Rituximab as a First-line Treatment for Autoimmune Hemolytic Anemia in Multicentric Castleman's Disease.

Castleman´s disease (CD) is a rare lymphoproliferative disorder. Concurrent autoimmune disease and CD are uncommon, but even more so, comorbid CD and autoimmune hemolytic anemia (AIHA). To the best of our knowledge, this case represents the first successful AIHA and multicentric CD (MCD) treatment using rituximab as first-line treatment. We present the case of a 53-year-old woman with a 10-year history of plasma cell variant CD who arrived at the emergency department with signs and symptoms of anemia. On admission, we made a preliminary diagnosis of hemolytic anemia and initiated immunosuppressive therapy with rituximab and steroids. After seven days, the patient recovered according to clinical and laboratory parameters, and we discharged her early. We portray a rare occurrence of CD and AIHA successfully treated with rituximab and steroid therapy, which makes our case unique.

Increasing access to transplantation through telemedicine and patient navigation.

BACKGROUND: Hematopoietic cell transplantation (HCT) is a promising treatment for hematological diseases, yet access barriers like cost and limited transplant centers persist. Telemedicine-based patient navigation (PN) has emerged as a solution. This study presents a cost-free PN telemedicine clinic (TC) in collaboration with the National Marrow Donor Program. AIM: to assess its feasibility and impac on HCT access determined by the cumulative incidence of transplantation. METHODS: In this single-center cohort study, patients of all ages and diagnoses referred for HCT participated. Two transplant physician-navigators established patient relationships via video calls, collecting medical history, offering HCT education and recommending pretransplant tests. The analysis involved descriptive statistics and intent-to-transplant survival assessment. RESULTS: One hundred and three patients were included of whom n = 78 were referred for allogeneic HCT (alloHCT), with a median age of 28 years. The median time from initial contact to the first consult was 5 days. The cumulative incidence of transplantation was 50% at 6 months and 61% at 12 months, with varying outcomes based on HCT type. Notably, 49 patients were not transplanted, primarily due to refractory disease, progression or relapse (57.1%). Autologous HCT candidates and physician referrals were correlated with higher transplant success compared to alloHCT candidates and patients who were not referred by a physician. CONCLUSION: Our pretransplant TC was feasible, facilitating access to HCT. Disease relapse posed a significant barrier. Enhancing timely physician referrals should be a focus for future efforts.

Expression and characterization of a novel ß-1,4-endoglucanase from Bacillus subtilis strain isolated from a pulp and paper mill wastewater.

The production of fermentable sugars from lignocellulosic biomass is achieved by the synergistic action of a group of enzymes called cellulases. Cellulose is a long chain of chemically linked glucoses by ß-1,4 bonds. The enzyme ß-1,4-endoglucanase is the first cellulase involved in the degradation, breaking the bond of the amorphous regions. A ß-1,4-endoglucanase enzyme with high activity was obtained from a Bacillus subtilis strain isolated from wastewater of a pulp and paper mill. Sequencing and bioinformatic analysis showed that the gene amplified by PCR consisting of 1407 nucleotides and coding for a ß-1,4-endoglucanase enzyme of approximately 55 kDa. The open reading frame (ORF) encoding the mature endoglucanase (eglS) was successfully inserted in a modified cloning plasmid (pITD03) and into the pYD1 plasmid used for its expression in yeast. Carboxymethylcellulose (CMC) plate assay, SDS-PAGE, and zymogram confirmed the production and secretion by the transformed E. coli BL21-SI strain of a 39 kDa ß-1,4-endoglucanase consistent with the catalytic domain without the cellulose-binding module (CBM). The results showed that the truncated ß-1,4-endoglucanase had higher activity and stability.

Nascent shifts in renal cellular metabolism, structure, and function due to chronic empagliflozin in prediabetic mice.

Sodium-glucose cotransporter, type 2 inhibitors (SGLT2i) are emerging as the gold standard for treatment of type 2 diabetes (T2D) with renal protective benefits independent of glucose lowering. We took a high-level approach to evaluate the effects of the SGLT2i, empagliflozin (EMPA) on renal metabolism and function in a prediabetic model of metabolic syndrome. Male and female 12-wk-old TallyHo (TH) mice, and their closest genetic lean strain (Swiss-Webster, SW) were treated with a high-milk-fat diet (HMFD) plus/minus EMPA (@0.01%) for 12-wk. Kidney weights and glomerular filtration rate were slightly increased by EMPA in the TH mice. Glomerular feature analysis by unsupervised clustering revealed sexually dimorphic clustering, and one unique cluster relating to EMPA. Periodic acid Schiff (PAS) positive areas, reflecting basement membranes and mesangium were slightly reduced by EMPA. Phasor-fluorescent life-time imaging (FLIM) of free-to-protein bound NADH in cortex showed a marginally greater reliance on oxidative phosphorylation with EMPA. Overall, net urine sodium, glucose, and albumin were slightly increased by EMPA. In TH, EMPA reduced the sodium phosphate cotransporter, type 2 (NaPi-2), but increased sodium hydrogen exchanger, type 3 (NHE3). These changes were absent or blunted in SW. EMPA led to changes in urine exosomal microRNA profile including, in females, enhanced levels of miRs 27a-3p, 190a-5p, and 196b-5p. Network analysis revealed "cancer pathways" and "FOXO signaling" as the major regulated pathways. Overall, EMPA treatment to prediabetic mice with limited renal disease resulted in modifications in renal metabolism, structure, and transport, which may preclude and underlie protection against kidney disease with developing T2D.NEW & NOTEWORTHY Renal protection afforded by sodium glucose transporter, type 2 inhibitors (SGLT2i), e.g., empagliflozin (EMPA) involves complex intertwined mechanisms. Using a novel mouse model of obesity with insulin resistance, the TallyHo/Jng (TH) mouse on a high-milk-fat diet (HMFD), we found subtle changes in metabolism including altered regulation of sodium transporters that line the renal tubule. New potential epigenetic determinants of metabolic changes relating to FOXO and cancer signaling pathways were elucidated from an altered urine exosomal microRNA signature.

Point of care thoracic ultrasound versus chest computed tomography in the approach of febrile neutropenia patients: A diagnostic accuracy cohort study.

Single-center prospective cohort diagnostic accuracy study. Our study aimed to evaluate the accuracy and reproducibility of Thoracic Ultrasound (TUS) in detecting pulmonary pathology in immunosuppressed patients. We conducted a single-center prospective study. Consecutive patients with febrile neutropenia who underwent CT (Computerized Tomography) underwent TUS evaluation within 24h of CT. Both studies were performed by an expert who was blinded to the clinical information and results of the alternative imaging modalities. 34 patients met the inclusion criteria. The median age was 39.9 years (±17 standard deviation). TUS as a diagnostic test had a sensitivity of 92.9% and specificity of 83.3%, negative predictive value of 71.4%, and positive predictive value of 96.3%. Substantial between-method agreement was demonstrated with a kappa of 0.71 (P = .001) between the TUS and chest CT findings. We obtained a kappa of 1 (P = .001) for the final diagnosis of Pleural Effusion (PE). We concluded that TUS is a promising screening test for immunocompromised individuals. The results showed good diagnostic performance of TUS compared to CT for the detection of pulmonary findings highly suggestive of pathology with high accuracy and reproducibility.

Graft-versus-host disease after an outpatient peripheral blood hematopoietic cell transplant using reduced-intensity conditioning: a single-center LATAM experience.

BACKGROUND: HLA compatibility predicts allogeneic hematopoietic cell transplant (allo-HCT) and graft-versus-host disease (GvHD) outcomes. There is insufficient information regarding GvHD outcomes for outpatient HLA-identical and haploidentical-HCT employing reduced-intensity conditioning (RIC). RESEARCH DESIGN AND METHODS: We compare GvHD outcomes between donor types and report risk factors associated with GvHD. Stem cell source was T-cell replete peripheral blood. GvHD prophylaxis was post-transplant cyclophosphamide (PT-CY), mycophenolic acid, and calcineurin inhibitors for haploidentical (n = 107) and oral cyclosporine (CsA) plus methotrexate i.v. for HLA-identical (n = 89) recipients. RESULTS: One hundred and ninety-six HCT transplant patients were included. aGvHD and cGvHD frequency were similar between HCT types. aGvHD severity was comparable, but severe cGvHD was less frequent in the haploidentical group (p = .011). One-hundred-day cumulative incidence (CI) of aGvHD for haploidentical and HLA-identical was 31% and 33% (p = .84); 2-year CI of cGvHD was 32% and 38% (p = .6), respectively. Haploidentical recipients had less steroid-refractory cGvHD (p = .043). Patients with cGvHD had less 2-year relapse (p = .003); both aGvHD and cGvHD conferred higher OS (p = .010 and p = .001), respectively. Male sex was protective for steroid-refractory cGvHD (p = .028). CONCLUSIONS: Acute and chronic GvHD rates were comparable between HLA-identical and haploidentical transplant groups. cGvHD severity was lower in the haploidentical group.

Fenotipos clínicos en el diagnóstico sicopedagógico de las necesidades educativas especiales

El desarrollo científico tecnológico caracterizado, entre otros por los avances en el campo de las ciencias biomédicas, trascienden a la educación, especialmente se denotan los nexos entre la genética médica y la educación especial. En la provincia de Camagüey se desarrolla una investigación entre los servicios de Genética y el Centro de Diagnóstico y Orientación de la educación especial. A partir del análisis de la interrelación entre ambas ciencias se proyectan en la práctica de la atención de educandos con necesidades educativas especiales enfoques multi, inter y transdisciplinarios con el fin de contribuir al perfeccionamiento del diagnóstico sicopedagógico. El estudio se desarrolla con la colaboración de la Benemérita Universidad Autónoma de Puebla.

Scientific and technological development, characterized among cons by advances in the field of biomedical sciences, transcend education, especially the links between medical genetics and special education. In the province of Camagüey, research is being carried out between the Genetics services and the Diagnosis and Guidance Center for special education. Based on the analysis of the interrelation between both sciences, multi, inter and transdisciplinary approaches are projected into the practice of caring for students with special educational needs, in order to contribute to the improvement of psychopedagogical diagnosis. The study is developed with the collaboration of the Benemérita Universidad Autónoma de Puebla.

Factores limitantes de la formación académica de posgrado en enfermeros

Introducción: La formación académica de posgrado es un proceso continuo de incorporación de conocimientos, que se puede ver afectado por factores intrínsecos y extrínsecos. Objetivo: Determinar los factores limitantes de la formación académica de posgrado en enfermeros. Métodos: Se realizó un estudio observacional descriptivo en el Hospital Pediátrico de Camagüey durante el primer semestre de 2022. El universo estuvo constituido por 275 enfermeros, y la muestra quedó conformada por 272 que se cumplieron con los criterios de selección. Se estudiaron las variables: grupo etario, factores limitantes de la superación profesional relacionados con los ambientes físico, psicológico, social, familiar y económico. Para el procesamiento de los datos se empleó el paquete estadístico para las ciencias sociales y se expresaron en valores absolutos y porcentajes. Resultados: En el estudio predominó el grupo etario de 20-29 años (29,0 %); condiciones de trabajo inadecuado (33,8 %); presencia de estrés (61,8 %) lo que se sumó la no disponibilidad de desarrollo o promoción (55,5 %) al igual que el bajo nivel retributivo como el principal factor limitante relacionado en la esfera económica (97,4 %). Conclusiones: Los factores que limitaron la formación académica de posgrado en enfermeros incluyen los relacionados con el ambiente físico, psicológico, social, laboral y económico, entre los que se encuentran las condiciones de trabajo inadecuadas, el estrés y el bajo nivel retributivo.

Introduction: Postgraduate academic training is a continuous process of incorporating knowledge, which can have effects due to intrinsic and extrinsic factors. Objective: To determine the limiting factors of nurse postgraduate academic training. Methods: A descriptive observational study was carried out at Camagüey Pediatric Hospital during the 2022 first semester. The universe consisted of 275 nurses and the sample was made up of 272, once the selection criteria were applied. The variables were studied age group, limiting factors of professional improvement related to the physical, psychological, social and family, and economic environments. The Social Science Statistical Package was used to process the data and they were expressed in absolute values and percentages. Results: The age group of 20-29 years predominated in the study (29.0%), with inadequate working conditions (33.8%), presence of stress (61.8%), which added to the lack of availability of development or promotion (55.5%), as well as the low level of remuneration as the main limiting factor related to the economic sphere (97.4%). Conclusions: The factors that limited nurse postgraduate academic training include those related to the physical, psychological, social, work and economic environment, among which are inadequate working conditions, stress and low remuneration.

Interactions between BRD4S, LOXL2, and MED1 drive cell cycle transcription in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) often develops resistance to single-agent treatment, which can be circumvented using targeted combinatorial approaches. Here, we demonstrate that the simultaneous inhibition of LOXL2 and BRD4 synergistically limits TNBC proliferation in vitro and in vivo. Mechanistically, LOXL2 interacts in the nucleus with the short isoform of BRD4 (BRD4S), MED1, and the cell cycle transcriptional regulator B-MyB. These interactions sustain the formation of BRD4 and MED1 nuclear transcriptional foci and control cell cycle progression at the gene expression level. The pharmacological co-inhibition of LOXL2 and BRD4 reduces BRD4 nuclear foci, BRD4-MED1 colocalization, and the transcription of cell cycle genes, thus suppressing TNBC cell proliferation. Targeting the interaction between BRD4S and LOXL2 could be a starting point for the development of new anticancer strategies for the treatment of TNBC.

Mutations on a conserved distal enhancer in the porcine C-reactive protein gene impair its expression in liver.

C-reactive protein (CRP) is an evolutionary highly conserved protein. Like humans, CRP acts as a major acute phase protein in pigs. While CRP regulatory mechanisms have been extensively studied in humans, little is known about the molecular mechanisms that control pig CRP gene expression. The main goal of the present work was to study the regulatory mechanisms and identify functional genetic variants regulating CRP gene expression and CRP blood levels in pigs. The characterization of the porcine CRP proximal promoter region revealed a high level of conservation with both cow and human promoters, sharing binding sites for transcription factors required for CRP expression. Through genome-wide association studies and fine mapping, the most associated variants with both mRNA and protein CRP levels were localized in a genomic region 39.3 kb upstream of CRP. Further study of the region revealed a highly conserved putative enhancer that contains binding sites for several transcriptional regulators such as STAT3, NF-kB or C/EBP-ß. Luciferase reporter assays showed the necessity of this enhancer-promoter interaction for the acute phase induction of CRP expression in liver, where differences in the enhancer sequences significantly modified CRP activity. The associated polymorphisms disrupted the putative binding sites for HNF4α and FOXA2 transcription factors. The high correlation between HNF4α and CRP expression levels suggest the participation of HNF4α in the regulatory mechanism of porcine CRP expression through the modification of its binding site in liver. Our findings determine, for the first time, the relevance of a distal regulatory element essential for the acute phase induction of porcine CRP in liver and identify functional polymorphisms that can be included in pig breeding programs to improve immunocompetence.

Impacto social de la ciencia y la tecnología cubana en el enfrentamiento a la COVID-19 / Social Impact of Cuban Science and Technology the Fight Against COVID-19

Introducción: La ciencia mediante la innovación de los servicios y la tecnología brinda importantes beneficios en función de la sociedad. Objetivo: Proporcionar información sistematizada sobre el impacto social de la ciencia y la tecnología cubana en el enfrentamiento a la COVID-19. Métodos: Se realizó una búsqueda bibliográfica en las bases de datos Scopus, SciELO, ScienceDirect y MEDLINE/PubMed. Para ello, se utilizaron los descriptores o palabras relacionadas con la temática (ciencia, tecnología, COVID-19). Se consultaron artículos de revisión, de posición, y metaanálisis de los años 2020, 2021 y 2022, de la búsqueda solo 30 artículos cumplieron con los criterios de selección. Resultados: En la etapa pandémica, Cuba depositó toda la confianza en sus científicos y sacó provecho a la industria biotecnológica en la búsqueda de salvaguardar la población. Gracias a la satisfactoria gestión del gobierno se obtuvieron resultados positivos en las investigaciones, a partir de la inventiva de los productos como jusvinza, nasalferon, biomodulina T, entre otros. Se inventó un ventilador pulmonar asistido de alta gama para el tratamiento de los adultos, de este modo se fortaleció el trabajo interinstitucional e intersectorial. Conclusiones: La ciencia, la tecnología y las innovaciones han sido cruciales para el manejo de la crisis sanitaria generada por la COVID-19. En Cuba, se obtuvieron valiosos resultados en diferentes niveles para el beneficio de la sociedad; como las vacunas soberana y Abdala(AU)

Introduction: Both science and technology justify their existence through the innovation of services and technologies for the benefit of society. Objective: To provide systematized information on the social impact of Cuban science and technology in the fight against COVID-19. Methods: A bibliographic search was carried out in Scopus, SciELO, ScienceDirect and MEDLINE/PubMed databases. Descriptors or words related to the theme (science, technology, COVID-19) were used. Review articles, position articles, and meta-analyses from 2020, 2021, and 2022 were consulted. Only 30 articles met the selection criteria. Results: In the pandemic stage, Cuba placed all its trust in its scientists and took advantage of the biotechnology industry in the search for the safeguarding of the population. Thanks to the satisfactory management of the government, good results were obtained in the investigations with the inventiveness of products such as Jusvinza, nasalferon, biomodulin T, among others. A high-end assisted lung ventilator was invented for treating adults, in the same way that inter-institutional and intersectoral work was strengthened. Conclusions: Science, technology, and innovations have been crucial in managing the health crisis caused by COVID-19. In Cuba, relevant results have been obtained at different levels for the benefit of society, among which Soberana and Abdala vaccines stand out(AU)

Long-Term Efficacy of High-Dose Imatinib in Hispanic Patients Without Access to Second-Generation Tyrosine Kinase Inhibitors Treated in LATAM Centers.

BACKGROUND: While second-generation tyrosine kinase inhibitors (TKI) revolutionized treatment for patients with chronic myeloid leukemia (CML) who developed a suboptimal response to imatinib, many patients in developing countries are fixed to the latter due to socioeconomic barriers. Despite this scenario, scarce information is available to evaluate the clinical prognosis of these patients. METHODS: We conducted a retrospective cohort analysis to compare the overall mortality of patients with CML who developed a suboptimal response to a standard dose of imatinib and were treated with either high-dose imatinib or a second-generation TKI. We created a marginal structural model with inverse probability weighting and stabilized weights. Our primary outcome was overall survival (OS) at 150 months. Our secondary outcomes were disease-free survival (DFS) at 150 months and adverse events. RESULTS: The cohort included 148 patients, of which 32 received high-dose imatinib and 116 a second-generation TKI. No difference was found in the 150-month overall survival risk (RR: 95% CI 0.91, 0.55-1.95, P-value = .77; RD: -0.04, -0.3 to 0.21, P-value = .78) and disease-free survival (RR: 1.02, 95% CI 0.53-2.71, P-value = .96; RD: 0.01, -0.26 to 0.22, P-value = .96). There was also no difference in the incidence of adverse events in either group. CONCLUSION: Ideally, patients who develop a suboptimal response to imatinib should be switched to a second-generation TKI. If impossible, however, our findings suggest that patients treated with high-dose imatinib have a similar overall survival and disease-free survival prognosis to patients receiving a second-generation TKI.

Copy Number Variation on ABCC2-DNMBP Loci Affects the Diversity and Composition of the Fecal Microbiota in Pigs.

Genetic variation in the pig genome partially modulates the composition of porcine gut microbial communities. Previous studies have been focused on the association between single nucleotide polymorphisms (SNPs) and the gut microbiota, but little is known about the relationship between structural variants and fecal microbial traits. The main goal of this study was to explore the association between porcine genome copy number variants (CNVs) and the diversity and composition of pig fecal microbiota. For this purpose, we used whole-genome sequencing data to undertake a comprehensive identification of CNVs followed by a genome-wide association analysis between the estimated CNV status and the fecal bacterial diversity in a commercial Duroc pig population. A CNV predicted as gain (DUP) partially harboring ABCC2-DNMBP loci was associated with richness (P = 5.41 × 10-5, false discovery rate [FDR] = 0.022) and Shannon α-diversity (P = 1.42 × 10-4, FDR = 0.057). The in silico predicted gain of copies was validated by real-time quantitative PCR (qPCR), and its segregation, and positive association with the richness and Shannon α-diversity of the porcine fecal bacterial ecosystem was confirmed in an unrelated F1 (Duroc × Iberian) cross. Our results advise the relevance of considering the role of host-genome structural variants as potential modulators of microbial ecosystems and suggest the ABCC2-DNMBP CNV as a host-genetic factor for the modulation of the diversity and composition of the fecal microbiota in pigs. IMPORTANCE A better understanding of the environmental and host factors modulating gut microbiomes is a topic of greatest interest. Recent evidence suggests that genetic variation in the pig genome partially controls the composition of porcine gut microbiota. However, since previous studies have been focused on the association between single nucleotide polymorphisms and the fecal microbiota, little is known about the relationship between other sources of genetic variation, like the structural variants and microbial traits. Here, we identified, experimentally validated, and replicated in an independent population a positive link between the gain of copies of ABCC2-DNMBP loci and the diversity and composition of pig fecal microbiota. Our results advise the relevance of considering the role of host-genome structural variants as putative modulators of microbial ecosystems and open the possibility of implementing novel holobiont-based management strategies in breeding programs for the simultaneous improvement of microbial traits and host performance.

In vitro nematicidal and acaricidal effect of biosurfactants produced by Bacillus against the root-knot nematode Nacobbus aberrans and the dust mite Tyrophagus putrescentiae.

In the present study, the nematicidal and acaricidal activity of three biosurfactants (BS) produced by strains of the Bacillus genus was evaluated. The BS produced by the Bacillus ROSS2 strain presented a mortality of 39.29% in juveniles (J2) of Nacobbus aberrans at a concentration of 30 mg/mL, this same strain is the one that presented the highest mortality in Tyrophagus putrescentiae, which was 57.97% at a concentration of 39 mg/mL. The BS were qualitatively identified by thin layer chromatography and are lipid in nature based on the retention factor (Rf). While the GC-MS analysis identified two main compounds that are 4,7-Methano-1H-indene-2,6-dicarboxylic acid, 3a,4,7,7a-tetrahydro-1, and Methyl 4-(pyrrol-1-yl)-1,2,5-oxadiazole-3-carboxylate1, which is the polar part indicated by the presence of dicarboxylic acid and carboxylate groups; while the non-polar portion can be interpreted as a hydrocarbon chain of variable length. Based on the present results, BS can be an alternative for the biocontrol of the root-knot nematode N. aberrans and the mite T. putrescentiae.

Infection-related mortality after HLA-identical and haploidentical hematopoietic cell transplantation using reduced-intensity conditioning in an outpatient setting.

BACKGROUND: Despite the improvements in supportive care for allogeneic-hematopoietic cell transplantation (allo-HCT) recipients, infectious complications and infection-related mortality (IRM) continue to be a major issue for transplantation centers. METHODS: We herein report the infectious complications and IRM of 107 and 89 patients that underwent haploidentical (haplo-HCT) or HLA-identical HCT at a tertiary referral center during 2013-2020. Patients in the haplo-HCT group received post-transplant cyclophosphamide (PT-Cy), and all received reduced-intensity conditioning regimens. RESULTS: More haplo-HCT recipients presented severe infections in the pre-engraftment period (22.4% vs. 6.7%, p = 0.003). Viral (14.9% vs. 4.5%, p = 0.016) and fungal (12.1% vs. 1.1%, p = 0.003) etiologies were more common in this period in this group. The 100-day and 2-year cumulative incidence of IRM was 15% and 21% for the haplo-HCT and 5.6% and 17% for the HLA-identical group; no significant differences were observed between the groups. Fungal pathogens mainly contributed to IRM (33.3%). Infections were the most common cause of mortality (40/81, 49.4%). There were significant differences in donor/recipient CMV serostatus between transplant groups (0.002). CONCLUSIONS: No differences in IRM were observed based on allo-HCT type, with more haplo-HCT patients suffering from severe infections in the pre-engraftment period. Studies to assess future prevention, diagnostic, and treatment strategies to reduce IRM are warranted.

Cerebral Creatine Deficiency Affects the Timing of Oligodendrocyte Myelination.

Cerebral creatine deficiency syndrome (CCDS) is an inborn error of metabolism characterized by intellectual delays, seizures, and autistic-like behavior. However, the role of endogenously synthesized creatine on CNS development and function remains poorly understood. Here, magnetic resonance spectroscopy of adult mouse brains from both sexes revealed creatine synthesis is dependent on the expression of the enzyme, guanidinoacetate methyltransferase (GAMT). To identify Gamt-expressed cells, and how Gamt affects postnatal CNS development, we generated a mouse line by knocking-in a GFP, which is expressed on excision of Gamt We found that Gamt is expressed in mature oligodendrocytes during active myelination in the developing postnatal CNS. Homozygous deletion of Gamt resulted in significantly reduced mature oligodendrocytes and delayed myelination in the corpus callosum. Moreover, the absence of endogenous creatine resulted in altered AMPK signaling in the brain, reduced brain creatine kinase expression in cortical neurons, and signs of axonal damage. Experimental demyelination in mice after tamoxifen-induced conditional deletion of Gamt in oligodendrocyte lineage cells resulted in delayed maturation of oligodendrocytes and myelin coverage in lesions. Moreover, creatine and cyclocreatine supplementation can enhance remyelination after demyelination. Our results suggest endogenously synthesized creatine controls the bioenergetic demand required for the timely maturation of oligodendrocytes during postnatal CNS development, and that delayed myelination and altered CNS energetics through the disruption of creatine synthesis might contribute to conditions, such as CCDS.SIGNIFICANCE STATEMENT Cerebral creatine deficiency syndrome is a rare disease of inborn errors in metabolism, which is characterized by intellectual delays, seizures, and autism-like behavior. We found that oligodendrocytes are the main source of endogenously synthesized creatine in the adult CNS, and the loss of endogenous creatine synthesis led to delayed myelination. Our study suggests impaired cerebral creatine synthesis affects the timing of myelination and may impact brain bioenergetics.

Genetic architecture of innate and adaptive immune cells in pigs.

Pig industry is facing new challenges that make necessary to reorient breeding programs to produce more robust and resilient pig populations. The aim of the present work was to study the genetic determinism of lymphocyte subpopulations in the peripheral blood of pigs and identify genomic regions and biomarkers associated to them. For this purpose, we stained peripheral blood mononuclear cells to measure ten immune-cell-related traits including the relative abundance of different populations of lymphocytes, the proportions of CD4+ T cells and CD8+ T cells, and the ratio of CD4+/CD8+ T cells from 391 healthy Duroc piglets aged 8 weeks. Medium to high heritabilities were observed for the ten immune-cell-related traits and significant genetic correlations were obtained between the proportion of some lymphocytes populations. A genome-wide association study pointed out 32 SNPs located at four chromosomal regions on pig chromosomes SSC3, SSC5, SSC8, and SSCX as significantly associated to T-helper cells, memory T-helper cells and γδ T cells. Several genes previously identified in human association studies for the same or related traits were located in the associated regions, and were proposed as candidate genes to explain the variation of T cell populations such as CD4, CD8A, CD8B, KLRC2, RMND5A and VPS24. The transcriptome analysis of whole blood samples from animals with extreme proportions of γδ T, T-helper and memory T-helper cells identified differentially expressed genes (CAPG, TCF7L1, KLRD1 and CD4) located into the associated regions. In addition, differentially expressed genes specific of different T cells subpopulations were identified such as SOX13 and WC1 genes for γδ T cells. Our results enhance the knowledge about the genetic control of lymphocyte traits that could be considered to optimize the induction of immune responses to vaccines against pathogens. Furthermore, they open the possibility of applying effective selection programs for improving immunocompetence in pigs and support the use of the pig as a very reliable human biomedical model.