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Genomic insights into natural selection in recent human history.

For over a century, scientists have debated the extent to which genetic and phenotypic variation among present-day humans is the result of natural selection - in which heritable traits influence survival or reproduction - versus neutral processes such as genetic drift or population history. The initial sequencing of the human genome and subsequent population resequencing studies enabled genome-scale searches for signatures of selection in present-day genomes. This first generation of genome-wide selection scans identified many targets but left open questions about the timing and nature of selection, making it challenging to identify environmental and biological drivers. Recent methodological advances based on reconstructing ancestral recombination graphs have increased the potential power and resolution of selection scans based on present-day genomes, while the availability of new data on ancient DNA has facilitated the direct reconstruction of genetic change through time. However, there is little consensus on how to use these data to detect and interpret signatures of selection, while avoiding confounders. Here, we review the current state of knowledge about the impact of selection on human genomic diversity and highlight conceptual advances in our understanding of human evolution over the past 10,000 years.

Journal Article

Lateralization in stroke syndromes as a factor in ambulation.

Lateralization should not be ignored in any rehabilitation program for patients with stroke syndromes. Despite the known differences resulting from the localization in the dominant versus the nondominant hemisphere (spatial perception, speech, etc.), practical application of this knowledge in gait training is sparse. The authors looked into different stages of ambulation and the time sequence between these stages and the onset of disease. Standing and walking in parallel bars and outside, as well as elevation activities were given numerical values in an effort to assess abilities quantitatively. The assessment of each patient was recorded graphically (stage of gait against time) and then the different graphs were summated in order to form a common right hemiparetic versus left hemiparetic curve. This study of 236 out of 298 patients (129 left hemiparetics and 107 right ones) showed the following: (1) The right hemiparetics progressed more rapidly in all stages of ambulation, statistically significant figures being obtained for the first two stages; (2) a greater percentage of right versus left hemiparetics reached the assigned levels of ambulation: and (3) 89% out of the 236 patients included in our study were able to ambulate in parallel bars, 81% outside the bars and 38.5% were proficient in stair climbing. Out of the original total number of patients (298), 64% were able able to ambulate outside the bars.

Adolescent

A laser densitometer for selective spot analysis on dot blots and two-dimensional gel autoradiograms.

We describe an inexpensive densitometer, employing a small HeNe laser and an IBM-compatible personal computer that performs accurate measurements of selected spots on two-dimensional gel autoradiograms or chromatograms with an accuracy and a sensitivity equal or superior to those of many commercial instruments. Our open-table design allows the operator to visually monitor the scanning process in room lighting, and provides great flexibility in both the size and the nature of items to be scanned. The instrument has two moving parts (a prism and a small motor). A commercially available software package (ASYST) acquires digital data, graphs the data on the TV monitor, converts the data to optical density or to radioactive incorporation (cpm), subtracts background, integrates peak areas, and stores data on disk. The total time for these operations is 20-30 s per spot. The instrument has a dynamic range of 0.25 to 3.0 OD units and can measure a 10,000-fold range of 14C or 35S isotope concentrations on autoradiograms. The complete device can be assembled with a hobbyist's knowledge of electronics, moderate programming abilities (no machine language required), and a cost of less than $3000, not including the IBM PC.

Costs and Cost Analysis

Mathematical assessment of the spatial distribution of Langerhans cells in guinea pig epidermis.

Two mathematical indexes, Hopkins-Skellam index (HSI) and Morisita index (MI), were applied to assess the distribution of ATPase-stained epidermal Langerhans cells (ELC) in the guinea pig skin. To our knowledge, this is the first report in which the degree of regularity has been expressed numerically by computation based on theoretical equations. The regularity of ELC in the normal skin was confirmed by the value of HSI (P < 0.0001). In the topical steroid applied skin, the number of ELC decreased significantly but the value of HSI was similar to that of the normal skin; while in the ultraviolet B (UVB) exposed skin, both number of ELC and regularity of ELC distribution decreased significantly. The graph of MI for the UVB exposed skin clearly showed that the distribution of ELC had local clumps. The two indexes, HSI and MI have been quite useful for determining the regularity of ELC. These indexes may have a wide application to other cells.

Animals

Biological applications of the SAS system: an overview.

The SAS system provides biologists with a flexible, easy to use software package for data analysis. Through a combination of data management tools, a wide variety of pre-programmed procedures for sorting, graphing, and statistical analysis and a sophisticated programming language, SAS software can perform all analytical needs for most problems. The recent availability of SAS software on mainframes other than IBM, and more recently on the microcomputer, means that most scientists can have access to the software. In this review we discuss the structure of the SAS language and demonstrate its power in the analysis of biological problems. Although to a lesser extent now than originally, the SAS system is statistically oriented and a working knowledge of statistics is recommended before using its statistical capabilities. However, all biologists will find its data management and summarization capabilities very useful.

Biology

Clinical trials in surgery.

Scientific knowledge is reliable because it has been built on accurate measurements. Clinical knowledge is not. The science of biometry was started in 1835 by the Belgian astronomer Adolphe Quetelet. In the last fifty years a precise set of rules have been invented for this science. The method is suitable for a wide range of problems in clinical medicine and as the result of its application in recent years a firm foundation has been laid upon which scientific clinical knowledge can be built. Surge-ns, particularly, have been slow to apply biometrical methods to their clinical problems; but a start has now been made. The outcome of a particular type of treatment is determined by a complex set of inter-acting factors. The basis of the appropriate biometrical method is the elimination of all bias in favour of one of the rival techniques being compared. If this precaution is taken the observed results of the trial can be fitted onto Quetelet's distribution graph, and the probability of the observed difference in the results being due to chance, and nothing else, can be measured mathematically. The accuracy of this measurement deteriorates the greater are the number of the patients who can not be found and examined at the end of the trial. To make this point two trials conducted by the author are used. In the trial designed to discover if postoperative deep vein thrombosis and pulmonary embolism could be prevented by electrically stimulating the patients legs during the operation there was no difficulty. All the patients were examined at the end of the trial, because it ended before any of the patients left the hospital. The trial to discover if the primary treatment of varicose veins ought to be by Fegan's sclerotherapy or by operation was the exact opposite. At the end of the first year of the two year trial 15% of the patients could not be traced. The results in these patients, therefore, was unknown. Because of this, elaborate mathematical calculations had to be made to try and reach a reliable conclusion to the trial. The loss of patients before the end of the trial is a very serious practical difficulty which besets all long-term clinical trials.

Clinical Trials as Topic

The biomechanics of the long jump.

The preceding review has been based on over 200 publications in Czech, English, French, German, Japanese, Polish, and Russian. Even a cursory perusal of these materials is sufficient to show that much has been done to try and obtain a scientific understanding of long jump techniques. It is clear, too, that still more remains to be done. Much of the work to date has been focused on just a few aspects of long jump technique. Other important aspects have received relatively little attention. The latter include the accuracy of the approach, the techniques used during the final strides of the approach, the role of elastic energy in the takeoff, the initiation and control of the jumper's angular momentum, and the techniques used in the landing. Future research efforts might well be directed towards resolving major issues concerning these aspects of long jump technique. The methods used to gather data in the studies reviewed have been rather unimaginative. Two-dimensional cinematography has been used in the vast majority of the studies and force platforms in a few. Other data-gathering procedures like three-dimensional cinematography, electromyography and accelerometry have rarely, if ever, been used. In only one or two studies was anything remotely approaching experimental or technological innovation in evidence. The methods used to analyze data have also been very limited. With the notable exception of a study by Ballreich, few papers have involved anything more sophisticated than means, standard deviations, correlation coefficients and an occasional multiple regression equation. Given these facts, it is hard to avoid the conclusion that our knowledge of long jump techniques might be greatly improved if the full range of available and appropriate procedures were turned to the purpose. Finally, no review of the literature on long jump techniques would be complete without reference to the level of scholarship displayed in the works under consideration. With only a few exceptions, the level shown in the scientific papers reviewed here left much to be desired. Time and again, variables were not defined, crucial measurement techniques were not described and major results were not presented or discussed. In addition, much of the data presented in tables and graphs were patently in error. In light of all this, it is clear that unless the level of scholarship improves, future progress in this area of sports biomechanics is likely to be very slow.

Biomechanical Phenomena

Isotachophoretic separation of organic acids in biological fluids.

The operating conditions for the isotachophoretic separation of organic acids were evaluated. At pH values ranging from 2.90 to 4.25 both relative step heights and molar flow-rates were determined experimentally for 26 anions. Comparing the observed values with simulated data, highly significant (p = 0.0001) correlation coefficients of 0.993 and 0.920, respectively, were found at pH 3.50. Whereas the concentration of the leading electrolyte did not affect the relative step heights, it increased the molar flow-rates significantly. The same applied to the detection current. The time of analysis was observed to be a function of the concentration of the leading electrolyte. However, the time elapsed between injection of the analyte and its detection depended solely on the volume and not on the amount of analyte injected. In isotachophoresis, incomplete separation of two compounds is indicated by the occurrence of a mixed zone which can hardly be distinguished from a pure zone. Thus, knowledge of the separation capacity is a prime prerequisite in optimizing the system for the analysis of biological fluids. The separability of nine equimolar pairs of anions was determined at pH values ranging from 2.90 to 4.25. Although two ionogenic constituents would separate only when their migration rates in the mixed state were different, no clear correlation was observed between separation capacity and difference in relative mobility. Separability, however, was found to increase with increasing concentration of the leading electrolyte. While the separation capacity was not influenced by the electric current, it was significantly affected by the volume injected. In subsequent analyses of serum, cerebrospinal fluid, seminal plasma and prostatic fluid, a variety of organic acids could be detected. Calibration graphs for the detected anions revealed a detection limit of 1 nmol and linearity over their biological concentration ranges. Further, the isotachophoretic results correlated well with high-performance liquid chromatographic and enzymatic analyses of citric acid and lactic acid in human seminal plasma and cerebrospinal fluid, respectively.

Acids

Adding meaning to a design copy task through representational stimuli.

Occupational therapists frequently use their knowledge of occupation to add meaning and purpose to therapeutic tasks. This study investigated the effects of an attempt to add meaning to a particular occupational situation--a design copy task. Added meaning was given to the design copy task through the use of stimulus figures that were representational of familiar objects--an arrow, a house, and a face. The control condition consisted of three nonrepresentational figures composed of the same geometric shapes, in the same locations on the paper as the representational figures, but combined differently. The order of presentation was controlled for. The study used 30 elderly subjects (22 women and 8 men) from six nursing homes. The accuracy of the drawings was measured by a blind rater using graph overlays and predetermined rules of scoring. A two-way analysis of variance with one repeated measure (Order X Type of Figure) indicated significant differences at the .01 level between the representational and nonrepresentational figures. This study demonstrates how added meaning can enhance performance on a visuomotor task in a vulnerable population.

Aged

The prenatal development of the normal human skeleton: a combined ultrasonographic and post-mortem radiographic study.

Post-mortem radiography of fetuses with skeletal dysplasia is essential for diagnostic classification. Interpretation of the radiographs should be based on the knowledge of morphology and dimensions of the normal skeleton in all stages of development. A retrospective post-mortem radiographic study is presented with measurements of the lengths of the long bones and thoracic and lumbar spine. The study included 69 fetuses and neonates with a normal skeleton, whose gestational age ranged from 13-42 weeks and who died perinatally or lived for less than one week. The measurements of the long bones were plotted on growth curves obtained from a prospective longitudinal ultrasonographic investigation of another group of 63 normal fetuses from 12-40 weeks of gestation. Thoracic and lumbar spine measurements by ultrasonography were not available. The radiographic data of thoracic and lumbar spine were, therefore, compared to radiographic studies from the literature. No disagreement with these studies was found. It can be concluded that measurements of bones from standardized post-mortem radiographs in cases of questionable gestational age or defects of bone development can be compared with ultrasonographic measurements. To illustrate the usefulness of the graphs, 13 fetuses with various types of skeletal dysplasia were evaluated retrospectively.

Bone Diseases, Developmental

Learning directed acyclic graphs for ligands and receptors based on spatially resolved transcriptomic data of ovarian cancer.

To unravel the mechanism of immune activation and suppression within tumors, a critical step is to identify transcriptional signals governing cell-cell communication between tumor and immune/stromal cells in the tumor microenvironment. Central to this communication are interactions between secreted ligands and cell-surface receptors, creating a highly connected signaling network among cells. Recent advancements in in situ-omics profiling, particularly spatial transcriptomic (ST) technology, provide unique opportunities to directly characterize ligand-receptor signaling networks that power cell-cell communication. In this paper, we propose a novel statistical method, LRnetST, to characterize the ligand-receptor interaction networks between adjacent tumor and immune/stroma cells based on ST data. LRnetST utilizes a directed acyclic graph model with a novel approach to handle the zero-inflated distributions of ST data. It also leverages existing ligand-receptor regulation databases as prior information, and employs a bootstrap aggregation strategy to achieve robust network estimation. Application of LRnetST to ST data of high-grade serous ovarian tumor samples revealed both common and distinct ligand-receptor regulations across different tumors. Some of these interactions were validated through both a MERFISH dataset and a CosMx SMI dataset of independent ovarian tumor samples. These results cast light on biological processes relating to the communication between tumor and immune/stromal cells in ovarian tumors. An open-source R package of LRnetST is available on GitHub at https://github.com/jie108/LRnetST.

Humans

[The effect of synchronization on estrus and pregnancy in sheep and on levels of thyroxine, triiodothyronine, 17 beta-estradiol, progesterone and cholesterol].

Knowledge of pathogenesis of sexual dysfunctions at altered thyroid activity is limited by the knowledge of multiple and ubiquitous action of its hormones throughout the organism. One of the possibilities of modulatory influence of thyroid hormones on sexual functions can be realized through the participation of thyroxine and triiodothyronine in the synthesis and metabolism of primary substrate of steroid synthesis--cholesterol. The presented work is aimed at the study of simultaneous dynamic changes of concentrations of thyroxine (T4), triiodothyronine (T3), 17 beta-estradiol (E2), progesterone (P4) and cholesterol (Chol) during synchronization of the rutting period and gravidity at parallel correlative evaluation of mutual relations of the followed parameters in ten Merino sheep in the seasonal period. Synchronization was achieved by chlorsuperlutin (Agelin--vaginal swabs, Spofa; 20 mg of chlorsuperlutin/swab) and PMSG (500 I. U./animal). Blood was sampled by means of a jugular vein puncture at the time of swab insertion (-13th day) and after three (-10th day) and seven (-7th day) following days, at the removal of swabs and application of PMSG (-3rd day), on the day of insemination (zero day), on the 7th, 14th and 17th day and in the middle of the 2nd, 3rd, 4th and 5th month of gravidity. In the phase of oestrus synchronization a significant increase of E2 concentrations on days -7 and -3 of the experiment (0.47 +/- 0.079 and 0.542 +/- 0.177 nmol.l-1 of serum, P less than 0.001; P less than 0.001) was observed compared to the E2 values on day -13 (0.084 +/- 0.036 nmol.l-1 of serum). Parallel to these observations, marked intermittent changes of T4 (Tab. I, Graph 1) were recorded with the lowest values of this parameter observed on days -10 (41.75 +/- 20.23, P less than 0.05) and -3 (50.22 +/- 18.77, P less than 0.05) and the highest on day -7 (96.77 +/- 17.51 nmol.l-1, P less than 0.01) and day zero (85.40 +/- 19.59 nmol.l-1 of serum, P less than 0.05) in comparison with the -13th day (67.22 +/- 18.29 nmol.l-1 of serum). Concentrations of P4 (Tab. I, Graph 4) declined to the lowest values on day zero observation (0.09 +/- 0.08 nmol.l-1 of serum, P less than 0.05 vs 3.40 +/- 3.61 nmol.l-1 on day -13). No significant changes of concentrations of T3 (Tab. I, Graph 2) and Chol (Tab. I, Graph 5) were observed during oestrus synchronization. During gravidity, concentrations of E2 (Tab. I Graph 3) showed an increasing trend compared to the -13th day.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals

[An experimental study of a hypertext as an innovative teaching tool in learning about occupational risks].

Among innovative techniques, computer-assisted instruction methods and hypertexts deserve particular attention due to the increasing availability of educational software. A hypertext is not a specific programme, rather a type of programme: hypertexts provide different combinations of texts, pictures, graphs, tables, so that learners can browse through information according to their wishes. This study was performed with the aim of comparing two teaching techniques (1. browsing a hypertext with the assistance of a computer, and 2. attending traditional lectures) in the field of occupational and environmental risks for human health. The whole second-year course (21 students) of the School of Environmental and Occupational Hygiene, Faculty of Medicine, University of Pavia, participated in the study. The experimental strategy consisted of 14 working sessions. Students were randomly assigned to 2 groups; one browsed the hypertext and the other attended the lectures. At the end of each session, students performed a 16-item multiple-choice test on the topic covered to assess learning levels. Each student was also requested to judge clarity, interest and usefulness on a 5-point scale. The performance of the students, expressed as a percentage of correct answers, showed that learning lectures is slightly more effective than learning from hypertext browsing. However, the chi 2-test revealed no significant differences between the 2 methods regarding performance when students with more than 75% correct answers were compared. Regarding acceptability of the techniques used, the students considered them equivalent as to interest and usefulness, whereas clarity of the lectures was slightly but significantly higher than the hypertext. Acceptability of hypertext browsing as a learning method was greatly appreciated. Most of the students considered their experience as highly positive: hypertext browsing was considered easy and amusing and the use of the computer for learning was judged most satisfying. Most of the students would like to have the possibility of learning at home, to repeat the experience and extend it to other disciplines. The negative characteristic of hypertext browsing was the "lack of human contact", which makes it impossible to widen knowledge.

Computer-Assisted Instruction

[Mechanical strain in the forearm bones].

Knowledge of the physiologic distribution of strain in bone is essential for a successful osteosynthesis by means of compression plate. This method guarantees optimum stability if the plate acts as a tension band. If the side of tensile stresses varies within the bone, strain may not only occur on the side of the plate but also on the opposite cortex. In such cases the distribution of pressure in the fracture gap is of special importance. For determining the distribution of strain on the radius, it is necessary to examine the forces caused by the flexor- and extensor muscles of the wrist and fingers. Additional forces come also from flexor- and extensor muscles of the elbow. The frame formed by the bow-shaped radius and the ulna is of further importance for the distribution of strain. Kind and amount of tension is fundamentally influenced by forearm rotation. Anatomic studies on post-mortem specimens showed how the direction of muscle action to wrist and fingers changed in relation to the position of a plate fixed to the proximal shaft of the radius. This already demonstrates possible variations in the bending forces caused by forearm rotation. An analysis of the distribution of strain in the forearm bones was carried out on a biomechanical model using strain gauges. This method allows the simulation of strain to the skeleton caused by muscle force and the influence of load. The distribution of strain can be studied on the same model in various different positions of elbow and forearm. Six muscles and two muscle groups were simulated by means of wire pulls with calibrated strain gauges; these muscles and muscle groups act, on account of the physiological cross section and their position, as bending forces to the forearm bones in a dorsovolar plane. The tensile force on radius and ulna were each controlled by three strain gauges in four sections. The characteristic quantities of these sections were determined by evaluation of the appropriate computertomograms. With the aid of three strain gauges per section it was possible to assess the strain at any one desired point. Distribution of strain was determined by pull to each "muscle" in the extreme position of forearm rotation and three different positions of flexion to the elbow. The tensile force was expressed on graphs as muscle tension of 2 kp/cm2 per cross section (ill. 6 to 12).(ABSTRACT TRUNCATED AT 400 WORDS)

Biomechanical Phenomena