Uncharted Territories: Dynamic Hip Screw Migration Into the Pelvis Requiring Laparotomy.

Hip fractures are common in patients with poor bone quality and are seen to affect the elderly and frail population. We report a case of implant failure after fixing an unstable intertrochanteric fracture with a dynamic hip screw (DHS). The patient presented with a DHS that had migrated into the pelvis approximately six months after surgery. Plain radiographs showed migration of the DHS through the acetabulum and into the pelvis. Migration of DHS into the pelvis is an extremely rare complication and has only been reported a few times. A 71-year-old man presented with a fall and confusion. The patient reported having a fall but could not recall the exact events. Past medical history included Alzheimer's dementia, osteoporosis, left total hip replacement, right DHS, peripheral neuropathy, and recurrent falls. He had undergone reduction and fixation of a right intertrochanteric fracture with DHS implant via direct lateral approach six months before hospital admission. On examination, he had right-sided hip pain and was unable to straighten leg raise. His abdomen was soft and non-tender, with no distension or palpable masses. Neurovascular status was normal, and no signs of infection were detected. On the anteroposterior radiograph, the implant seemed to have migrated through the acetabulum and into the abdomen. A CT of the abdomen and pelvis was performed to identify any visceral injuries (negative) and for surgical planning. The patient underwent a midline laparotomy to remove the implant. Although the exact reason for the implant failure is unknown, the migration of an unbroken hip screw into the abdomen and pelvis requiring laparotomy has not been reported in literature.

The Impact of Concomitant Neck of Femur Fractures and Upper Limb Fractures on Length of Stay and Key Performance Indicators: A Single-Centre Study.

Background Hip fractures are one of the most common serious injuries seen today and constitute one of the most serious healthcare problems affecting the elderly worldwide. Due to the elderly population, associated falls and osteoporosis increase the incidence of hip fractures. Patients may remain hospitalized for several weeks, leading to one and a half million hospital bed days used each year. The reported incidence of a concurrent upper limb and a lower limb fracture is between 3% and 5%. It has been shown in the literature that patients who sustain both a hip fracture and an upper limb fracture have difficulties with rehabilitation which causes prolonged stays. The available literature on concomitant hip fracture and upper extremity fracture is limited. This study aimed to review patients with concurrent upper limb injury and hip fractures and to analyse the pattern of associated upper limb fractures, management of these fractures, length of hospital stay, mortality rates, and complications. Methodology We performed a retrospective data collection of all patients with a concomitant upper limb fracture and hip fracture from January 2017 to December 2020 at the University Hospital of Wales, Cardiff, United Kingdom. Patients were identified from the registers maintained in the ward. All patients aged over 60 years with a fragility hip fracture (managed operatively) and a concurrent upper limb fracture were included in the study. Patients aged less than 60 years were excluded. The local research department registered and approved this study as a service evaluation and therefore did not need ethical committee approval. The anatomical location of the upper limb and hip fractures was confirmed using the imaging database (Synapse). Results Of the 760 patients admitted with neck of femur fractures during this period, 39 (5.1%) patients had concomitant upper limb fractures. Only one upper limb fracture was managed with fixation, and for this study, that patient was excluded. Our retrospective search identified 38 patients, of whom 11 were men and 27 were women. Distal radius fractures were the most commonly associated upper limb fractures (55%). There was a significant increase in length of stay (43.6 days vs. 16.6 days) and delay in mobilization (58.9% vs. 81%) compared to an isolated hip fracture. There was no difference in the 30-day mortality rates. We were unable to collect the data for the Key Performance Indicator (KPI) of the National Institute for Health and Care Excellence compliant surgery, and this KPI was excluded from our study. Of the remaining five KPIs, our group of patients displayed better averages in three of the five categories, including prompt orthogeriatric review (92%), not delirious postoperatively (87%), and return to original residence (79%). Conclusions Due to the ageing population, hip fractures are increasing, and within one year of operation, have shown higher mortality rates. Annually, reports show that the worldwide incidence of fractures in the adult population ranges between 9.0 and 22.8 per 1,000. These fractures are more frequent in osteoporotic patients with weak bone quality. Following hip fractures, upper extremity fractures are the second most common among the osteoporotic, elderly population, with distal radius fractures being the most common. With the length of stay almost tripled (from 16.6 to 44.4 days), one can see this has a very big effect on costs in the National Health Service system.

In vivo reduction of RAD51-mediated homologous recombination triggers aging but impairs oncogenesis.

Homologous recombination (HR) is a prominent DNA repair pathway maintaining genome integrity. Mutations in many HR genes lead to cancer predisposition. Paradoxically, the implication of the pivotal HR factor RAD51 on cancer development remains puzzling. Particularly, no RAD51 mouse models are available to address the role of RAD51 in aging and carcinogenesis in vivo. We engineered a mouse model with an inducible dominant-negative form of RAD51 (SMRad51) that suppresses RAD51-mediated HR without stimulating alternative mutagenic repair pathways. We found that in vivo expression of SMRad51 led to replicative stress, systemic inflammation, progenitor exhaustion, premature aging and reduced lifespan, but did not trigger tumorigenesis. Expressing SMRAD51 in a breast cancer predisposition mouse model (PyMT) decreased the number and the size of tumors, revealing an anti-tumor activity of SMRAD51. We propose that these in vivo phenotypes result from chronic endogenous replication stress caused by HR decrease, which preferentially targets progenitors and tumor cells. Our work underlines the importance of RAD51 activity for progenitor cell homeostasis, preventing aging and more generally for the balance between cancer and aging.

Fetal Muse-based therapy prevents lethal radio-induced gastrointestinal syndrome by intestinal regeneration.

BACKGROUND: Human multilineage-differentiating stress enduring (Muse) cells are nontumorigenic endogenous pluripotent-like stem cells that can be easily obtained from various adult or fetal tissues. Regenerative effects of Muse cells have been shown in some disease models. Muse cells specifically home in damaged tissues where they exert pleiotropic effects. Exposition of the small intestine to high doses of irradiation (IR) delivered after radiotherapy or nuclear accident results in a lethal gastrointestinal syndrome (GIS) characterized by acute loss of intestinal stem cells, impaired epithelial regeneration and subsequent loss of the mucosal barrier resulting in sepsis and death. To date, there is no effective medical treatment for GIS. Here, we investigate whether Muse cells can prevent lethal GIS and study how they act on intestinal stem cell microenvironment to promote intestinal regeneration. METHODS: Human Muse cells from Wharton's jelly matrix of umbilical cord (WJ-Muse) were sorted by flow cytometry using the SSEA-3 marker, characterized and compared to bone-marrow derived Muse cells (BM-Muse). Under gas anesthesia, GIS mice were treated or not through an intravenous retro-orbital injection of 50,000 WJ-Muse, freshly isolated or cryopreserved, shortly after an 18 Gy-abdominal IR. No immunosuppressant was delivered to the mice. Mice were euthanized either 24 h post-IR to assess early small intestine tissue response, or 7 days post-IR to assess any regenerative response. Mouse survival, histological stainings, apoptosis and cell proliferation were studied and measurement of cytokines, recruitment of immune cells and barrier functional assay were performed. RESULTS: Injection of WJ-Muse shortly after abdominal IR highly improved mouse survival as a result of a rapid regeneration of intestinal epithelium with the rescue of the impaired epithelial barrier. In small intestine of Muse-treated mice, an early enhanced secretion of IL-6 and MCP-1 cytokines was observed associated with (1) recruitment of monocytes/M2-like macrophages and (2) proliferation of Paneth cells through activation of the IL-6/Stat3 pathway. CONCLUSION: Our findings indicate that a single injection of a small quantity of WJ-Muse may be a new and easy therapeutic strategy for treating lethal GIS.

Melanophages give rise to hyperreflective foci in AMD, a disease-progression marker.

Retinal melanosome/melanolipofuscin-containing cells (MCCs), clinically visible as hyperreflective foci (HRF) and a highly predictive imaging biomarker for the progression of age-related macular degeneration (AMD), are widely believed to be migrating retinal pigment epithelial (RPE) cells. Using human donor tissue, we identify the vast majority of MCCs as melanophages, melanosome/melanolipofuscin-laden mononuclear phagocytes (MPs). Using serial block-face scanning electron microscopy, RPE flatmounts, bone marrow transplantation and in vitro experiments, we show how retinal melanophages form by the transfer of melanosomes from the RPE to subretinal MPs when the "don't eat me" signal CD47 is blocked. These melanophages give rise to hyperreflective foci in Cd47-/--mice in vivo, and are associated with RPE dysmorphia similar to intermediate AMD. Finally, we show that Cd47 expression in human RPE declines with age and in AMD, which likely participates in melanophage formation and RPE decline. Boosting CD47 expression in AMD might protect RPE cells and delay AMD progression.

In Vivo Monitoring of Polycythemia Vera Development Reveals Carbonic Anhydrase 1 as a Potent Therapeutic Target.

Current murine models of myeloproliferative neoplasms (MPNs) cannot examine how MPNs progress from a single bone marrow source to the entire hematopoietic system. Thus, using transplantation of knock-in JAK2V617F hematopoietic cells into a single irradiated leg, we show development of polycythemia vera (PV) from a single anatomic site in immunocompetent mice. Barcode experiments reveal that grafted JAK2V617F stem/progenitor cells migrate from the irradiated leg to nonirradiated organs such as the contralateral leg and spleen, which is strictly required for development of PV. Mutant cells colonizing the nonirradiated leg efficiently induce PV in nonconditioned recipient mice and contain JAK2V617F hematopoietic stem/progenitor cells that express high levels of carbonic anhydrase 1 (CA1), a peculiar feature also found in CD34+ cells from patients with PV. Finally, genetic and pharmacologic inhibition of CA1 efficiently suppresses PV development and progression in mice and decreases PV patients' erythroid progenitors, strengthening CA1 as a potent therapeutic target for PV. SIGNIFICANCE: Follow-up of hematopoietic malignancies from their initiating anatomic site is crucial for understanding their development and discovering new therapeutic avenues. We developed such an approach, used it to characterize PV progression, and identified CA1 as a promising therapeutic target of PV. This article is highlighted in the In This Issue feature, p. 265.

Mouse model of radiation-induced premature ovarian insufficiency reveals compromised oocyte quality: implications for fertility preservation.

RESEARCH QUESTION: What is the impact of radiation exposure on oocyte quality and female fertility? DESIGN: Prepubertal mice underwent whole-body irradiation with a single dose (0.02, 0.1, 0.5, 2, 8 Gy) of gamma- or X-rays. Oocytes were quantified in irradiated (n = 36) and sham-treated (n = 8) mice. After a single exposure to 2 Gy, formation of DNA double-strand breaks (n = 10), activation of checkpoint kinase (Chk2) (n = 10) and dynamics of follicular growth (n = 18) were analysed. Fertility assessment was performed in adult irradiated mice and controls from the number of pups per mouse (n = 28) and the fetal abortion rate (n = 24). Ploidy of mature oocytes (n = 20) was analysed after CREST immunostaining, and uterine sections were examined. RESULTS: Radiation exposure induced a massive loss of primordial follicles with LD50 below 50 mGy for both gamma and X-rays. Growing follicles survived doses up to 8 Gy. This difference in radiosensitivity was not due to a different amount of radio-induced DNA damage, and Chk2 was activated in all oocytes. Exposure to a 2 Gy dose abolished the long-term fertility of females due to depletion of the ovarian reserve. Detailed analysis indicates that surviving oocytes were able to complete folliculogenesis and could be fertilized. This transient fertility allowed irradiated females to produce a single litter albeit with a high rate of fetal abortion (23%, P = 0.0096), related to altered ploidy in the surviving oocytes (25.5%, P = 0.0035). CONCLUSIONS: The effects of radiation on surviving oocyte quality question natural conception as a first-line approach in cancer survivors. Together, the data emphasize the need for fertility preservation before radiation exposure and call for reassessment of the use of cryopreserved oocytes.

The effect of intraocular pressure elevation and related ocular biometry changes on corneal OCT speckle distribution in porcine eyes.

The aim of this study was to evaluate the influence of increase in intraocular pressure (IOP) and cooccurring changes in ocular biometry parameters on the corneal optical coherence tomography (OCT) speckle distribution in ex-vivo experiments on porcine intact eyes. Twenty-three eyeballs were used in the inflation test where IOP in the anterior chamber was precisely set from 10 mmHg to 40 mmHg in steps of 5 mmHg and where eye biometry was utilized (IOL Master 700). To assess the influence of the duration of the experiment on the OCT speckle statistics, the second experiment was performed with 10 eyeballs at the constant IOP of 15 mmHg. Based on the OCT scans of central cornea (Copernicus REVO), spatial maps of the scale parameter (a) and the shape parameter (v) of the gamma distribution speckle model were estimated. The means of both parameters for each spatial map were computed within the 2 mm of the central stroma. Both distributional parameters statistically significantly varied with IOP and time (one way repeated measures ANOVA, all p-values < 0.001). The a parameter revealed a faster statistically significant increase in IOP up to 25 mmHg, regardless of time. Central corneal thickness (CCT), the anterior chamber depth, and the mean equivalent spherical power varied significantly with IOP, whereas CCT and axial length changed statistically significantly with time. Statistically significant correlation was found between CCT and the a parameter, after removing IOP as a confounding factor (r = -0.576, p < 0.001). The parameters of the gamma distribution can be used not only for identifying IOP induced changes in the optical scattering within the corneal stroma, but also in corneal geometry. The approach of corneal speckle analysis could be potentially utilized for an indirect and noninvasive assessment of some properties of corneal stroma.

Mild dyserythropoiesis and ß-like globin gene expression imbalance due to the loss of histone chaperone ASF1B.

The expression of the human ß-like globin genes follows a well-orchestrated developmental pattern, undergoing two essential switches, the first one during the first weeks of gestation (ε to γ), and the second one during the perinatal period (γ to ß). The γ- to ß-globin gene switching mechanism includes suppression of fetal (γ-globin, HbF) and activation of adult (ß-globin, HbA) globin gene transcription. In hereditary persistence of fetal hemoglobin (HPFH), the γ-globin suppression mechanism is impaired leaving these individuals with unusual elevated levels of fetal hemoglobin (HbF) in adulthood. Recently, the transcription factors KLF1 and BCL11A have been established as master regulators of the γ- to ß-globin switch. Previously, a genomic variant in the KLF1 gene, identified by linkage analysis performed on twenty-seven members of a Maltese family, was found to be associated with HPFH. However, variation in the levels of HbF among family members, and those from other reported families carrying genetic variants in KLF1, suggests additional contributors to globin switching. ASF1B was downregulated in the family members with HPFH. Here, we investigate the role of ASF1B in γ- to ß-globin switching and erythropoiesis in vivo. Mouse-human interspecies ASF1B protein identity is 91.6%. By means of knockdown functional assays in human primary erythroid cultures and analysis of the erythroid lineage in Asf1b knockout mice, we provide evidence that ASF1B is a novel contributor to steady-state erythroid differentiation, and while its loss affects the balance of globin expression, it has no major role in hemoglobin switching.

A sensitive S-Trap-based approach to the analysis of T cell lipid raft proteome.

The analysis of T cell lipid raft proteome is challenging due to the highly dynamic nature of rafts and the hydrophobic character of raft-resident proteins. We explored an innovative strategy for bottom-up lipid raftomics based on suspension-trapping (S-Trap) sample preparation. Mouse T cells were prepared from splenocytes by negative immunoselection, and rafts were isolated by a detergent-free method and OptiPrep gradient ultracentrifugation. Microdomains enriched in flotillin-1, LAT, and cholesterol were subjected to proteomic analysis through an optimized protocol based on S-Trap and high pH fractionation, followed by nano-LC-MS/MS. Using this method, we identified 2,680 proteins in the raft-rich fraction and established a database of 894 T cell raft proteins. We then performed a differential analysis on the raft-rich fraction from nonstimulated versus anti-CD3/CD28 T cell receptor (TCR)-stimulated T cells. Our results revealed 42 proteins present in one condition and absent in the other. For the first time, we performed a proteomic analysis on rafts from ex vivo T cells obtained from individual mice, before and after TCR activation. This work demonstrates that the proposed method utilizing an S-Trap-based approach for sample preparation increases the specificity and sensitivity of lipid raftomics.

Corneal pulsation and biomechanics during induced ocular pulse. An ex-vivo pilot study.

The purpose of this study was to ascertain the relationships between the amplitude of the corneal pulse (CP) signal and the parameters of corneal biomechanics during ex-vivo intraocular pressure (IOP) elevation experiments on porcine eyes with artificially induced ocular pulse cycles. Two experiments were carried out using porcine eyes. In the first one, a selected eye globe was subjected to three IOP levels (15, 30 and 45 mmHg), where changes in physical ocular pulse amplitude were controlled by infusion/withdrawal volumes (ΔV). In the second experiment, six eyes were subjected to IOP from 15 mmHg to 45 mmHg in steps of 5 mmHg with a constant ΔV, where corneal deformation parameters were measured using Corvis ST. In both experiments, at each IOP, the CP and IOP signals were acquired synchronically using a non-contact ultrasonic distance sensor and a pressure transmitter, respectively. Based on the amplitudes of the CP and IOP signals ocular pulse based corneal rigidity index (OPCRI) was calculated. Results indicate positive correlations between ΔV and the physical ocular pulse amplitude, and between ΔV and the corneal pulse amplitude (both p < 0.001). OPCRI was found to increase with elevated IOP. Furthermore, IOP statistically significantly differentiated changes in OPCRI, the amplitudes of CP and IOP signals and in most of the corneal deformation parameters (p < 0.05). The partial correlation analysis, with IOP as a control variable, revealed a significant correlation between the length of the flattened cornea during the first applanation (A1L) and the corneal pulse amplitude (p = 0.002), and between A1L and OPCRI (p = 0.003). In conclusion, this study proved that natural corneal pulsations, detected with a non-contact ultrasonic technique, reflect pressure-volume dynamics and can potentially be utilized to assess stiffness of the cornea. The proposed new rigidity index could be a simple approach to estimating corneal rigidity.

TRIM33 deficiency in monocytes and macrophages impairs resolution of colonic inflammation.

BACKGROUND: Mature myeloid cells play a crucial role in Crohn's disease (CD) but the molecular players that regulate their functions in CD are not fully characterized. We and others have shown that TRIM33 is involved in the innate immune response and in the inflammatory response but TRIM33 role in intestinal inflammation is not known. In this study, we investigated the role of TRIM33 in myeloid cells during dextran sulfate sodium (DSS)-induced colitis. METHODS: We study the role of TRIM33 during DSS-induced colitis which mimics intestinal inflammation using mice deleted for Trim33 only in mature myeloid cells (Trim33-/- mice) FINDINGS: We first show that Trim33 mRNA level is decreased in CD patient's blood monocytes suggesting a role of TRIM33 in CD. Using Trim33-/- mice, we show that these mice display an impaired resolution of colonic inflammation with an increased number of blood and colon monocytes and a decreased number of colonic macrophages. Trim33-/- monocytes are less competent for recruitment and macrophage differentiation. Finally, during resolution of inflammation, Trim33-/- colonic macrophages display an impaired M1/M2 switch and express a low level of membrane-bound TNF that is associated with an increased number of colonic neutrophils. INTERPRETATION: Our study shows an important role of TRIM33 in monocytes/macrophages during DSS-induced colitis and suggests that the decreased expression of TRIM33 in CD patient's blood monocytes might not be a consequence but might be involved in CD progression. FUND: La Ligue contre le Cancer (équipe labelisée), INSERM, CEA, Université Paris-Diderot, Université Paris-Sud.

Modeling of Magnetorheological Elastomers Using the Elastic⁻Plastic Model with Kinematic Hardening.

The paper describes the modeling process of the magnetomechanical properties of magnetorheological elastomers. Unlike the primary sources in which a viscoelastic model is commonly used, in this work, the elastic⁻plastic model with linear hardening was adopted. Its parameters were determined from data obtained in an experiment. Measurement data encompassed a range of various strain rates and amplitudes, as well as a range of magnetic field values. Model parameters as a function of a magnetic field were obtained as a result of identification. The correctness of data correlation was shown by comparing hysteresis loops τ ( γ ) . Satisfactory consistency between experimental and model research was achieved on the assumption that the model was applied only to higher strain rates, above the boundary value γ ˙ A = 0.025 ( 1 / s ) .

The Effect of Low-Magnitude Low-Frequency Vibrations (LMLF) on Osteogenic Differentiation Potential of Human Adipose Derived Mesenchymal Stem Cells.

INTRODUCTION: In the current study, we investigated the effect of low magnitude, low frequency (LMLF) mechanical vibrations on the osteogenic differentiation potential of human adipose derived mesenchymal stem cells (hASC), taken from elderly patients. METHODS: During 21 days in osteogenic culture medium, cells were periodically exposed to three different frequencies (25, 35 and 45 Hz) of continuous sinusoidal oscillation, using a vibration generator. We measured cell proliferation, cell morphology, calcium and phosphorus deposition using Almar Blue assay, fluorescence microscopy, scanning electron microscopy, and a EDX detector, respectively. Osteogenic differentiation was measured by assessing protein and mRNA levels. Osteogenesis was confirmed by detection of specific markers with alkaline phosphatase and enzyme-linked immunosorbent assays for: bone morphogenetic protein 2 (BMP-2), osteocalcin (OCL) and osteopontin (OPN). RESULTS: We found that 25 Hz vibrations had the greatest impact on hASC morphology, ultrastructure, and proliferation. We observed the formation of osteocyte- and hydroxyapatite-like structures, an increased quantity of calcium and phosphorus deposits, and increased differentiation in the stimulated groups. CONCLUSIONS: Our findings suggest that LMLF vibrations could be used to enhance cell-based therapies for treatment of bone deficits, particularly in elderly patients, where the need is greatest.

Low-Dose Irradiation Promotes Persistent Oxidative Stress and Decreases Self-Renewal in Hematopoietic Stem Cells.

Despite numerous observations linking protracted exposure to low-dose (LD) radiation and leukemia occurrence, the effects of LD irradiation on hematopoietic stem cells (HSCs) remain poorly documented. Here, we show that adult HSCs are hypersensitive to LD irradiation. This hyper-radiosensitivity is dependent on an immediate increase in the levels of reactive oxygen species (ROS) that also promotes autophagy and activation of the Keap1/Nrf2 antioxidant pathway. Nrf2 activation initially protects HSCs from the detrimental effects of ROS, but protection is transient, and increased ROS levels return, promoting a long-term decrease in HSC self-renewal. In vivo, LD total body irradiation (TBI) does not decrease HSC numbers unless the HSC microenvironment is altered by an inflammatory insult. Paradoxically, such an insult, in the form of granulocyte colony-stimulating factor (G-CSF) preconditioning, followed by LD-TBI facilitates efficient bone marrow transplantation without myeloablation. Thus, LD irradiation has long-term detrimental effects on HSCs that may result in hematological malignancies, but LD-TBI may open avenues to facilitate autologous bone marrow transplantation.

A Software Tool for Estimation of Burden of Infectious Diseases in Europe Using Incidence-Based Disability Adjusted Life Years.

The burden of disease framework facilitates the assessment of the health impact of diseases through the use of summary measures of population health such as Disability-Adjusted Life Years (DALYs). However, calculating, interpreting and communicating the results of studies using this methodology poses a challenge. The aim of the Burden of Communicable Disease in Europe (BCoDE) project is to summarize the impact of communicable disease in the European Union and European Economic Area Member States (EU/EEA MS). To meet this goal, a user-friendly software tool (BCoDE toolkit), was developed. This stand-alone application, written in C++, is open-access and freely available for download from the website of the European Centre for Disease Prevention and Control (ECDC). With the BCoDE toolkit, one can calculate DALYs by simply entering the age group- and sex-specific number of cases for one or more of selected sets of 32 communicable diseases (CDs) and 6 healthcare associated infections (HAIs). Disease progression models (i.e., outcome trees) for these communicable diseases were created following a thorough literature review of their disease progression pathway. The BCoDE toolkit runs Monte Carlo simulations of the input parameters and provides disease-specific results, including 95% uncertainty intervals, and permits comparisons between the different disease models entered. Results can be displayed as mean and median overall DALYs, DALYs per 100,000 population, and DALYs related to mortality vs. disability. Visualization options summarize complex epidemiological data, with the goal of improving communication and knowledge transfer for decision-making.

Static magnetic field enhances the viability and proliferation rate of adipose tissue-derived mesenchymal stem cells potentially through activation of the phosphoinositide 3-kinase/Akt (PI3K/Akt) pathway.

The aim of this work was to investigate the effects of 0.5T static magnetic field (sMF) on the viability and proliferation rate of human adipose-derived mesenchymal stromal stem cells (hASCs) via activation of the phosphoinositide 3-kinase/Akt (PI3K/Akt) signaling pathway. In a 7-d culture we examined cell growth kinetic and population doubling time (PDT). We also examined cell morphology and the cellular senescence markers level. Exposure to sMF enhanced the viability of these cells. However, the effect was blocked by treating the cells with LY294002, a P13K inhibitor. We compared this effect by Western Blot analysis of Akt protein expression. We also examined whether the cell response on sMF stimulation is dependent on integrin engagement and we measured integrin gene expression. Our results suggest that stimulation using sMF is a viable method to improve hASC viability. sMF is involved in mechanisms associated with controlling cell proliferative potential signaling events.

Macrophage production and activation are dependent on TRIM33.

The tripartite motif (TRIM) family of proteins plays important roles in innate immunity and antimicrobial infection. None of these proteins has been shown to directly regulate transcription of genes in monocyte/macrophage except TRIM33 that we have recently shown to be a macrophage specific transcriptional inhibitor of Ifnb1. Using ChIP-seq analyses, we now report that TRIM33 is bound to two fold more genes in immature than in mature myeloid cell lines. When located near the same genes, TRIM33 is bound to different sequences in the two cell lines suggesting a role of TRIM33 in both immature and mature myeloid cells. Accordingly, expression of TRIM33 in immature myeloid cells is necessary for efficient production of small peritoneal macrophages, monocytes and bone marrow derived macrophage (BMDM) and TRIM33 targets a subset of genes involved in the inflammatory response only in mature myeloid cells. Functionally, this targeting is associated with impaired repression of pathways regulating the late phases of lipopolysaccharide (LPS) activation of BMDM and a high sensitivity to LPS in vivo when the trim33 gene is inactivated in mature myeloid cells. These findings pinpoint TRIM33 as an important transcriptional actor of monocyte/macrophage mediated inflammation.

Paternal Insulin-like Growth Factor 2 (Igf2) Regulates Stem Cell Activity During Adulthood.

Insulin-like Growth Factor 2 (IGF2) belongs to the IGF/Insulin pathway, a highly conserved evolutionarily network that regulates growth, aging and lifespan. Igf2 is highly expressed in the embryo and in cancer cells. During mouse development, Igf2 is expressed in all sites where hematopoietic stem cells (HSC) successively expand, then its expression drops at weaning and becomes undetectable when adult HSC have reached their niches in bones and start to self-renew. In the present study, we aim to discover the role of IGF2 during adulthood. We show that Igf2 is specifically expressed in adult HSC and we analyze HSC from adult mice deficient in Igf2 transcripts. We demonstrate that Igf2 deficiency avoids the age-related attrition of the HSC pool and that Igf2 is necessary for tissue homeostasis and regeneration. Our study reveals that the expression level of Igf2 is critical to maintain the balance between stem cell self-renewal and differentiation, presumably by regulating the interaction between HSC and their niche. Our data have major clinical interest for transplantation: understanding the changes in adult stem cells and their environments will improve the efficacy of regenerative medicine and impact health- and life-span.