MYC directly transactivates CR2/CD21, the receptor of the Epstein-Barr virus, enhancing the viral infection of Burkitt lymphoma cells.

MYC is an oncogenic transcription factor dysregulated in about half of total human tumors. While transcriptomic studies reveal more than 1000 genes regulated by MYC, a much smaller fraction of genes is directly transactivated by MYC. Virtually all Burkitt lymphoma (BL) carry chromosomal translocations involving MYC oncogene. Most endemic BL and a fraction of sporadic BL are associated with Epstein-Barr virus (EBV) infection. The currently accepted mechanism is that EBV is the BL-causing agent inducing MYC translocation. Herein we show that the EBV receptor, CR2 (also called CD21), is a direct MYC target gene. This is based on several pieces of evidence: MYC induces CR2 expression in both proliferating and arrested cells and in the absence of protein synthesis, binds the CR2 promoter and transactivates CR2 in an E-box-dependent manner. Moreover, using mice with conditional MYC ablation we show that MYC induces CR2 in primary B cells. Importantly, modulation of MYC levels directly correlates with EBV's ability of infection in BL cells. Altogether, in contrast to the widely accepted hypothesis for the correlation between EBV and BL, we propose an alternative hypothesis in which MYC dysregulation could be the first event leading to the subsequent EBV infection.

NUAK Kinases: Brain-Ovary Axis.

Liver kinase B (LKB1) and adenosine monophosphate (AMP)-activated protein kinase (AMPK) are two major kinases that regulate cellular metabolism by acting as adenosine triphosphate (ATP) sensors. During starvation conditions, LKB1 and AMPK activate different downstream pathways to increase ATP production, while decreasing ATP consumption, which abrogates cellular proliferation and cell death. Initially, LKB1 was considered to be a tumor suppressor due to its loss of expression in various tumor types. Additional studies revealed amplifications in LKB1 and AMPK kinases in several cancers, suggesting a role in tumor progression. The AMPK-related proteins were described almost 20 years ago as a group of key kinases involved in the regulation of cellular metabolism. As LKB1-downstream targets, AMPK-related proteins were also initially considered to function as tumor suppressors. However, further research demonstrated that AMPK-related kinases play a major role not only in cellular physiology but also in tumor development. Furthermore, aside from their role as regulators of metabolism, additional functions have been described for these proteins, including roles in the cell cycle, cell migration, and cell death. In this review, we aim to highlight the major role of AMPK-related proteins beyond their functions in cellular metabolism, focusing on cancer progression based on their role in cell migration, invasion, and cell survival. Additionally, we describe two main AMPK-related kinases, Novel (nua) kinase family 1 (NUAK1) and 2 (NUAK2), which have been understudied, but play a major role in cellular physiology and tumor development.

Minimum Effects of Sampling Time on the Apparent Digestibility of Nutrients and Blood Protein Catabolites in Light Lambs.

This experiment aimed to evaluate the effects of sampling time on organic matter (OM), crude protein (CP) and phosphorous (P) apparent digestibility and plasma urea and creatinine concentration in growing and finishing male Ripollesa lambs fed different CP concentrations in the diet. Twenty-four male Ripollesa lambs with 14.5 kg body weight (BW) were randomly assigned to two groups differing in CP content in the growing (14 to 19 kg of BW) and finishing (19 to 25 kg of BW) phases (20% vs. 18% CP and 19% vs. 17% CP, respectively). Faeces collected from the rectum and blood samples collected from the jugular vein were taken at 8:00 a.m., 12:00 p.m., and 4:00 p.m. During the growing period, the OM, CP and P apparent digestibility were higher in the lower CP diet (p < 0.05), but only P was affected by the sampling time, being highest at 8:00 a.m. (p < 0.05) compared to other sampling hours. During the finishing period, there were no differences in these digestibility coefficients between diets or sampling times (p > 0.05). Sampling time did not affect (p > 0.05) plasma urea concentrations either in the growing or finishing period. Plasma creatinine concentrations did not differ (p > 0.05) between lambs receiving 18% or 20% CP diets, but during the finishing period, it was lower at 4:00 p.m. in lambs fed 17% CP (p < 0.05) than those offered 19% CP. Overall, the results suggest that the collection schedule to evaluate the protein nutritional status can be shortened through one spot sample of faeces or blood in the morning.

AMPKα-like proteins as LKB1 downstream targets in cell physiology and cancer.

One of the key events in cancer development is the ability of tumor cells to overcome nutrient deprivation and hypoxia. Among proteins performing metabolic adaptation to the various cellular nutrient conditions, liver kinase B 1 (LKB1) and its main downstream target adenosine monophosphate (AMP)-activated protein kinase α (AMPKα) are important sensors of energy requirements within the cell. Although LKB1 was originally described as a tumor suppressor, given its role in metabolism, it potentially acts as a double-edged sword. AMPKα, a master regulator of cell energy demands, is activated when ATP level drops under a certain threshold, responding accordingly through its downstream targets. Twelve downstream kinase targets of LKB1 have been described as AMPKα-like proteins. This group is comprised of novel (nua) kinase family (NUAK) kinases (NUAK1 and 2) linked to cell cycle progression and ultraviolet (UV)-damage; microtubule affinity regulating kinases (MARKs) (MARK1, MARK2, MARK3, and MARK4) that are involved in cell polarity; salt inducible kinases (SIK) (SIK1, SIK2, also known as Qin-induced kinase or QIK and SIK3) that are implicated in cell metabolism and adipose tissue development and mitotic regulation; maternal embryonic leuzine zipper kinase (MELK) that regulate oocyte maturation; and finally brain selective kinases (BRSKs) (BRSK1 and 2), which have been mainly characterized in the brain due to their role in neuronal polarization. Thus, many efforts have been made in order to harness LKB1 kinase and its downstream targets as a possible therapeutic hub in tumor development and propagation. In this review, we describe LKB1 and its downstream target AMPK summarize major functions of various AMPK-like proteins, while focusing on biological functions of BRSK1 and 2 in different models.

The MNT transcription factor autoregulates its expression and supports proliferation in MYC-associated factor X (MAX)-deficient cells.

The MAX network transcriptional repressor (MNT) is an MXD family transcription factor of the basic helix-loop-helix (bHLH) family. MNT dimerizes with another transcriptional regulator, MYC-associated factor X (MAX), and down-regulates genes by binding to E-boxes. MAX also dimerizes with MYC, an oncogenic bHLH transcription factor. Upon E-box binding, the MYC-MAX dimer activates gene expression. MNT also binds to the MAX dimerization protein MLX (MLX), and MNT-MLX and MNT-MAX dimers co-exist. However, all MNT functions have been attributed to MNT-MAX dimers, and no functions of the MNT-MLX dimer have been described. MNT's biological role has been linked to its function as a MYC oncogene modulator, but little is known about its regulation. We show here that MNT localizes to the nucleus of MAX-expressing cells and that MNT-MAX dimers bind and repress the MNT promoter, an effect that depends on one of the two E-boxes on this promoter. In MAX-deficient cells, MNT was overexpressed and redistributed to the cytoplasm. Interestingly, MNT was required for cell proliferation even in the absence of MAX. We show that in MAX-deficient cells, MNT binds to MLX, but also forms homodimers. RNA-sequencing experiments revealed that MNT regulates the expression of several genes even in the absence of MAX, with many of these genes being involved in cell cycle regulation and DNA repair. Of note, MNT-MNT homodimers regulated the transcription of some genes involved in cell proliferation. The tight regulation of MNT and its functionality even without MAX suggest a major role for MNT in cell proliferation.

Myc stimulates cell cycle progression through the activation of Cdk1 and phosphorylation of p27.

Cell cycle stimulation is a major transforming mechanism of Myc oncoprotein. This is achieved through at least three concomitant mechanisms: upregulation of cyclins and Cdks, downregulation of the Cdk inhibitors p15 and p21 and the degradation of p27. The Myc-p27 antagonism has been shown to be relevant in human cancer. To be degraded, p27 must be phosphorylated at Thr-187 to be recognized by Skp2, a component of the ubiquitination complex. We previously described that Myc induces Skp2 expression. Here we show that not only Cdk2 but Cdk1 phosphorylates p27 at the Thr-187. Moreover, Myc induced p27 degradation in murine fibroblasts through Cdk1 activation, which was achieved by Myc-dependent cyclin A and B induction. In the absence of Cdk2, p27 phosphorylation at Thr-187 was mainly carried out by cyclin A2-Cdk1 and cyclin B1-Cdk1. We also show that Cdk1 inhibition was enough for the synthetic lethal interaction with Myc. This result is relevant because Cdk1 is the only Cdk strictly required for cell cycle and the reported synthetic lethal interaction between Cdk1 and Myc.

Effects of maternal subnutrition during early pregnancy on cow hematological profiles and offspring physiology and vitality in two beef breeds.

This experiment evaluated the effects of subnutrition during early gestation on hematology in cows (Bos Taurus) and on hematological, metabolic, endocrine, and vitality parameters in their calves. Parda de Montaña and Pirenaica dams were inseminated and assigned to either a control (CONTROL, 100% requirements) or a nutrient-restricted group (SUBNUT, 65%) during the first third of gestation. Dam blood samples were collected on days 20 and 253 of gestation, and calf samples were obtained during the first days of life. Pirenaica dams presented higher red series parameters than Parda de Montaña dams, both in the first and the last months of gestation. During early pregnancy, granulocyte numbers and mean corpuscular hemoglobin were lower in Pirenaica-SUBNUT than in Pirenaica-CONTROL cows. Calves from the SUBNUT cows did not show a physiological reduction in red series values in early life, suggesting later maturation of the hematopoietic system. Poor maternal nutrition affected calf endocrine parameters. Newborns from dystocic parturitions showed lower NEFA concentrations and weaker vitality responses. In conclusion, maternal nutrition had short-term effects on cow hematology, Pirenaica cows showing a higher susceptibility to undernutrition; and a long-term effect on their offspring endocrinology, SUBNUT newborns showing lower levels of IGF-1 and higher levels of cortisol.

Morbimortalidad en el servicio de cuidados intensivos / Morbimortality at the intensive care service

Se realizó un estudio descriptivo transversal para conocer la morbimortalidad de los pacientes ingresados en la Unidad de Cuidados Intensivos del Hospital Provincial Docente Clínico Quirúrgico ”Amalia Simoni” de la provincia de Camagüey. El universo estuvo constituido por los pacientes ingresados en esta unidad desde enero de 2001 a diciembre de 2003. Las variables estudiadas fueron la edad, el sexo, las causas de ingreso, causas directas de muertes más frecuentes por necropsia, mortalidad y letalidad. La principal causa de ingreso fue la cardiopatía isquémica con 48.8 por ciento y la de muerte por necropsia la hernia de amígdalas cerebrales con 20.6 por ciento. La mortalidad en el trienio se comportó para el accidente vascular encefálico y el infarto agudo del miocardio con tendencia a la disminución, se redujo la letalidad del paciente ventilado de forma decreciente en un 28.5 por ciento. La mortalidad bruta del servicio fue de 17.1 por ciento

Morbimortalidad en el servicio de cuidados intensivos / Morbimortality at the intensive care service

Se realizó un estudio descriptivo transversal para conocer la morbimortalidad de los pacientes ingresados en la Unidad de Cuidados Intensivos del Hospital Provincial Docente Clínico Quirúrgico ”Amalia Simoni” de la provincia de Camagüey. El universo estuvo constituido por los pacientes ingresados en esta unidad desde enero de 2001 a diciembre de 2003. Las variables estudiadas fueron la edad, el sexo, las causas de ingreso, causas directas de muertes más frecuentes por necropsia, mortalidad y letalidad. La principal causa de ingreso fue la cardiopatía isquémica con 48.8 por ciento y la de muerte por necropsia la hernia de amígdalas cerebrales con 20.6 por ciento. La mortalidad en el trienio se comportó para el accidente vascular encefálico y el infarto agudo del miocardio con tendencia a la disminución, se redujo la letalidad del paciente ventilado de forma decreciente en un 28.5 por ciento. La mortalidad bruta del servicio fue de 17.1 por ciento(AU)