Quantitative subcellular acyl-CoA analysis reveals distinct nuclear metabolism and isoleucine-dependent histone propionylation.

Quantitative subcellular metabolomic measurements can explain the roles of metabolites in cellular processes but are subject to multiple confounding factors. We developed stable isotope labeling of essential nutrients in cell culture-subcellular fractionation (SILEC-SF), which uses isotope-labeled internal standard controls that are present throughout fractionation and processing to quantify acyl-coenzyme A (acyl-CoA) thioesters in subcellular compartments by liquid chromatography-mass spectrometry. We tested SILEC-SF in a range of sample types and examined the compartmentalized responses to oxygen tension, cellular differentiation, and nutrient availability. Application of SILEC-SF to the challenging analysis of the nuclear compartment revealed a nuclear acyl-CoA profile distinct from that of the cytosol, with notable nuclear enrichment of propionyl-CoA. Using isotope tracing, we identified the branched chain amino acid isoleucine as a major metabolic source of nuclear propionyl-CoA and histone propionylation, thus revealing a new mechanism of crosstalk between metabolism and the epigenome.

O-GlcNAc transferase enables AgRP neurons to suppress browning of white fat.

Induction of beige cells causes the browning of white fat and improves energy metabolism. However, the central mechanism that controls adipose tissue browning and its physiological relevance are largely unknown. Here, we demonstrate that fasting and chemical-genetic activation of orexigenic AgRP neurons in the hypothalamus suppress the browning of white fat. O-linked ß-N-acetylglucosamine (O-GlcNAc) modification of cytoplasmic and nuclear proteins regulates fundamental cellular processes. The levels of O-GlcNAc transferase (OGT) and O-GlcNAc modification are enriched in AgRP neurons and are elevated by fasting. Genetic ablation of OGT in AgRP neurons inhibits neuronal excitability through the voltage-dependent potassium channel, promotes white adipose tissue browning, and protects mice against diet-induced obesity and insulin resistance. These data reveal adipose tissue browning as a highly dynamic physiological process under central control, in which O-GlcNAc signaling in AgRP neurons is essential for suppressing thermogenesis to conserve energy in response to fasting.

Surfactant effect on energy storage performance of hydrothermally synthesized Ni3V2O8.

We report a study to improve the ternary oxide Ni3V2O8's electrochemical energy storage capabilities through correct surfactanization during hydrothermal synthesis. In this study, Ni3V2O8nanomaterials were synthesized in three different forms: one with a cationic surfactant (CTAB), one with an anionic surfactant (SLS), and one without any surfactant. FESEM study reveals that all the synthesized Ni3V2O8nanomaterials had a small stone-like morphology. The electrochemical study showed that anionic surfactant-assisted Ni3V2O8(NVSLS) had a maximum of 972 F g-1specific capacitance at 1 A g-1current density, whereas cationic surfactant-assisted Ni3V2O8(NVCTAB) had the lowest specific capacitance of 162 F g-1. The specific capacitance and the capacitance retention of the NVSLS(85% after 4000 cycles) based electrode was much better than that of the NVCTAB(76% after 4000 cycles) based electrode. The improved energy storage properties of the NVSLSelectrode are attributed to its high diffusion coefficient, high surface area, and enriched elemental nickel, as compared to the NVCTABelectrode. All these excellent electrochemical properties of NVSLSelectrode indicates their potential usage in asymmetric supercapacitor application.

Synergistic effect between ZnCo2O4 and Co3O4 induces superior electrochemical performance as anodes for lithium-ion batteries.

The current work describes a facile synthesis of spinel-type ZnCo2O4 along with an additional phase, Co3O4, by simply maintaining a non-stoichiometric ratio of Zn and Co precursors. Pure ZnCo2O4 and Co3O4 were also synthesized using the same method to compare results. The obtained morphologies of samples show that small-sized nanoparticles are interconnected and form a porous nanosheet-like structure. When used as anode materials for Li-ion batteries, the ZnCo2O4/Co3O4 nanocomposite electrode exhibits a highly stable charge capacity of 1146.2 mA h g-1 at 0.5C after 350 cycles, which is superior to those of other two pure electrodes, which can be attributed to its optimum porosity, synergistic effect of ZnCo2O4 and Co3O4, increased active sites for Li+ ion diffusion, and higher electrical conductivity. Although the pure Co3O4 electrode displayed a much higher rate capability than the ZnCo2O4/Co3O4 nanocomposite electrode at all investigated current rates, the Co3O4 morphology apparently could not withstand long-term cycling, and the electrode became pulverized due to the repeated volume expansion/contraction, resulting in a rapid decrease in the capacity.

Association of Leukocyte Subpopulations Identified by Flow Cytometry with Outcomes of Sepsis in a Respiratory Intensive Care Unit: An Observational Study.

INTRODUCTION: The dysregulated host immune response in sepsis is orchestrated by peripheral blood leukocytes. This study explored the associations of the peripheral blood leukocyte subpopulations with early clinical deterioration and mortality in sepsis. METHODS: We performed a prospective observational single-center study enrolling adult subjects with sepsis within 48 h of hospital admission. Peripheral blood flow cytometry was performed for the patients at enrolment and after 5 days. The primary outcome was to explore the association between various leukocyte subpopulations at enrolment and early clinical deterioration [defined as an increase in the sequential organ failure assessment (SOFA) score between enrolment and day 5, or death before day 5]. Other pre-specified outcomes explored associations of leukocyte subpopulations at enrolment and on day 5 with in-hospital mortality. RESULTS: A total of 100 patients, including 47 with septic shock were enrolled. The mean (SD) age of the patients was 53.99 (14.93) years. Among them, 26 patients had early clinical deterioration, whereas 41 died during hospitalization. There was no significant association between the leukocyte subpopulations at enrolment and early clinical deterioration on day 5. On multivariate logistic regression, a reduced percentage of CD8 + CD25+ T-cells at enrolment was associated with in-hospital mortality [odds ratio (OR), 0.82 (0.70-0.97); p-value = 0.02]. A reduced lymphocyte percentage on day 5 was associated with in-hospital mortality [OR, 0.28 (0.11-0.69); p-value = 0.01]. In a post-hoc analysis, patients with "very early" deterioration within 48 h had an increased granulocyte CD64 median fluorescent intensity (MFI) [OR, 1.07 (1.01-1.14); p-value = 0.02] and a reduced granulocyte CD16 MFI [OR, 0.97 (0.95-1.00); p-value = 0.04] at enrolment. CONCLUSIONS: None of the leukocyte subpopulations showed an association with early clinical deterioration at day 5. Impaired lymphocyte activation and lymphocytopenia indicative of adaptive immune dysfunction may be associated with in-hospital mortality.

Testing prescribed burning to shift an agronomic grass community to a diverse native plant community.

Prescribed burning can be an effective land management tool. Here, we study changes in plant diversity and composition following experimental fire disturbance in microcosm units extracted from a twenty-five-year-old historically reclaimed grassland located at Highland Valley Copper mine in British Columbia (B.C.), Canada. Experimental microcosm units were dominated by agronomic grass species Elymus lanceolatus, Thinopyrum intermedium and Bromus inermis. The disturbance treatment was fire intensity, represented by three levels (light, moderate, and heavy), replicated six times per treatment. Fire intensity was controlled by modifying the weight of dried litter applied to each microcosm unit (50 g,150 g, 200g), along with the time each grass turf was burned (10 s, 15 s, 20 s). One day after the fire treatment was applied, microcosm units were seeded with a native species mix consisting of six grassland species common to southern B.C. to examine effectiveness of plant establishment postburn. Disturbance treatments resulted in higher overall alpha diversity, richness, evenness, and beta diversity. Plant community changes included colonization of seeded native forbs, grasses, and legumes in response to disturbance. Aboveground net primary productivity (ANPP) was net neutral within the light and moderate burning disturbance treatments but resulted in increased ANPP with heavy disturbance. Litter mass reduced plant diversity and ANPP, indicating that litter was a major factor in plant community dynamics. These results suggest disturbance by burning leads to short term positive plant community response towards increasing diversity of semi-arid grasslands, and aids in shifting plant communities to higher diversity composed of an increase in native plant species. Our results also suggest that without active management the gains observed in native species establishment might quickly be out shadowed and restricted by the previously dominant agronomic plant community.

How Does Literacy Affect Speech Processing? Not by Enhancing Cortical Responses to Speech, But by Promoting Connectivity of Acoustic-Phonetic and Graphomotor Cortices.

Previous research suggests that literacy, specifically learning alphabetic letter-to-phoneme mappings, modifies online speech processing and enhances brain responses, as indexed by the BOLD, to speech in auditory areas associated with phonological processing (Dehaene et al., 2010). However, alphabets are not the only orthographic systems in use in the world, and hundreds of millions of individuals speak languages that are not written using alphabets. In order to make claims that literacy per se has broad and general consequences for brain responses to speech, one must seek confirmatory evidence from nonalphabetic literacy. To this end, we conducted a longitudinal fMRI study in India probing the effect of literacy in Devanagari, an abubgida, on functional connectivity and cerebral responses to speech in 91 variously literate Hindi-speaking male and female human participants. Twenty-two completely illiterate participants underwent 6 months of reading and writing training. Devanagari literacy increases functional connectivity between acoustic-phonetic and graphomotor brain areas, but we find no evidence that literacy changes brain responses to speech, either in cross-sectional or longitudinal analyses. These findings shows that a dramatic reconfiguration of the neurofunctional substrates of online speech processing may not be a universal result of learning to read, and suggest that the influence of writing on speech processing should also be investigated.SIGNIFICANCE STATEMENT It is widely claimed that a consequence of being able to read is enhanced auditory processing of speech, reflected by increased cortical responses in areas associated with phonological processing. Here we find no relationship between literacy and the magnitude of brain response to speech stimuli in individuals who speak Hindi, which is written using a nonalphabetic script, Devanagari, an abugida. We propose that the exact nature of the script under examination must be considered before making sweeping claims about the consequences of literacy for the brain. Further, we find evidence that literacy enhances functional connectivity between auditory processing areas and graphomotor areas, suggesting a mechanism whereby learning to write might influence speech perception.

Expression Profile, Molecular Association, and Clinical Significance of POLD4 in Glioblastoma.

The POLD4 gene encodes a subunit (δ4) of DNA polymerase delta, which is a key enzyme involved in DNA replication and repair. Recent studies have suggested that POLD4 plays a crucial role in developing certain cancers. However, there is a lack of knowledge regarding the role of POLD4 in the context of glioblastoma (GBM). Therefore, in this study we have used various cancer bioinformatics tools to explore the role of POLD4 in glioblastoma. Data from various sources were accessed to analyze POLD4 gene expression and estimate tumor-infiltrating immune cells in glioblastoma. Methylation data were retrieved using the MEXPRESS web browser and analyzed. UALCAN webserver was used to analyze the protein expression of POLD4. Gene correlation and pathway enrichment analysis were performed using cBioPortal and GSEA software, respectively. Afterward, survival analysis was performed. POLD4 was significantly upregulated in glioblastoma at both gene and protein levels in GBM, and ROC curve analysis revealed it as a potential biomarker in glioblastoma. GSEA analysis of TCGA-GBM pan-cancer study exhibited that POLD4 expression was associated with critical pathways, such as interferon-gamma response, G2M checkpoint, inflammatory response, E2F targets, EMT transition, and KRAS signaling pathways. Furthermore, POLD4 expression was positively correlated with DNA methylation at 3 CpG sites, including Cg16509978, with a Pearson correlation coefficient value of 0.398 (p-value ≤ 0.01), while the promoter region had a positive correlation but was not significant. In addition, POLD4 is significantly linked with poor OS, PFS, and DFS. We also found association of POLD4 expression with altered immune cell infiltration. In conclusion, POLD4 is significantly upregulated in glioblastoma and may be used as a potential diagnostic or prognostic biomarker for GBM patients. However, to establish the same a large cohort study is needed. Using TCGA data and various cancer bioinformatics tools mentioned above we observed very high level of gene and protein expression of POLD4 in glioblastoma patients. The expression of POLD4 was significantly correlated with inflammatory and oncogenic pathways and it also has a significant correlation with adverse outcome in patients with glioblastoma.

Multifunctional Cu:ZnS quantum dots for degradation of Amoxicillin and Dye Sulphon Fast Black-F and efficient determination of urea for assessing environmental aspects.

This work is particularly aimed at the preparation of ZnS and Cu doped ZnS (Cu:ZnS) QDs by facile and easy technique, chemical precipitation method for the degradation of water pollutants and a simple scheme was proposed to prepare the urea-sensing system. The morphological and optical properties of the synthesized QDs was studied using high resolution transmission and scanning electron microscopes, X-ray diffraction, energy dispersive X-ray analysis, fluorescence and ultraviolet-visible spectroscopy, differential thermal and thermogravimetric analyses, Brunauer-Emmett-Teller analysis. The photocatalytic performance was systematically assessed by the photodegradation of an important pharmaceutical water pollutant, Amoxicillin (AMX) and a dye Fast Sulphon Black F (SFBF) in aqueous medium under UV light irradiation. Also, a very sensitive system was prepared by depositing the dots over an indium-tin-oxide (ITO) glass substrate for the sensing of biologically active molecule urea as it is an important monitor of public health in water and soil productivity. The results illustrated excellent photocatalytic efficiency (86.46% for AMX and 99.41% for SFBF) with stability up to four cycles of degradation reaction. The optimal photocatalyst dosage for achieving maximum removal of AMX was found to be 70 mg at a pH of 9.5, with a treatment time of 40 min. Similarly, for SFBF, the optimal photocatalyst dosage was determined to be 60 mg at pH 9, with a treatment time of 60 min. Further, the electrochemical analysis was done by fabricating Urease enzyme (UR)/Cu:ZnS QDs/ITO bioelectrode and then the fabricated bioelectrode, was utilized to determine the different concentrations of urea by cyclic voltammetry. Thus, the obtained limit of detection and sensitivity of the fabricated biosensing device for urea detection was obtained to be 0.0092 µM and 12 µA µM-1cm-2, respectively; under the optimized experimental conditions. Hence, it is anticipated that Cu:ZnS QDs can also successfully be applied as a promising material for fabrication of novel bioelectrode for urea determination and the biosensing platform is desirable and viable.

Advancement in precision diagnosis and therapeutic for triple-negative breast cancer: Harnessing diagnostic potential of CRISPR-cas & engineered CAR T-cells mediated therapeutics.

Cancer is characterized by uncontrolled cell growth, disrupted regulatory pathways, and the accumulation of genetic mutations. These mutations across different types of cancer lead to disruptions in signaling pathways and alterations in protein expression related to cellular growth and proliferation. This review highlights the AKT signaling cascade and the retinoblastoma protein (pRb) regulating cascade as promising for novel nanotheranostic interventions. Through synergizing state-of-the-art gene editing tools like the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas system with nanomaterials and targeting AKT, there is potential to enhance cancer diagnostics significantly. Furthermore, the integration of modified CAR-T cells into multifunctional nanodelivery systems offers a promising approach for targeted cancer inhibition, including the eradication of cancer stem cells (CSCs). Within the context of highly aggressive and metastatic Triple-negative Breast Cancer (TNBC), this review specifically focuses on devising innovative nanotheranostics. For both pre-clinical and post-clinical TNBC detection, the utilization of the CRISPR-Cas system, guided by RNA (gRNA) and coupled with a fluorescent reporter specifically designed to detect TNBC's mutated sequence, could be promising. Additionally, a cutting-edge approach involving the engineering of TNBC-specific iCAR and syn-Notch CAR T-cells, combined with the co-delivery of a hybrid polymeric nano-liposome encapsulating a conditionally replicative adenoviral vector (CRAdV) against CSCs, could present an intriguing intervention strategy. This review thus paves the way for exciting advancements in the field of nanotheranostics for the treatment of TNBC and beyond.

Gold nanoparticle assisted colorimetric biosensors for rapid polyethylene terephthalate (PET) sensing for sustainable environment to monitor microplastics.

The extremely widespread and ubiquitous nature of plastics, estimated to boost its global production by 26 billion tons till 2050. The large chunks of plastic waste that decomposed down to micro- or nano plastics (MNPs) leads to various ill effects on biological entities. The conventional PET detection methods lack rapid detection of microplastics due to variances in microplastic features, long-drawn-out sample pre-processing procedures and complex instrumentation. Therefore, an instantaneous colorimetric evaluation of microplastic will ensures the simplicity of conducting assays on field. Several nanoparticle-based biosensors that detects proteins, nucleic acids, metabolites operate on either cluster or disperse state of nanoparticle. However, gold nanoparticle (AuNPs) emerges an ideal scaffold for sensory element in lateral flow biosensors due to their simple surface functionalization, unique optoelectronic properties and varied colour spectrum depending on morphologies and aggregation state. In this paper an effort has been made in the form of a hypothesis using in silico tools as a basis to detect polyethylene terephthalate (PET) - most abundant type of microplastic using gold nanoparticle based lateral flow biosensor. We retrieved sequences of PET-binding synthetic peptides and modelled their 3-D structure using I-Tasser server. The best protein model for each peptide sequences are docked with PET monomers - BHET, MHET and other PET polymeric ligands, to evaluate their binding affinities. The synthetic peptide SP 1 (WPAWKTHPILRM) docked with BHET and (MHET)4 exhibits 1.5-fold increases in binding affinity as compared to reference PET anchor peptide Dermaseptin SI (DSI). The GROMACS molecular dynamics simulation studies of synthetic peptide SP 1 - BHET & - (MHET)4 complexes for 50 ns further confirmed the stable binding. RMSF, RMSD, hydrogen bonds, Rg and SASA analysis provides useful structural insights of the SP 1 complexes as compared to reference DSI. Furthermore, SP 1 functionalized AuNP-based colorimetric device was described in detail for detection of PET.

Smart and intelligent optical materials for sensing applications.

This special issue (SI) entitled 'Smart and intelligent optical materials for sensing applications', published by Luminescence, Wiley focuses on the recent advancement of smart and intelligent optical materials for the fabrication of sensor technology for use in numerous fields such as pharmaceutical, biomedical, and environmental. Also, detailed highlights of their prospects in the fields, for example, of personalized health care, wearable devices, and plant stress monitoring are given. This SI includes 46 peer-reviewed articles, of which 15 are reviews written by well established researchers with expertise in the field, and the remaining 31 are research articles from world-leading scientists.

Electro-optical behaviour of CuFe2 O4 @rGO nanocomposite for nonenzymatic detection of uric acid via the electrochemical method.

Uric acid (UA) is a blood and urine component obtained as a metabolic by-product of purine nucleotides. Abnormalities in UA metabolism cause crystal deposition as monosodium urate and lead to various diseases such as gout, hyperuricemia, Lesch-Nyhan syndrome, etc. Monitoring these diseases requires a rapid, sensitive, selective, and portable detection approach. Therefore, this study demonstrates the hydrothermal synthesis of CuFe2 O4 /reduced graphene oxide (rGO) nanocomposite for selective detection of UA. After the nanocomposite synthesis, characterization was performed by X-ray diffraction spectroscopy, Fourier transform infrared spectroscopy, Raman spectroscopy, X-ray photoelectron spectroscopy, UV-visible spectrometry, atomic force spectroscopy, scanning electron microscopy, and electrochemical analysis. Furthermore, from the electrochemical analysis using cyclic voltammetry (CV), kinetic studies were carried out by varying the scan rate to obtain the diffusion coefficient, surface concentration, and rate of charge transfer to achieve a calibration curve that indicates the quasi reversible nature of the fabricated electrode with a linear regression coefficient of oxidation (R2 : 0.9992) and reduction (R2 : 0.9971) peaks. Moreover, the fabricated nonenzymatic amperometric sensor to detect UA with a linearity (R2 : 0.9989) of 1-400 µM was highly sensitive (2.75 × 10-4  mAµM-1  cm-2 ) and had a lower limit of detection (0.01231 µM) at pH 7.5 in phosphate-buffered saline solution. Therefore, the CuFe2 O4 /rGO/ITO-based nonenzymatic sensor could detect interfering agents and spiked real bovine serum samples with higher sensitivity and selectivity for UA detection.

Synthesis, characterization, and electrocatalytic behaviour of hydrothermally grown nanostructured La2 O3 and La2 O3 /K-complex.

Rare earth metals play a conspicuous role in magnetic resonance imaging (MRI) for detecting cancerous cells. The alkali metal potassium is a neurotransmitter in the sodium-potassium pump in biomedical sciences. This unique property of rare earth metals and potassium drew our attention to carry forward this study. Therefore, in this work, previously synthesized potassium (K) complexes formed by the reflux of 4-N,N-dimethylaminobenzoic acid (DBA) and potassium hydroxide in methanol, and named [(µ2-4-N,N-dimethylaminobenzoate-κO)(µ2-4-N,N-dimethylaminobenzoic acid-κO)(4-N,N-dimethylaminobenzoic acid-κO) potassium(I) coordination polymer)] were treated hydrothermally with La2 O3 nanomaterials to obtain a nanohybrid La2 O3 /K-complex. After that, the K-complex was analyzed using single-crystal X-ray diffraction and 1 H and 13 C NMR spectroscopy. In addition, the structural and morphological properties of the as-prepared nanostructured La2 O3 /K-complex were also characterized, which involved an investigation using X-ray diffraction (XRD)spectroscopy, Fourier transform infrared (FTIR) spectroscopy, atomic force spectroscopy (AFM), transmission electron microscopy (TEM), and energy dispersive X-ray (EDX) analysis. After this, the electrochemical redox behaviour of the synthesized nanohybrid material was studied using cyclic voltammetry (CV) and differential pulse voltammetry (DPV). Therefore, the results from these studies revealed that the as-prepared material was a La2 O3 /K-complex that has a promising future role in sensing various analytes, as it showed effective electrocatalytic behaviour.

Potentialities of fluorescent carbon nanomaterials as sensor for food analysis.

Food safety and quality are among the most significant and prevalent research areas worldwide. The fabrication of appropriate technical procedures or devices for the recognition of hazardous features in foods is essential to safeguard food materials. In the recent era, developing high-performance sensors based on carbon nanomaterial for food safety investigation has made noteworthy progress. Hence this review briefly highlights the different detection approaches (colorimetric sensor, fluorescence sensor, surface-enhanced Raman scattering, surface plasmon resonance, chemiluminescence, and electroluminescence), functional carbon nanomaterials with various dimensions (quantum dots, graphene quantum dots) and detection mechanisms. Further, this review emphasizes the assimilation of carbon nanomaterials with optical sensors to identify multiple contaminants in food products. The insights of carbon-based nanomaterials optical sensors for pesticides and insecticides, toxic metals, antibiotics, microorganisms, and mycotoxins detection are described in detail. Finally, the opportunities and future perspectives of nanomaterials-based optical analytical approaches for detecting various food contaminants are discussed.

Recent advances in ZnO nanostructure as a gas-sensing element for an acetone sensor: a short review.

Air pollution is a severe concern globally as it disturbs the health conditions of living beings and the environment because of the discharge of acetone molecules. Metal oxide semiconductor (MOS) nanomaterials are crucial for developing efficient sensors because of their outstanding chemical and physical properties, empowering the inclusive developments in gas sensor productivity. This review presents the ZnO nanostructure state of the art and notable growth, and their structural, morphological, electronic, optical, and acetone-sensing properties. The key parameters, such as response, gas detection limit, sensitivity, reproducibility, response and recovery time, selectivity, and stability of the acetone sensor, have been discussed. Furthermore, gas-sensing mechanism models based on MOS for acetone sensing are reported and discussed. Finally, future possibilities and challenges for MOS (ZnO)-based gas sensors for acetone detection have also been explored.

The steroid hormone estriol (E3) regulates epigenetic programming of fetal mouse brain and reproductive tract.

BACKGROUND: Estriol (E3) is a steroid hormone formed only during pregnancy in primates including humans. Although E3 is synthesized at large amounts through a complex pathway involving the fetus and placenta, it is not required for the maintenance of pregnancy and has classically been considered virtually inactive due to associated very weak canonical estrogen signaling. However, estrogen exposure during pregnancy may have an effect on organs both within and outside the reproductive system, and compounds with binding affinity for estrogen receptors weaker than E3 have been found to impact reproductive organs and the brain. Here, we explore potential effects of E3 on fetal development using mouse as a model system. RESULTS: We administered E3 to pregnant mice, exposing the fetus to E3. Adult females exposed to E3 in utero (E3-mice) had increased fertility and superior pregnancy outcomes. Female and male E3-mice showed decreased anxiety and increased exploratory behavior. The expression levels and DNA methylation patterns of multiple genes in the uteri and brains of E3-mice were distinct from controls. E3 promoted complexing of estrogen receptors with several DNA/histone modifiers and their binding to target genes. E3 functions by driving epigenetic change, mediated through epigenetic modifier interactions with estrogen receptors rather than through canonical nuclear transcriptional activation. CONCLUSIONS: We identify an unexpected functional role for E3 in fetal reproductive system and brain. We further identify a novel mechanism of estrogen action, through recruitment of epigenetic modifiers to estrogen receptors and their target genes, which is not correlated with the traditional view of estrogen potency.

Direct anabolic metabolism of three-carbon propionate to a six-carbon metabolite occurs in vivo across tissues and species.

Anabolic metabolism of carbon in mammals is mediated via the one- and two-carbon carriers S-adenosyl methionine and acetyl-coenzyme A. In contrast, anabolic metabolism of three-carbon units via propionate has not been shown to extensively occur. Mammals are primarily thought to oxidize the three-carbon short chain fatty acid propionate by shunting propionyl-CoA to succinyl-CoA for entry into the TCA cycle. Here, we found that this may not be absolute as, in mammals, one nonoxidative fate of propionyl-CoA is to condense to two three-carbon units into a six-carbon trans-2-methyl-2-pentenoyl-CoA (2M2PE-CoA). We confirmed this reaction pathway using purified protein extracts provided limited substrates and verified the product via LC-MS using a synthetic standard. In whole-body in vivo stable isotope tracing following infusion of 13C-labeled valine at steady state, 2M2PE-CoA was found to form via propionyl-CoA in multiple murine tissues, including heart, kidney, and to a lesser degree, in brown adipose tissue, liver, and tibialis anterior muscle. Using ex vivo isotope tracing, we found that 2M2PE-CoA also formed in human myocardial tissue incubated with propionate to a limited extent. While the complete enzymology of this pathway remains to be elucidated, these results confirm the in vivo existence of at least one anabolic three- to six-carbon reaction conserved in humans and mice that utilizes propionate.

BAALC gene expression tells a serious patient outcome tale in NPM1-wild type/FLT3-ITD negative cytogenetically normal-acute myeloid leukemia in adults.

Acute myeloid leukemia with normal cytogenetics (CN-AML) is the largest group of AML patients which is associated with a variegated patient outcome. Multiple molecular markers have been used to risk-stratify these patients. Estimation of expression of BAALC gene (Brain and Acute Leukemia, Cytoplasmic) mRNA level is one of the predictive markers which has been identified in multiple studies. In this study, we examined the clinical and prognostic value of BAALC gene expression in 149 adult CN-AML patients. We also utilized multi-omics databases to ascertain the association of BAALC gene expression with comprehensive molecular and clinicopathologic features in AML. BAALC overexpression was associated with CD34 positivity on leukemic blasts (p = 0.0026) and the absence of NPM1 gene mutation (p < 0.0001), presence of RUNX1 gene mutation (p < 0.001) and poor patient outcomes, particularly in NPM1-wild type/FLT3-ITD negative adult CN-AML patients. Additionally, BAALC expression was associated with the alteration of methylation of its promoter. Further, pathway analysis revealed that BAALC expression is correlated with MYC targets and Ras signalling. We conclude that high BAALC expression associates with poor patient outcome in NPM1-wild type/FLT3-ITD negative adult CN-AML patients.

Prognostic utility of key copy number alterations in T cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease, characterized by an abnormal transformation of T cells into highly proliferative leukemic lymphoblasts. Identification of common genetic alterations has provided promising opportunities for better risk stratification in T-ALL. Current treatment in T-ALL still poses the major challenge of integrating the knowledge of molecular alterations in the clinical setting. We utilized the Multiplex Ligation Dependent Probe Amplification (MLPA) method to determine the frequency of common copy number alterations (CNAs) in 128 newly diagnosed T-ALL patients. We also studied the association of these CNAs with patient's clinical characteristics and survival. The highest frequency of deletion was observed in CDKN2A (59.38%), followed by CDKN2B (46.88%), LMO1 (37.5%), and MTAP (28.12%). PTPN2 (22.66%), PHF6 (14.06%), and MYB (14.06%) had the highest number of duplication events. A total of 89.06% patients exhibited CNAs. STIL::TAL1, NUP214::ABL1, and LMO2::RAG2 fusions were observed in 5.47%, 3.12%, and 0.78% of patients, respectively. CDKN2A, CDKN2B, and PTPN2 gene deletions were mainly observed in pediatric patients, while CNAs of NF1 and SUZ12 were observed more frequently in adults. In pediatric patients, alterations in CDKN2B, CASP8AP2, and AHI1 were associated with poor prognosis, while SUZ12 and NF1 CNAs were associated with favorable prognosis. In adult patients, ABL1 CNA emerged as an independent indicator of poor prognosis. The observed molecular heterogeneity in T-ALL may provide the basis for variations observed in clinical response in T-ALL and MLPA based CNA detection may help in risk stratification of these patients.