Galunisertib downregulates mutant type I collagen expression and promotes MSCs osteogenesis in pediatric osteogenesis imperfecta.

Qualitative alterations in type I collagen due to pathogenic variants in the COL1A1 or COL1A2 genes, result in moderate and severe Osteogenesis Imperfecta (OI), a rare disease characterized by bone fragility. The TGF-ß signaling pathway is overactive in OI patients and certain OI mouse models, and inhibition of TGF-ß through anti-TGF-ß monoclonal antibody therapy in phase I clinical trials in OI adults is rendering encouraging results. However, the impact of TGF-ß inhibition on osteogenic differentiation of mesenchymal stem cells from OI patients (OI-MSCs) is unknown. The following study demonstrates that pediatric skeletal OI-MSCs have imbalanced osteogenesis favoring the osteogenic commitment. Galunisertib, a small molecule inhibitor (SMI) that targets the TGF-ß receptor I (TßRI), favored the final osteogenic maturation of OI-MSCs. Mechanistically, galunisertib downregulated type I collagen expression in OI-MSCs, with greater impact on mutant type I collagen, and concomitantly, modulated the expression of unfolded protein response (UPR) and autophagy markers. In vivo, galunisertib improved trabecular bone parameters only in female oim/oim mice. These results further suggest that type I collagen is a tunable target within the bone ECM that deserves investigation and that the SMI, galunisertib, is a promising new candidate for the anti-TGF-ß targeting for the treatment of OI.

Functional and Molecular Analysis of Human Osteoarthritic Chondrocytes Treated with Bone Marrow-Derived MSC-EVs.

Osteoarthritis (OA) is a degenerative joint disease, causing impaired mobility. There are currently no effective therapies other than palliative treatment. Mesenchymal stromal cells (MSCs) and their secreted extracellular vesicles (MSC-EVs) have shown promise in attenuating OA progression, promoting chondral regeneration, and modulating joint inflammation. However, the precise molecular mechanism of action driving their beneficial effects has not been fully elucidated. In this study, we analyzed MSC-EV-treated human OA chondrocytes (OACs) to assess viability, proliferation, migration, cytokine and catabolic protein expression, and microRNA and mRNA profiles. We observed that MSC-EV-treated OACs displayed increased metabolic activity, proliferation, and migration compared to the controls. They produced decreased proinflammatory (Il-8 and IFN-γ) and increased anti-inflammatory (IL-13) cytokines, and lower levels of MMP13 protein coupled with reduced expression of MMP13 mRNA, as well as negative microRNA regulators of chondrogenesis (miR-145-5p and miR-21-5p). In 3D models, MSC-EV-treated OACs exhibited enhanced chondrogenesis-promoting features (elevated sGAG, ACAN, and aggrecan). MSC-EV treatment also reversed the pathological impact of IL-1ß on chondrogenic gene expression and extracellular matrix component (ECM) production. Finally, MSC-EV-treated OACs demonstrated the enhanced expression of genes associated with cartilage function, collagen biosynthesis, and ECM organization and exhibited a signature of 24 differentially expressed microRNAs, associated with chondrogenesis-associated pathways and ECM interactions. In conclusion, our data provide new insights on the potential mechanism of action of MSC-EVs as a treatment option for early-stage OA, including transcriptomic analysis of MSC-EV-treated OA, which may pave the way for more targeted novel therapeutics.

Trend and Seasonality of Hip Fractures in Catalonia, Spain: Exploring the Influence of Climate.

To describe the secular trend and seasonality of the incidence of hip fracture (HF) and its relationship with climatic variables during the period 2010-2019 in Catalonia in people aged ≥ 65 years. The results were analyzed by sex, age groups (65-74, 75-84, and ≥ 85), and types of fracture (extracapsular and intracapsular). Data on sex, age, type of fracture, year, and month of hospitalization of patients admitted with a diagnosis of HF between January 1, 2010 and December 31, 2019 were collected. Crude and standardized HF incidence (HFi) rates were obtained. Data on the monthly mean of climatological variables (temperature, insolation, icy days, rain, relative humidity, atmospheric pressure, and wind force) were obtained from the network of meteorological stations in Catalonia. Time series analytical statistics were used to identify trends and seasonality. Linear regression and a seasonal autoregressive integrated moving average (ARIMA) were used to analyze the relationship of each climatic parameter with fracture rates. In addition, generalized additive models were used to ascertain the best predictive model. The total number of HF episodes was 90,149 (74.1% in women and 25.9% in men). The total number of HFs increased by 6.4% between 2010 and 2019. The median age (SD) was 84.5 (7.14) and 54% of patients were ≥ 85 years of age. Extracapsular fractures were the most common (55%). The standardized incidence rates decreased from 728.1/100,000 (95% CI 738.6-769.3) to 624.5/100,000 (95% CI 648.7-677.0), which represents a decrease of 14.2% (p < 0.05). The decline was greater at older ages. There were seasonal variations, with higher incidences in autumn (27.2%) and winter (25.7%) and lower rates in summer (23.5%) and spring (23.6%). Seasonality was more pronounced in elderly people and men. In the bivariate regression analysis, high temperatures and greater insolation were negatively associated with the HF rate, while the number of icy days, rainy days, and high relative humidity were associated with a higher incidence of fractures in all age groups and sexes. In the regression analysis using the seasonal ARIMA model, only insolation had a consistently significant association with overall HFi, after adjusting by trend and other climatic parameters. While the global number of HFs grew in Catalonia due to increases in the elderly population, the standardized HF rate decreased during the years 2010-2019. There was a seasonal trend, with predominance in the cold months and correlations with climatic parameters, especially with insolation.

Inverse regulation of SOS1 and HKT1 protein localization and stability by SOS3/CBL4 in Arabidopsis thaliana.

To control net sodium (Na+) uptake, Arabidopsis plants utilize the plasma membrane (PM) Na+/H+ antiporter SOS1 to achieve Na+ efflux at the root and Na+ loading into the xylem, and the channel-like HKT1;1 protein that mediates the reverse flux of Na+ unloading off the xylem. Together, these opposing transport systems govern the partition of Na+ within the plant yet they must be finely co-regulated to prevent a futile cycle of xylem loading and unloading. Here, we show that the Arabidopsis SOS3 protein acts as the molecular switch governing these Na+ fluxes by favoring the recruitment of SOS1 to the PM and its subsequent activation by the SOS2/SOS3 kinase complex under salt stress, while commanding HKT1;1 protein degradation upon acute sodic stress. SOS3 achieves this role by direct and SOS2-independent binding to previously unrecognized functional domains of SOS1 and HKT1;1. These results indicate that roots first retain moderate amounts of salts to facilitate osmoregulation, yet when sodicity exceeds a set point, SOS3-dependent HKT1;1 degradation switches the balance toward Na+ export out of the root. Thus, SOS3 functionally links and co-regulates the two major Na+ transport systems operating in vascular plants controlling plant tolerance to salinity.

Subtilase-mediated biogenesis of the expanded family of SERINE RICH ENDOGENOUS PEPTIDES.

Plant signalling peptides are typically released from larger precursors by proteolytic cleavage to regulate plant growth, development and stress responses. Recent studies reported the characterization of a divergent family of Brassicaceae-specific peptides, SERINE RICH ENDOGENOUS PEPTIDES (SCOOPs), and their perception by the leucine-rich repeat receptor kinase MALE DISCOVERER 1-INTERACTING RECEPTOR-LIKE KINASE 2 (MIK2). Here, we reveal that the SCOOP family is highly expanded, containing at least 50 members in the Columbia-0 reference Arabidopsis thaliana genome. Notably, perception of these peptides is strictly MIK2-dependent. How bioactive SCOOP peptides are produced, and to what extent their perception is responsible for the multiple physiological roles associated with MIK2 are currently unclear. Using N-terminomics, we validate the N-terminal cleavage site of representative PROSCOOPs. The cleavage sites are determined by conserved motifs upstream of the minimal SCOOP bioactive epitope. We identified subtilases necessary and sufficient to process PROSCOOP peptides at conserved cleavage motifs. Mutation of these subtilases, or their recognition motifs, suppressed PROSCOOP cleavage and associated overexpression phenotypes. Furthermore, we show that higher-order mutants of these subtilases show phenotypes reminiscent of mik2 null mutant plants, consistent with impaired PROSCOOP biogenesis, and demonstrating biological relevance of SCOOP perception by MIK2. Together, this work provides insights into the molecular mechanisms underlying the functions of the recently identified SCOOP peptides and their receptor MIK2.

Ergonomia en actividades académicas desde casa

Introducción: A consecuencia de la emergencia sanitaria por el virus SARS-CoV2, las actividades académicas migraron de forma repentina a un entorno de trabajo remoto; esto provocó que los hogares de todo el mundo se convirtieran en el asentamiento urgente de las estaciones de trabajo académico. La ergonomia como disciplina científica cobra relevancia al ser un aliado subsanador para mitigar los riesgos asociados con la aparición de lesiones musculoesqueléticas. De acuerdo con la memoria estadística del Instituto Mexicano de Seguridad Social, IMSS1, en el primer año de pandemia de COVID-19 se registraron 30 860 atenciones por lesiones en la región de manos y muñecas, 9696 en la zona de cabeza y cuello, 6251 dorsopatías y 1673 atenciones por astenopia a jóvenes de entre 18 a 29 años que desarrollaban actividades escolares. Objetivo: En este sentido, se aborda la presente investigación para conocer la composición de los espacios de trabajo académico en casa y analizar si existen factores o elementos que incidan en el riesgo de lesiones musculoesqueléticas en los estudiantes del nivel superior. Metodología: A través de un modelo de ecuaciones estructurales que cuenta con el constructo latente de las posibles lesiones (PL) en manos, espalda, piernas, cabeza, vista, oído, agotamiento físico y la respiración, las variables observables se atribuyen a los espacios utilizados para las actividades académicas en casa, muebles y equipos, Condiciones y Medio Ambiente (CyMAT). Resultados y discusión: Se encontró que un mal diseño de la estación de trabajo académico en casa, aunado a la utilización inadecuada de los muebles y equipos, aumenta la posibilidad de presentar síntomas asociados con las LMEs y, por tanto, daños en la salud del estudiante. Conclusión: La mediación de las estaciones de trabajo a través de la implementación de elementos ergonómicos mejora de forma sustancial la calidad de trabajo académico en casa, y hace evidente la importancia de la ergonomía como disciplina científica.

Introduction: As a result of the health emergency of the SARS-CoV2 virus, academic activities suddenly migrated to a remote work environment, causing homes around the world to become the urgent settlement of academic workstations. Ergonomics as a scientific discipline becomes relevant as it is a healing ally to mitigate the risks associated with the appearance of musculoskeletal injuries. According to the statistical report of the Mexican Institute of Social Security, IMSS1, in the first year of the COVID 19 pandemic, 30,860 care for injuries in the hands and wrists region, 9,696 in the head and neck area, 6,251 dorsopathies and 1,673 care for asthenopia were registered to young people between 18 and 29 years old who develop school activities. Objective: In this sense, this research is addressed to know the composition of academic workspaces at home and analyze if some factors or elements affect the risk of musculoskeletal injuries in students of the higher level. Methodology: Through a structural equations model that has the latent construct of possible injuries (PL) in the hands, back, legs, head, eyesight, hearing, physical exhaustion, and breathing; the observable variables are attributed to the spaces used for academic activities at home, furniture and equipment, conditions and environment (CyMAT) Results and discussion: It is explored that a bad design of the academic workstation at home coupled with the inappropriate use of furniture and equipment increases the possibility of presenting symptoms associated with SCI and therefore, damage to the student's health. Conclusion: The mediation of workstations through the implementation of ergonomic elements substantially improves the quality of academic work at home, making evident the importance of ergonomics as a scientific discipline

Soil-borne fungi alter the apoplastic purinergic signaling in plants by deregulating the homeostasis of extracellular ATP and its metabolite adenosine.

Purinergic signaling activated by extracellular nucleotides and their derivative nucleosides trigger sophisticated signaling networks. The outcome of these pathways determine the capacity of the organism to survive under challenging conditions. Both extracellular ATP (eATP) and Adenosine (eAdo) act as primary messengers in mammals, essential for immunosuppressive responses. Despite the clear role of eATP as a plant damage-associated molecular pattern, the function of its nucleoside, eAdo, and of the eAdo/eATP balance in plant stress response remain to be fully elucidated. This is particularly relevant in the context of plant-microbe interaction, where the intruder manipulates the extracellular matrix. Here, we identify Ado as a main molecule secreted by the vascular fungus Fusarium oxysporum. We show that eAdo modulates the plant's susceptibility to fungal colonization by altering the eATP-mediated apoplastic pH homeostasis, an essential physiological player during the infection of this pathogen. Our work indicates that plant pathogens actively imbalance the apoplastic eAdo/eATP levels as a virulence mechanism.

The importance of CXCR4 expression in tumor stroma as a potential biomarker in pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the main causes of cancer mortality in the world. A characteristic feature of this cancer is that a large part of the tumor volume is composed of a stroma with different cells and factors. Among these, we can highlight the cytokines, which perform their function through binding to their receptors. Given the impact of the CXCR4 receptor in the interactions between tumor cells and their microenvironment and its involvement in important signaling pathways in cancer, it is proposed as a very promising prognostic biomarker and as a goal for new targeted therapies. Numerous studies analyze the expression of CXCR4 but we suggest focusing on the expression of CXCR4 in the stroma. METHODS: Expression of CXCR4 in specimens from 33 patients with PDAC was evaluated by immunohistochemistry techniques and matched with clinicopathological parameters, overall and disease-free survival rates. RESULTS: The percentage of stroma was lower in non-tumor tissue (32.4 ± 5.2) than in tumor pancreatic tissue (67.4 ± 4.8), P-value = 0.001. The level of CXCR4 expression in stromal cells was diminished in non-tumor tissue (8.7 ± 4.6) and higher in tumor pancreatic tissue (23.5 ± 6.1), P-value = 0.022. No significant differences were identified in total cell count and inflammatory cells between non-tumor tissue and pancreatic tumor tissue. No association was observed between CXCR4 expression and any of the clinical or pathological data, overall and disease-free survival rates. Analyzing exclusively the stroma of tumor samples, the CXCR4 expression was associated with tumor differentiation, P-value = 0.05. CONCLUSIONS: In this study, we reflect the importance of CXCR4 expression in the stroma of patients diagnosed with PDAC. Our results revealed a high CXCR4 expression in the tumor stroma, which is related to a poor tumor differentiation. On the contrary, we could not find an association between CXCR4 expression and survival and the rest of the clinicopathological variables. Focusing the study on the CXCR4 expression in the tumor stroma could generate more robust results. Therefore, we consider it key to develop more studies to enlighten the role of this receptor in PDAC and its implication as a possible biomarker.

An LRR receptor kinase controls ABC transporter substrate preferences during plant growth-defense decisions.

The exporter of the auxin precursor indole-3-butyric acid (IBA), ABCG36/PDR8/PEN3, from the model plant Arabidopsis has recently been proposed to also function in the transport of the phytoalexin camalexin. Based on these bonafide substrates, it has been suggested that ABCG36 functions at the interface between growth and defense. Here, we provide evidence that ABCG36 catalyzes the direct, ATP-dependent export of camalexin across the plasma membrane. We identify the leucine-rich repeat receptor kinase, QIAN SHOU KINASE1 (QSK1), as a functional kinase that physically interacts with and phosphorylates ABCG36. Phosphorylation of ABCG36 by QSK1 unilaterally represses IBA export, allowing camalexin export by ABCG36 conferring pathogen resistance. As a consequence, phospho-dead mutants of ABCG36, as well as qsk1 and abcg36 alleles, are hypersensitive to infection with the root pathogen Fusarium oxysporum, caused by elevated fungal progression. Our findings indicate a direct regulatory circuit between a receptor kinase and an ABC transporter that functions to control transporter substrate preference during plant growth and defense balance decisions.

The WAK-like protein RFO1 acts as a sensor of the pectin methylation status in Arabidopsis cell walls to modulate root growth and defense.

Most organisms adjust their development according to the environmental conditions. For the majority, this implies the sensing of alterations to cell walls caused by different cues. Despite the relevance of this process, few molecular players involved in cell wall sensing are known and characterized. Here, we show that the wall-associated kinase-like protein RESISTANCE TO FUSARIUM OXYSPORUM 1 (RFO1) is required for plant growth and early defense against Fusarium oxysporum and functions by sensing changes in the pectin methylation levels in the cell wall. The RFO1 dwell time at the plasma membrane is affected by the pectin methylation status at the cell wall, regulating MITOGEN-ACTIVATED PROTEIN KINASE and gene expression. We show that the extracellular domain of RFO1 binds de-methylated pectin in vitro, whose distribution in the cell wall is altered during F. oxysporum infection. Further analyses also indicate that RFO1 is required for the BR-dependent plant growth alteration in response to inhibition of pectin de-methyl-esterase activity at the cell wall. Collectively, our work demonstrates that RFO1 is a sensor of the pectin methylation status that plays a unique dual role in plant growth and defense against vascular pathogens.

Generation of human immortalized chondrocytes from osteoarthritic and healthy cartilage : a new tool for cartilage pathophysiology studies.

AIMS: After a few passages of in vitro culture, primary human articular chondrocytes undergo senescence and loss of their phenotype. Most of the available chondrocyte cell lines have been obtained from cartilage tissues different from diarthrodial joints, and their utility for osteoarthritis (OA) research is reduced. Thus, the goal of this research was the development of immortalized chondrocyte cell lines proceeded from the articular cartilage of patients with and without OA. METHODS: Using telomerase reverse transcriptase (hTERT) and SV40 large T antigen (SV40LT), we transduced primary OA articular chondrocytes. Proliferative capacity, degree of senescence, and chondrocyte surface antigen expression in transduced chondrocytes were evaluated. In addition, the capacity of transduced chondrocytes to synthesize a tissue similar to cartilage and to respond to interleukin (IL)-1ß was assessed. RESULTS: Coexpression of both transgenes (SV40 and hTERT) were observed in the nuclei of transduced chondrocytes. Generated chondrocyte cell lines showed a high proliferation capacity and less than 2% of senescent cells. These cell lines were able to form 3D aggregates analogous to those generated by primary articular chondrocytes, but were unsuccessful in synthesizing cartilage-like tissue when seeded on type I collagen sponges. However, generated chondrocyte cell lines maintained the potential to respond to IL-1ß stimulation. CONCLUSION: Through SV40LT and hTERT transduction, we successfully immortalized chondrocytes. These immortalized chondrocytes were able to overcome senescence in vitro, but were incapable of synthesizing cartilage-like tissue under the experimental conditions. Nonetheless, these chondrocyte cell lines could be advantageous for OA investigation since, similarly to primary articular chondrocytes, they showed capacity to upregulate inflammatory mediators in response to the IL-1ß cytokine.Cite this article: Bone Joint Res 2023;12(1):46-57.

S-acylated and nucleus-localized SALT OVERLY SENSITIVE3/CALCINEURIN B-LIKE4 stabilizes GIGANTEA to regulate Arabidopsis flowering time under salt stress.

The precise timing of flowering in adverse environments is critical for plants to secure reproductive success. We report a mechanism in Arabidopsis (Arabidopsis thaliana) controlling the time of flowering by which the S-acylation-dependent nuclear import of the protein SALT OVERLY SENSITIVE3/CALCINEURIN B-LIKE4 (SOS3/CBL4), a Ca2+-signaling intermediary in the plant response to salinity, results in the selective stabilization of the flowering time regulator GIGANTEA inside the nucleus under salt stress, while degradation of GIGANTEA in the cytosol releases the protein kinase SOS2 to achieve salt tolerance. S-acylation of SOS3 was critical for its nuclear localization and the promotion of flowering, but partly dispensable for salt tolerance. SOS3 interacted with the photoperiodic flowering components GIGANTEA and FLAVIN-BINDING, KELCH REPEAT, F-BOX1 and participated in the transcriptional complex that regulates CONSTANS to sustain the transcription of CO and FLOWERING LOCUS T under salinity. Thus, the SOS3 protein acts as a Ca2+- and S-acylation-dependent versatile regulator that fine-tunes flowering time in a saline environment through the shared spatial separation and selective stabilization of GIGANTEA, thereby connecting two signaling networks to co-regulate the stress response and the time of flowering.

Peripheral membrane proteins modulate stress tolerance by safeguarding cellulose synthases.

Controlled primary cell wall remodeling allows plant growth under stressful conditions, but how these changes are conveyed to adjust cellulose synthesis is not understood. Here, we identify the TETRATRICOPEPTIDE THIOREDOXIN-LIKE (TTL) proteins as new members of the cellulose synthase complex (CSC) and describe their unique and hitherto unknown dynamic association with the CSC under cellulose-deficient conditions. We find that TTLs are essential for maintaining cellulose synthesis under high-salinity conditions, establishing a stress-resilient cortical microtubule array, and stabilizing CSCs at the plasma membrane. To fulfill these functions, TTLs interact with CELLULOSE SYNTHASE 1 (CESA1) and engage with cortical microtubules to promote their polymerization. We propose that TTLs function as bridges connecting stress perception with dynamic regulation of cellulose biosynthesis at the plasma membrane.

Chondrogenic Differentiation of Human Mesenchymal Stem Cells via SOX9 Delivery in Cationic Niosomes.

Gene transfer to mesenchymal stem cells constitutes a powerful approach to promote their differentiation into the appropriate cartilage phenotype. Although viral vectors represent gold standard vehicles, because of their high efficiency, their use is precluded by important concerns including an elevated immunogenicity and the possibility of insertional mutagenesis. Therefore, the development of new and efficient non-viral vectors is under active investigation. In the present study, we developed new non-viral carriers based on niosomes to promote the effective chondrogenesis of human MSCs. Two different niosome formulations were prepared by varying their composition on non-ionic surfactant, polysorbate 80 solely (P80), or combined with poloxamer 407 (P80PX). The best niosome formulation was proven to transfer a plasmid, encoding for the potent chondrogenic transcription factor SOX9 in hMSC aggregate cultures. Transfection of hMSC aggregates via nioplexes resulted in an increased chondrogenic differentiation with reduced hypertrophy. These results highlight the potential of niosome formulations for gene therapy approaches focused on cartilage repair.

Influence of Casein Hydrolysates and Yeast on the Rheological Properties of Wheat Dough.

The influence of casein hydrolysates (CHs) and yeast on the viscoelasticity of wheat dough at 25 °C were analysed. Three wheat doughs were studied: the unyeasted dough (UYD), the unyeasted dough with CHs (UYD-C) and the yeasted dough (YD). The characteristic parameters in the linear viscoelastic range (LVER) were analysed by stress sweep at 6.3 rad/s: UYD-C dough exhibited higher values of stress (σmax) and strain (γmax) amplitudes, and softer gel network (lower complex modulus, G*) comparing with UYD dough. The oscillatory data suggest that CHs would work as (energy and time) stabilising-agents based on the greatest reticular energy (E parameter) and the lowest frequency dependence of phase angle (δ) at the low frequency range. The rotatory tests show that CHs may act as shear thinning agents in the gluten-starch network, facilitating the solid-fluid transition at the yield point (UYD-C dough). The yeasted dough (YD) exhibited a more shear sensitive structure, evidenced in the highest influence of frequency on the elastic (G') and viscous (G″) parameters, and gel to sol transition at 0.23 rad/s was observed.

The root apoplastic pH as an integrator of plant signaling.

Plant nutrition, growth, and response to environmental stresses are pH-dependent processes that are regulated at the apoplastic and subcellular levels. The root apoplastic pH is especially sensitive to external cues and can also be modified by intracellular inputs, such as hormonal signaling. Optimal crosstalk of the mechanisms involved in the extent and span of the apoplast pH fluctuations promotes plant resilience to detrimental biotic and abiotic factors. The fact that variations in local pHs are a standard mechanism in different signaling pathways indicates that the pH itself can be the pivotal element to provide a physiological context to plant cell regions, allowing a proportional reaction to different situations. This review brings a collective vision of the causes that initiate root apoplastic pHs variations, their interaction, and how they influence root response outcomes.

Impairment of the cellulose degradation machinery enhances Fusarium oxysporum virulence but limits its reproductive fitness.

Fungal pathogens grow in the apoplastic space, in constant contact with the plant cell wall (CW) that hinders microbe progression while representing a source of nutrients. Although numerous fungal CW modifying proteins have been identified, their role during host colonization remains underexplored. Here, we show that the root-infecting plant pathogen Fusarium oxysporum (Fo) does not require its complete arsenal of cellulases to infect the host plant. Quite the opposite: Fo mutants impaired in cellulose degradation become hypervirulent by enhancing the secretion of virulence factors. On the other hand, the reduction in cellulase activity had a severe negative effect on saprophytic growth and microconidia production during the final stages of the Fo infection cycle. These findings enhance our understanding of the function of plant CW degradation on the outcome of host-microbe interactions and reveal an unexpected role of cellulose degradation in a pathogen's reproductive success.

Circulating TGF-ß Pathway in Osteogenesis Imperfecta Pediatric Patients Subjected to MSCs-Based Cell Therapy.

Osteogenesis Imperfecta (OI) is a rare genetic disease characterized by bone fragility, with a wide range in the severity of clinical manifestations. The majority of cases are due to mutations in COL1A1 or COL1A2, which encode type I collagen. There is no cure for OI, and real concerns exist for current therapeutic approaches, mainly antiresorptive drugs, regarding their effectiveness and security. Safer and effective therapeutic approaches are demanded. Cell therapy with mesenchymal stem cells (MSCs), osteoprogenitors capable of secreting type I collagen, has been tested to treat pediatric OI with encouraging outcomes. Another therapeutic approach currently under clinical development focuses on the inhibition of TGF-ß pathway, based on the excessive TGF-ß signaling found in the skeleton of severe OI mice models, and the fact that TGF-ß neutralizing antibody treatment rescued bone phenotypes in those OI murine models. An increased serum expression of TGF-ß superfamily members has been described for a number of bone pathologies, but still it has not been addressed in OI patients. To delve into this unexplored question, in the present study we investigated serum TGF-ß signalling pathway in two OI pediatric patients who participated in TERCELOI, a phase I clinical trial based on reiterative infusions of MSCs. We examined not only the expression and bioactivity of circulating TGF-ß pathway in TERCELOI patients, but also the effects that MSCs therapy could elicit. Strikingly, basal serum from the most severe patient showed an enhanced expression of several TGF-ß superfamily members and increased TGF-ß bioactivity, which were modulated after MSCs therapy.

Plant-microbe interactions in the apoplast: Communication at the plant cell wall.

The apoplast is a continuous plant compartment that connects cells between tissues and organs and is one of the first sites of interaction between plants and microbes. The plant cell wall occupies most of the apoplast and is composed of polysaccharides and associated proteins and ions. This dynamic part of the cell constitutes an essential physical barrier and a source of nutrients for the microbe. At the same time, the plant cell wall serves important functions in the interkingdom detection, recognition, and response to other organisms. Thus, both plant and microbe modify the plant cell wall and its environment in versatile ways to benefit from the interaction. We discuss here crucial processes occurring at the plant cell wall during the contact and communication between microbe and plant. Finally, we argue that these local and dynamic changes need to be considered to fully understand plant-microbe interactions.