The Bioperl toolkit: Perl modules for the life sciences

The Bioperl project is an international open-source collaboration of biologists, bioinformaticians, and computer scientists that has evolved over the past 7 yr into the most comprehensive library of Perl modules available for managing and manipulating life-science information. Bioperl provides an easy-to-use, stable, and consistent programming interface for bioinformatics application programmers. The Bioperl modules have been successfully and repeatedly used to reduce otherwise complex tasks to only a few lines of code. The Bioperl object model has been proven to be flexible enough to support enterprise-level applications such as EnsEMBL, while maintaining an easy learning curve for novice Perl programmers. Bioperl is capable of executing analyses and processing results from programs such as BLAST, ClustalW, or the EMBOSS suite. Interoperation with modules written in Python and Java is supported through the evolving BioCORBA bridge. Bioperl provides access to data stores such as GenBank and SwissProt via a flexible series of sequence input/output modules, and to the emerging common sequence data storage format of the Open Bioinformatics Database Access project. This study describes the overall architecture of the toolkit, the problem domains that it addresses, and gives specific examples of how the toolkit can be used to solve common life-sciences problems. We conclude with a discussion of how the open-source nature of the project has contributed to the development effort.     

Paranoid beliefs and self‐criticism in students

Paranoid beliefs are associated with negative and malevolent views of others. This study, however, explored hostile and compassionate self‐to‐self relating in regard to paranoid beliefs. A total of 131 students were given a series of scales measuring paranoid ideation, forms and functions of self‐criticism, self‐reassurance, self‐compassion and depression. Test scores were subjected to correlation and hierarchical regression analyses to explore the relative contribution of study variables to paranoid beliefs. In this population, paranoid beliefs were associated with forms and functions of self‐criticism, especially self‐hating and self‐persecution. Paranoid beliefs were negatively correlated with self‐kindness and abilities to be self‐reassuring. These variables were also associated with depression (as were paranoid beliefs). A hierarchical regression found that self‐hatred remained a predictor of paranoid ideation even after controlling for depression and self‐reassurance. Paranoid beliefs seem to be associated with a critical and even hating experience of self. These inner experiences of self may be profitable targets for therapeutic interventions. Copyright © 2007 John Wiley & Sons, Ltd.     

Immunoglobulin allotypic specificities in mixed leucocyte cultures

γG immunoglobulin synthesis was shown in mixed lymphocyte cultures.

Presence in the supernatants after 6, 8 or 9 days of Gm(1) and Gm(17) specificities lacking in the lymphocyte donors' phenotypes confirmed the results already obtained in cultures with PHA.

Gm(4) and Gm(11) allotypes, as well as Gm(14) and Gm(23) in the cases investigated, were found in supernatants after cultures from Gm(-4,-11,-14,-23) lymphocyte donors. With unmixed Negro lymphocyte donors, production of Gm(2), Gm(4) and Gm(21) uncommonly found in Negroes without Caucasian admixture, was demonstrated.

Presence in the supernatant after culture of Gm allotypes lacking in the donors' serum phenotypes suggested that the structural genes might be under the control of regulatory genes.

     

Breast cancer prediction and the Wolfe classification of mammograms

Mammographic parenchymal patterns have been proposed as a method of determining women at high risk of developing breast cancer. Wolfe's original report of relative risks as high as 37:1 for "dysplastic" breasts (DY) as compared with adipose breasts (N1), with intermediate values of P1 and P2, were not uniformly confirmed by others. (Relative risks are used here as the equivalent of odds ratios.) A case-control study of 706 breast cancers, each with two matching controls, drawn from 40,000 participants in four Breast Cancer Detection Demonstration Project clinics, was conducted to assess the role of the Wolfe classification of breast parenchymal patterns as a breast-cancer risk factor together with a set of well-established risk factors for breast cancer. Relative risks of 3.1 for DY to N1, 3.5 for P2 to N1, and 2.0 for P1 to N1 were determined. These are comparable to or greater than other known risk factors found in the same population. The Wolfe classification of parenchymal patterns strengthens the basis for clinical judgment, but should not be used exclusively to determine intervention in an individual patient's care.     

The pathological basis of conduction block in human neuropathies.

Conduction block was detected in patients with neuropathy by measuring a decrease in the size of the compound muscle action potential of more than 20% on proximal versus distal stimulation of the peroneal, median or ulnar nerve in the absence of excess temporal dispersion of the potential. The teased fibre analyses of nerve biopsies from four patients with "definite" and six patients with "probable" conduction block and from seven patients with neuropathy but without conduction block were compared. All patients with conduction block had significant demyelination (X% demyelinated and remyelinated fibres = 50%) while those without conduction block did not (X = 5.0%). Demyelination is the pathological basis of conduction block in human neuropathies.     

Membrane interlocking domains in the lens

"Ball and socket"-like membrane processes interlock fiber cells in the sheep lens cortex, but appear reduced deeper in the lens. Wheat germ agglutinin (WGA) binds preferentially to these ball and socket structures, and more weakly to other membrane regions. On protein blots, 125I WGA binds to glycoproteins with 140,000 and 32,000 apparent molecular weight, the smaller protein also binding 125I fibronectin. In two animal cataract models, the intense WGA labeling of globular bodies replaces the spotty WGA staining pattern associated with the ball and sockets in the normal lens.     

Response of the ENPP1-Deficient Skeletal Phenotype to Oral Phosphate Supplementation and/or Enzyme Replacement Therapy: Comparative Studies in Humans and Mice

Inactivating mutations in human ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) may result in early-onset osteoporosis (EOOP) in haploinsufficiency and autosomal recessive hypophosphatemic rickets (ARHR2) in homozygous deficiency. ARHR2 patients are frequently treated with phosphate supplementation to ameliorate the rachitic phenotype, but elevating plasma phosphorus concentrations in ARHR2 patients may increase the risk of ectopic calcification without increasing bone mass. To assess the risks and efficacy of conventional ARHR2 therapy, we performed comprehensive evaluations of ARHR2 patients at two academic medical centers and compared their skeletal and renal phenotypes with ENPP1-deficient Enpp1^asj/asj mice on an acceleration diet containing high phosphate treated with recombinant murine Enpp1-Fc. ARHR2 patients treated with conventional therapy demonstrated improvements in rickets, but all adults and one adolescent analyzed continued to exhibit low bone mineral density (BMD). In addition, conventional therapy was associated with the development of medullary nephrocalcinosis in half of the treated patients. Similar to Enpp1^asj/asj mice on normal chow and to patients with mono- and biallelic ENPP1 mutations, 5-week-old Enpp1^asj/asj mice on the high-phosphate diet exhibited lower trabecular bone mass, reduced cortical bone mass, and greater bone fragility. Treating the Enpp1^asj/asj mice with recombinant Enpp1-Fc protein between weeks 2 and 5 normalized trabecular bone mass, normalized or improved bone biomechanical properties, and prevented the development of nephrocalcinosis and renal failure. The data suggest that conventional ARHR2 therapy does not address low BMD inherent in ENPP1 deficiency, and that ENPP1 enzyme replacement may be effective for correcting low bone mass in ARHR2 patients without increasing the risk of nephrocalcinosis. © 2021 American Society for Bone and Mineral Research (ASBMR).