Molecular Mechanisms Regulating GRF Activity in Plant Growth, Development, and Environmental Responses.

Plants rely on complex regulatory mechanisms to ensure proper growth and development. As sessile organisms, these mechanisms must be flexible enough to adapt to changes in the environment. The GROWTH-REGULATING FACTORs (GRFs) are plant-specific transcription factors that act as a central hub controlling plant growth and development, offering promising biotechnological applications to enhance plant performance. Here, we analyze the complex molecular mechanisms that regulate GRF activity, and how their natural and synthetic variants can impact on plant growth and development. We describe the biological roles of the GRFs and examine how they regulate gene expression and contribute to the control of organ growth and the plant's response to a changing environment. This review focuses on the premise that unlocking their full biotechnological potential requires a thorough understanding of the various regulatory layers governing GRF activity, the functional divergence among GRF family members and the gene networks that they regulate.

Successful hemodialysis treatment of a Quarter Horse mare with silver maple leaf toxicity and acute kidney injury.

An adult American Quarter Horse mare presented for pigmenturia and lethargy of 12 hours' duration and was diagnosed with silver maple leaf toxicity. The mare had intravascular hemolysis and azotemia. The mare was treated with a transfusion of whole blood, fluids administered IV, antibiotics, oxygen insufflation, and supportive care. The azotemia persisted despite conventional medical management and hemodialysis was elected. After 2 intermittent hemodialysis treatments over 3 days, the azotemia almost resolved, clinical signs improved, and the mare was discharged. The blood urea nitrogen, creatinine, and electrolyte concentrations remained normal 6 months later after examination by the referring veterinarian. Hemodialysis treatment can be feasible in horses if equipment and expertise are available and should be considered as a treatment option if indicated.

Metabolic and Endocrine Insights in Donkeys.

Donkey medicine is gaining attention due to their increased use as companion animals, in shows, asinotherapy, etc. The increasing demand and unique aspects call for specialized care, requiring new information (physiology, infectious disorders, pharmacology, etc.). Since obesity is common in this species, hyperlipemia, metabolic syndrome and insulin dysregulation (ID) are common disorders in donkeys, in some cases with high mortality, either directly (multiorgan dysfunction) or indirectly due to poor quality of life (chronic laminitis). Donkeys have long-life expectancy and are often afflicted with pituitary pars intermedia dysfunction (PPID), a neurodegenerative and endocrine disease. Hyperlipemia is diagnosed based on high plasma triglyceride concentration in association with clinical findings and laboratory abnormalities from affected tissues (liver, kidney and pancreas). The measurement of resting serum insulin and plasma ACTH concentrations is the first step in ID and PPID diagnosis. In donkeys with clinical signs of ID (obesity or recurrent laminitis) or PPID (hypertrichosis, regional adiposity, laminitis and weight loss), where these hormones are in the normal or non-diagnostic range (donkey-specific cut-off values and reference ranges need to be established), dynamic tests are recommended (oral sugar test or thyrotropin-releasing hormone, respectively). Equine treatment protocols apply to donkeys, although pharmacological studies for most drugs, except pergolide, are lacking.

The effects of food on the pharmacokinetics of mycophenolate mofetil in healthy horses.

Additional immunomodulatory treatment is needed for the management of immune-mediated disease in horses. Mycophenolate mofetil (MMF) is an immunomodulatory agent used in human and veterinary medicine for the prevention of graft rejection and the management of autoimmune diseases. Few studies exist investigating the pharmacokinetics of MMF in horses. The aim of this study was to evaluate the pharmacokinetics of a single dose of MMF in healthy horses in the fed vs. fasted state. Six healthy Standardbred mares were administered MMF 10 mg/kg by a nasogastric (NG) tube in a fed and fasted state. A six-day washout period was performed between the two doses. No statistically significant differences in mycophenolic acid (MPA) concentrations were seen at any time point apart from 8 h, when plasma metabolite concentrations were significantly higher in the fasted state compared to the fed state (p = .038). Evidence of enterohepatic recirculation was seen only in the fasted state; this did not yield clinical differences in horses administered a single-dose administration but may be significant in horses receiving long-term MMF treatment.

Association of the neutrophil-lymphocyte ratio with outcome in sick hospitalized neonatal foals.

BACKGROUND: The neutrophil-lymphocyte ratio (NLR) in human medicine is an objective biomarker that reflects prognosis. The NLR as an independent biomarker to help predict nonsurvival in hospitalized neonatal foals has not been thoroughly interrogated. OBJECTIVES/HYPOTHESIS: Retrospectively evaluate if the NLR at admission is associated with nonsurvival in sick hospitalized foals <4 days old. We hypothesized that a lower NLR will be associated with nonsurvival. ANIMALS: One thousand one hundred ninety-six client-owned foals <4 days old of any breed and sex: 993 hospitalized foals and 203 healthy foals. METHODS: Retrospective multicenter study. Medical records of foals presenting to 3 equine referral hospitals were reviewed. Foals were included if they had complete CBCs, sepsis scores, and outcome data. The NLR was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. Data were analyzed by nonparametric methods and univariate analysis. RESULTS: Of the 993 sick hospitalized foals, 686 were sick nonseptic and 307 were septic. The median NLR was lower in sick hospitalized foals (median [95% confidence interval], 3.55 [0.5-13.9]) compared with healthy foals (6.61 [3.06-18.1]). Septic foals had the lowest NLR (2.00 [0.20-9.71]). The NLR was lower in nonsurviving (1.97 [1.67-2.45]) compared with surviving foals (4.10 [3.76-4.33]). Nonsurviving septic foals had the lowest NLR (1.47 [1.70-3.01]). Foals with a NLR of <3.06 or <1.6 at admission had odds ratio of 3.21 (2.24-4.29) and 4.03 (2.86-5.67) for nonsurvival, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: A NLR < 3.06 at admission in sick hospitalized foals is readily available and clinically useful variable to provide prognostic information.

Methylation of histone H3 lysine 36 is a barrier for therapeutic interventions of head and neck squamous cell carcinoma.

Approximately 20% of head and neck squamous cell carcinomas (HNSCCs) exhibit reduced methylation on lysine 36 of histone H3 (H3K36me) due to mutations in histone methylase NSD1 or a lysine-to-methionine mutation in histone H3 (H3K36M). Whether such alterations of H3K36me can be exploited for therapeutic interventions is still unknown. Here, we show that HNSCC models expressing H3K36M can be divided into two groups: those that display aberrant accumulation of H3K27me3 and those that maintain steady levels of H3K27me3. The former group exhibits reduced proliferation, genome instability, and heightened sensitivity to genotoxic agents like PARP1/2 inhibitors. Conversely, H3K36M HNSCC models with constant H3K27me3 levels lack these characteristics unless H3K27me3 is elevated by DNA hypomethylating agents or inhibiting H3K27me3 demethylases KDM6A/B. Mechanistically, H3K36M reduces H3K36me by directly impeding the activities of the histone methyltransferase NSD3 and the histone demethylase LSD2. Notably, aberrant H3K27me3 levels induced by H3K36M expression are not a bona fide epigenetic mark because they require continuous expression of H3K36M to be inherited. Moreover, increased sensitivity to PARP1/2 inhibitors in H3K36M HNSCC models depends solely on elevated H3K27me3 levels and diminishing BRCA1- and FANCD2-dependent DNA repair. Finally, a PARP1/2 inhibitor alone reduces tumor burden in a H3K36M HNSCC xenograft model with elevated H3K27me3, whereas in a model with consistent H3K27me3, a combination of PARP1/2 inhibitors and agents that up-regulate H3K27me3 proves to be successful. These findings underscore the crucial balance between H3K36 and H3K27 methylation in maintaining genome instability, offering new therapeutic options for patients with H3K36me-deficient tumors.

Effect of 5'-adenosine monophosphate-activated protein kinase agonists on insulin and glucose dynamics in experimentally induced insulin dysregulation in horses.

BACKGROUND: 5'-adenosine monophosphate-activated protein kinase (AMPK) agonists, particularly resveratrol (RES), have not been extensively evaluated for their effect on insulin dysregulation (ID) in horses. OBJECTIVES: Evaluate the effects of treatment with RES (10 mg/kg PO q12h), metformin (MET; 30 mg/kg PO q12h), and aspirin (ASP; 20 mg/kg PO q24h) on experimentally induced ID. ANIMALS: Thirty-three healthy, adult, light-breed horses. METHODS: Unblinded, placebo-controlled, experimental trial evaluating effects of AMPK agonists (RES, MET, and ASP) on experimentally induced ID. Horses were randomly assigned to a treatment group (RES, MET/ASP, RES/ASP, RES/MET/ASP, or placebo [CON]) after induction of ID with dexamethasone (0.08 mg/kg PO q24h for 7 days). Frequently sampled insulin-modified IV glucose tolerance tests (FSIGTT) and oral sugar tests (OST) were performed at baseline, 7 days after ID, and ID plus 7 days of treatment. Minimal model and OST variables were compared between (1-way ANOVA) and within (1-way ANOVA for repeated measures) groups over time to determine effects of treatment on ID. RESULTS: Administration of dexamethasone for 14 days resulted in significantly altered insulin and glucose dynamics (SI, DI, basal [glucose], and [insulin]) and produced clinical signs of laminitis in 5 out of 33 (15%) of horses included in the study. Combination therapy with RES, MET, and ASP did not significantly improve insulin and glucose dynamics in horses with experimentally induced ID. CONCLUSIONS AND CLINICAL IMPORTANCE: Metabolic testing before glucocorticoid administration should be considered in horses with clinical signs of metabolic syndrome.

PRAME induces genomic instability in uveal melanoma.

PRAME is a CUL2 ubiquitin ligase subunit that is normally expressed in the testis but becomes aberrantly overexpressed in many cancer types in association with aneuploidy and metastasis. Here, we show that PRAME is expressed predominantly in spermatogonia around the time of meiotic crossing-over in coordination with genes mediating DNA double strand break repair. Expression of PRAME in somatic cells upregulates pathways involved in meiosis, chromosome segregation and DNA repair, and it leads to increased DNA double strand breaks, telomere dysfunction and aneuploidy in neoplastic and non-neoplastic cells. This effect is mediated at least in part by ubiquitination of SMC1A and altered cohesin function. PRAME expression renders cells susceptible to inhibition of PARP1/2, suggesting increased dependence on alternative base excision repair pathways. These findings reveal a distinct oncogenic function of PRAME that can be targeted therapeutically in cancer.

Methylation of histone H3 lysine 36 is a barrier for therapeutic interventions of head and neck squamous cell carcinoma.

Approximately 20% of head and neck squamous cell carcinomas (HNSCC) exhibit reduced methylation on lysine 36 of histone H3 (H3K36me) due to mutations in histone methylase NSD1 or a lysine-to-methionine mutation in histone H3 (H3K36M). Whether such alterations of H3K36me can be exploited for therapeutic interventions is still unknown. Here, we show that HNSCC models expressing H3K36M can be divided into two groups: those that display aberrant accumulation of H3K27me3 and those that maintain steady levels of H3K27me3. The first group shows decreased proliferation, genome instability, and increased sensitivity to genotoxic agents, such as PARP1/2 inhibitors. In contrast, the H3K36M HNSCC models with steady H3K27me3 levels do not exhibit these characteristics unless H3K27me3 levels are elevated, either by DNA hypomethylating agents or by inhibiting the H3K27me3 demethylases KDM6A/B. Mechanistically, we found that H3K36M reduces H3K36me by directly impeding the activities of the histone methyltransferase NSD3 and the histone demethylase LSD2. Notably, we found that aberrant H3K27me3 levels induced by H3K36M expression is not a bona fide epigenetic mark in HNSCC since it requires continuous expression of H3K36M to be inherited. Moreover, increased sensitivity of H3K36M HNSCC models to PARP1/2 inhibitors solely depends on the increased H3K27me3 levels. Indeed, aberrantly high H3K27me3 levels decrease BRCA1 and FANCD2-dependent DNA repair, resulting in higher sensitivity to DNA breaks and replication stress. Finally, in support of our in vitro findings, a PARP1/2 inhibitor alone reduce tumor burden in a H3K36M HNSCC xenograft model with elevated H3K27me3, whereas in a H3K36M HNSCC xenograft model with consistent H3K27me3 levels, a combination of PARP1/2 inhibitors and agents that upregulate H3K27me3 proves to be successful. In conclusion, our findings underscore a delicate balance between H3K36 and H3K27 methylation, essential for maintaining genome stability. This equilibrium presents promising therapeutic opportunities for patients with H3K36me-deficient tumors.

Survival rates and factors associated with survival and laminitis of horses with acute diarrhoea admitted to referral institutions.

BACKGROUND: Clinicopathological findings and their association with the outcome and development of laminitis in horses with acute diarrhoea has not been investigated in a multicentre study across different geographic regions. OBJECTIVES: Describe and compare clinicopathologic findings of diarrhoeic horses between different geographic regions, survival rates and factors associated with non-survival and laminitis. STUDY DESIGN: Multicentre retrospective case series. METHODS: Information from horses with acute diarrhoea presenting to participating institutions between 2016 and 2020 was collected, and clinicopathological data were compared between surviving and non-surviving horses and horses that did and did not develop laminitis. Survival rates and seasonal and geographic differences were also investigated. RESULTS: One thousand four hundred thirty-eight horses from 26 participating institutions from 4 continents were included; 76% survived to discharge with no differences identified between geographic regions. The survival proportion of horses with SIRS and creatinine concentrations > 159 µmol/L was 55% (154/279) compared with 81% (358/437) for those with SIRS and creatinine concentrations < 159 µmol/L (p < 0.001). The survival proportion of horses with SIRS that had an L-lactate concentration > 2.8 mmol/L was 59% (175/298) compared with 81% (240/296) in horses with SIRS and L-lactate concentration < 2.8 mmol/L (p < 0.001). The proportion of horses that developed laminitis was lower in Europe (4%, 19/479) compared with North America (8%, 52/619), Australia (8%, 12/138) and Latin America (11%, 16/146) (p < 0.05). More horses developed laminitis in the summer (46%, 39/85) compared with winter (18%, 15/85), spring (18%, 15/85) and fall (19%, 16/85) (p < 0.01). Horses with laminitis had greater odds of non-survival than those without laminitis (OR: 3.73, 95% CI: 2.47-5.65). MAIN LIMITATIONS: Not all variables were available for all horses due to the retrospective nature. CONCLUSIONS: Clinicopathological findings in horses with acute diarrhoea and their association with survival are similar across geographic regions. However, developing laminitis secondary to diarrhoea is less common in Europe. In addition, factors associated with non-survival were indicative of disease severity and subsequent cardiovascular compromise.

CONTEXTO: Achados clínico-patológicos e suas associações com o sobrevivência e desenvolvimento de laminite em cavalos com diarreia aguda não foram investigados em um estudo multicêntrico envolvendo diferentes regiões geográficas. OBJETIVOS: Descrever e comparar achados clínico-patológicos de cavalos com diarreia em diferentes regiões geográficas, taxa de sobrevivência e fatores associados com mortalidade e laminite. DELINEAMENTO DO ESTUDO: Estudo multicêntrico retrospectivo de série de casos. METODOLOGIA: Informação sobre equinos com diarreia aguda apresentados às instituições participantes entre 2016 e 2020 foram coletados, e dados clínico-patológicos foram comparados entre sobreviventes e não-sobreviventes, e cavalos que desenvolveram ou não laminite. Taxa de sobrevivência, e diferenças sazonais e geográficas também foram investigadas. RESULTADOS: 1438 cavalos de 26 instituições participantes de 4 continentes foram incluídos; 76% sobreviveram e receberam alta e nenhuma diferença foi observada entre as diferentes regiões geográficas. A proporção de cavalos que sobreviveram com SIRS e concentração de creatinina > 1.8 mg/dL foi 55% (154/279) comparado com 81% (358/437) dos cavalos com SIRS e concentração de creatinina < 1.8 mg/dL (p < 0.001). A proporção de cavalos com SIRS que tinham concentração de L-lactato > 2.8 mmol que sobreviveram foi 59% (175/298) comparado com 81% (240/296) dos cavalos com SIRS e concentração de L-lactato < 2.8 mmol/L (p < 0.001). A proporção de cavalos que desenvolveram laminite foi menor na Europa (4%, 19/479) comparado com a América do Norte (8%, 52/619), Austrália (8%, 12/138) e América Latina (11% 16/146) (p < 0.05). Mais cavalos desenvolveram laminite no verão (46%, 39/8) comparado com inverno (18%, 15/85), primavera (18%, 15/85) e outono (19%, 16/85) (p < 0.01). Cavalos com laminite tiveram chances maior de não sobreviver do que aqueles que não desenvolveram laminite (OR: 3.73, 95% CI: 2.47 a 5.65). PRINCIPAIS LIMITAÇÕES: Algumas variáveis não estavam disponíveis para alguns cavalos devido à natureza retrospectiva deste estudo. CONCLUSÕES: Achados clínico-patológicos em equinos com diarreia aguda e sua associação com sobrevivência é similar entre as diferentes regiões geográficas. Contudo, o desenvolvimento de laminite secundário à diarreia é menos comum na Europa. Além disso, fatores associados com não-sobrevivência foram indicativos de severidade da doença e subsequente comprometimento cardiovascular.

Diagnostic approaches, aetiological agents and their associations with short-term survival and laminitis in horses with acute diarrhoea admitted to referral institutions.

BACKGROUND: An international description of the diagnostic approaches used in different institutions to diagnose acute equine diarrhoea and the pathogens detected is lacking. OBJECTIVES: To describe the diagnostic approach, aetiological agents, outcome, and development of laminitis for diarrhoeic horses worldwide. STUDY DESIGN: Multicentre retrospective case series. METHODS: Information from horses with acute diarrhoea presenting to participating institutions between 2016 and 2020, including diagnostic approaches, pathogens detected and their associations with outcomes, were compared between institutions or geographic regions. RESULTS: One thousand four hundred and thirty-eight horses from 26 participating institutions from 4 continents were included. Overall, aetiological testing was limited (44% for Salmonella spp., 42% for Neorickettsia risticii [only North America], 40% for Clostridiodes difficile, and 29% for ECoV); however, 13% (81/633) of horses tested positive for Salmonella, 13% (35/262) for N. risticii, 9% (37/422) for ECoV, and 5% (27/578) for C. difficile. C. difficile positive cases had greater odds of non-survival than horses negative for C. difficile (OR: 2.69, 95%CI: 1.23-5.91). In addition, horses that were positive for N. risticii had greater odds of developing laminitis than negative horses (OR: 2.76, 95%CI: 1.12-6.81; p = 0.029). MAIN LIMITATIONS: Due to the study's retrospective nature, there are missing data. CONCLUSIONS: This study highlighted limited diagnostic investigations in cases of acute equine diarrhoea. Detection rates of pathogens are similar to previous reports. Non-survival and development of laminitis are related to certain detected pathogens.

Pharmacokinetics and tolerability of multiple-day oral dosing of mycophenolate mofetil in healthy horses.

BACKGROUND: Additional efficacious immunomodulatory treatment is needed for the management of immune-mediated disease in horses. Mycophenolate mofetil (MMF) is an immunosuppressive drug that warrants assessment as a viable therapeutic agent for horses. HYPOTHESIS/OBJECTIVES: To evaluate the pharmacokinetics (PK) of multiple-day oral dosing of MMF in healthy horses and to determine the tolerability of this dosing regimen. ANIMALS: Six healthy Standardbred mares. METHODS: Horses received MMF 10 mg/kg PO q12h for 7 days in the fed state. Serial sampling was performed over 12 hours on Days 1 and 7 with trough samples collected every 24 hours, immediately before morning drug administration. Noncompartmental PK analyses were performed to determine primary PK parameters, followed by calculation of geometric means and coefficients of variation. A CBC, serum biochemical profile, physical examination, and fecal scoring were used to assess dose tolerability. RESULTS: Seven days of treatment resulted in a mycophenolic acid (MPA) area under the curve (AUC0-12 ) of 12 594 h × ng/mL (8567-19 488 h × ng/mL) and terminal half-life (T1/2 ) of 11.3 hours (7.5-15.9 hours), yielding minor metabolite accumulation in all horses treated. Salmonellosis was detected in the feces of 2 horses by Day 7, and all horses developed myelosuppression, hyperbilirubinemia, hyporexia, decreased gastrointestinal motility, and decreased fecal output by the seventh day of treatment. CONCLUSION AND CLINICAL IMPORTANCE: Administration of MMF at 10 mg/kg PO q12h resulted in hematologic and clinical toxicity within 1 week of treatment. A decreased MMF dose, frequency, or both is needed to avoid colic. Drug monitoring should include frequent hemograms, serum biochemical profiles, and strict biosecurity protocols.

The nuclear localization sequence and C-terminus of parathyroid hormone-related protein regulate normal pancreatic islet development and function.

Parathyroid hormone-related protein (PTHrP) is a pleiotropic hormone essential for morphogenesis, tissue differentiation, as well as cell regulation and function. PTHrP is expressed by pancreatic beta cells which are responsible for insulin secretion. Previous studies have reported that N-terminal PTHrP stimulated proliferation in beta cells in rodents. We have developed a knockin mouse model (PTHrP Δ/Δ) lacking the C-terminal and nuclear localization sequence (NLS) of PTHrP. These mice die at ∼day 5, are severely stunted in growth, weigh 54% less than control mice at day 1-2 and eventually fail to grow. PTHrP Δ/Δ mice are also hypoinsulinemic and hypoglycemic yet have nutrient intake proportional to size. To characterize the pancreatic islets in these mice, islets (∼10-20) were isolated from 2 to 5 day-old-mice using collagenase digestion. Islets from PTHrP Δ/Δ mice were smaller in size but secreted more insulin than littermate controls. PTHrP Δ/Δ and control mice islets were exposed to various glucose concentrations and intracellular calcium, the trigger for insulin release, was elevated for glucose concentrations of 8-20 mM. Immunofluorescence staining showed less glucagon-stained area in islets from PTHrP Δ/Δ mice (∼250 µm2) compared to islets from control mice (∼900 µm2), and ELISA confirmed there was reduced glucagon content. These data collectively demonstrate increased insulin secretion and reduced glucagon at the islet level, which may contribute to the observed hypoglycemia and early death in PTHrP Δ/Δ mice. Thus, the C-terminus and NLS of PTHrP are crucial to life, including regulation of glucose homeostasis and islet function.

PRAME induces genomic instability in uveal melanoma.

PRAME is a CUL2 ubiquitin ligase subunit that is normally expressed in the testis but becomes aberrantly overexpressed in many cancer types in association with aneuploidy and metastasis. Here, we show that PRAME is expressed predominantly in spermatogonia around the time of meiotic crossing-over in coordination with genes mediating DNA double strand break repair. Expression of PRAME in somatic cells upregulates pathways involved in meiosis, chromosome segregation and DNA repair, and it leads to increased DNA double strand breaks, telomere dysfunction and aneuploidy in neoplastic and non-neoplastic cells. This effect is mediated at least in part by ubiquitination of SMC1A and altered cohesin function. PRAME expression renders cells susceptible to inhibition of PARP1/2, suggesting increased dependence on alternative base excision repair pathways. These findings reveal a distinct oncogenic function of PRAME than can be targeted therapeutically in cancer.

Oxidized mC modulates synthetic lethality to PARP inhibitors for the treatment of leukemia.

TET2 haploinsufficiency is a driving event in myeloid cancers and is associated with a worse prognosis in patients with acute myeloid leukemia (AML). Enhancing residual TET2 activity using vitamin C increases oxidized 5-methylcytosine (mC) formation and promotes active DNA demethylation via base excision repair (BER), which slows leukemia progression. We utilize genetic and compound library screening approaches to identify rational combination treatment strategies to improve use of vitamin C as an adjuvant therapy for AML. In addition to increasing the efficacy of several US Food and Drug Administration (FDA)-approved drugs, vitamin C treatment with poly-ADP-ribosyl polymerase inhibitors (PARPis) elicits a strong synergistic effect to block AML self-renewal in murine and human AML models. Vitamin-C-mediated TET activation combined with PARPis causes enrichment of chromatin-bound PARP1 at oxidized mCs and γH2AX accumulation during mid-S phase, leading to cell cycle stalling and differentiation. Given that most AML subtypes maintain residual TET2 expression, vitamin C could elicit broad efficacy as a PARPi therapeutic adjuvant.

BfmRS encodes a regulatory system involved in light signal transduction modulating motility and desiccation tolerance in the human pathogen Acinetobacter baumannii.

We have previously shown that Acinetobacter baumannii as well as other relevant clinical bacterial pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa, perceive and respond to light at 37 °C, the normal temperature in mammal hosts. In this work, we present evidence indicating that the two-component system BfmRS transduces a light signal in A. baumannii at this temperature, showing selective involvement of the BfmR and BfmS components depending on the specific cellular process. In fact, both BfmR and BfmS participate in modulation of motility by light, while only BfmR is involved in light regulation of desiccation tolerance in this microorganism. Neither BfmR nor BfmS contain a photoreceptor domain and then most likely, the system is sensing light indirectly. Intriguingly, this system inhibits blsA expression at 37 °C, suggesting antagonistic functioning of both signaling systems. Furthermore, we present evidence indicating that the phosphorylatable form of BfmR represses motility. Overall, we provide experimental evidence on a new biological function of this multifaceted system that broadens our understanding of A. baumannii's physiology and responses to light.

SCARECROW-LIKE28 modulates organ growth in Arabidopsis by controlling mitotic cell cycle exit, endoreplication, and cell expansion dynamics.

The processes that contribute to plant organ morphogenesis are spatial-temporally organized. Within the meristem, mitosis produces new cells that subsequently engage in cell expansion and differentiation programs. The latter is frequently accompanied by endoreplication, being an alternative cell cycle that replicates the DNA without nuclear division, causing a stepwise increase in somatic ploidy. Here, we show that the Arabidopsis SCL28 transcription factor promotes organ growth by modulating cell expansion dynamics in both root and leaf cells. Gene expression studies indicated that SCL28 regulates members of the SIAMESE/SIAMESE-RELATED (SIM/SMR) family, encoding cyclin-dependent kinase inhibitors with a role in promoting mitotic cell cycle (MCC) exit and endoreplication, both in response to developmental and environmental cues. Consistent with this role, mutants in SCL28 displayed reduced endoreplication, both in roots and leaves. We also found evidence indicating that SCL28 co-expresses with and regulates genes related to the biogenesis, assembly, and remodeling of the cytoskeleton and cell wall. Our results suggest that SCL28 controls, not only cell proliferation as reported previously but also cell expansion and differentiation by promoting MCC exit and endoreplication and by modulating aspects of the biogenesis, assembly, and remodeling of the cytoskeleton and cell wall.

Endocrine resistance and breast cancer plasticity are controlled by CoREST.

Resistance to cancer treatment remains a major clinical hurdle. Here, we demonstrate that the CoREST complex is a key determinant of endocrine resistance and ER+ breast cancer plasticity. In endocrine-sensitive cells, CoREST is recruited to regulatory regions co-bound to ERα and FOXA1 to regulate the estrogen pathway. In contrast, during temporal reprogramming towards a resistant state, CoREST is recruited to AP-1 sites. In reprogrammed cells, CoREST favors chromatin opening, cJUN binding to chromatin, and gene activation by controlling SWI/SNF recruitment independently of the demethylase activity of the CoREST subunit LSD1. Genetic and pharmacological CoREST inhibition reduces tumorigenesis and metastasis of endocrine-sensitive and endocrine-resistant xenograft models. Consistently, CoREST controls a gene signature involved in invasiveness in clinical breast tumors resistant to endocrine therapies. Our studies reveal CoREST functions that are co-opted to drive cellular plasticity and resistance to endocrine therapies and tumorigenesis, thus establishing CoREST as a potential therapeutic target for the treatment of advanced breast cancer.

Energy endocrine physiology, pathophysiology, and nutrition of the foal.

Most homeostatic systems in the equine neonate should be functional during the transition from intra- to extrauterine life to ensure survival during this critical period. Endocrine maturation in the equine fetus occurs at different stages, with a majority taking place a few days prior to parturition and continuing after birth. Cortisol and thyroid hormones are good examples of endocrine and tissue interdependency. Cortisol promotes skeletal, respiratory, cardiovascular, thyroid gland, adrenomedullary, and pancreatic differentiation. Thyroid hormones are essential for cardiovascular, respiratory, neurologic, skeletal, adrenal, and pancreatic function. Hormonal imbalances at crucial stages of development or in response to disease can be detrimental to the newborn foal. Other endocrine factors, including growth hormone, glucagon, catecholamines, ghrelin, adipokines (adiponectin, leptin), and incretins, are equally important in energy homeostasis. This review provides information specific to nutrition and endocrine systems involved in energy homeostasis in foals, enhancing our understanding of equine neonatal physiology and pathophysiology and our ability to interpret clinical and laboratory findings, therefore improving therapies and prognosis.

Arboviral Equine Encephalitides.

A number of viruses transmitted by biological vectors or through direct contact, air, or ingestion cause neurologic disease in equids. Of interest are viruses of the Togaviridae, Flaviviridae, Rhabdoviridae, Herpesviridae, Bornaviridae, and Bunyaviridae families. Many are classified as arboviruses because they use arthropod vectors, whereas others are transmitted directly via ingestion, inhalation, or integument damage. The goal of this article is to provide an overview on pathophysiologic and clinical aspects of arboviruses of equine importance, including alphaviruses (Togaviridae) and flaviviruses (Flaviviridae).