Cortical assembloids support the development of fast-spiking human PVALB+ cortical interneurons and uncover schizophrenia-associated defects.

Disruption of parvalbumin positive (PVALB+) cortical interneurons is implicated in the pathogenesis of schizophrenia. However, how these defects emerge during brain development remains poorly understood. The protracted maturation of these cells during postnatal life has made their derivation from human pluripotent stem cells (hPSCs) extremely difficult, precluding hPSC-based disease modeling of their role in neuropsychiatric disease.

Suppression of ferroptosis by vitamin A or radical-trapping antioxidants is essential for neuronal development.

The development of functional neurons is a complex orchestration of multiple signaling pathways controlling cell proliferation and differentiation. Because the balance of antioxidants is important for neuronal survival and development, we hypothesized that ferroptosis must be suppressed to gain neurons. We find that removal of antioxidants diminishes neuronal development and laminar organization of cortical organoids, which is fully restored when ferroptosis is inhibited by ferrostatin-1 or when neuronal differentiation occurs in the presence of vitamin A.

Generation of human cerebral organoids with a structured outer subventricular zone.

Outer radial glia (oRG) emerge as cortical progenitor cells that support the development of an enlarged outer subventricular zone (oSVZ) and the expansion of the neocortex. The in vitro generation of oRG is essential to investigate the underlying mechanisms of human neocortical development and expansion. By activating the STAT3 signaling pathway using leukemia inhibitory factor (LIF), which is not expressed in guided cortical organoids, we define a cortical organoid differentiation method from human pluripotent stem cells (hPSCs) that recapitulates the expansion of a progenitor pool into the oSVZ.

Epigenetic control and manipulation of neuronal maturation timing.

During brain development, the sequence of developmental steps and the underlying transcriptional regulatory logic are largely conserved across species. However, the temporal unfolding of developmental programs varies dramatically across species and within a given species varies across brain regions and cell identities. The maturation of neurons in the human cerebral cortex is particularly slow and lasts for many years compared with only a few weeks for the corresponding mouse neurons.

Combined small-molecule treatment accelerates maturation of human pluripotent stem cell-derived neurons.

The maturation of human pluripotent stem cell (hPSC)-derived neurons mimics the protracted timing of human brain development, extending over months to years for reaching adult-like function. Prolonged in vitro maturation presents a major challenge to stem cell-based applications in modeling and treating neurological disease. Therefore, we designed a high-content imaging assay based on morphological and functional readouts in hPSC-derived cortical neurons which identified multiple compounds that drive neuronal maturation including inhibitors of lysine-specific demethylase 1 and disruptor of telomerase-like 1 and activators of calcium-dependent transcription.

Clinical characterization and whole genome sequence-based typing of two cases of endophthalmitis due to Listeria monocytogenes.

Endophthalmitis due to Listeria monocytogenes is a rare form of listeriosis. Here, we report two cases that occurred in patients with different medical history, a 46-years-old woman with no comorbidities and an elderly man with several comorbidities. There was no history of trauma or surgery in either patient suggesting an endogenous origin.

Activation of HERV-K(HML-2) disrupts cortical patterning and neuronal differentiation by increasing NTRK3.

The biological function and disease association of human endogenous retroviruses (HERVs) are largely elusive. HERV-K(HML-2) has been associated with neurotoxicity, but there is no clear understanding of its role or mechanistic basis. We addressed the physiological functions of HERV-K(HML-2) in neuronal differentiation using CRISPR engineering to activate or repress its expression levels in a human-pluripotent-stem-cell-based system.

Fully defined human pluripotent stem cell-derived microglia and tri-culture system model C3 production in Alzheimer's disease.

Aberrant inflammation in the CNS has been implicated as a major player in the pathogenesis of human neurodegenerative disease. We developed a new approach to derive microglia from human pluripotent stem cells (hPSCs) and built a defined hPSC-derived tri-culture system containing pure populations of hPSC-derived microglia, astrocytes, and neurons to dissect cellular cross-talk along the neuroinflammatory axis in vitro. We used the tri-culture system to model neuroinflammation in Alzheimer's disease with hPSCs harboring the APP+/+ mutation and their isogenic control.

TLR3 controls constitutive IFN-β antiviral immunity in human fibroblasts and cortical neurons.

Human herpes simplex virus 1 (HSV-1) encephalitis can be caused by inborn errors of the TLR3 pathway, resulting in impairment of CNS cell-intrinsic antiviral immunity. Deficiencies of the TLR3 pathway impair cell-intrinsic immunity to vesicular stomatitis virus (VSV) and HSV-1 in fibroblasts, and to HSV-1 in cortical but not trigeminal neurons. The underlying molecular mechanism is thought to involve impaired IFN-α/β induction by the TLR3 recognition of dsRNA viral intermediates or by-products.

Laboratory-based surveillance of invasive listeriosis in Northern Italy over a fourteen-year period: epidemiological and clinical results.

Introduction: Invasive listeriosis is a rare foodborne disease with a significant impact on public health worldwide, because of the severity of its clinical manifestations and high fatality rate. In this study, we provide a snapshot of epidemiology of listeriosis in Lombardy Region, Northern Italy, reviewing enhanced surveillance data collected over fourteen years, after the implementation of a voluntary laboratory-based surveillance system for the referral of clinical isolates of Listeria monocytogenes to a regional reference laboratory, since 2005.

Methods: Invasive listeriosis cases data from 2005 to 2018 were extracted from the regional laboratory-based surveillance system database and compared with the regional mandatory notification disease system data.

A Human Pluripotent Stem Cell-based Platform to Study SARS-CoV-2 Tropism and Model Virus Infection in Human Cells and Organoids.

SARS-CoV-2 has caused the COVID-19 pandemic. There is an urgent need for physiological models to study SARS-CoV-2 infection using human disease-relevant cells. COVID-19 pathophysiology includes respiratory failure but involves other organ systems including gut, liver, heart, and pancreas.

Measles surveillance activities in the Metropolitan Area of Milan during 2017-2018.

Introduction: In Italy, the transmission of measles is still endemic, and 7,919 cases were reported to the National Surveillance System between January 2017 and December 2018. Aim of this study is to report the results of the measles surveillance activities in the Metropolitan City of Milan from March 2017 to December 2018, and to evaluate the surveillance performance WHO indicators.

Methods: The Local Health Units (LHUs) carried out case investigations and collected specimens to send to the EpiSoMI Lab (Subnational Reference Laboratory, SRL) of the University of Milan for cases/outbreaks confirmation and genotyping performed according to the WHO Guidelines.

A stochastic framework of neurogenesis underlies the assembly of neocortical cytoarchitecture.

The cerebral cortex contains multiple areas with distinctive cytoarchitectonic patterns, but the cellular mechanisms underlying the emergence of this diversity remain unclear. Here, we have investigated the neuronal output of individual progenitor cells in the developing mouse neocortex using a combination of methods that together circumvent the biases and limitations of individual approaches. Our experimental results indicate that progenitor cells generate pyramidal cell lineages with a wide range of sizes and laminar configurations.

Loss of SATB1 Induces p21-Dependent Cellular Senescence in Post-mitotic Dopaminergic Neurons.

Cellular senescence is a mechanism used by mitotic cells to prevent uncontrolled cell division. As senescent cells persist in tissues, they cause local inflammation and are harmful to surrounding cells, contributing to aging. Generally, neurodegenerative diseases, such as Parkinson's, are disorders of aging.