A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies.

Splicing factor mutations are common in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but how they alter cellular functions is unclear. We show that the pathogenic SRSF2P95H/+ mutation disrupts the splicing of mitochondrial mRNAs, impairs mitochondrial complex I function, and robustly increases mitophagy. We also identified a mitochondrial surveillance mechanism by which mitochondrial dysfunction modifies splicing of the mitophagy activator PINK1 to remove a poison intron, increasing the stability and abundance of PINK1 mRNA and protein. SRSF2P95H-induced mitochondrial dysfunction increased PINK1 expression through this mechanism, which is essential for survival of SRSF2P95H/+ cells. Inhibition of splicing with a glycogen synthase kinase 3 inhibitor promoted retention of the poison intron, impairing mitophagy and activating apoptosis in SRSF2P95H/+ cells. These data reveal a homeostatic mechanism for sensing mitochondrial stress through PINK1 splicing and identify increased mitophagy as a disease marker and a therapeutic vulnerability in SRSF2P95H mutant MDS and AML.

A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies.

Splicing factor mutations are common in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but how they alter cellular functions is unclear. We show that the pathogenic SRSF2P95H/+ mutation disrupts the splicing of mitochondrial mRNAs, impairs mitochondrial complex I function, and robustly increases mitophagy. We also identified a mitochondrial surveillance mechanism by which mitochondrial dysfunction modifies splicing of the mitophagy activator PINK1 to remove a poison intron, increasing the stability and abundance of PINK1 mRNA and protein. SRSF2P95H-induced mitochondrial dysfunction increased PINK1 expression through this mechanism, which is essential for survival of SRSF2P95H/+ cells. Inhibition of splicing with a glycogen synthase kinase 3 inhibitor promoted retention of the poison intron, impairing mitophagy and activating apoptosis in SRSF2P95H/+ cells. These data reveal a homeostatic mechanism for sensing mitochondrial stress through PINK1 splicing and identify increased mitophagy as a disease marker and a therapeutic vulnerability in SRSF2P95H mutant MDS and AML.

Using Social Media and Artificial Intelligence to Find Your Purpose.

These days, the distractions of the digital world often obscure the journey to discover one's purpose. Yet these distractions hold clues to that very purpose. This article explores social media and artificial intelligence (AI) as tools to assist individuals in uncovering and expressing their purpose. As a test subject, my social media data were analyzed by AI to identify my purpose, using accounts from LinkedIn, Facebook, Instagram, and WhatsApp. This led to my creating an AI bot named Purpose GPT, which is customized to facilitate the exploration of purpose across personal growth, professional development, thought leadership, and legacy-building dimensions. Purpose GPT employs ChatGPT 4 and the Educated Change Digital Twin technology to provide a nuanced approach to understanding and discovering one's multi-dimensional purpose in this world.

Acetylcholine receptor based chemogenetics engineered for neuronal inhibition and seizure control assessed in mice.

Epilepsy is a prevalent disorder involving neuronal network hyperexcitability, yet existing therapeutic strategies often fail to provide optimal patient outcomes. Chemogenetic approaches, where exogenous receptors are expressed in defined brain areas and specifically activated by selective agonists, are appealing methods to constrain overactive neuronal activity. We developed BARNI (Bradanicline- and Acetylcholine-activated Receptor for Neuronal Inhibition), an engineered channel comprised of the α7 nicotinic acetylcholine receptor ligand-binding domain coupled to an α1 glycine receptor anion pore domain. Here we demonstrate that BARNI activation by the clinical stage α7 nicotinic acetylcholine receptor-selective agonist bradanicline effectively suppressed targeted neuronal activity, and controlled both acute and chronic seizures in male mice. Our results provide evidence for the use of an inhibitory acetylcholine-based engineered channel activatable by both exogenous and endogenous agonists as a potential therapeutic approach to treating epilepsy.

DR.BEAT: Initial Functional Testing of a BCG Wearable Prototype for Recording Ballistocardiographic Signals.

DR.BEAT ("Digital Research on Ballistocardiography for Extraterrestrial And Terrestrial use") develops a miniaturized sensor system with signal processing to interpret ballistocardiographic signals and implements an application oriented user interface. Presented is a breadboard prototype's functional tests with regard to data completeness and plausibility. The analysis confirmed a reliability of 99.99995% over the tests and the signals displayed the expected heart-specific characteristics. These results support the ethical justifiability of an initial study.

Right Colectomy for an Inflammatory Mass in the Cecum Later Found to Be Tuberculosis.

Gastrointestinal tuberculosis (TB) is a rare manifestation of extra-pulmonary TB that is known to mimic many different gastrointestinal diseases. We present a case of an 85-year-old male patient with delayed diagnosis of gastrointestinal TB who underwent colonic resection for a cecal mass that was initially suspected to be malignant. Acid-fast staining of the surgical specimen later revealed acid-fast bacilli and multiple lymph nodes with necrotizing granulomas. The purpose of this study is to stress the importance of including gastrointestinal TB as a differential diagnosis for patients with suspected colorectal malignancy, especially when initial biopsy results do not reveal malignant features.

Adsorption of Diclofenac and PFBS on a Hair Keratin Dimer.

Environmental pollution by man-made toxic and persistent organic compounds, found throughout the world in surface and groundwater, has various negative effects on aquatic life systems and even humans. Therefore, it is important to develop and improve water treatment technologies capable of removing such substances from wastewater and purifying drinking water. The two substances investigated are the widely used painkiller diclofenac and a member of the class of "forever chemicals", perfluorobutanesulfonate. Both are known to have serious negative effects on living organisms, especially under long-term exposure, and are detectable in human hair, suggesting adsorption to a part of the hair fiber complex. In this study, a human hair keratin dimer is investigated for its ability to absorb diclofenac and perfluorobutanesulfonate. Initial predictions for binding sites are obtained via molecular docking and subjected to molecular dynamics simulations for more than 1 µs. The binding affinities obtained by the linear interaction energy method are high enough to motivate further research on human hair keratins as a sustainable, low-cost, and easily allocatable filtration material.

Expansion of human hematopoietic stem cells by inhibiting translation.

Hematopoietic stem cell (HSC) transplantation using umbilical cord blood (UCB) is a potentially life-saving treatment for leukemia and bone marrow failure but is limited by the low number of HSCs in UCB. The loss of HSCs after ex vivo manipulation is also a major obstacle to gene editing for inherited blood disorders. HSCs require a low rate of translation to maintain their capacity for self-renewal, but hematopoietic cytokines used to expand HSCs stimulate protein synthesis and impair long-term self-renewal. We previously described cytokine-free conditions that maintain but do not expand human and mouse HSCs ex vivo. Here we performed a high throughput screen and identified translation inhibitors that allow ex vivo expansion of human HSCs while minimizing cytokine exposure. Transplantation assays show a ~5-fold expansion of long-term HSCs from UCB after one week of culture in low cytokine conditions. Single cell transcriptomic analysis demonstrates maintenance of HSCs expressing mediators of the unfolded protein stress response, further supporting the importance of regulated proteostasis in HSC maintenance and expansion. This expansion method maintains and expands human HSCs after CRISPR/Cas9 editing of the BCL11A+58 enhancer, overcoming a major obstacle to ex vivo gene correction for human hemoglobinopathies.

DR.BEAT: First Insights into a Study to Collect Baseline BCG Data with a Sensor-Based Wearable Prototype in Heart-Healthy Adults.

The DR.BEAT project aims at the further development of a measurement system for recording ballistocardiographic signals into a body-worn sensor system combined with extensive signal processing, data evaluation and visualization. With a first breadboard prototype, an explorative feasibility study for acquiring initial signals of healthy cardiac activity in adults was performed. This paper briefly presents the DR.BEAT project, the breadboard prototype, the study conducted, and initial insights into the study results. The signals obtained in the study exhibit the seismocardiographic characteristics as reported in the literature and form the basis for further development of the hardware as well as the pre-processing and automated analysis algorithms in the DR.BEAT project.Clinical Relevance- The characteristics of ballisto- and seismocardiographic signals allow to infer about the mechanical work of the heart. The development of a body-worn sensor system to record ballisto- and seismocardiographic signals, compact enough for everyday wear, enables the acquisition of heart-specific parameters in terrestrial as well as extraterrestrial application scenarios. Combined with extensive signal analysis and visualization, it holds the potential to monitor heart health in a variety of contexts and support its maintenance and improvement.

When You Come to a Fork in the Road, Take It: Wnt Signaling Activates Multiple Pathways through the APC/Axin/GSK-3 Complex.

The Wnt signaling pathway is a highly conserved regulator of metazoan development and stem cell maintenance. Activation of Wnt signaling is an early step in diverse malignancies. Work over the past four decades has defined a "canonical" Wnt pathway that is initiated by Wnt proteins, secreted glycoproteins that bind to a surface receptor complex and activate intracellular signal transduction by inhibiting a catalytic complex composed of the classical tumor suppressor Adenomatous Polyposis Coli (APC), Axin, and Glycogen Synthase Kinase-3 (GSK-3). The best characterized effector of this complex is ß-catenin, which is stabilized by inhibition of GSK-3, allowing ß-catenin entrance to the nucleus and activation of Wnt target gene transcription, leading to multiple cancers when inappropriately activated. However, canonical Wnt signaling through the APC/Axin/GSK-3 complex impinges on other effectors, independently of ß-catenin, including the mechanistic Target of Rapamycin (mTOR), regulators of protein stability, mitotic spindle orientation, and Hippo signaling. This review focuses on these alternative effectors of the canonical Wnt pathway and how they may contribute to cancers.

Adsorption of Diclofenac and Its UV Phototransformation Products in an Aqueous Solution on PVDF: A Molecular Modeling Study.

The presence of pharmaceuticals in drinking water has generated considerable scientific interest in potential improvements to polymeric membranes for water purification at the nanoscale. In this work, we investigate the adsorption of diclofenac and its ultraviolet (UV) phototransformation products on amorphous and crystalline poly(vinylidene difluoride) (PVDF) membrane surfaces at the nanoscale using molecular modeling. We report binding affinities by determining the free energy landscape via the extended adaptive biasing force method. The high binding affinities of the phototransformation products found are consistent with qualitative experimental results. For diclofenac, we found similar or better affinities than those for the phototransformation products, which seems to be in contrast to the experimental findings. This discrepancy can only be explained if the maximum adsorption density of diclofenac is much lower than that of the products. Overall, negligible differences between the adsorption affinities of the crystalline phases are observed, suggesting that no tuning of the PVDF surfaces is necessary to optimize filtration capabilities.

The Tumor Suppressor Adenomatous Polyposis Coli (apc) Is Required for Neural Crest-Dependent Craniofacial Development in Zebrafish.

Neural crest (NC) is a unique vertebrate cell type arising from the border of the neural plate and epidermis that gives rise to diverse tissues along the entire body axis. Roberto Mayor and colleagues have made major contributions to our understanding of NC induction, delamination, and migration. We report that a truncating mutation of the classical tumor suppressor Adenomatous Polyposis Coli (apc) disrupts craniofacial development in zebrafish larvae, with a marked reduction in the cranial neural crest (CNC) cells that contribute to mandibular and hyoid pharyngeal arches. While the mechanism is not yet clear, the altered expression of signaling molecules that guide CNC migration could underlie this phenotype. For example, apcmcr/mcr larvae express substantially higher levels of complement c3, which Mayor and colleagues showed impairs CNC cell migration when overexpressed. However, we also observe reduction in stroma-derived factor 1 (sdf1/cxcl12), which is required for CNC migration into the head. Consistent with our previous work showing that APC directly enhances the activity of glycogen synthase kinase 3 (GSK-3) and, independently, that GSK-3 phosphorylates multiple core mRNA splicing factors, we identify 340 mRNA splicing variations in apc mutant zebrafish, including a splice variant that deletes a conserved domain in semaphorin 3f (sema3f), an axonal guidance molecule and a known regulator of CNC migration. Here, we discuss potential roles for apc in CNC development in the context of some of the seminal findings of Mayor and colleagues.

Novel Echinacea formulations for the treatment of acute respiratory tract infections in adults-A randomized blinded controlled trial.

Background: Echinacea purpurea has clinical antiviral activity against respiratory viruses and modulates immune functions. In this study, we compared higher doses of new Echinacea formulations with conventional formulations at lower, preventive doses for therapy of respiratory tract infections (RTIs). Methods: In this randomized, blinded, controlled trial, healthy adults (n = 409) were randomized between November 2018 and January 2019 to one of four Echinacea formulations, which were taken in case of an RTI for up to 10 days. New formulations A (lozenges) and B (spray) delivered an increased dose of 16,800 mg/d Echinacea extract during days 1-3 and 2,240-3,360 mg/d afterward; as controls, conventional formulations C (tablets) and D (drops) delivered a lower daily dose of 2,400 mg, usually taken for prevention. The primary endpoint was time to clinical remission of first RTI episodes based on the Kaplan-Meier analysis of patient-reported, investigator-confirmed, respiratory symptoms assessed for up to 10 days. In a sensitivity analysis, the mean time to remission beyond day 10 was calculated by extrapolating the treatment effects observed on days 7 to 10. Results: A total of 246 participants (median age 32 years, 78% female participants) were treated for at least one RTI. Recovery by day 10 (complete absence of symptoms) was achieved in 56 and 44% of patients with the new and conventional formulations, respectively, showing a median time to recovery of 10 and 11 days, respectively (p = 0.10 in intention-to-treat analysis, p = 0.07 in per-protocol analysis). In the extrapolated sensitivity analysis, new formulations resulted in a significantly shorter mean time to remission (9.6 vs. 11.0 days, p < 0.001). Among those with an identified respiratory virus, viral clearance until day 10 based on real-time PCR from nasopharyngeal swabs was more frequent with new formulations (70 vs. 53%, p = 0.046). Tolerability and safety (adverse events: 12 vs. 6%, p = 0.19) were good and similar between formulations. There was one severe adverse event with a potential hypersensitivity reaction in a recipient of the novel spray formulation. Conclusion: In adults with acute RTI, new Echinacea formulations with higher doses resulted in faster viral clearance than conventional formulations in prophylactic dosages. The trend for faster clinical recovery was not significant by day 10 but became so upon extrapolation. A dose increase during acute respiratory symptoms might improve the clinical benefits of orally administered Echinacea formulations. Trial registration: The study was registered in the Swiss National Clinical Trials Portal (SNCTP000003069) and on ClinicalTrials.gov (NTC03812900; URL https://clinicaltrials.gov/ct2/show/NCT03812900?cond=echinacea&draw=3&rank=14).

Reduction of Viral Load in Patients with Acute Sore Throats: Results from an Observational Clinical Trial with Echinacea/Salvia Lozenges.

BACKGROUND: Acute tonsillopharyngitis or sore throat is an initial sign of viral respiratory tract infection (RTI) and an optimal indicator for early antiviral and anti-inflammatory intervention. Both of these actions have been attributed to Echinacea purpurea and Salvia officinalis. METHODS: 74 patients (age 13-69 years) with acute sore throat symptoms (<48 h) were treated with five Echinacea/Salvia lozenges per day (4,000 mg Echinacea purpurea extract [Echinaforce®] and 1,893 mg Salvia officinalis extract [A. Vogel AG, Switzerland] daily) for 4 days. Symptom intensities were recorded in a diary and oropharyngeal swab samples collected for virus detection and quantification via RT-qPCR. RESULTS: The treatment was exceptionally well tolerated, no complicated RTI developed, and no antibiotic treatment was required. A single lozenge reduced throat pain by 48% (p < 0.001) and tonsillopharyngitis symptoms by 34% (p < 0.001). Eighteen patients tested virus positive at inclusion. Viral loads in these patients was reduced by 62% (p < 0.03) after intake of a single lozenge and by 96% (p < 0.02) after 4 days of treatment compared to pre-treatment. CONCLUSIONS: Echinacea/Salvia lozenges represent a valuable and safe option for the early treatment of acute sore throats capable to alleviate symptoms and contribute to reducing viral loads in the throat.Akute Tonsillopharyngitis oder Halsschmerzen/entzündungen sind ein erstes Anzeichen einer viralen Atemwegsinfektion (vAWI) und ein optimaler Indikator für eine frühzeitige antivirale und entzündungshemmende Intervention. Beide Wirkungen werden Echinacea purpurea und Salvia officinalis zugeschrieben.74 Patienten (Alter 13­69 Jahre) mit akuten Halsschmerzen/entzündungen (<48 h) wurden mit fünf Echinacea/Salvia-Lutschtabletten pro Tag (Tagesdosis: 4'000 mg Echinacea purpurea-Extrakt [Echinaforce®] und 1'893 mg Salvia officinalis Extrakt [A. Vogel AG, Schweiz]) behandelt für 4 Tage. Die Symptomintensität wurde in einem Tagebuch aufgezeichnet und Rachenabstrichproben wurden zum Virusnachweis und zur Quantifizierung mittels RT-qPCR entnommen.Die Behandlung wurde außergewöhnlich gut vertragen, es entwickelte sich keine komplizierten AWI und es waren keine Antibiotikabehandlungen erforderlich. Eine einzelne Lutschtablette reduzierte die akuten Halsschmerzen um 48% (p < 0,001) und die allgemeinen Tonsillopharyngitis Symptome um 34% (p < 0,001). Achtzehn Patienten wurden bei der Aufnahme viruspositiv getestet. Die Viruslast wurde bei diesen Patienten nach Einnahme einer einzigen Lutschtablette um 62% (p < 0,03), und nach 4-tägiger Behandlung um 96% (p < 0,02) reduziert im Vergleich zu vor der Behandlung.Echinacea/Salvia-Lutschtabletten stellen eine sichere Option für die frühzeitige Behandlung akuter Halsschmerzen/entzündungen dar, die Symptome lindern, und zur Verringerung der Viruslast im Hals beitragen können.

Galactic cosmic radiation exposure causes multifaceted neurocognitive impairments.

Technological advancements have facilitated the implementation of realistic, terrestrial-based complex 33-beam galactic cosmic radiation simulations (GCR Sim) to now probe central nervous system functionality. This work expands considerably on prior, simplified GCR simulations, yielding new insights into responses of male and female mice exposed to 40-50 cGy acute or chronic radiations relevant to deep space travel. Results of the object in updated location task suggested that exposure to acute or chronic GCR Sim induced persistent impairments in hippocampus-dependent memory formation and reconsolidation in female mice that did not manifest robustly in irradiated male mice. Interestingly, irradiated male mice, but not females, were impaired in novel object recognition and chronically irradiated males exhibited increased aggressive behavior on the tube dominance test. Electrophysiology studies used to evaluate synaptic plasticity in the hippocampal CA1 region revealed significant reductions in long-term potentiation after each irradiation paradigm in both sexes. Interestingly, network-level disruptions did not translate to altered intrinsic electrophysiological properties of CA1 pyramidal cells, whereas acute exposures caused modest drops in excitatory synaptic signaling in males. Ultrastructural analyses of CA1 synapses found smaller postsynaptic densities in larger spines of chronically exposed mice compared to controls and acutely exposed mice. Myelination was also affected by GCR Sim with acutely exposed mice exhibiting an increase in the percent of myelinated axons; however, the myelin sheathes on small calibur (< 0.3 mm) and larger (> 0.5 mm) axons were thinner when compared to controls. Present findings might have been predicted based on previous studies using single and mixed beam exposures and provide further evidence that space-relevant radiation exposures disrupt critical cognitive processes and underlying neuronal network-level plasticity, albeit not to the extent that might have been previously predicted.

Sampling the Bulk Viscosity of Water with Molecular Dynamics Simulation in the Canonical Ensemble.

The bulk viscosity, a transport coefficient in the Navier-Stokes equation, is often neglected in the continuum mechanics of Newtonian fluids. Recently, however, the role of the bulk viscosity is highlighted in the area of surface and interface-related phenomena, in systematic model up-scaling and as an important quantity for the interpretation of acoustic sensor data. The prediction of the bulk viscosity usually employs molecular dynamics and the Green-Kubo linear response theory, which is used to sample transport properties in general from molecular trajectories. Since simulations are usually carried out at specified state points in concert with the evaluation of other thermodynamic properties, the role of thermostats in molecular dynamics needs to be explored systematically. In this work, we carefully investigate the role of thermostatting schemes and numerical implementations of the Green-Kubo formalism, in particular in the canonical ensemble, using two popular water force field models. It turns out that the sampling of the bulk and shear viscosities is a delicate challenge since details of thermostatting and numerical subtleties may have an influence on the results beyond statistical uncertainties. Based on the present findings, we conclude with hints on how to construct robust sampling in the canonical ensemble for the bulk viscosity.

Toward Understanding the Diverse Roles of Perisomatic Interneurons in Epilepsy.

Epileptic seizures are associated with excessive neuronal spiking. Perisomatic γ-aminobutyric acid (GABA)ergic interneurons specifically innervate the subcellular domains of postsynaptic excitatory cells that are critical for spike generation. With a revolution in transcriptomics-based cell taxonomy driving the development of novel transgenic mouse lines, selectively monitoring and modulating previously elusive interneuron types is becoming increasingly feasible. Emerging evidence suggests that the three types of hippocampal perisomatic interneurons, axo-axonic cells, along with parvalbumin- and cholecystokinin-expressing basket cells, each follow unique activity patterns in vivo, suggesting distinctive roles in regulating epileptic networks.

Echinacea as a Potential Force against Coronavirus Infections? A Mini-Review of Randomized Controlled Trials in Adults and Children.

Echinacea purpurea has been shown to broadly inhibit coronaviruses and SARS-CoV-2 in vitro. This review discusses the available clinical evidence from randomized, blinded and controlled human studies. Two RCTs capturing incidence of viral respiratory tract infections during Echinacea preventative treatment were identified including coronavirus infections. Incidence and/or viral loads were measured by RT-PCR and symptom severity was recorded. In a first study, Jawad et al. collected nasopharyngeal swabs from adults (N = 755) over 4 months of continuous prevention. Overall, 24 and 47 enveloped virus infections occurred, including 21 and 33 coronavirus detections (229E; HKU1; OC43) with Echinaforce® extract (2400 mg daily) and placebo, respectively (p = 0.0114). In a separate study, Ogal et al. administered the same extract (1200 mg) or control for 4 months to children (4-12 years) (N = 203). Echinacea reduced the incidence of enveloped virus infections from 47 to 29 (p = 0.0038) whereas 11 and 13 coronavirus detections (229E, OC43, NL63) were counted (p > 0.05). Respiratory symptoms during coronavirus infections were significantly lower with area-under-curve AUC = 75.8 (+/-50.24) versus 27.1 (+/-21.27) score points (p = 0.0036). Importantly, viral loads in nasal secretions were significantly reduced by 98.5% in the Echinacea group, with Ct-values 31.1 [95% CI 26.3; 35.9] versus 25.0 [95% CI 20.5; 29.5] in the control group (p = 0.0479). Results from clinical studies confirm the antiviral activity found for Echinacea in vitro, embracing enveloped respiratory pathogens and therefore coronaviruses as well. Substantiating results from a new, completed study seem to extrapolate these effects to the prevention of SARS-CoV-2 infections. As hypothesized, the established broad antiviral activity of Echinacea extract appears to be inclusive for SARS-CoV-2.

Effects of lithium administration on vertebral bone disease in mucopolysaccharidosis I dogs.

Mucopolysaccharidosis (MPS) I is a lysosomal storage disease characterized by deficient activity of the enzyme alpha-L-iduronidase, leading to abnormal accumulation of heparan and dermatan sulfate glycosaminoglycans in cells and tissues. Patients commonly exhibit progressive skeletal abnormalities, in part due to failures of endochondral ossification during postnatal growth. Previously, using the naturally-occurring canine model, we showed that bone and cartilage cells in MPS I exhibit elevated lysosomal storage from an early age and that animals subsequently exhibit significantly diminished vertebral trabecular bone formation. Wnts are critical regulators of endochondral ossification that depend on glycosaminoglycans for signaling. The objective of this study was to examine whether lithium, a glycogen synthase kinase-3 inhibitor and stimulator of Wnt/beta-catenin signaling, administered during postnatal growth could attenuate progression of vertebral trabecular bone disease in MPS I. MPS I dogs were treated orally with therapeutic levels of lithium carbonate from 14 days to 6 months-of-age. Untreated heterozygous and MPS I dogs served as controls. Serum was collected at 3 and 6 months for assessment of bone turnover markers. At the study end point, thoracic vertebrae were excised and assessed using microcomputed tomography and histology. Lithium-treated animals exhibited significantly improved trabecular spacing, number and connectivity density, and serum bone-specific alkaline phosphatase levels compared to untreated animals. Growth plates from lithium-treated animals exhibited increased numbers of hypertrophic chondrocytes relative to both untreated MPS I and heterozygous animals. These findings suggest that bone and cartilage cells in MPS I are still capable of responding to exogenous osteogenic signals even in the presence of significant lysosomal storage, and that targeted osteogenic therapies may represent a promising approach for attenuating bone disease progression in MPS I.

Supramammillary regulation of locomotion and hippocampal activity.

Locomotor speed is a basic input used to calculate one's position, but where this signal comes from is unclear. We identified neurons in the supramammillary nucleus (SuM) of the rodent hypothalamus that were highly correlated with future locomotor speed and reliably drove locomotion when activated. Robust locomotion control was specifically identified in Tac1 (substance P)­expressing (SuMTac1+) neurons, the activation of which selectively controlled the activity of speed-modulated hippocampal neurons. By contrast, Tac1-deficient (SuMTac1−) cells weakly regulated locomotion but potently controlled the spike timing of hippocampal neurons and were sufficient to entrain local network oscillations. These findings emphasize that the SuM not only regulates basic locomotor activity but also selectively shapes hippocampal neural activity in a manner that may support spatial navigation.