Alteration of centrosome function and dynamics results in major defects during chromosome segregation and is associated with primary autosomal microcephaly (MCPH). Despite the knowledge accumulated ...in the last few years, why some centrosomal defects specifically affect neural progenitors is not clear. We describe here that the centrosomal kinase PLK1 controls centrosome asymmetry and cell fate in neural progenitors during development. Gain- or loss-of-function mutations in Plk1, as well as deficiencies in the MCPH genes Cdk5rap2 (MCPH3) and Cep135 (MCPH8), lead to abnormal asymmetry in the centrosomes carrying the mother and daughter centriole in neural progenitors. However, whereas loss of MCPH proteins leads to increased centrosome asymmetry and microcephaly, deficient PLK1 activity results in reduced asymmetry and increased expansion of neural progenitors and cortical growth during mid-gestation. The combination of PLK1 and MCPH mutations results in increased microcephaly accompanied by more aggressive centrosomal and mitotic abnormalities. In addition to highlighting the delicate balance in the level and activity of centrosomal regulators, these data suggest that human PLK1, which maps to 16p12.1, may contribute to the neurodevelopmental defects associated with 16p11.2-p12.2 microdeletions and microduplications in children with developmental delay and dysmorphic features.
Fibrous Dysplasia/McCune-Albright Syndrome (FD/MAS) is characterized by a spectrum of manifestations that may include fibrous dysplasia of bone and multiple endocrinopathies.
To describe the clinical ...spectrum, the study and follow-up of patients with FD/MAS cared at our institution.
Review of medical records of 12 pediatric and adult patients (11 women) who met the clinical and genetic diagnostic criteria for FD/ MAS.
The patients' mean age at diagnosis was 4.9 ± 5.5 years. The most common initial clinical manifestation was peripheral precocious puberty (PPP) in 67% of patients and 75% had café-au-lait spots. Fibrous dysplasia was present in 75% of patients and the mean age at diagnosis was 7.9 ± 4.7 years. Ten patients had a bone scintigraphy, with an age at the first examination that varied between 2 and 38 years of age. The most frequent location of dysplasia was craniofacial and appendicular. No patient had a recorded history of cholestasis, hepatitis, or pancreatitis. In four patients, a genetic study was performed that was positive for the pathogenic variant of guanine nucleotide binding protein, alpha stimulating (GNAS).
These patients demonstrate the variable nature of the clinical presentation and study of FD/MAS. It is essential to increase the index of diagnostic suspicion and adherence to international recommendations.
The cell type specific sequences of transcriptional programs during lung regeneration have remained elusive. Using time-series single cell RNA-seq of the bleomycin lung injury model, we resolved ...transcriptional dynamics for 28 cell types. Trajectory modeling together with lineage tracing revealed that airway and alveolar stem cells converge on a unique Krt8 + transitional stem cell state during alveolar regeneration. These cells have squamous morphology, feature p53 and NFkB activation and display transcriptional features of cellular senescence. The Krt8+ state appears in several independent models of lung injury and persists in human lung fibrosis, creating a distinct cell-cell communication network with mesenchyme and macrophages during repair. We generated a model of gene regulatory programs leading to Krt8+ transitional cells and their terminal differentiation to alveolar type-1 cells. We propose that in lung fibrosis, perturbed molecular checkpoints on the way to terminal differentiation can cause aberrant persistence of regenerative intermediate stem cell states.
Bone marrow fibrosis (BMF) develops in various hematological and non-hematological conditions and is a central pathological feature of myelofibrosis. Effective cell-targeted therapeutics are needed, ...but the cellular origin of BMF remains elusive. Here, we show using genetic fate tracing in two murine models of BMF that Gli1+ mesenchymal stromal cells (MSCs) are recruited from the endosteal and perivascular niche to become fibrosis-driving myofibroblasts in the bone marrow. Genetic ablation of Gli1+ cells abolished BMF and rescued bone marrow failure. Pharmacological targeting of Gli proteins with GANT61 inhibited Gli1+ cell expansion and myofibroblast differentiation and attenuated fibrosis severity. The same pathway is also active in human BMF, and Gli1 expression in BMF significantly correlates with the severity of the disease. In addition, GANT61 treatment reduced the myofibroblastic phenotype of human MSCs isolated from patients with BMF, suggesting that targeting of Gli proteins could be a relevant therapeutic strategy.
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•Bone marrow Gli1+ mesenchymal stromal cells (MSCs) differentiate into myofibroblasts•Targeting Gli1+ cells with GANT61 ameliorates bone marrow fibrosis (BMF)•Cxcl4 induces Gli1+ stromal cell migration and differentiation into myofibroblasts•Gli1+ MSCs also expand in human BMF and are sensitive to GANT61 inhibition
Schneider and colleagues show that Gli1+ bone marrow mesenchymal stromal cells are an important source of fibrotic cells during bone marrow fibrosis and that targeting of Gli proteins with GANT61 holds promise for amelioration of this disease.
Background
Studies using fast‐acting subcutaneous (SQ) insulin analogs in diabetic ketoacidosis (DKA) have demonstrated efficacy, safety, and cost‐effectiveness, allowing treatment of ...mild‐to‐moderate (MTM)‐severity DKA patients in non–intensive care unit (ICU) settings. However, emergency department (ED)‐based studies are few, with limited exploration of impacts on operational metrics.
Methods
We implemented the SQuID (Subcutaneous Insulin in Diabetic Ketoacidosis) protocol for adults with MTM‐severity DKA in an urban academic ED, collecting data from August 1, 2021, to February 28, 2022. We examined fidelity (frequency of required q2h glucose checks), safety (proportion of patients administered rescue dextrose for hypoglycemia), and ED length of stay (EDLOS) for the SQuID cohort compared to patients (non‐ICU) treated with a traditional insulin infusion. We also examined ICU admission rate among MTM‐severity DKA patients after introduction of SQuID to two historical control periods (pre‐intervention and pre‐COVID). We used Mann–Whitney U to test for differences in EDLOS distributions, bootstrapped (n = 1000) confidence intervals (CIs) for EDLOS median differences, and the two‐sample z‐test for differences in ICU admissions.
Results
We identified 177 MTM‐severity DKA patients in the study period (78 SQuID, 99 traditional cohort) and 163 preintervention and 161 pre‐COVID historical control patients. Fidelity to the SQuID pathway was good, with glucose checks exceeding the q2‐h requirement. We found no difference in the proportion of rescue dextrose administration compared to the traditional pathway. We observed significant reductions in median EDLOS for the SQuID cohort compared to the traditional cohort during the study period (−3.0, 95% CI −8.5 to −1.4), the preintervention period (−1.4, 95% CI −3.1 to −0.1), and the pre‐COVID control period (−3.6, 95% CI −7.5 to −1.8).
Conclusions
In this single‐center study at an academic ED, treatment of patients with MTM‐severity DKA with a SQ insulin protocol was effective, demonstrated equivalent safety, and reduced ED length of stay.
Opioids, agonists of µ-opioid receptors (µORs), are the strongest pain killers clinically available. Their action includes a strong central component, which also causes important adverse effects. ...However, µORs are also found on the peripheral endings of nociceptors and their activation there produces meaningful analgesia. The cellular mechanisms downstream of peripheral µORs are not well understood. Here, we show in neurons of murine dorsal root ganglia that pro-nociceptive TRPM3 channels, present in the peripheral parts of nociceptors, are strongly inhibited by µOR activation, much more than other TRP channels in the same compartment, like TRPV1 and TRPA1. Inhibition of TRPM3 channels occurs via a short signaling cascade involving Gβγ proteins, which form a complex with TRPM3. Accordingly, activation of peripheral µORs in vivo strongly attenuates TRPM3-dependent pain. Our data establish TRPM3 inhibition as important consequence of peripheral µOR activation indicating that pharmacologically antagonizing TRPM3 may be a useful analgesic strategy.
•Food system transformation is urgent, requiring rigorous, science-based monitoring to guide public and private decisions and support those who hold decision-makers to account.•Monitoring the whole ...of food systems and the interactions between their components is essential to support the immediate course corrections required to meet global sustainable development goals.•A food systems framework is proposed to define the architecture for a comprehensive monitoring agenda covering five thematic areas and their component indicator domains.•An inclusive process is called for that would select and track indicators for analysis of food systems performance and accountability.
Food systems that support healthy diets in sustainable, resilient, just, and equitable ways can engender progress in eradicating poverty and malnutrition; protecting human rights; and restoring natural resources. Food system activities have contributed to great gains for humanity but have also led to significant challenges, including hunger, poor diet quality, inequity, and threats to nature. While it is recognized that food systems are central to multiple global commitments and goals, including the Sustainable Development Goals, current trajectories are not aligned to meet these objectives. As mounting crises further stress food systems, the consequences of inaction are clear. The goal of food system transformation is to generate a future where all people have access to healthy diets, which are produced in sustainable and resilient ways that restore nature and deliver just, equitable livelihoods.
A rigorous, science-based monitoring framework can support evidence-based policymaking and the work of those who hold key actors accountable in this transformation process. Monitoring can illustrate current performance, facilitate comparisons across geographies and over time, and track progress. We propose a framework centered around five thematic areas related to (1) diets, nutrition, and health; (2) environment and climate; and (3) livelihoods, poverty, and equity; (4) governance; and (5) resilience and sustainability. We hope to call attention to the need to monitor food systems globally to inform decisions and support accountability for better governance of food systems as part of the transformation process. Transformation is possible in the next decade, but rigorous evidence is needed in the countdown to the 2030 SDG global goals.
Over the past 15 yr, examples of exotic radio-quiet quasars with intrinsically weak or absent broad emission line regions (BELRs) have emerged from large-scale spectroscopic sky surveys. Here, we ...present spectroscopy of seven such weak emission line quasars (WLQs) at moderate redshifts (z = 1.4-1.7) using the X-shooter spectrograph, which provides simultaneous optical and near-infrared spectroscopy covering the rest-frame ultraviolet (UV) through optical. These new observations effectively double the number of WLQs with spectroscopy in the optical rest-frame, and they allow us to compare the strengths of (weak) high-ionization emission lines (e.g., C IV) to low-ionization lines (e.g., Mg II, Hbeta, Halpha) in individual objects. We detect broad Hbeta and Halpha emission in all objects, and these lines are generally toward the weaker end of the distribution expected for typical quasars (e.g., Hbeta has rest-frame equivalent widths ranging from 15-40 A). However, these low-ionization lines are not exceptionally weak, as is the case for high-ionization lines in WLQs. The X-shooter spectra also display relatively strong optical Fe II emission, HbetaFWHM lap 4000 km s super(-1), and significant C IV blueshifts ( approximately 1000-5500 km s super(-1)) relative to the systemic redshift; two spectra also show elevated UV Fe II emission, and an outflowing component to their (weak) Mg II emission lines. These properties suggest that WLQs are exotic versions of "wind-dominated" quasars. Their BELRs either have unusual high-ionization components, or their BELRs are in an atypical photoionization state because of an unusually soft continuum.
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