Animal design advantage from the analogy between friction and body heat loss.

When a fluid accelerates as it sweeps a solid surface there are two consequences: the friction and the heat transfer (thermal contact) between fluid and solid increase simultaneously. This is known as the universal analogy between fluid friction and heat transfer. In thermal engineering these two effects are problematic because improved thermal contact is beneficial, and increased friction (i.e., pumping power) is detrimental to overall performance. In the present article we question whether the 'analogy' between these conflicting effects hampers the performance of animal movement. The theory focuses on warm-blooded swimmers and the effects (friction, heat transfer) that result from one change in the configuration of the body. Selected for analysis is a breaststroke swimmer. During gliding while reaching forward the 'one change' is from (a) legs spread apart, to (b) legs held tight together. The theory shows that the change from (a) to (b) has two consequences: greater swimming speed, and reduced body heat loss. In animal design both effects are beneficial, unlike in engineered flow systems. The analogy between fluid friction and heat transfer accelerated the evolution of animal design, and accounts for the 'divergent evolution' of fish and mammals.

Evaluation of the Michigan Clinical Consultation and Care Program: An Evidence-Based Approach to Perinatal Mental Healthcare.

Mood and anxiety disorders affect pregnant individuals and their families at increased rates throughout the perinatal period. Geographic, financial, and social barriers often preclude adequate diagnosis and treatment. The aim of this manuscript is to describe the consultation and care arms of the Michigan Clinical Consultation and Care (MC3) program, a statewide program designed to facilitate access to perinatal mental healthcare for OB/Gyn patients, and to describe the participants engaged in the program, examine the predictors of participant retention, and provide preliminary data regarding participants' mental health outcomes. We enrolled 209 participants to the clinical care arm, of which 48 were lost to follow-up, while 107 remained enrolled at the time of data analysis. A total of 54 participants met their treatment goals. A total of 97% of participants asserted they were satisfied with the services they received. Black race and public insurance predicted faster attrition from the care arm treatment; risks for interpersonal violence exposure and substance use were unrelated to attrition. Preliminary mental health outcomes showed significant decreases in anxiety and depression, with the most dramatic decreases in the first month of treatment. Overall, the MC3 clinical care arm shows promising rates of adherence, excellent program satisfaction, and a positive impact on perinatal mental health, supporting continued program implementation and ongoing evaluation.

A Procedure to Study Stress-induced Relapse of Heroin Seeking after Punishment-imposed Abstinence.

The punishment-imposed abstinence procedure models the self-imposed abstinence that humans initiate due to the adverse consequences associated with drug-taking. This model has been implemented in experiments using different types of substances of abuse such as methamphetamine, cocaine, and alcohol. However, punishment-induced abstinence in heroin-trained animals has not been demonstrated. Furthermore, acute stress is a key trigger for relapse in humans and animal models. It was previously demonstrated that acute food deprivation robustly induced reinstatement of extinguished cocaine and heroin seeking. The procedure described here can be used to assess the effects of acute stress exposure on heroin seeking after punishment-imposed abstinence. A total of 8 rats were implanted with chronic intravenous (i.v.) catheters and trained to self-administer heroin (0.1 mg/kg/infusion) for 18 days under a seek-take chained schedule. Completing the seek link gave access to the take lever, which was paired with a heroin infusion. The seek lever was programmed with a variable interval 60 schedule of reinforcement (VI60), and the take lever was programmed with a fixed-ratio 1 reinforcement schedule (FR1). Following self-administration training, a mild foot shock was delivered on 30% of the completed seek links instead of the extension of the take lever. Footshock intensity was increased by 0.1 mA per daily session from 0.2 mA to 1.0 mA. Heroin-seeking tests were performed after 24 h of food deprivation (FD) or sated conditions. Rats under acute food deprivation condition robustly increased heroin seeking after punishment-imposed abstinence.

How asymmetric DNA replication achieves symmetrical fidelity.

Accurate DNA replication of an undamaged template depends on polymerase selectivity for matched nucleotides, exonucleolytic proofreading of mismatches, and removal of remaining mismatches via DNA mismatch repair (MMR). DNA polymerases (Pols) δ and ε have 3'-5' exonucleases into which mismatches are partitioned for excision in cis (intrinsic proofreading). Here we provide strong evidence that Pol δ can extrinsically proofread mismatches made by itself and those made by Pol ε, independently of both Pol δ's polymerization activity and MMR. Extrinsic proofreading across the genome is remarkably efficient. We report, with unprecedented accuracy, in vivo contributions of nucleotide selectivity, proofreading, and MMR to the fidelity of DNA replication in Saccharomyces cerevisiae. We show that extrinsic proofreading by Pol δ improves and balances the fidelity of the two DNA strands. Together, we depict a comprehensive picture of how nucleotide selectivity, proofreading, and MMR cooperate to achieve high and symmetrical fidelity on the two strands.

Reexamining performance validity cutoffs within the Complex Ideational Material and the Boston Naming Test-Short Form using an experimental malingering paradigm.

OBJECTIVE: This study was designed to cross-validate previously published performance validity cutoffs embedded within the Complex Ideational Material (CIM) and the Boston Naming Test-Short Form (BNT-15). METHOD: Seventy healthy undergraduate students were randomly assigned to either a control condition (n = 40) and instructed to perform to the best of their ability or an experimental malingering (n = 30) condition and instructed to feign cognitive impairment while avoiding detection. All participants were administered the same battery of neuropsychological tests. RESULTS: Previously published validity cutoffs within the CIM (raw score ≤9 or T-score ≤29) and BNT-15 (≤12) produced good classification accuracy using both experimental malingering and psychometrically defined invalid responding as criterion variable. However, a BNT-15 completion time ≥85 s produced a better signal detection profile than BNT-15 accuracy scores. CONCLUSIONS: Results support the clinical utility of existing cutoffs. Given the relatively high base rate of failure even in the control group (5-15%), and the perfect specificity of CIM ≤9 and BNT-15 ≤ 11 to noncredible responding, relabeling this range of performance as "Abnormal" instead of "Impaired" would better capture the uncertainty in its clinical interpretation.

Evaluating Interaction of Cord Blood Hematopoietic Stem/Progenitor Cells with Functionally Integrated Three-Dimensional Microenvironments.

Despite advances in ex vivo expansion of cord blood-derived hematopoietic stem/progenitor cells (CB-HSPC), challenges still remain regarding the ability to obtain, from a single unit, sufficient numbers of cells to treat an adolescent or adult patient. We and others have shown that CB-HSPC can be expanded ex vivo in two-dimensional (2D) cultures, but the absolute percentage of the more primitive stem cells decreases with time. During development, the fetal liver is the main site of HSPC expansion. Therefore, here we investigated, in vitro, the outcome of interactions of primitive HSPC with surrogate fetal liver environments. We compared bioengineered liver constructs made from a natural three-dimensional-liver-extracellular-matrix (3D-ECM) seeded with hepatoblasts, fetal liver-derived (LvSt), or bone marrow-derived stromal cells, to their respective 2D culture counterparts. We showed that the inclusion of cellular components within the 3D-ECM scaffolds was necessary for maintenance of HSPC viability in culture, and that irrespective of the microenvironment used, the 3D-ECM structures led to the maintenance of a more primitive subpopulation of HSPC, as determined by flow cytometry and colony forming assays. In addition, we showed that the timing and extent of expansion depends upon the biological component used, with LvSt providing the optimal balance between preservation of primitive CB HSPC and cellular differentiation. Stem Cells Translational Medicine 2018;7:271-282.

Quantifying the contributions of base selectivity, proofreading and mismatch repair to nuclear DNA replication in Saccharomyces cerevisiae.

Mismatches generated during eukaryotic nuclear DNA replication are removed by two evolutionarily conserved error correction mechanisms acting in series, proofreading and mismatch repair (MMR). Defects in both processes are associated with increased susceptibility to cancer. To better understand these processes, we have quantified base selectivity, proofreading and MMR during nuclear DNA replication in Saccharomyces cerevisiae. In the absence of proofreading and MMR, the primary leading and lagging strand replicases, polymerase ɛ and polymerase δ respectively, synthesize DNA in vivo with somewhat different error rates and specificity, and with apparent base selectivity that is more than 100 times higher than measured in vitro. Moreover, leading and lagging strand replication fidelity rely on a different balance between proofreading and MMR. On average, proofreading contributes more to replication fidelity than does MMR, but their relative contributions vary from nearly all proofreading of some mismatches to mostly MMR of other mismatches. Thus accurate replication of the two DNA strands results from a non-uniform and variable balance between error prevention, proofreading and MMR.

High-resolution mapping of two types of spontaneous mitotic gene conversion events in Saccharomyces cerevisiae.

Gene conversions and crossovers are related products of the repair of double-stranded DNA breaks by homologous recombination. Most previous studies of mitotic gene conversion events have been restricted to measuring conversion tracts that are <5 kb. Using a genetic assay in which the lengths of very long gene conversion tracts can be measured, we detected two types of conversions: those with a median size of ∼6 kb and those with a median size of >50 kb. The unusually long tracts are initiated at a naturally occurring recombination hotspot formed by two inverted Ty elements. We suggest that these long gene conversion events may be generated by a mechanism (break-induced replication or repair of a double-stranded DNA gap) different from the short conversion tracts that likely reflect heteroduplex formation followed by DNA mismatch repair. Both the short and long mitotic conversion tracts are considerably longer than those observed in meiosis. Since mitotic crossovers in a diploid can result in a heterozygous recessive deleterious mutation becoming homozygous, it has been suggested that the repair of DNA breaks by mitotic recombination involves gene conversion events that are unassociated with crossing over. In contrast to this prediction, we found that ∼40% of the conversion tracts are associated with crossovers. Spontaneous mitotic crossover events in yeast are frequent enough to be an important factor in genome evolution.

High-resolution mapping of spontaneous mitotic recombination hotspots on the 1.1 Mb arm of yeast chromosome IV.

Although homologous recombination is an important pathway for the repair of double-stranded DNA breaks in mitotically dividing eukaryotic cells, these events can also have negative consequences, such as loss of heterozygosity (LOH) of deleterious mutations. We mapped about 140 spontaneous reciprocal crossovers on the right arm of the yeast chromosome IV using single-nucleotide-polymorphism (SNP) microarrays. Our mapping and subsequent experiments demonstrate that inverted repeats of Ty retrotransposable elements are mitotic recombination hotspots. We found that the mitotic recombination maps on the two homologs were substantially different and were unrelated to meiotic recombination maps. Additionally, about 70% of the DNA lesions that result in LOH are likely generated during G1 of the cell cycle and repaired during S or G2. We also show that different genetic elements are associated with reciprocal crossover conversion tracts depending on the cell cycle timing of the initiating DSB.

High-resolution genome-wide analysis of irradiated (UV and γ-rays) diploid yeast cells reveals a high frequency of genomic loss of heterozygosity (LOH) events.

In diploid eukaryotes, repair of double-stranded DNA breaks by homologous recombination often leads to loss of heterozygosity (LOH). Most previous studies of mitotic recombination in Saccharomyces cerevisiae have focused on a single chromosome or a single region of one chromosome at which LOH events can be selected. In this study, we used two techniques (single-nucleotide polymorphism microarrays and high-throughput DNA sequencing) to examine genome-wide LOH in a diploid yeast strain at a resolution averaging 1 kb. We examined both selected LOH events on chromosome V and unselected events throughout the genome in untreated cells and in cells treated with either γ-radiation or ultraviolet (UV) radiation. Our analysis shows the following: (1) spontaneous and damage-induced mitotic gene conversion tracts are more than three times larger than meiotic conversion tracts, and conversion tracts associated with crossovers are usually longer and more complex than those unassociated with crossovers; (2) most of the crossovers and conversions reflect the repair of two sister chromatids broken at the same position; and (3) both UV and γ-radiation efficiently induce LOH at doses of radiation that cause no significant loss of viability. Using high-throughput DNA sequencing, we also detected new mutations induced by γ-rays and UV. To our knowledge, our study represents the first high-resolution genome-wide analysis of DNA damage-induced LOH events performed in any eukaryote.

Meiotic chromosome segregation in triploid strains of Saccharomyces cerevisiae.

Meiosis in triploids results in four highly aneuploid gametes because six copies of each homolog must be segregated into four meiotic products. Using DNA microarrays and other physical approaches, we examined meiotic chromosome segregation in triploid strains of Saccharomyces cerevisiae. In most tetrads with four viable spores, two of the spores had two copies of a given homolog and two spores had only one copy. Chromosomes segregated randomly into viable spores without preferences for generating near haploid or near diploid spores. Using single-nucleotide polymorphisms, we showed that, in most tetrads, all three pairs of homologs recombined. Strains derived from some of the aneuploid spore colonies had very high frequencies of mitotic chromosome loss, resulting in genetically diverse populations of cells.

The evolution of speed, size and shape in modern athletics.

In the present study, we show that the fastest runners and swimmers are becoming not only faster but also heavier, taller and more slender. During the past century, the world record speeds for 100 m-freestyle and 100 m-dash have increased with body mass (M) raised to the power 1/6, in accordance with the constructal scaling of animal locomotion. The world records also show that the speeds have increased in proportion with body heights (H) raised to the power 1/2, in accordance with animal locomotion scaling. If the athlete's body is modeled with two length scales (H, body width L), the (M, H) data can be used to calculate the slenderness of the body, H/L. The world records show that the body slenderness is increasing very slowly over time.

Impact of a hypomorphic Artemis disease allele on lymphocyte development, DNA end processing, and genome stability.

Artemis was initially discovered as the gene inactivated in human radiosensitive T(-)B(-) severe combined immunodeficiency, a syndrome characterized by the absence of B and T lymphocytes and cellular hypersensitivity to ionizing radiation. Hypomorphic Artemis alleles have also been identified in patients and are associated with combined immunodeficiencies of varying severity. We examine the molecular mechanisms underlying a syndrome of partial immunodeficiency caused by a hypomorphic Artemis allele using the mouse as a model system. This mutation, P70, leads to premature translation termination that deletes a large portion of a nonconserved C terminus. We find that homozygous Artemis-P70 mice exhibit reduced numbers of B and T lymphocytes, thereby recapitulating the patient phenotypes. The hypomorphic mutation results in impaired end processing during the lymphoid-specific DNA rearrangement known as V(D)J recombination, defective double-strand break repair, and increased chromosomal instability. Biochemical analyses reveal that the Artemis-P70 mutant protein interacts with the DNA-dependent protein kinase catalytic subunit and retains significant, albeit reduced, exo- and endonuclease activities but does not undergo phosphorylation. Together, our findings indicate that the Artemis C terminus has critical in vivo functions in ensuring efficient V(D)J rearrangements and maintaining genome integrity.