Activating stress memory: eustressors as potential tools for plant breeding.

Plants are continuously exposed to stress conditions, such that they have developed sophisticated and elegant survival strategies, which are reflected in their phenotypic plasticity, priming capacity, and memory acquisition. Epigenetic mechanisms play a critical role in modulating gene expression and stress responses, allowing malleability, reversibility, stability, and heritability of favourable phenotypes to enhance plant performance. Considering the urgency to improve our agricultural system because of going impacting climate change, potential and sustainable strategies rely on the controlled use of eustressors, enhancing desired characteristics and yield and shaping stress tolerance in crops. However, for plant breeding purposes is necessary to focus on the use of eustressors capable of establishing stable epigenetic marks to generate a transgenerational memory to stimulate a priming state in plants to face the changing environment.

Is off-label thrombolysis safe and effective in a real-life primary stroke center? A retrospective analysis of data from a 5-year prospective database.

BACKGROUND: Intravenous thrombolysis (IVT) use for acute ischemic stroke (AIS) varies among countries, partly due to guidelines and product labeling changes. The study aim was to identify the characteristics of patients with AIS treated with off-label IVT and to determine its safety when performed in a primary stroke center (PSC). METHODS: This observational, single-center study included all consecutive patients admitted to Perpignan PSC for AIS and treated with IVT and patients transferred for EVT, between January 1, 2015 and December 31, 2019. Data of patients treated with IVT according to ("in-label group") or outside ("off-label") the initial guidelines and manufacturer's product specification were compared. Safety was assessed using symptomatic intracerebral hemorrhage (SIH) as the main adverse event. RESULTS: Among the 892 patients in the database (834 screened by MRI, 93.5%), 746 were treated by IVT: 185 (24.8%) "in-label" and 561 (75.2%) "off-label". In the "off-label" group, 316 (42.4% of the cohort) had a single criterion for "off-label" use, 197 (26.4%) had two, and 48 (6.4%) had three or more criteria, without any difference in IVT safety pattern among them. SIH rates were comparable between the "off-label" and "in-label" groups (2.7% vs. 1.1%, P=0.21); early neurological deterioration and systematic adverse event due to IVT treatment were similar in the 2 groups. "Off-label" patients had higher in-hospital (8.7% vs. 3.8%, P=0.05) and 3-month mortality rates (12.1% vs 5.4%, P<0.01), but this is explained by confounding factors as they were older (76 vs 67 years, P<0.0001) and more dependent (median modified Rankin scale score 0.4 vs 0.1, P<0.0001) at admission. CONCLUSIONS: "Off-label" thrombolysis for AIS seems to be safe and effective in the routine setting of a primary stroke center.

Niemann-Pick disease type-B: a unique case report with compound heterozygosity and complicated lipid management.

BACKGROUND: Niemann-Pick disease (NPD) is a rare autosomal recessive hereditary disease characterized by deficient activity of acid sphingomyelinase. CASE PRESENTATION: We present a case of NPD type B with a unique compound heterozygosity for SMPD1 (NM_000543.4:c.[84delC];[96G > A]) in which both mutations that induce an early stop codon are located before the second in-frame initiation codon. The clinical presentation of the patient is compatible with NPD type B. She was initially diagnosed of Gaucher Disease, but her altered lipid profile led to a clinical suspicion of NPD. Combined high doses of atorvastatin and ezetimibe were given to treat the severe hypercholesterolemia. CONCLUSIONS: The pharmacological management of the lipid profile in these patients is important. A unique compound mutation in SMPD1 gene is described.

Elastic modulus and migration capability of drug treated leukemia cells K562.

Leukemia is a commonly seen disease caused by abnormal differentiation of hematopoietic stem cells and blasting in bone marrow. Despite drugs are used to treat the disease clinically, the influence of these drugs on leukemia cells' biomechanical properties, which are closely related to complications like leukostasis or infiltration, is still unclear. Due to non-adherent and viscoelastic nature of leukemia cells, accurate measurement of their elastic modulus is still a challenging issue. In this study, we adopted rate-jump method together with optical tweezers indentation to accurately measure elastic modulus of leukemia cells K562 after phorbol 12-myristate 13-acetate (PMA), all-trans retinoic acid (ATRA), Cytoxan (CTX), and Dexamethasone (DEX) treatment, respectively. We found that compared to control sample, K562 cells treated by PMA showed nearly a threefold increase in elastic modulus. Transwell experiment results suggested that the K562 cells treated with PMA have the lowest migration capability. Besides, it was shown that the cytoskeleton protein gene α-tubulin and vimentin have a significant increase in expression after PMA treatment by qPCR. The results indicate that PMA has a significant influence on protein expression, stiffness, and migration ability of the leukemia cell K562, and may also play an important role in the leukostasis in leukemia.

The effect of post-stroke hyperglycaemia on the levels of brain damage and repair-related circulating biomarkers: the Glycaemia in Acute Stroke Study II.

BACKGROUND AND PURPOSE: The aim was to identify whether post-stroke hyperglycaemia (PSH) influences the levels of circulating biomarkers of brain damage and repair, and to explore whether these biomarkers mediate the effect of PSH on the ischaemic stroke (IS) outcome. METHODS: This was a secondary analysis of the Glycaemia in Acute Stroke II study. Biomarkers of inflammation, prothrombotic activity, endothelial dysfunction, blood-brain barrier rupture, cell death and brain repair processes were analysed at 24-48 h (baseline) and 72-96 h (follow-up) after IS. The associations of the biomarkers and stroke outcome (modified Rankin Scale score at 3 months) based on the presence of PSH were compared. RESULTS: A total of 174 patients participated in this sub-study. Brain-derived neurotrophic factor (BDNF) at admission was negatively correlated with glucose levels. PSH was associated with a trend toward higher levels of endothelial progenitor cells (EPCs) at baseline. The EPCs in the PSH group then decreased in the follow-up samples (-8.5 ± 10.3) compared with the non-PSH group (4.7 ± 7.33; P = 0.024). However, neither BDNF nor EPC values had correlation with the 3-month outcome. Higher interleukin-6 at follow-up was associated with poor outcomes (modified Rankin Scale > 2) independently of PSH. CONCLUSION: Post-stroke hyperglycaemia appears to be associated with a negative regulation of BDNF and a different reaction in EPC levels. However, neither BDNF nor EPCs showed significant mediation of the PSH association with IS outcome, and only higher interleukin-6 in the follow-up samples (72-96 h) was related to poor outcomes, independently of PSH status. Further studies are needed to achieve definite conclusions.

Draft genome of the fungicidal biological control agent Burkholderia anthina strain XXVI.

Burkholderia anthina XXVI is a rhizosphere bacterium isolated from a mango orchard in Mexico. This strain has a significant biological control activity against the causal agent of mango anthracnose, Colletotrichum gloeosporioides, likely through the production of siderophores and other secondary metabolites. Here, we present a draft genome sequence of B. anthina XXVI (approximately 7.7 Mb; and G + C content of 67.0%), with the aim of gaining insight into the genomic basis of antifungal modes of action, ecological success as a biological control agent, and full biosynthetic potential.

Alignment sensing for optical cavities using radio-frequency jitter modulation.

Alignment sensing is often required in precision interferometry applications such as Advanced LIGO in order to achieve the optimum performance. Currently favored sensing schemes rely on the use of two separate radio-frequency (RF) quadrant photodetectors and Gouy phase telescopes to determine the alignment of a beam relative to an optical cavity axis. In this paper, we demonstrate an alternative sensing scheme that has potential advantages over the current standard schemes. We show that by using electro-optic beam deflectors to impose RF jitter sidebands on a beam, it is possible to extract full alignment signals for two in-line optical cavities from just one single-element photodetector in reflection of each cavity.

Pazopanib in pretreated advanced neuroendocrine tumors: a phase II, open-label trial of the Spanish Task Force Group for Neuroendocrine Tumors (GETNE).

BACKGROUND: The management of advanced neuroendocrine tumors (NETs) has recently changed. We assessed the activity of pazopanib after failure of other systemic treatments in advanced NETs. METHODS: This was a multicenter, open-label, phase II study evaluating pazopanib as a single agent in advanced NETs (PAZONET study). The clinical benefit rate (CBR) at 6 months was the primary end point. Translational correlation of radiological response and progression-free survival (PFS) with circulating and tissue biomarkers was also evaluated. RESULTS: A total of 44 patients were enrolled. Twenty-five patients (59.5%) were progression-free at 6 months (4 partial responses, 21 stable diseases) with a median PFS of 9.5 months [95% confidence interval (CI) 4.8-14.1]. The CBR varied according to prior therapy received, with 73%, 60% and 25% in patients treated with prior multitarget inhibitors, prior mTOR inhibitors and both agents, respectively. A nonsignificant increase in PFS was observed in patients presenting lower baseline circulating tumor cell (CTC) counts (9.1 versus 5.8 months; P = 0.22) and in those with decreased levels of soluble-vascular endothelial growth factor receptor-2 (sVEGFR-2) (12.6 versus 9.1 months; P = 0.067). A trend toward reduced survival was documented in patients with VEGFR3 rs307821 and rs307826 missense polymorphisms [hazard ratio (HR): 12.3; 95% CI 1.09-139.2; P = 0.042 and HR: 6.9; 95% CI 0.96-49.9; P = 0.055, respectively]. CONCLUSIONS: Pazopanib showed clinical activity in patients with advanced NETs regardless of previous treatments. Additionally, CTCs, soluble-s VEFGR-2 and VEGFR3 gene polymorphisms constitute potential biomarkers for selecting patients for pazopanib (NCT01280201). CLINICAL TRIAL NUMBER: NCT01280201.

Cerebral venous thrombosis.

Cerebral venous thrombosis is part of the so-called thrombosis in unusual sites. It is defined as an occlusion in the cerebral venous territory. Its incidence is progressively increasing, especially in developing countries. It is more frequently observed in young women, with hormonal factors such as pregnancy or hormonal contraception being significant risk factors in the development of this condition. The clinical presentation will depend fundamentally on the topography of the thrombosis, with a confirmatory diagnosis based mainly on imaging tests. The treatment generally consists of anticoagulation, and other options may be considered depending on the severity of the case. Overall, the prognosis is better than that of other intracranial vascular disorders. This review describes the current evidence available regarding cerebral venous thrombosis.

Medial tab-type fasciocutaneous flap as an alternative for the management of soft tissue defects of the leg. / Colgajo fasciocutáneo tipo lengüeta medial como alternativa para el manejo de defectos de tejidos blandos en la pierna.

BACKGROUND: Selecting the right technique for lower limb soft tissue reconstruction is a therapeutic challenge. Despite having several reconstruction options, it's important to choose a technique that is effective and with the least possible donor site morbidity. OBJECTIVE: Demonstrate the therapeutic efficacy of the medial tab flap in soft tissue reconstruction on the leg, compared to conventional flaps. MATERIALS AND METHODS: Cohort study matched by age. 64 patients with soft tissue defects were selected and according to the intervention divided in: group 1)medial tab flap, and group 2)conventional flaps (sural, soleus, gastrocnemius) followed up to one year postoperatively. OUTCOME VARIABLES: surgical time in minutes, healing, healing time in days, complications. RESULTS: The patients who underwent surgery with medial tab flap and with conventional flaps healed completely. The healing time was 16.2±11.2 days in the tab flap and 16.1±11.2 days in conventional flaps, no statistically significant differences were found between the groups (P=.89). The surgical time for tab flaps was 225.2±117.8minutes, and 191.3±117.2minutes for the comparison flaps (P=.65), there were no statistically significant differences. There were no complications in the medial tab flaps. CONCLUSION: The findings suggest that the medial tab flap technique is as effective as the conventional flap technique, with complete flap survival and healing, and without any major complications in this studied group.

Osteogenic-angiogenic coupled response of cobalt-containing mesoporous bioactive glasses in vivo.

The incorporation of cobalt ions into the composition of bioactive glasses has emerged as a strategy of interest for bone regeneration purposes. In the present work, we have designed a set of bioactive mesoporous glasses SiO2-CaO-P2O5-CoO (Co-MBGs) with different amounts of cobalt. The physicochemical changes introduced by the Co2+ ion, the in vitro effects of Co-MBGs on preosteoblasts and endothelial cells and their in vivo behaviour using them as bone grafts in a sheep model were studied. The results show that Co2+ ions neither destroy mesoporous ordering nor inhibit in vitro bioactive behaviour, exerting a dual role as network former and modifier for CoO concentrations above 3 % mol. On the other hand, the activity of Co-MBGs on MC3T3-E1 preosteoblasts and HUVEC vascular endothelial cells is dependent on the concentration of CoO present in the glass. For low Co-MBGs concentrations (1mg/ml) cell viability is not affected, while the expression of osteogenic (ALP, RUNX2 and OC) and angiogenic (VEGF) genes is stimulated. For Co-MBGs concentration of 5 mg/ml, cell viability decreases as a function of the CoO content. In vivo studies show that the incorporation of Co2+ ions to the MBGs improves the bone regeneration activity of these materials, despite the deleterious effect that this ion has on bone-forming cells for any of the Co-MBG compositions studied. This contradictory effect is explained by the marked increase in angiogenesis that takes place inside the bone defect, leading to an angiogenesis-osteogenesis coupling that compensates for the partial decrease in osteoblast cells. STATEMENT OF SIGNIFICANCE: The development of new bone grafts implies to address the need for osteogenesis-angiogenesis coupling that allows bone regeneration with viable tissue in the long term. In this sense the incorporation of cobalt ions into the composition of bioactive glasses has emerged as a strategy of great interest in this field. Due to the potential cytotoxic effect of cobalt ions, there is an important controversy regarding the suitability of their incorporation in bone grafts. In this work, we address this controversy after the implantation of cobalt-doped mesoporous bioactive glasses in a sheep model. The incorporation of cobalt ions in bioactive glasses improves the bone regeneration ability of these bone grafts, due to enhancement of the angiogenesis-osteogenesis coupling.

Charge density waves tuned by biaxial tensile stress.

The precise arrangement and nature of atoms drive electronic phase transitions in condensed matter. To explore this tenuous link, we developed a true biaxial mechanical deformation device working at cryogenic temperatures, compatible with x-ray diffraction and transport measurements, well adapted to layered samples. Here we show that a slight deformation of TbTe3 can have a dramatic influence on its Charge Density Wave (CDW), with an orientational transition from c to a driven by the a/c parameter, a tiny coexistence region near a = c, and without space group change. The CDW transition temperature Tc displays a linear dependence with a / c - 1 while the gap saturates out of the coexistence region. This behaviour is well accounted for within a tight-binding model. Our results question the relationship between gap and Tc in RTe3 systems. This method opens a new route towards the study of coexisting or competing electronic orders in condensed matter.

Surface bioactivation of Polyetheretherketone (PEEK) by magnesium chondroitin sulfate (MgCS) as orthopedic implants for reconstruction of skeletal defects.

Polyether-ether-ketone (PEEK) is clinically used as a bio-implant for the healing of skeletal defects. However, the osseointegration of clinical-sized bone grafts remains limited. In this study, surface-porous PEEK was created by using a sulfonation method and a metal-polysaccharide complex MgCS was introduced on the surface of sulfonated PEEK to form MgCS@SPEEK. The as-prepared MgCS@SPEEK was found to have a porous surface with good hydrophilicity and bioactivity. This was followed by an investigation into whether MgCS loaded onto sulfonated PEEK surfaces could promote osseointegration and angiogenesis. The in vitro results showed that MgCS@SPEEK had a positive effect on reducing the expression levels of inflammatory genes and promoting osteogenesis and angiogenesis-related genes expression levels. Furthermore, porous MgCS@SPEEK was implanted in critical-sized rat tibial defects for in vivo evaluation of osseointegration. The micro-computed tomography evaluation results revealed substantial bone formation at 4 and 8 weeks. Collectively, these findings indicate that MgCS@SPEEK could provide improved osseointegration and an attractive strategy for orthopaedic applications.

Relationship of dehydroepiandrosterone sulfate with overweight and insulin sensitivity in 12-16-year-old Spanish children.

DHEA-S is the most abundant steroid hormone in human circulation. Although a relationship of DHEA-S with obesity-related diseases has been reported, the metabolic role of this hormone remains unclear, particularly in children. In our study, we have investigated the relationship of DHEA-S levels with anthropometric variables, insulin, HOMA, and free fatty acids in adolescents. The study sample included 812 healthy 12-16-year-old children (383 boys and 429 girls). Plasma DHEA-S was determined by RIA, insulin concentrations by IRMA, and free fatty acids by using a commercial kit. Insulin resistance was estimated using the HOMA index. No significant differences in plasma DHEA-S levels were found between sexes. DHEA-S levels in overweight children were significantly higher than in normal-weight children. DHEA-S levels were significantly correlated with weight and BMI after adjusting for age. Significant positive correlations between DHEA-S and free fatty acids levels were found after adjusting for age and BMI, particularly in boys, but not between DHEA-S levels and insulin or HOMA in either gender. DHEA-S levels in 12-16-year-old children are correlated with weight and BMI independently of age. We failed to find any association between DHEA-S and insulin levels, but we did find a -significant correlation between DHEA-S and free fatty acids levels, suggesting that its association with free fatty acids may be related to the onset of the association of DHEA-S with insulin resi-stance.

Dissemination of hepatocellular carcinoma in subcutaeous tissue after fine needle aspiration cytology (FNAC).

The hepatocellular carcinoma (HCC) is the fifth most frequent tumor in the world, and the third cause of death related to cancer. Histological samples obtained from diseased liver likely to have HCC are currently prescribed in selected patients in whose imaging studies and tumor markers are not sufficient for the diagnosis. In recent years, a risk of tumoral seeding along needle tract of FNAC to obtain histological samples has been reported. We present a case of tumor implantation of HCC cells in the needle tract, a year and four months after a percutaneous fine needle aspiration cytology (FNAC).

Correlation between contrast sensitivity and morphological features obtained by OCT in patients with age-related macular degeneration treated with a loading dose of vascular endothelial growth factor inhibitors.

OBJECTIVE: To determine the correlation between contrast sensitivity and morphological characteristics obtained by Optical Coherence Tomography (OCT) in patients with Age-Related Macular Degeneration treated with a loading dose of vascular endothelial growth factor inhibitors (anti-VEGF). DESIGN: This is an ambispective (prospective + retrospective) observational, cross-sectional, and analytical study. PARTICIPANTS: All patients over 55 years of age with Age-Related Macular Degeneration who attended the Retina service of the Ophthalmology department and met the inclusion criteria between March-May 2022. METHODS: Data collection was carried out by reviewing the records of patients diagnosed with Age-Related Macular Degeneration of the neovascular variety treated with the loading dose of anti-VEGF. OCT studies obtained by Optovue® iVue80 prior to the application of intravitreal injections of patients who met the inclusion criteria and were currently in the first month after the last dose of anti-VEGF were analyzed. A total of 33 subjects were included, of which 30 continued follow-ups. The subjects underwent a new ophthalmological evaluation and new retinal measurements of the affected eye. Normality tests (Shapiro‒Wilk) were performed where a nonparametric data distribution was demonstrated. RESULTS: A linear regression analysis was performed comparing the logarithmic values of both visual acuity and contrast sensitivity, obtaining a significant relationship between both values after the application of treatment (P = <.0001***). Likewise, correlation was demonstrated between the decrease in contrast sensitivity values and all the characteristics evaluated in the patients' OCT. CONCLUSIONS: Antiangiogenesis strategies can lead to better results in global visual function, positively impacting contrast sensitivity.

HIF-1 inactivation empowers HIF-2 to drive hypoxia adaptation in aggressive forms of medulloblastoma.

Medulloblastoma (MB) is the most prevalent brain cancer in children. Four subgroups of MB have been identified; of these, Group 3 is the most metastatic. Its genetics and biology remain less clear than the other groups, and it has a poor prognosis and few effective treatments available. Tumor hypoxia and the resulting metabolism are known to be important in the growth and survival of tumors but, to date, have been only minimally explored in MB. Here we show that Group 3 MB tumors do not depend on the canonical transcription factor hypoxia-inducible factor-1α (HIF-1α) to mount an adaptive response to hypoxia. We discovered that HIF-1α is rendered inactive either through post-translational methylation, preventing its nuclear localization specifically in Group 3 MB, or by a low expression that prevents modulation of HIF-target genes. Strikingly, we found that HIF-2 takes over the role of HIF-1 in the nucleus and promotes the activation of hypoxia-dependent anabolic pathways. The exclusion of HIF-1 from the nucleus in Group 3 MB cells enhances the reliance on HIF-2's transcriptional role, making it a viable target for potential anticancer strategies. By combining pharmacological inhibition of HIF-2α with the use of metformin, a mitochondrial complex I inhibitor to block respiration, we effectively induced Group 3 MB cell death, surpassing the effectiveness observed in Non-Group 3 MB cells. Overall, the unique dependence of MB cells, but not normal cells, on HIF-2-mediated anabolic metabolism presents an appealing therapeutic opportunity for treating Group 3 MB patients with minimal toxicity.

Kidney transplantation outcomes in African-, Hispanic- and Caucasian-Americans with lupus.

African-American recipients of kidney transplants with lupus have high allograft failure risk. We studied their risk adjusting for: (1) socio-demographic factors: donor age, gender and race-ethnicity; recipient age, gender, education and insurance; donor-recipient race-ethnicity match; (2) immunologic factors: donor type, panel reactive antibodies, HLA mismatch, ABO blood type compatibility, pre-transplant dialysis, cytomegalovirus risk and delayed graft function (DGF); (3) rejection and recurrent lupus nephritis (RLN). Two thousand four hundred and six African-, 1132 Hispanic-, and 2878 Caucasian-Americans were followed for 12 years after transplantation. African- versus Hispanic- and Caucasian-Americans received more kidneys from deceased donors (71.6%, 57.3% and 55.1%) with higher two HLA loci mismatches for HLA-A (50%, 39.6% and 32.4%), HLA-B (52%, 42.8% and 35.6%) and HLA-DR (30%, 24.5% and 21.1%). They developed more DGF (19.5%, 13.6% and 13.4%). More African- versus Hispanic- and Caucasian-Americans developed rejection (41.7%, 27.6% and 35.9%) and RLN (3.2, 1.8 and 1.8%). 852 African-, 265 Hispanic-, and 747 Caucasian-Americans had allograft failure (p < 0.0001). After adjusting for transplant era, socio-demographic-immunologic differences, rejection and RLN, the increased hazard ratio for allograft failure of African- compared with Caucasian-Americans became non-significant (1.26 [95% confidence interval 0.78-2.04]). African-Americans with lupus have high prevalence of risk factors for allograft failure that can explain poor outcomes.