To what extent does IQ 'explain' socio-economic variations in function?

Background  

The aims of this study were to examine the extent to which higher intellectual abilities protect higher socio-economic groups from functional decline and to examine whether the contribution of intellectual abilities is independent of childhood deprivation and low birth weight and other socio-economic and developmental factors in early life.     

Survival of Single Positive Thymocytes Depends upon Developmental Control of RIPK1 Kinase Signaling by the IKK Complex Independent of NF-κB

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Heterogeneity of monoclonal antibody-reactive epitopes on mycobacterial 30-kilodalton-region proteins and the secreted antigen 85 complex and demonstration of antigen 85B on the Mycobacterium leprae cell wall surface.

Proteins of the antigen 85 complex in the 30-kDa region secreted by live mycobacteria are important in the immune response against mycobacterial infections and may play an important biological role in the host-parasite interaction. In the present study, we have characterized epitopes of the 30-kDa-region proteins and the antigen 85 complex by using a panel of 13 monoclonal antibodies (MAbs) reacting with these antigens, 6 of which have not been described before. By using five previously characterized related secreted proteins of Mycobacterium tuberculosis, MPT44 (85A), MPT59 (85B), MPT45 (85C), MPT51 (27 kDa), and MPT64 (26 kDa), we have identified at least 10 different MAb-reactive epitopes on the proteins of the antigen 85 complex. A heterogeneous distribution of epitopes was observed within the components of the antigen 85 complex. Two distinct epitopes specific for antigen 85B and two other epitopes restricted to the 85A and 85B components were recognized. Two of them were shared with a previously unidentified 27-kDa protein present in M. tuberculosis culture fluid from which all MPT proteins were derived. The rest of the MAb-reactive epitopes were found to be present mostly in antigens 85A and 85B and to a lesser extent in antigen 85C. None of these MAbs recognized component 85C alone nor did they bind to the related MPT51 and MPT64 proteins. Interestingly, most of the MAbs reacted with purified native proteins of the antigen 85 complex but not to them in their denatured forms. In contrast, reactivity of the MAbs with the cytosol fraction of M. tuberculosis in immunoblotting revealed that they bound to a closely related cytosolic 30-kDa protein(s) even when they were denatured. Heterogeneity of these MAb-reactive epitopes of the antigen 85 complex was further evident as they were found to be distributed in various patterns among 19 different mycobacterial species. By using fusion proteins of the Mycobacterium leprae 30/31-kDa antigen 85 complex, we have localized at least six different epitopes within amino acid residues 55 to 266 of the M. leprae antigen 85 complex. Finally, by immunohistochemical analysis, we have demonstrated the in situ expression of one of the novel MAb-reactive epitopes specific for antigen 85B on the cell wall surface of M. leprae within macrophages in lepromatous leprosy lesions and thus provide direct evidence for the presence of the B component of the antigen 85 complex on the surface of intact M. leprae.     

Identification of Mycobacterium leprae antigens from a cosmid library: characterization of a 15-kilodalton antigen that is recognized by both the humoral and cellular immune systems in leprosy patients.

Screening of the Mycobacterium leprae cosmid library with pooled sera from lepromatous leprosy (LL) patients by a colony immunoblot technique resulted in the identification of about 100 colonies that produced immunologically reactive proteins. Twenty-four of these clones were purified, analyzed, and found to comprise two groups according to the reactivity of the recombinant proteins with LL sera and to the DNA restriction patterns of the recombinant plasmids and cosmids. Proteins specified by clones from group I reacted strongly with LL patients' sera on a Western blot (immunoblot), demonstrating a 15-kDa protein band designated A15. The A15 antigen also reacted with pooled sera from patients with tuberculoid leprosy from the United States and Brazil. Clones from group II did not show any reactive protein band on a Western blot, when reacted with patients' sera. DNAs from cosmids of group II all contain a 10-kb PstI fragment that hybridized to the unique repetitive M. leprae DNA. Sequence analysis of a 1.2-kb fragment containing the entire coding sequence of A15 revealed three open reading frames (ORFs), only one of which (ORF II) contains sufficient genetic information to encode for A15. Part of the A15 gene was found to exist also in a group of lambda gt11:M. leprae clones previously isolated in our laboratory by immunological screening with LL patients' sera. One of the lambda gt11 clones (L8) expresses a beta-galactosidase fusion protein with 89 amino acids from the C terminus of A15. An important result was that the fusion protein was clearly recognized by T cells from leprosy patients. Interestingly, Mycobacterium tuberculosis-stimulated T cells from M. leprae nonresponder (LL as well as borderline tuberculoid) patients were able to respond to the isolated recombinant M. leprae antigen, indicating that nonresponsiveness to M. leprae antigens can be reversible. The sequence of the M. leprae DNA fused to the beta-galactosidase gene of lambda gt11 clone L8 was identical to that of a lambda gt11:M. leprae clone isolated recently that expresses an immunologically reactive fusion protein (S. Laal, Y. D. Sharma, H. K. Prasad, A. Murtaza, S. Singh, S. Tangri, R. Misra, and I. Nath, Proc. Natl. Acad. Sci. USA 88:1054-1058, 1991). Besides the complete sequence of the A15 gene, sequencing data of two flanking ORFs are presented. Downstream from ORF II (A15), ORF III has a high degree of similarity to the genes for tomato ATP-dependent proteases that are members of a larger class of highly conserved proteases ubiquitous among prokaryotes and eukaryotes.(ABSTRACT TRUNCATED AT 400 WORDS)     

Characterization of a Mycobacterium leprae antigen related to the secreted Mycobacterium tuberculosis protein MPT32.

Secreted proteins may serve as major targets in the immune response to mycobacteria. To identify potentially secreted Mycobacterium leprae antigens, antisera specific for culture filtrate proteins of Mycobacterium tuberculosis were used to screen a panel of recombinant antigens selected previously by leprosy patient sera. Four potentially secreted antigens were identified by this approach, and one was recognized by antibodies specific for MPT32, a secreted M. tuberculosis protein. The DNA coding for the M. leprae antigen, which we have designated 43L, was isolated and characterized and found to encode a 25.5-kDa protein that is preceded by a consensus signal peptide of 39 amino acids. The N-terminal amino acid sequence of 43L shows 50% homology with the 20 known N-terminal amino acids of MPT32, and 47% homology was found with the N terminus of a 45/47-kDa antigen complex identified in Mycobacterium bovis BCG. These findings indicate that 43L represents an antigen related to MPT32 and the M. bovis BCG 45/47-kDa complex and that 43L is likely to be a protein secreted by M. leprae. Purified recombinant 43L protein is recognized by antibodies and T cells from healthy contacts and leprosy patients, illustrating that secreted proteins are of importance in the immune response to M. leprae.     

Systematic review of accelerometer-based methods for 24-h physical behavior assessment in young children (0–5 years old)

Background

Accurate accelerometer-based methods are required for assessment of 24-h physical behavior in young children. We aimed to summarize evidence on measurement properties of accelerometer-based methods for assessing 24-h physical behavior in young children.

Methods

We searched PubMed (MEDLINE) up to June 2021 for studies evaluating reliability or validity of accelerometer-based methods for assessing physical activity (PA), sedentary behavior (SB), or sleep in 0–5-year-olds. Studies using a subjective comparison measure or an accelerometer-based device that did not directly output time series data were excluded. We developed a Checklist for Assessing the Methodological Quality of studies using Accelerometer-based Methods (CAMQAM) inspired by COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN).

Results

Sixty-two studies were included, examining conventional cut-point-based methods or multi-parameter methods. For infants (0—12 months), several multi-parameter methods proved valid for classifying SB and PA. From three months of age, methods were valid for identifying sleep. In toddlers (1—3 years), cut-points appeared valid for distinguishing SB and light PA (LPA) from moderate-to-vigorous PA (MVPA). One multi-parameter method distinguished toddler specific SB. For sleep, no studies were found in toddlers. In preschoolers (3—5 years), valid hip and wrist cut-points for assessing SB, LPA, MVPA, and wrist cut-points for sleep were identified. Several multi-parameter methods proved valid for identifying SB, LPA, and MVPA, and sleep.

Despite promising results of multi-parameter methods, few models were open-source. While most studies used a single device or axis to measure physical behavior, more promising results were found when combining data derived from different sensor placements or multiple axes.

Conclusions

Up to age three, valid cut-points to assess 24-h physical behavior were lacking, while multi-parameter methods proved valid for distinguishing some waking behaviors. For preschoolers, valid cut-points and algorithms were identified for all physical behaviors. Overall, we recommend more high-quality studies evaluating 24-h accelerometer data from multiple sensor placements and axes for physical behavior assessment. Standardized protocols focusing on including well-defined physical behaviors in different settings representative for children’s developmental stage are required. Using our CAMQAM checklist may further improve methodological study quality.

PROSPERO Registration number

CRD42020184751.

     

Construction and murine immunogenicity of recombinant Bacille Calmette Guérin vaccines expressing the B subunit of Escherichia coli heat labile enterotoxin

Three recombinant strains of Mycobacterium bovis Bacille Calmette Guerin (rBCG) were prepared in which the immunogenic B subunit of human Escherichia coli heat labile enterotoxin (LT-Bh) was expressed either as a cytoplasm protein, a cell wall associated lipoprotein or a secreted protein. Intraperitoneal immunisation of mice with these rBCG induced IgG and IgA antibodies to LT-Bh and shifted the serum IgG subclass response to subsequent challenge with purified LT-Bh from IgG1 to an IgG2a. Oral administration of recombinant BCG induced mucosal and serum IgA antibodies to LT-Bh which peaked four months after immunisation. Antibody responses were greater when LT-Bh was expressed as a secreted protein or lipoprotein rather than in the cytoplasm. Oral vaccination with recombinant BCG may be an effective approach, particularly to induce mucosal IgA and prime for a serum TH1 recall response.     

Maternal death reviews at a rural hospital in Malawi

ObjectiveTo analyze maternal deaths at Nkhoma Church of Central Africa Presbyterian (CCAP) Hospital and identify factors causing delays in care.MethodsMaternal death audits are performed after every maternal death at Nkhoma CCAP Hospital. Information regarding the care provided at the health facility, the referral process, and any delays in the community was collected by an audit team using a structured approach. Data from August 2007 to September 2011 were analyzed retrospectively.ResultsIn total, 61 maternal deaths occurred during the study period, of which 58 were analyzed. Most deaths were categorized as indirect (n = 34 [58.6%]). Non-pregnancy-related infections were the leading cause of indirect death (n = 22), with meningitis the most common (n = 13). Most patients experienced a delay in seeking care (n = 37 [63.8%]), a transport delay (n = 43 [74.1%]), or a delay in receiving adequate care (n = 34 [58.6%]).ConclusionMost maternal deaths had indirect causes and were associated with delays in all phases. An audit makes clear which part of the referral chain needs to be strengthened. Nkhoma CCAP Hospital has taken steps to address all phases of delay.     

Phage Display-directed Discovery of LEDGF/p75 Binding Cyclic Peptide Inhibitors of HIV Replication

The interaction between the human immunodeficiency virus (HIV) integrase (IN) and its cellular cofactor lens epithelium-derived growth factor (LEDGF/p75) is crucial for HIV replication. While recently discovered LEDGINs inhibit HIV-1 replication by occupying the LEDGF/p75 pocket in IN, it remained to be demonstrated whether LEDGF/p75 by itself can be targeted. By phage display we identified cyclic peptides (CPs) as the first LEDGF/p75 ligands that inhibit the LEDGF/p75–IN interaction. The CPs inhibit HIV replication in different cell lines without overt toxicity. In accord with the role of LEDGF/p75 in HIV integration and its inhibition by LEDGINs, CP64, and CP65 block HIV replication primarily by inhibiting the integration step. The CPs retained activity against HIV strains resistant to raltegravir or LEDGINs. Saturation transfer difference (STD) NMR showed residues in CP64 that strongly interact with LEDGF/p75 but not with HIV IN. Mutational analysis identified tryptophan as an important residue responsible for the activity of the peptides. Serial passaging of virus in the presence of CPs did not yield resistant strains. Our work provides proof-of-concept for direct targeting of LEDGF/p75 as novel therapeutic strategy and the CPs thereby serve as scaffold for future development of new HIV therapeutics.