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Leukocyte Trafficking and Regulation of Murine Hematopoietic Stem Cells and Their Niches
Hematopoietic stem cells (HSC) are the most powerful type of adult stem cell found in the body. Hematopoietic stem cells are multipotent and capable of giving rise to all other types of hematopoietic cells found in the organism. A single HSC is capable of regenerating a functional hematopoietic system when transplanted into a recipient. Hematopoietic stem cells reside in the bone marrow in specific multicellular structures called niches. These niches are indispensable for maintaining and regulating HSC numbers and function. It has become increasingly clearer that HSC and their niches can also be regulated by migrating leukocytes. Here we will discuss the composition of murine bone marrow niches and how HSC and their niches are regulated by different types of leukocytes that traffic between the periphery and the niche. Unless otherwise indicated all the studies discussed below were performed in mouse models.
Journal Article
The last age of magic
\"Led by Wonder Woman this team of Zatanna, Swamp Thing, Man-Bat and Detective Chimp must bring the fight against all supernatural foes too big for the World's Greatest Super Heroes! Earth's magic once belonged to them. Now they want the magic back. But who exactly are they? It's up to the new Justice League Dark to find out and stop this nightmarish new threat at all costs! After the events of NO JUSTICE, Wonder Woman guides the misfit magic mix against enemies too fantastic even for the Justice League. Plus, what awful things are coming through the Tree of Wonder? Dark days ahead.\"-- Provided by publisher.
Book
Efficacy and safety of transcranial direct current stimulation as an add-on treatment for obsessive-compulsive disorder: a randomized, sham-controlled trial
Obsessive-compulsive disorder (OCD) is a frequent, disabling disorder with high rates of treatment resistance. Transcranial direct current stimulation (tDCS) is a safe, tolerable noninvasive neuromodulation therapy with scarce evidence for OCD. This double-blind, randomized, and sham-controlled study investigates the efficacy of tDCS as add-on treatment for treatment-resistant OCD (failure to respond to at least one previous pharmacological treatment). On 20 consecutive weekdays (4 weeks), 43 patients with treatment-resistant OCD underwent 30 min active or sham tDCS sessions, followed by a 8 week follow-up. The cathode was positioned over the supplementary motor area (SMA) and the anode over the left deltoid. The primary outcome was the change in baseline Y-BOCS score at week 12. Secondary outcomes were changes in mood and anxiety and the occurrence of adverse events. Response was evaluated considering percent decrease of baseline Y-BOCS scores and the Improvement subscale of the Clinical Global Impression (CGI-I) between baseline and week 12. Patients that received active tDCS achieved a significant reduction of OCD symptoms than sham, with mean (SD) Y-BOCS score changes of 6.68 (5.83) and 2.84 (6.3) points, respectively (Cohen’s d: 0.62 (0.06–1.18), p = 0.03). We found no between-group differences in responders (four patients in the active tDCS and one in the sham group). Active tDCS of the SMA was not superior to sham in reducing symptoms of depression or anxiety. Patients in both groups reported mild adverse events. Our results suggest that cathodal tDCS over the SMA is an effective add-on strategy in treatment-resistant OCD.
Journal Article
Arteriolar niches maintain haematopoietic stem cell quiescence
Cell cycle quiescence is a critical feature contributing to haematopoietic stem cell (HSC) maintenance. Although various candidate stromal cells have been identified as potential HSC niches, the spatial localization of quiescent HSCs in the bone marrow remains unclear. Here, using a novel approach that combines whole-mount confocal immunofluorescence imaging techniques and computational modelling to analyse significant three-dimensional associations in the mouse bone marrow among vascular structures, stromal cells and HSCs, we show that quiescent HSCs associate specifically with small arterioles that are preferentially found in endosteal bone marrow. These arterioles are ensheathed exclusively by rare NG2 (also known as CSPG4)
+
pericytes, distinct from sinusoid-associated leptin receptor (LEPR)
+
cells. Pharmacological or genetic activation of the HSC cell cycle alters the distribution of HSCs from NG2
+
periarteriolar niches to LEPR
+
perisinusoidal niches. Conditional depletion of NG2
+
cells induces HSC cycling and reduces functional long-term repopulating HSCs in the bone marrow. These results thus indicate that arteriolar niches are indispensable for maintaining HSC quiescence.
Immunofluorescence imaging and computational modelling are used to study the spatial distribution of different cell types within the haematopoietic stem cell (HSC) niche; findings show that quiescent HSCs associate specifically with small arterioles that are preferentially found in the endosteal bone marrow and are essential in maintaining this quiescence.
Haematopoietic stem cell niche characterized
Paul Frenette and colleagues used whole-mount confocal immunofluorescence imaging and computational modelling to study the spatial distribution of different cell types within the hematopoietic stem cell (HSC) niche. They found that quiescent HSCs associate specifically with small arterioles that are preferentially found in endosteal bone marrow and that these arterioles are essential in maintaining HSC quiescence. These results thus suggest that distinct HSC niches, quiescent or proliferative, are conferred by distinct blood vessel types.
Journal Article
Hox11 expressing regional skeletal stem cells are progenitors for osteoblasts, chondrocytes and adipocytes throughout life
Multipotent mesenchymal stromal cells (MSCs) are required for skeletal formation, maintenance, and repair throughout life; however, current models posit that postnatally arising long-lived adult MSCs replace transient embryonic progenitor populations. We previously reported exclusive expression and function of the embryonic patterning transcription factor, Hoxa11, in adult skeletal progenitor-enriched MSCs. Here, using a newly generated
Hoxa11-CreER
T2
lineage-tracing system, we show
Hoxa11
-lineage marked cells give rise to all skeletal lineages throughout the life of the animal and persist as MSCs.
Hoxa11
lineage-positive cells give rise to previously described progenitor-enriched MSC populations marked by
LepR-Cre
and
Osx-CreER
, placing them upstream of these populations. Our studies establish that Hox-expressing cells are skeletal stem cells that arise from the earliest stages of skeletal development and self-renew throughout the life of the animal.
Prior evidence suggested mesenchymal stromal cells (MSCs) required for skeletal formation, maintenance, and repair arise postnatally. Here, the authors show that Hoxa11 lineage-marked cells give rise to all skeletal lineages from embryogenesis through adulthood and are upstream progenitors of LepR- and Osx-lineage MSCs
Journal Article
Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration
Many chemotherapy drugs cause sensory nerve damage as well as long-lasting damage to hematopoietic regeneration in the bone marrow. Paul Frenette and his colleagues show that this hematopoietic damage is caused by injury to bone marrow sympathetic nerve fibers, disrupting the hematopoietic stem cell niche. These findings point to the potential of neuroprotective agents in preserving hematopoietic function in chemotherapy-treated patients with cancer.
Anticancer chemotherapy drugs challenge hematopoietic tissues to regenerate but commonly produce long-term sequelae. Chemotherapy-induced deficits in hematopoietic stem or stromal cell function have been described, but the mechanisms mediating hematopoietic dysfunction remain unclear. Administration of multiple cycles of cisplatin chemotherapy causes substantial sensory neuropathy. Here we demonstrate that chemotherapy-induced nerve injury in the bone marrow of mice is a crucial lesion impairing hematopoietic regeneration. Using pharmacological and genetic models, we show that the selective loss of adrenergic innervation in the bone marrow alters its regeneration after genotoxic insult. Sympathetic nerves in the marrow promote the survival of constituents of the stem cell niche that initiate recovery. Neuroprotection by deletion of
Trp53
in sympathetic neurons or neuroregeneration by administration of 4-methylcatechol or glial-derived neurotrophic factor (GDNF) promotes hematopoietic recovery. These results demonstrate the potential benefit of adrenergic nerve protection for shielding hematopoietic niches from injury.
Journal Article
The intergenerational relationship between conditional cash transfers and newborn health
Background
Lack of nutrition, inadequate housing, low education and limited access to quality care can negatively affect children’s health over their lifetime. Implemented in 2003, the Bolsa Familia (“Family Stipend”) Program (PBF) is a conditional cash transfer program targeting poor households in Brazil. This study investigates the long-term benefits of cash transfers through intergenerational transmission of health and poverty by assessing the early life exposure of the mother to the PBF.
Methods
We used data from the 100M SINASC-SIM cohort compiled and managed by the Center for Data and Knowledge Integration for Health (CIDACS), containing information about participation in the PBF and socioeconomic and health indicators. We analyzed five measures of newborn health: low (less than 2,500 g) and very low (less than 1,500 g) birth weight, premature (less than 37 weeks of gestation) and very premature (less than 28 weeks of gestation) birth, and the presence of some type of malformation (according to ICD-10 codes). Furthermore, we measured the early life exposure to the PBF of the mother as PBF coverage in the previous decade in the city where the mother was born. We applied multilevel logistic regression models to assess the associations between birth outcomes and PBF exposures.
Results
Results showed that children born in a household where the mother received BF were less likely to have low birth weight (OR 0.93, CI; 0.92-0.94), very low birth weight (0.87, CI; 0.84-0.89), as well as to be born after 37 weeks of gestation (OR 0.98, CI; 0.97-0.99) or 28 weeks of gestation (OR 0.93, CI; 0.88-0.97). There were no significant associations between households where the mother received BF and congenital malformation.
On average, the higher the early life exposure to the PBF of the mother, the lower was the prevalence of low birth weight, very low birth weight and congenital malformation of the newborn. No trend was noted for preterm birth.
Conclusion
The PBF might have indirect intergenerational effects on children’s health. These results provide important implications for policymakers who have to decide how to effectively allocate resources to improve child health.
Journal Article
Nutritional and productive parameters of Holstein/Zebu cows fed diets containing cactus pear
ObjectiveThis study ascertained effects of cactus pear in association with different roughage in the diet of F1 Holstein/Zebu cows on intake, nutrient digestibility, nitrogen balance, ingestive behavior and performance.MethodsEight cows with 72±11 days of lactation were used. The experimental design was simultaneous in two 4×4 Latin squares. Four experimental diets were used: Diet 1, sorghum silage as exclusive roughage; Diet 2, sorghum silage associated with cactus pear in a proportion of 50% of the roughage (dry matter basis); Diet 3, elephant grass (Pennisetum purpureum cv. Roxo) as exclusive roughage; Diet 4, elephant grass associated with cactus pear in a proportion of 50% of the roughage. The roughage:concentrate ratio was 75:25.ResultsDry matter intake (p = 0.01) was higher with sorghum silage. There were differences in dry matter intake (p = 0.01), crude protein (p<0.01), ether extract (p = 0.01), non-fibrous carbohydrates (p<0.01) and total digestible nutrients (p = 0.01) among the diets. Cactus pear in the diet reduced water intake by 44.52% (p<0.01). The nitrogen balance was 59.71% and 27.49% lower in animals treated with exclusive sorghum silage and sorghum silage associated with cactus pear in relation to diets with elephant grass and elephant grass associated with cactus pear, respectively (p<0.01). The diets did not influence the milk production (p = 0.70), 3.5% fat corrected milk production (p = 0.72) or feed efficiency (p = 0.61).ConclusionThe association of cactus pear with sorghum or elephant grass silage does not alter milk production, reduces the intake of dry matter and water and improves the digestibility of nutrients.
Journal Article
Validity Analysis of Monocular Human Pose Estimation Models Interfaced with a Mobile Application for Assessing Upper Limb Range of Motion
Human Pose Estimation (HPE) is a computer vision application that utilizes deep learning techniques to precisely locate Key Joint Points (KJPs), enabling the accurate description of a person’s pose. HPE models can be extended to facilitate Range of Motion (ROM) assessment by leveraging patient photographs. This study aims to evaluate and compare the performance of HPE models for assessing upper limbs ROM. A physiotherapist evaluated the degrees of ROM in shoulders (flexion, extension, and abduction) and elbows (flexion and extension) for fifty-two participants using both Universal Goniometer (UG) and five HPE models. Participants were instructed to repeat each movement three times to obtain measurements with the UG, then positioned while photos were captured using the NLMeasurer mobile application. The paired t-test, bias, and error measures were employed to evaluate the difference and agreement between measurement methods. Results indicated that the MoveNet Thunder INT16 model exhibited superior performance. Root Mean Square Errors obtained through this model were <10° in 8 of 10 analyzed movements. HPE models demonstrated better performance in shoulder flexion and abduction movements while exhibiting unsatisfactory performance in elbow flexion. Challenges such as image perspective distortion, environmental lighting conditions, images in monocular view, and complications in the pose may influence the models’ performance. Nevertheless, HPE models show promise in identifying KJPs and facilitating ROM measurements, potentially enhancing convenience and efficiency in assessments. However, their current accuracy for this application is unsatisfactory, highlighting the need for caution when considering automated upper limb ROM measurement with them. The implementation of these models in clinical practice does not diminish the crucial role of examiners in carefully inspecting images and making adjustments to ensure measurement reliability.
Journal Article