Specificity of microRNA target selection in translational repression

MicroRNAs (miRNAs) are a class of noncoding RNAs found in organisms as evolutionarily distant as plants and mammals, yet most of the mRNAs they regulate are unknown. Here we show that the ability of an miRNA to translationally repress a target mRNA is largely dictated by the free energy of binding of the first eight nucleotides in the 5' region of the miRNA. However, G:U wobble base-pairing in this region interferes with activity beyond that predicted on the basis of thermodynamic stability. Furthermore, an mRNA can be simultaneously repressed by more than one miRNA species. The level of repression achieved is dependent on both the amount of mRNA and the amount of available miRNA complexes. Thus, predicted miRNA:mRNA interactions must be viewed in the context of other potential interactions and cellular conditions.     

Cell-mediated immune responses to chlamydial antigens in guinea pigs injected with inactivated chlamydiae

Cell-mediated immunity (CMI) to chlamydial antigens was readily induced in guinea pigs by a single injection of Betaprone-inactivated chlamydiae in complete Freund adjuvant. The CMI was measured in vivo by delayed hypersensitivity skin tests, and in vitro by inhibition of migration of peritoneal exudate cells and by proliferation of lymph node lymphocytes. There was an overall correlation between in vivo and in vitro responses. Of the in vitro assays, migration inhibition reflected the state of sensitization, as judged by skin tests, more uniformly than lymphocyte stimulation. Extensive inter- and intra-species cross-reactivity was noted between LB-1, a strain ofC. trachomatis, and three strains ofC. psittaci, 6BC, GPIC, and 562F. Cross-reactivity between LB-1 and 6BC was one-way only, by all three parameters: LB-1 elicited strong cross-reactions in 6BC-immunized animals but not vice versa. Antichlamydial antibodies could not be demonstrated in any of the animals by microimmunofluorescence.     

Spectrum of CLN6 mutations in variant late infantile neuronal ceroid lipofuscinosis

The neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessive neurodegenerative diseases of childhood. CLN6, the gene mutated in variant late infantile NCL (vLINCL), was recently cloned. We report the identification of eight further mutations in CLN6 making a total of 18 reported mutations. These mutations include missense, nonsense, small deletions or insertions, and two splice-site mutations. Ten mutations affect single amino acids, all of which are conserved across vertebrate species. Minor differences in the pattern of disease symptom evolution can be identified. One patient with a more protracted disease progression was a compound heterozygote for a missense mutation and an unidentified mutation. Fifteen CLN6 mutations occur in one or two families only, and families from the same country do not all share the same mutation. Unlike NCLs caused by mutations in CLN1, CLN3, CLN5, and CLN8, there is no major founder mutation in CLN6. However, one mutation (E72X) is significantly more common in patients from Costa Rica than two other mutations present in that same population. In addition, a 1-bp insertion (c.316insC) is associated with families from Pakistan and I154del may be common in Portugal. A group of Roma Gypsy families from the Czech Republic share two disease-associated haplotypes, one of which is also present in a Pakistani family, consistent with the proposed migration of the Roma from the Indian subcontinent 1,000 years ago. All mutations are recorded in the NCL Mutation Database together with their country of origin for use in the development of rapid screening assays to confirm diagnosis and to facilitate carrier testing appropriate to a population.     

The cost of lost productivity due to premature mortality associated with COVID-19: a Pan-European study

The European Journal of Health Economics - Economic cost estimates have the potential to provide a valuable alternative perspective on the COVID-19 burden. We estimate the premature mortality...     

What can and should be done to reduce publication bias? The perspective of an editor

"Publication bias" has three facets: (1) bias perceived by disappointed authors, (2) bias that journal policy may introduce, and (3) bias intrinsic in design and interpretation of the work itself. The third type, though a target of peer review, is not considered here, and the first type is more often imagined than real. However, general journals have to adopt policies on priorities that an outsider may see as bias, in the broadest sense. Opportunities for bias exist (18 varieties are listed here), but more objective evaluation is required before journals need to alter their peer review practices. In terms of work load and financial considerations, the price of some proposed correctives is high. Journals should monitor refereeing systems and allow appeals, but the case for policing systems--"blinding" referees (and, logically, editors), introducing tight codes of practice, and seeking solemn declarations of integrity, for example--needs more hard evidence.     

Tutorial: chaos theory--a primer for health care

Chaos theory, also called nonlinear systems theory, provides new insights into processes previously thought to be unpredictable and random. It also provides a new set of tools that can be used to analyze common administrative and clinical data. This tutorial provides an introduction to chaos theory. Subsequent articles will address applications of those principles to the administrative activities of health care organizations, implications of those principles for clinical data, and application of chaos theory concepts to our understanding of organizational dynamics.