typically show a bimodal age distribution (5-15 years and 45-60 years), while papillary craniopharyngiomas are limited to adult patients, especially in the fifth and sixth decades of life.

Benign and Malignant Tumors of the Pituitary Gland.

Pituitary gland tumors represent approximately 10-15% of all brain tumors and the most common neoplasms of the sellar region. Among them, pituitary adenomas are the widespread accounting for more than 80%. Recently, the fourth edition of the World Health Organization (WHO) 2017 classified pituitary tumors focusing on histopathologic and molecular genetics features and introduced new entities like pituitary blastoma.

A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2.

A lingering question in developmental biology has centered on how transcription factors with widespread distribution in vertebrate embryos can perform tissue-specific functions. Here, using the murine hindlimb as a model, we investigate the elusive mechanisms whereby PBX TALE homeoproteins, viewed primarily as HOX cofactors, attain context-specific developmental roles despite ubiquitous presence in the embryo. We first demonstrate that mesenchymal-specific loss of PBX1/2 or the transcriptional regulator HAND2 generates similar limb phenotypes.