ResearchPad - protein-complexes https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[The degradation-promoting roles of deubiquitinases Ubp6 and Ubp3 in cytosolic and ER protein quality control]]> https://www.researchpad.co/article/elastic_article_14498 The quality control of intracellular proteins is achieved by degrading misfolded proteins which cannot be refolded by molecular chaperones. In eukaryotes, such degradation is handled primarily by the ubiquitin-proteasome system. However, it remained unclear whether and how protein quality control deploys various deubiquitinases. To address this question, we screened deletions or mutation of the 20 deubiquitinase genes in Saccharomyces cerevisiae and discovered that almost half of the mutations slowed the removal of misfolded proteins whereas none of the remaining mutations accelerated this process significantly. Further characterization revealed that Ubp6 maintains the level of free ubiquitin to promote the elimination of misfolded cytosolic proteins, while Ubp3 supports the degradation of misfolded cytosolic and ER luminal proteins by different mechanisms.

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<![CDATA[Genetic identification of the functional surface for RNA binding by <i>Escherichia coli</i> ProQ]]> https://www.researchpad.co/article/N5450feb3-1628-4bb4-b1ba-e6e2944bb4b8 The FinO-domain-protein ProQ is an RNA-binding protein that has been known to play a role in osmoregulation in proteobacteria. Recently, ProQ has been shown to act as a global RNA-binding protein in Salmonella and Escherichia coli, binding to dozens of small RNAs (sRNAs) and messenger RNAs (mRNAs) to regulate mRNA-expression levels through interactions with both 5′ and 3′ untranslated regions (UTRs). Despite excitement around ProQ as a novel global RNA-binding protein, and its potential to serve as a matchmaking RNA chaperone, significant gaps remain in our understanding of the molecular mechanisms ProQ uses to interact with RNA. In order to apply the tools of molecular genetics to this question, we have adapted a bacterial three-hybrid (B3H) assay to detect ProQ’s interactions with target RNAs. Using domain truncations, site-directed mutagenesis and an unbiased forward genetic screen, we have identified a group of highly conserved residues on ProQ’s NTD as the primary face for in vivo recognition of two RNAs, and propose that the NTD structure serves as an electrostatic scaffold to recognize the shape of an RNA duplex.

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<![CDATA[Long noncoding RNA HCP5 participates in premature ovarian insufficiency by transcriptionally regulating MSH5 and DNA damage repair via YB1]]> https://www.researchpad.co/article/Nbd8d15e0-13a5-401a-b593-49210179af13 The genetic etiology of premature ovarian insufficiency (POI) has been well established to date, however, the role of long noncoding RNAs (lncRNAs) in POI is largely unknown. In this study, we identified a down-expressed lncRNA HCP5 in granulosa cells (GCs) from biochemical POI (bPOI) patients, which impaired DNA damage repair and promoted apoptosis of GCs. Mechanistically, we discovered that HCP5 stabilized the interaction between YB1 and its partner ILF2, which could mediate YB1 transferring into the nucleus of GCs. HCP5 silencing affected the localization of YB1 into nucleus and reduced the binding of YB1 to the promoter of MSH5 gene, thereby diminishing MSH5 expression. Taken together, we identified that the decreased expression of HCP5 in bPOI contributed to dysfunctional GCs by regulating MSH5 transcription and DNA damage repair via the interaction with YB1, providing a novel epigenetic mechanism for POI pathogenesis.

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<![CDATA[Deletion of Endonuclease V suppresses chemically induced hepatocellular carcinoma]]> https://www.researchpad.co/article/N71abc15b-ba7b-4237-9cf3-374d0fc7ebc4 Endonuclease V (EndoV) is a conserved inosine-specific ribonuclease with unknown biological function. Here, we present the first mouse model lacking EndoV, which is viable without visible abnormalities. We show that endogenous murine EndoV cleaves inosine-containing RNA in vitro, nevertheless a series of experiments fails to link an in vivo function to processing of such transcripts. As inosine levels and adenosine-to-inosine editing often are dysregulated in hepatocellular carcinoma (HCC), we chemically induced HCC in mice. All mice developed liver cancer, however, EndoV−/− tumors were significantly fewer and smaller than wild type tumors. Opposed to human HCC, adenosine deaminase mRNA expression and site-specific editing were unaltered in our model. Loss of EndoV did not affect editing levels in liver tumors, however mRNA expression of a selection of cancer related genes were reduced. Inosines are also found in certain tRNAs and tRNAs are cleaved during stress to produce signaling entities. tRNA fragmentation was dysregulated in EndoV−/− livers and apparently, inosine-independent. We speculate that the inosine-ribonuclease activity of EndoV is disabled in vivo, but RNA binding allowed to promote stabilization of transcripts or recruitment of proteins to fine-tune gene expression. The EndoV−/− tumor suppressive phenotype calls for related studies in human HCC.

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<![CDATA[The most abundant maternal lncRNA Sirena1 acts post-transcriptionally and impacts mitochondrial distribution]]> https://www.researchpad.co/article/N3e6d0fb9-3522-4bad-a0c7-0899189f694e

Abstract

Tens of thousands of rapidly evolving long non-coding RNA (lncRNA) genes have been identified, but functions were assigned to relatively few of them. The lncRNA contribution to the mouse oocyte physiology remains unknown. We report the evolutionary history and functional analysis of Sirena1, the most expressed lncRNA and the 10th most abundant poly(A) transcript in mouse oocytes. Sirena1 appeared in the common ancestor of mouse and rat and became engaged in two different post-transcriptional regulations. First, antisense oriented Elob pseudogene insertion into Sirena1 exon 1 is a source of small RNAs targeting Elob mRNA via RNA interference. Second, Sirena1 evolved functional cytoplasmic polyadenylation elements, an unexpected feature borrowed from translation control of specific maternal mRNAs. Sirena1 knock-out does not affect fertility, but causes minor dysregulation of the maternal transcriptome. This includes increased levels of Elob and mitochondrial mRNAs. Mitochondria in Sirena1−/− oocytes disperse from the perinuclear compartment, but do not change in number or ultrastructure. Taken together, Sirena1 contributes to RNA interference and mitochondrial aggregation in mouse oocytes. Sirena1 exemplifies how lncRNAs stochastically engage or even repurpose molecular mechanisms during evolution. Simultaneously, Sirena1 expression levels and unique functional features contrast with the lack of functional importance assessed under laboratory conditions.

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<![CDATA[Correlation between equi-partition of aminoacyl-tRNA synthetases and amino-acid biosynthesis pathways]]> https://www.researchpad.co/article/N3c595c04-005d-46ad-a809-124898c099b3

Abstract

The partition of aminoacyl-tRNA synthetases (aaRSs) into two classes of equal size and the correlated amino acid distribution is a puzzling still unexplained observation. We propose that the time scale of the amino-acid synthesis, assumed to be proportional to the number of reaction steps (NE) involved in the biosynthesis pathway, is one of the parameters that controlled the timescale of aaRSs appearance. Because all pathways are branched at fructose-6-phosphate on the metabolic pathway, this product is defined as the common origin for the NE comparison. For each amino-acid, the NE value, counted from the origin to the final product, provides a timescale for the pathways to be established. An archeological approach based on NE reveals that aaRSs of the two classes are generated in pair along this timescale. The results support the coevolution theory for the origin of the genetic code with an earlier appearance of class II aaRSs.

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<![CDATA[Good guide, bad guide: spacer sequence-dependent cleavage efficiency of Cas12a]]> https://www.researchpad.co/article/N0957aa3a-4769-4a20-9561-ac0ce59ebfb1

Abstract

Genome editing has recently made a revolutionary development with the introduction of the CRISPR–Cas technology. The programmable CRISPR-associated Cas9 and Cas12a nucleases generate specific dsDNA breaks in the genome, after which host DNA-repair mechanisms can be manipulated to implement the desired editing. Despite this spectacular progress, the efficiency of Cas9/Cas12a-based engineering can still be improved. Here, we address the variation in guide-dependent efficiency of Cas12a, and set out to reveal the molecular basis of this phenomenon. We established a sensitive and robust in vivo targeting assay based on loss of a target plasmid encoding the red fluorescent protein (mRFP). Our results suggest that folding of both the precursor guide (pre-crRNA) and the mature guide (crRNA) have a major influence on Cas12a activity. Especially, base pairing of the direct repeat, other than with itself, was found to be detrimental to the activity of Cas12a. Furthermore, we describe different approaches to minimize base-pairing interactions between the direct repeat and the variable part of the guide. We show that design of the 3′ end of the guide, which is not involved in target strand base pairing, may result in substantial improvement of the guide's targeting potential and hence of its genome editing efficiency.

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<![CDATA[rRNA expansion segment 27Lb modulates the factor recruitment capacity of the yeast ribosome and shapes the proteome]]> https://www.researchpad.co/article/N38d0ed33-e3ef-416d-ad62-dc0799eae104

Abstract

Fine-tuned regulation of protein biosynthesis is crucial for cellular fitness and became even more vital when cellular and organismal complexity increased during the course of evolution. In order to cope with this augmented demand for translation control, eukaryal ribosomes have gained extensions both at the ribosomal protein and rRNA levels. Here we analyze the functional role of ES27L, an rRNA expansion segment in the large ribosomal subunit of Saccharomyces cerevisiae. Deletion of the b-arm of this expansion segment, called ES27Lb, did not hamper growth during optimal conditions, thus demonstrating that this 25S rRNA segment is not inherently crucial for ribosome functioning. However, reductive stress results in retarded growth and rendered unique protein sets prone to aggregation. Lack of ES27Lb negatively affects ribosome-association of known co-translational N-terminal processing enzymes which in turn contributes to the observed protein aggregation. Likely as a compensatory response to these challenges, the truncated ribosomes showed re-adjusted translation of specific sets of mRNAs and thus fine-tune the translatome in order to re-establish proteostasis. Our study gives comprehensive insight into how a highly conserved eukaryal rRNA expansion segment defines ribosomal integrity, co-translational protein maturation events and consequently cellular fitness.

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<![CDATA[Genome-wide analysis reveals a switch in the translational program upon oocyte meiotic resumption]]> https://www.researchpad.co/article/N2bfac294-fad7-4a1a-ad6a-ee3240de3046

Abstract

During oocyte maturation, changes in gene expression depend exclusively on translation and degradation of maternal mRNAs rather than transcription. Execution of this translation program is essential for assembling the molecular machinery required for meiotic progression, fertilization, and embryo development. With the present study, we used a RiboTag/RNA-Seq approach to explore the timing of maternal mRNA translation in quiescent oocytes as well as in oocytes progressing through the first meiotic division. This genome-wide analysis reveals a global switch in maternal mRNA translation coinciding with oocyte re-entry into the meiotic cell cycle. Messenger RNAs whose translation is highly active in quiescent oocytes invariably become repressed during meiotic re-entry, whereas transcripts repressed in quiescent oocytes become activated. Experimentally, we have defined the exact timing of the switch and the repressive function of CPE elements, and identified a novel role for CPEB1 in maintaining constitutive translation of a large group of maternal mRNAs during maturation.

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<![CDATA[An internal deletion of ADAR rescued by MAVS deficiency leads to a minute phenotype]]> https://www.researchpad.co/article/N0ad513a8-c08e-42f1-b25a-10638beb8544

Abstract

The RNA-editing protein ADAR is essential for early development in the mouse. Genetic evidence suggests that A to I editing marks endogenous RNAs as ‘self’. Today, different Adar knockout alleles have been generated that show a common phenotype of apoptosis, liver disintegration, elevated immune response and lethality at E12.5. All the Adar knockout alleles can be rescued by a concomitant deletion of the innate immunity genes Mavs or Ifih1 (MDA5), albeit to different extents. This suggests multiple functions of ADAR. We analyze AdarΔ7-9 mice that show a unique growth defect phenotype when rescued by Mavs. We show that AdarΔ7-9 can form a truncated, unstable, editing deficient protein that is mislocalized. Histological and hematologic analysis of these mice indicate multiple tissue- and hematopoietic defects. Gene expression profiling shows dysregulation of Rps3a1 and Rps3a3 in rescued AdarΔ7-9. Consistently, a distortion in 40S and 60S ribosome ratios is observed in liver cells. This dysregulation is also seen in AdarΔ2-13; Mavs−/− but not in AdarE861A/E861A; Ifih1−/− mice, suggesting editing-independent functions of ADAR in regulating expression levels of Rps3a1 and Rps3a3. In conclusion, our study demonstrates the importance of ADAR in post-natal development which cannot be compensated by ADARB1.

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<![CDATA[Gene fragmentation and RNA editing without borders: eccentric mitochondrial genomes of diplonemids]]> https://www.researchpad.co/article/N2413ba3b-5c85-472d-b929-694346044274

Abstract

Diplonemids are highly abundant heterotrophic marine protists. Previous studies showed that their strikingly bloated mitochondrial genome is unique because of systematic gene fragmentation and manifold RNA editing. Here we report a comparative study of mitochondrial genome architecture, gene structure and RNA editing of six recently isolated, phylogenetically diverse diplonemid species. Mitochondrial gene fragmentation and modes of RNA editing, which include cytidine-to-uridine (C-to-U) and adenosine-to-inosine (A-to-I) substitutions and 3′ uridine additions (U-appendage), are conserved across diplonemids. Yet as we show here, all these features have been pushed to their extremes in the Hemistasiidae lineage. For example, Namystynia karyoxenos has its genes fragmented into more than twice as many modules than other diplonemids, with modules as short as four nucleotides. Furthermore, we detected in this group multiple A-appendage and guanosine-to-adenosine (G-to-A) substitution editing events not observed before in diplonemids and found very rarely elsewhere. With >1,000 sites, C-to-U and A-to-I editing in Namystynia is nearly 10 times more frequent than in other diplonemids. The editing density of 12% in coding regions makes Namystynia’s the most extensively edited transcriptome described so far. Diplonemid mitochondrial genome architecture, gene structure and post-transcriptional processes display such high complexity that they challenge all other currently known systems.

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<![CDATA[The SINEB1 element in the long non-coding RNA Malat1 is necessary for TDP-43 proteostasis]]> https://www.researchpad.co/article/Nedd2dc89-f839-46b6-a862-bca4d29eac62

Abstract

Transposable elements (TEs) comprise a large proportion of long non-coding RNAs (lncRNAs). Here, we employed CRISPR to delete a short interspersed nuclear element (SINE) in Malat1, a cancer-associated lncRNA, to investigate its significance in cellular physiology. We show that Malat1 with a SINE deletion forms diffuse nuclear speckles and is frequently translocated to the cytoplasm. SINE-deleted cells exhibit an activated unfolded protein response and PKR and markedly increased DNA damage and apoptosis caused by dysregulation of TDP-43 localization and formation of cytotoxic inclusions. TDP-43 binds stronger to Malat1 without the SINE and is likely ‘hijacked’ by cytoplasmic Malat1 to the cytoplasm, resulting in the depletion of nuclear TDP-43 and redistribution of TDP-43 binding to repetitive element transcripts and mRNAs encoding mitotic and nuclear-cytoplasmic regulators. The SINE promotes Malat1 nuclear retention by facilitating Malat1 binding to HNRNPK, a protein that drives RNA nuclear retention, potentially through direct interactions of the SINE with KHDRBS1 and TRA2A, which bind to HNRNPK. Losing these RNA–protein interactions due to the SINE deletion likely creates more available TDP-43 binding sites on Malat1 and subsequent TDP-43 aggregation. These results highlight the significance of lncRNA TEs in TDP-43 proteostasis with potential implications in both cancer and neurodegenerative diseases.

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<![CDATA[A versatile cis-acting element reporter system to study the function, maturation and stability of ribosomal RNA mutants in archaea]]> https://www.researchpad.co/article/N481ae59b-2264-4796-bc8d-d412c1f2a212

Abstract

General molecular principles of ribosome biogenesis have been well explored in bacteria and eukaryotes. Collectively, these studies have revealed important functional differences and few similarities between these processes. Phylogenetic studies suggest that the information processing machineries from archaea and eukaryotes are evolutionary more closely related than their bacterial counterparts. These observations raise the question of how ribosome synthesis in archaea may proceed in vivo. In this study, we describe a versatile plasmid-based cis-acting reporter system allowing to analyze in vivo the consequences of ribosomal RNA mutations in the model archaeon Haloferax volcanii. Applying this system, we provide evidence that the bulge-helix-bulge motif enclosed within the ribosomal RNA processing stems is required for the formation of archaeal-specific circular-pre-rRNA intermediates and mature rRNAs. In addition, we have collected evidences suggesting functional coordination of the early steps of ribosome synthesis in H. volcanii. Together our investigation describes a versatile platform allowing to generate and functionally analyze the fate of diverse rRNA variants, thereby paving the way to better understand the cis-acting molecular determinants necessary for archaeal ribosome synthesis, maturation, stability and function.

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<![CDATA[Staufen1 reads out structure and sequence features in ARF1 dsRNA for target recognition]]> https://www.researchpad.co/article/Nfe85f2ab-6616-4916-998d-57e7a1a740ae

Abstract

Staufen1 (STAU1) is a dsRNA binding protein mediating mRNA transport and localization, translational control and STAU1-mediated mRNA decay (SMD). The STAU1 binding site (SBS) within human ADP-ribosylation factor1 (ARF1) 3′UTR binds STAU1 and this downregulates ARF1 cytoplasmic mRNA levels by SMD. However, how STAU1 recognizes specific mRNA targets is still under debate. Our structure of the ARF1 SBS–STAU1 complex uncovers target recognition by STAU1. STAU1 dsRNA binding domain (dsRBD) 4 interacts with two pyrimidines and one purine from the minor groove side via helix α1, the β1–β2 loop anchors the dsRBD at the end of the dsRNA and lysines in helix α2 bind to the phosphodiester backbone from the major groove side. STAU1 dsRBD3 displays the same binding mode with specific recognition of one guanine base. Mutants disrupting minor groove recognition of ARF1 SBS affect in vitro binding and reduce SMD in vivo. Our data thus reveal how STAU1 recognizes minor groove features in dsRNA relevant for target selection.

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<![CDATA[Ribosome assembly defects subvert initiation Factor3 mediated scrutiny of bona fide start signal]]> https://www.researchpad.co/article/N7711f58c-b0b2-44ca-86bd-c733caff0a8c

Abstract

In bacteria, the assembly factors tightly orchestrate the maturation of ribosomes whose competency for protein synthesis is validated by translation machinery at various stages of translation cycle. However, what transpires to the quality control measures when the ribosomes are produced with assembly defects remains enigmatic. In Escherichia coli, we show that 30S ribosomes that harbour assembly defects due to the lack of assembly factors such as RbfA and KsgA display suboptimal initiation codon recognition and bypass the critical codon–anticodon proofreading steps during translation initiation. These premature ribosomes on entering the translation cycle compromise the fidelity of decoding that gives rise to errors during initiation and elongation. We show that the assembly defects compromise the binding of initiation factor 3 (IF3), which in turn appears to license the rapid transition of 30S (pre) initiation complex to 70S initiation complex by tempering the validation of codon–anticodon interaction during translation initiation. This suggests that the premature ribosomes harbouring the assembly defects subvert the IF3 mediated proofreading of cognate initiation codon to enter the translation cycle.

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<![CDATA[Bias-minimized quantification of microRNA reveals widespread alternative processing and 3′ end modification]]> https://www.researchpad.co/article/5c9bc653d5eed0c484ee9b11

Abstract

MicroRNAs (miRNAs) modulate diverse biological and pathological processes via post-transcriptional gene silencing. High-throughput small RNA sequencing (sRNA-seq) has been widely adopted to investigate the functions and regulatory mechanisms of miRNAs. However, accurate quantification of miRNAs has been limited owing to the severe ligation bias in conventional sRNA-seq methods. Here, we quantify miRNAs and their variants (known as isomiRs) by an improved sRNA-seq protocol, termed AQ-seq (accurate quantification by sequencing), that utilizes adapters with terminal degenerate sequences and a high concentration of polyethylene glycol (PEG), which minimize the ligation bias during library preparation. Measurement using AQ-seq allows us to correct the previously misannotated 5′ end usage and strand preference in public databases. Importantly, the analysis of 5′ terminal heterogeneity reveals widespread alternative processing events which have been underestimated. We also identify highly uridylated miRNAs originating from the 3p strands, indicating regulations mediated by terminal uridylyl transferases at the pre-miRNA stage. Taken together, our study reveals the complexity of the miRNA isoform landscape, allowing us to refine miRNA annotation and to advance our understanding of miRNA regulation. Furthermore, AQ-seq can be adopted to improve other ligation-based sequencing methods including crosslinking-immunoprecipitation-sequencing (CLIP-seq) and ribosome profiling (Ribo-seq).

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<![CDATA[Leisure-time physical activity and DNA damage among Japanese workers]]> https://www.researchpad.co/article/5c706785d5eed0c4847c717f

Background

It remains unclear whether daily physical activity is associated with DNA damage. This cross-sectional study examined the association between leisure-time physical activity and urinary 8-hydroxydeoxyguanosine (8-OH-dG), a biomarker of oxidative DNA damage, or urinary 7-methylguanine (m7Gua), a biomarker of methylating DNA damage.

Methods

Participants included 501 workers (294 men and 207 women), aged 20–65 years, from municipal offices in Japan. Urinary 8-OH-dG and m7Gua were measured using column-switching HPLC. Physical activity was evaluated using a self-reported questionnaire. The associations between leisure-time physical activity and urinary DNA damage markers were assessed by multiple linear regression analysis, with stratification by occupational physical activity.

Results

After adjusting for covariates, leisure-time physical activity showed a suggestive inverse correlation with urinary 8-OH-dG levels (P for trend = 0.06), and a significant inverse association with urinary m7Gua levels (P for trend = 0.03). In analysis stratified by occupation, inverse correlations were observed in sedentary workers (walking < 30 min/day at work: P for trend = 0.06 and = 0.03 for urinary 8-OH-dG and m7Gua, respectively), but not in physically active workers (walking ≥ 30 min/day at work). In analysis for each intensity of leisure-time physical activity, light-intensity exercise was associated with lower levels of urinary 8-OH-dG (P for trend = 0.03), whereas moderate-to-high-intensity exercise was associated with lower levels of urinary m7Gua (P for trend = 0.02).

Conclusions

Our results suggest that high levels of leisure-time physical activity are associated with decreased levels of DNA damage in individuals with low physical activity at work.

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<![CDATA[Genes encoding SATB2-interacting proteins in adult cerebral cortex contribute to human cognitive ability]]> https://www.researchpad.co/article/5c648d17d5eed0c484c81f75

During CNS development, the nuclear protein SATB2 is expressed in superficial cortical layers and determines projection neuron identity. In the adult CNS, SATB2 is expressed in pyramidal neurons of all cortical layers and is a regulator of synaptic plasticity and long-term memory. Common variation in SATB2 locus confers risk of schizophrenia, whereas rare, de novo structural and single nucleotide variants cause severe intellectual disability and absent or limited speech. To characterize differences in SATB2 molecular function in developing vs adult neocortex, we isolated SATB2 protein interactomes at the two ontogenetic stages and identified multiple novel SATB2 interactors. SATB2 interactomes are highly enriched for proteins that stabilize de novo chromatin loops. The comparison between the neonatal and adult SATB2 protein complexes indicates a developmental shift in SATB2 molecular function, from transcriptional repression towards organization of chromosomal superstructure. Accordingly, gene sets regulated by SATB2 in the neocortex of neonatal and adult mice show limited overlap. Genes encoding SATB2 protein interactors were grouped for gene set analysis of human GWAS data. Common variants associated with human cognitive ability are enriched within the genes encoding adult but not neonatal SATB2 interactors. Our data support a shift in the function of SATB2 in cortex over lifetime and indicate that regulation of spatial chromatin architecture by the SATB2 interactome contributes to cognitive function in the general population.

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<![CDATA[Multiple micronutrient status and predictors of anemia in young children aged 12-23 months living in New Delhi, India]]> https://www.researchpad.co/article/5c6730acd5eed0c484f37e90

Anemia has been identified as a severe public health concern among young children in India, however, information on the prevalence of anemia attributed to micronutrient deficiencies is lacking. We aimed to assess multiple micronutrient status (iron, zinc, selenium, vitamin A, vitamin D, folate and vitamin B12) in young Indian children and to investigate the role of these seven micronutrients and other non-nutritional factors on hemoglobin concentrations and anemia. One-hundred and twenty children aged 12 to 23 months were included in a cross-sectional nutritional assessment survey, of which 77 children provided a blood sample. Hemoglobin (Hb), serum ferritin, soluble transferrin receptor (sTfR), total body iron, zinc, selenium, retinol binding protein (RBP), folate, vitamin B12 and 25-hydroxyvitamin D (25(OH)D) were measured, and adjusted for inflammation using C-reactive protein (CRP) and α-1-acid glycoprotein (AGP), where appropriate. Predictors for hemoglobin and anemia were identified in multiple regression models. Most of the children were classified as anemic, of which 86 to 93% was associated with iron deficiency depending on the indicator applied. Deficiencies of folate (37%), and notably vitamin D (74%) were also common; fewer children were classified with deficiencies of vitamin B12 (29%), zinc (25%), and vitamin A (17%) and selenium deficiency was nearly absent. Multiple micronutrient deficiencies were common with over half (57%) deficient in three or more micronutrients, and less than 10% of children were classified with adequate status for all the micronutrients measured. Iron status was found to be the only nutritional factor statistically significantly inversely associated with anemia (P = 0.003) in multivariate analysis after controlling for sex. A coordinated multi-micronutrient program is urgently needed to combat the co-existing micronutrient deficiencies in these young children to improve micronutrient status and reduce the high burden of childhood anemia.

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<![CDATA[Health effects of micronutrient fortified dairy products and cereal food for children and adolescents: A systematic review]]> https://www.researchpad.co/article/5c52185fd5eed0c484797e44

Introduction

Micronutrient (MN) deficiencies cause a considerable burden of disease for children in many countries. Dairy products or cereals are an important food component during adolescence. Fortification of dairy products or cereals with MN may be an effective strategy to overcome MN deficiencies, but their specific impact on health in this age group is poorly documented.

Methods

We performed a systematic review and meta-analysis (registration number CRD42016039554) to assess the impact of MN fortified dairy products and cereal food on the health of children and adolescents (aged 5–15 years) compared with non-fortified food. We reviewed randomised controlled trials (RCT) using electronic databases (MEDLINE, EMBASE, Cochrane library; latest search: January 2018), reference list screening and citation searches. Three pairs of reviewers assessed 2048 studies for eligibility and extracted data. We assessed the risk of bias and applied GRADE to rate quality of evidence.

Results

We included 24 RCT (often multi MN fortification) with 30 pair-wise comparisons mainly from low- and middle income countries. A very small and non-significant increase of haemoglobin values emerged (0.09 g/dl [95%-CI: -0.01 to 0.18]; 13 RCT with iron fortification; very low quality of evidence). No significant difference was found on anaemia risk (risk ratio 0.87 [95%-CI: 0.76 to 1.01]; 12 RCT; very low quality), but a significant difference in iron deficiency anaemia favouring fortified food was found (risk ratio 0.38 [95%-CI: 0.18 to 0.81]; 5 RCT; very low quality). Similar effects were seen for fortified dairy products and cereals and different fortification strategies (mono- vs. dual- vs. multi-MN). Follow-up periods were often short and the impact on anthropometric measures was weak (low quality of evidence) Very low quality of evidence emerged for the improvement of cognitive performance, functional measures and morbidity.

Conclusions

Fortification of dairy products and cereal food had only marginal health effects in our sample population from 5–15 years. Further evidence is needed to better understand the health impact of fortified dairy products and cereals in this age group.

Systematic review registration

The study protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on 26 May 2016 (registration number CRD42016039554).

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