The evolution of masturbation is associated with postcopulatory selection and pathogen avoidance in primates.

Masturbation occurs throughout the animal kingdom. At first glance, however, the fitness benefits of this self-directed behaviour are unclear. Regardless, several drivers have been proposed. Non-functional hypotheses posit that masturbation is either a pathology, or a byproduct of high underlying sexual arousal, whereas functional hypotheses argue an adaptive benefit. The Postcopulatory Selection Hypothesis states that masturbation aids the chances of fertilization, while the Pathogen Avoidance Hypothesis states that masturbation helps reduce host infection by flushing pathogens from the genital tract. Here, we present comprehensive new data documenting masturbation across the primate order and use these, in conjunction with phylogenetic comparative methods, to reconstruct the evolutionary pathways and correlates of masturbation. We find that masturbation is an ancient trait within the primate order, becoming a more common aspect of the haplorrhine behavioural repertoire after the split from tarsiers. Our analyses provide support for both the Postcopulatory Selection and Pathogen Avoidance Hypotheses in male primates, suggesting that masturbation may be an adaptive trait, functioning at a macroevolutionary scale.

Ins and Outs of Rocker Switch Mechanism in Major Facilitator Superfamily of Transporters.

The major facilitator superfamily (MFS) of transporters consists of three classes of membrane transporters: symporters, uniporters, and antiporters. Despite such diverse functions, MFS transporters are believed to undergo similar conformational changes within their distinct transport cycles, known as the rocker-switch mechanism. While the similarities between conformational changes are noteworthy, the differences are also important since they could potentially explain the distinct functions of symporters, uniporters, and antiporters of the MFS superfamily. We reviewed a variety of experimental and computational structural data on a select number of antiporters, symporters, and uniporters from the MFS family to compare the similarities and differences of the conformational dynamics of three different classes of transporters.

Competition and co-association, but not phosphorous availability, shape the benefits of phosphate-solubilizing root bacteria for maize (Zea mays).

Predicting the conditions under which rhizobacteria benefit plant growth remains challenging. Here we tested the hypothesis that benefits from inoculation with phosphate-solubilizing rhizobacteria will depend upon two environmental conditions: phosphate availability and competition between bacteria. We used maize-associated rhizobacteria with varying phosphate solubilization ability in experiments in soil, sterilized soil and gnotobiotic microcosms under conditions of varying orthophosphate availability, while we manipulated the intensity of competition by varying the number of isolates in plant inocula. Growth promotion by microbes did not depend on phosphate availability but was affected by interactions between inoculants: the beneficial effects of one Serratia isolate were only detectable when plants were inoculated with a single strain and the beneficial effects of a competition-sensitive Rhizobium was only detectable in sterilized soil or in microcosms inoculated with single strains. Moreover, microcosm experiments suggested that facilitation of a parasitic isolate, not competitive interactions between bacteria, prevented plants from gaining benefits from a potential mutualist. Competition and facilitation affected colonization of plants in microcosms but growth promotion by Serratia was more affected by inoculation treatment than culturable densities on roots. Experimental manipulation of seed inocula can reveal whether plant growth stimulation is robust with respect to competition, as well as the ecological strategies of different rhizobacteria. From an applied perspective, phosphate solubilization may not provide the mechanism for bacterial growth promotion but may indicate mutualistic potential due to phylogenetic associations. Importantly, benefits to plants are vulnerable to interactions between rhizobacteria and may not persist in mixed inoculations.

There are similarities between rheumatic disease with lung involvement and COVID-19 pneumonia.

INTRODUCTION: There is considerable overlap between the clinical manifestations of covid-19 pneumonia and the acute interstitial lung disease seen in certain rheumatic disorders. In addition, pulmonary fibrosis is increasingly recognised as a potentially serious consequence of both. METHODS: This review explores this overlap of clinical features, risk factors and causation, offering insights into the immune mechanisms that contribute to both sets of disorders. RESULTS: The therapeutic role of immunosuppression and biologic agents in the treatment of covid-19 is explained in the light of this. DISCUSSION: We propose how lessons learned from the insights recently gained into each disorder can improve our insight into immunological mechanisms and application of therapeutic interventions in the other.

Dung beetles as samplers of mammals in Malaysian Borneo-a test of high throughput metabarcoding of iDNA.

Invertebrate-derived DNA (iDNA) sampling in biodiversity surveys is becoming increasingly widespread, with most terrestrial studies relying on DNA derived from the gut contents of blood-feeding invertebrates, such as leeches and mosquitoes. Dung beetles (superfamily Scarabaeoidea) primarily feed on the faecal matter of terrestrial vertebrates and offer several potential benefits over blood-feeding invertebrates as samplers of vertebrate DNA. Importantly, these beetles can be easily captured in large numbers using simple, inexpensive baited traps, are globally distributed, and occur in a wide range of habitats. To build on the few existing studies demonstrating the potential of dung beetles as sources of mammalian DNA, we subjected the large-bodied, Bornean dung beetle (Catharsius renaudpauliani) to a controlled feeding experiment. We analysed DNA from gut contents at different times after feeding using qPCR techniques. Here, we first describe the window of DNA persistence within a dung beetle digestive tract. We found that the ability to successfully amplify cattle DNA decayed over relatively short time periods, with DNA copy number decreasing by two orders of magnitude in just 6 h. In addition, we sampled communities of dung beetles from a lowland tropical rainforest in Sabah, Malaysia, in order to test whether it is possible to identify vertebrate sequences from dung beetle iDNA. We sequenced both the gut contents from large dung beetle species, as well as whole communities of smaller beetles. We successfully identified six mammalian species from our samples, including the bearded pig (Sus barbatus) and the sambar deer (Rusa unicolor)-both vulnerable species on the IUCN red list. Our results represent the first use of dung beetle iDNA to sample Southeast Asian vertebrate fauna, and highlight the potential for dung beetle iDNA to be used in future biodiversity monitoring surveys.

Convergent Phenotypic Evolution of Rhodopsin for Dim-Light Sensing across Deep-Diving Vertebrates.

Rhodopsin comprises an opsin attached to a retinal chromophore and is the only visual pigment conferring dim-light vision in vertebrates. On activation by photons, the retinal group becomes detached from the opsin, which is then inactive until it is recharged. Of all vertebrate species, those that dive face unique visual challenges, experiencing rapid decreases in light level and hunting in near darkness. Here, we combine sequence analyses with functional assays to show that the rhodopsin pigments of four divergent lineages of deep-diving vertebrates have undergone convergent increases in their retinal release rate. We compare gene sequences and detect parallel amino acids between penguins and diving mammals and perform mutagenesis to show that a single critical residue fully explains the observed increases in retinal release rate in both the emperor penguin and beaked whale. At the same time, we find that other shared sites have no significant effect on retinal release, implying that convergence does not always signify adaptive significance. We propose that accelerated retinal release confers rapid rhodopsin recharging, enabling the visual systems of diving species to adjust quickly to changing light levels as they descend through the water column. This contrasts with nocturnal species, where adaptation to darkness has been attributed to slower retinal release rates.

Positive Selection and Inactivation in the Vision and Hearing Genes of Cetaceans.

The transition to an aquatic lifestyle in cetaceans (whales and dolphins) resulted in a radical transformation in their sensory systems. Toothed whales acquired specialized high-frequency hearing tied to the evolution of echolocation, whereas baleen whales evolved low-frequency hearing. More generally, all cetaceans show adaptations for hearing and seeing underwater. To determine the extent to which these phenotypic changes have been driven by molecular adaptation, we performed large-scale targeted sequence capture of 179 sensory genes across the Cetacea, incorporating up to 54 cetacean species from all major clades as well as their closest relatives, the hippopotamuses. We screened for positive selection in 167 loci related to vision and hearing and found that the diversification of cetaceans has been accompanied by pervasive molecular adaptations in both sets of genes, including several loci implicated in nonsyndromic hearing loss. Despite these findings, however, we found no direct evidence of positive selection at the base of odontocetes coinciding with the origin of echolocation, as found in studies examining fewer taxa. By using contingency tables incorporating taxon- and gene-based controls, we show that, although numbers of positively selected hearing and nonsyndromic hearing loss genes are disproportionately high in cetaceans, counts of vision genes do not differ significantly from expected values. Alongside these adaptive changes, we find increased evidence of pseudogenization of genes involved in cone-mediated vision in mysticetes and deep-diving odontocetes.

Adaptive responses to cool climate promotes persistence of a non-native lizard.

Successful establishment and range expansion of non-native species often require rapid accommodation of novel environments. Here, we use common-garden experiments to demonstrate parallel adaptive evolutionary response to a cool climate in populations of wall lizards (Podarcis muralis) introduced from southern Europe into England. Low soil temperatures in the introduced range delay hatching, which generates directional selection for a shorter incubation period. Non-native lizards from two separate lineages have responded to this selection by retaining their embryos for longer before oviposition--hence reducing the time needed to complete embryogenesis in the nest--and by an increased developmental rate at low temperatures. This divergence mirrors local adaptation across latitudes and altitudes within widely distributed species and suggests that evolutionary responses to climate can be very rapid. When extrapolated to soil temperatures encountered in nests within the introduced range, embryo retention and faster developmental rate result in one to several weeks earlier emergence compared with the ancestral state. We show that this difference translates into substantial survival benefits for offspring. This should promote short- and long-term persistence of non-native populations, and ultimately enable expansion into areas that would be unattainable with incubation duration representative of the native range.

Outcomes of hip arthroscopy in patients aged 50 years or older compared with a matched-pair control of patients aged 30 years or younger.

PURPOSE: Age has been suggested as a negative prognostic factor for hip arthroscopy. The purpose of this study was to compare patient characteristics and outcomes after hip arthroscopy in patients aged 50 years or older with a matched control group of patients aged 30 years or younger at a minimum postoperative follow-up of 2 years. METHODS: Between September 2008 and March 2010, data were prospectively collected on all patients aged 50 years or older undergoing primary hip arthroscopy. Fifty-two patients met our inclusion and matching criteria, of whom all 52 (100%) were available for follow-up at a minimum of 2 years. This cohort was compared with a matched-pair control group of patients aged 30 years or younger who underwent similar procedures. RESULTS: The mean age of the study group was 54.8 years (range, 50 to 69 years), and that of the control group was 20.3 years (range, 13 to 30 years). The groups were matched at a 1:1 ratio, including 18 male patients (34.6%) and 34 female patients (65.4%) in each group, with a mean follow-up period of 32 months (range, 24 to 54 months). In the younger control group, the score improvement from preoperatively to 2 years' follow-up was 62.9 to 84.2 for the modified Harris Hip Score, 60.5 to 84.2 for the Non-Arthritic Hip Score, 63.1 to 86.5 for the Hip Outcome Score-Activities of Daily Living, and 42.2 to 72.7 for the Hip Outcome Score-Sport-Specific Subscale. In the older study group, the score improvement from preoperatively to 2 years' follow-up was 61.2 to 82.2 for the modified Harris Hip Score, 59.9 to 80.4 for the Non-Arthritic Hip Score, 63.9 to 83 for the Hip Outcome Score-Activities of Daily Living, and 41.2 to 64.6 for the Hip Outcome Score-Sport-Specific Subscale. All improvements in both groups were statistically significant at the 2-year postoperative follow-up (P < .001). There was no significant difference for all patient-reported outcome (PRO) scores at final follow-up between both groups. When we compared the change in PRO scores (Δ) from preoperatively to 2 years postoperatively, there was no significant difference between both groups. The overall survivorship rate was 98.1% for the younger control group and 82.7% for the older study group. CONCLUSIONS: Survivors aged 50 years or older show similar improvement to patients aged 30 years or younger in PRO and patient satisfaction scores. The 2-year survivorship rate was 98.1% for the younger control group and 82.7% for the older study group. Therefore we believe that hip arthroscopy should be considered a valid treatment option when treating hip pain in patients aged 50 years or older with a Tönnis arthritic grade of 0 or 1. Older patients should be counseled on the possibility of later conversion to total hip arthroplasty. Future work may include development of a decision-making tool to assess for prognosis to better delineate the indications for hip arthroscopy in the older population. LEVEL OF EVIDENCE: Level III, therapeutic case-control study.

Genomic evolution and polymorphism: segmental duplications and haplotypes at 108 regions on 21 chromosomes.

We describe here extensive, previously unknown, genomic polymorphism in 120 regions, covering 19 autosomes and both sex chromosomes. Each contains duplication within multigene clusters. Of these, 108 are extremely polymorphic with multiple haplotypes. We used the genomic matching technique (GMT), previously used to characterise the major histocompatibility complex (MHC) and regulators of complement activation (RCA). This genome-wide extension of this technique enables the examination of many underlying cis, trans and epistatic interactions responsible for phenotypic differences especially in relation to individuality, evolution and disease susceptibility. The extent of the diversity could not have been predicted and suggests a new model of primate evolution based on conservation of polymorphism rather than de novo mutation.

Almost total protection from age-related macular degeneration by haplotypes of the Regulators of Complement Activation.

Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. It has been proposed that the polymorphism encoding Y402H (T1277C) in the complement factor H gene (CFH) is one of the main determinants of disease. We genotyped the polymorphism at a number of loci in the region encompassing the Regulators of Complement Activation (RCA) on chromosome 1, including T1277C SNP, in 187 patients and 146 controls. Haplotypes have been classified as protective (P) or susceptible (S) with respect to AMD. This included the identification of an S haplotype with a T at 1277. The results show that no single locus should be assumed to be directly responsible for AMD, but rather argue for the existence of RCA haplotypes, which can be assigned meaningful predictive values for AMD. We conclude that the critical sequences are within a region 450 kb centromeric to 128 kb telomeric of CFH.

Genomic evolution in domestic cattle: ancestral haplotypes and healthy beef.

We have identified numerous Ancestral Haplotypes encoding a 14-Mb region of Bota C19. Three are frequent in Simmental, Angus and Wagyu and have been conserved since common progenitor populations. Others are more relevant to the differences between these 3 breeds including fat content and distribution in muscle. SREBF1 and Growth Hormone, which have been implicated in the production of healthy beef, are included within these haplotypes. However, we conclude that alleles at these 2 loci are less important than other sequences within the haplotypes. Identification of breeds and hybrids is improved by using haplotypes rather than individual alleles.

Genesis of ancestral haplotypes: RNA modifications and reverse transcription-mediated polymorphisms.

Understanding the genesis of the block haplotype structure of the genome is a major challenge. With the completion of the sequencing of the Human Genome and the initiation of the HapMap project the concept that the chromosomes of the mammalian genome are a mosaic, or patchwork, of conserved extended block haplotype sequences is now accepted by the mainstream genomics research community. Ancestral Haplotypes (AHs) can be viewed as a recombined string of smaller Polymorphic Frozen Blocks (PFBs). How have such variant extended DNA sequence tracts emerged in evolution? Here the relevant literature on the problem is reviewed from various fields of molecular and cell biology particularly molecular immunology and comparative and functional genomics. Based on our synthesis we then advance a testable molecular and cellular model. A critical part of the analysis concerns the origin of the strand biased mutation signatures in the transcribed regions of the human and higher primate genome, A-to-G versus T-to-C (ratio ∼ 1.5 fold) and C-to-T versus G-to-A (≥ 1.5 fold). A comparison and evaluation of the current state of the fields of immunoglobulin Somatic Hypermutation (SHM) and Transcription-Coupled DNA Repair focused on how mutations in newly synthesized RNA might be copied back to DNA thus accounting for some of the genome-wide strand biases (e.g., the A-to-G vs T-to-C component of the strand biased spectrum). We hypothesize that the genesis of PFBs and extended AHs occurs during mutagenic episodes in evolution (e.g., retroviral infections) and that many of the critical DNA sequence diversifying events occur first at the RNA level, e.g., recombination between RNA strings resulting in tandem and dispersed RNA duplications (retroduplications), RNA mutations via adenosine-to-inosine pre-mRNA editing events as well as error prone RNA synthesis. These are then copied back into DNA by a cellular reverse transcription process (also likely to be error-prone) that we have called "reverse transcription-mediated long DNA conversion." Finally we suggest that all these activities and others can be envisaged as being brought physically under the umbrella of special sites in the nucleus involved in transcription known as "transcription factories."

Fractal topology of gene promoter networks at phase transitions.

Much is known regarding the structure and logic of genetic regulatory networks. Less understood is the contextual organization of promoter signals used during transcription initiation, the most pivotal stage during gene expression. Here we show that promoter networks organize spontaneously at a dimension between the 1-dimension of the DNA and 3-dimension of the cell. Network methods were used to visualize the global structure of E. coli sigma (sigma) recognition footprints using published promoter sequences (RegulonDB). Footprints were rendered as networks with weighted edges representing bp-sharing between promoters (nodes). Serial thresholding revealed phase transitions at positions predicted by percolation theory, and nuclei denoting short steps through promoter space with geometrically constrained linkages. The network nuclei are fractals, a power-law organization not yet described for promoters. Genome-wide promoter abundance also scaled as a power-law. We propose a general model for the development of a fractal nucleus in a transcriptional grammar.

Early neural and vascular dysfunctions in diabetic rats are largely sequelae of increased sorbitol oxidation.

These experiments were undertaken to assess the importance of cytoplasmic (c) sorbitol oxidation versus mitochondrial (m) pyruvate oxidation in mediating neural and vascular dysfunction attributable to hyperglycemia in diabetic rats. Increased oxidation of sorbitol is coupled to enzymatic reduction of free oxidized NAD(+)c to reduced NADHc, manifested by an increased ratio of NADH to NAD(+)c. Likewise, increased oxidation of pyruvate is coupled to reduction of NAD(+)m to NADHm, which increases the NADH/NAD(+)m ratio. Specific inhibitors of sorbitol production or sorbitol oxidation normalized: increased diabetic nerve NADH/NAD(+)c, impaired nerve-conduction velocity, and vascular dysfunction in sciatic nerve, retina, and aorta; however, they had little or no impact on increased NADH/NAD(+)m. These observations provide, for the first time, strong in vivo evidence for the primacy of sorbitol oxidation versus. pyruvate oxidation in mediating the metabolic imbalances, impaired nerve conduction, and vascular dysfunction evoked by diabetes. These findings are consistent with (a) the fact that oxidation of sorbitol produces "prooxidant" NADHc uncoupled from subsequent production of "antioxidant" pyruvate required for reoxidation of NADHc to NAD(+)c by lactate dehydrogenase, and (b) the hypothesis that neural and vascular dysfunction in early diabetes are caused primarily by increased NADHc, which fuels superoxide production by NADH-driven oxidases.

Novel sequence elements define ancestral haplotypes of the region encompassing complement factor H.

The genomic region encompassing complement factor H (CFH) is thought to be important in determining susceptibility to inflammatory diseases such as age-related macular degeneration, but only limited polymorphism has been described. After applying the genomic matching technique to three-generation families and an ethnically diverse reference panel we have demonstrated that the polymorphism resembles that found in the major histocompatibility complex. The different ancestral haplotypes carry either T or C at T1277C but also other more polymorphic alleles over a region of 2 Mb. Thus the association between age-related macular degeneration and T1277 or Y402 actually reflects multiple linked polymorphisms including an indel that cannot be dissected from any direct effect of Y402 and may be more important. We show for the first time that simple algorithms can identify genomic sequence elements that appear to be more useful haplospecific markers than single nucleotide polymorphism or microsatellites.

Vertebrate species profiling in one step using a single primer.

Current species profiling techniques usually require several steps to identify an unknown species in quarantine cases and other forensic applications. Here we have developed a species profiling test that produces unique profiles for all vertebrate species tested using a single primer in a polymerase chain reaction. Samples tested included a range of mammals and other vertebrates such as fish and marsupials; a group of animals yet to be characterized with molecular speciation techniques. Species-specific profiles were shown to be reproducible and able to be generated from less than 10 ng of total DNA, comparable to DNA quantities used in conventional species profiling techniques. A case study demonstrates the utility of the technique by distinguishing between commercial and protected species of the Macropodidae (kangaroo) superfamily.

Extensive genomic and functional polymorphism of the complement control proteins.

Using combinations of genomic markers, we describe more than 20 distinct ancestral haplotypes (AH) of complement control proteins (CCPs), located within the regulators of complement activation (RCA) alpha block at 1q32. This extensive polymorphism, including functional sites, is important because CCPs are involved in the regulation of complement activation whilst also serving as self and viral receptors. To identify haplotypes, we used the genomic matching technique (GMT) based on the pragmatic observation that extreme nucleotide polymorphism is packaged with duplicated sequences as polymorphic frozen blocks (PFB). At each PFB, there are many alternative sequences (haplotypes) which are inherited faithfully from very remote ancestors. We have compared frequencies of RCA haplotypes and report differences in recurrent spontaneous abortion (RSA) and psoriasis vulgaris (PV).

Reactive carbonyls and polyunsaturated fatty acids produce a hydroxyl radical-like species: a potential pathway for oxidative damage of retinal proteins in diabetes.

The pattern of oxidized amino acids in aortic proteins of nonhuman primates suggests that a species resembling hydroxyl radical damages proteins when blood glucose levels are high. However, recent studies argue strongly against a generalized increase in diabetic oxidative stress, which might instead be confined to the vascular wall. Here, we describe a pathway for glucose-stimulated protein oxidation and provide evidence of its complicity in diabetic microvascular disease. Low density lipoprotein incubated with pathophysiological concentrations of glucose became selectively enriched in ortho-tyrosine and meta-tyrosine, implicating a hydroxyl radical-like species in protein damage. Model system studies demonstrated that the reaction pathway requires both a reactive carbonyl group and a polyunsaturated fatty acid, involves lipid peroxidation, and is blocked by the carbonyl scavenger aminoguanidine. To explore the physiological relevance of the pathway, we used mass spectrometry and high pressure liquid chromatography to quantify oxidation products in control and hyperglycemic rats. Hyperglycemia raised levels of ortho-tyrosine, meta-tyrosine, and oxygenated lipids in the retina, a tissue rich in polyunsaturated fatty acids. Rats that received aminoguanidine did not show this increase in protein and lipid oxidation. In contrast, rats with diet-induced hyperlipidemia in the absence of hyperglycemia failed to exhibit increased protein and lipid oxidation products in the retina. Our observations suggest that generation of a hydroxyl radical-like species by a carbonyl/polyunsaturated fatty acid pathway might promote localized oxidative stress in tissues vulnerable to diabetic damage. This raises the possibility that antioxidant therapies that specifically inhibit the pathway might delay the vascular complications of diabetes.

A potent sorbitol dehydrogenase inhibitor exacerbates sympathetic autonomic neuropathy in rats with streptozotocin-induced diabetes.

We have developed an animal model of diabetic sympathetic autonomic neuropathy which is characterized by neuroaxonal dystrophy (NAD), an ultrastructurally distinctive axonopathy, in chronic streptozotocin (STZ)-diabetic rats. Diabetes-induced alterations in the sorbitol pathway occur in sympathetic ganglia and therapeutic agents which inhibit aldose reductase or sorbitol dehydrogenase improve or exacerbate, respectively, diabetes-induced NAD. The sorbitol dehydrogenase inhibitor SDI-711 (CP-470711, Pfizer) is approximately 50-fold more potent than the structurally related compound SDI-158 (CP 166,572) used in our earlier studies. Treatment with SDI-711 (5 mg/kg/day) for 3 months increased ganglionic sorbitol (26-40 fold) and decreased fructose content (20-75%) in control and diabetic rats compared to untreated animals. SDI-711 treatment of diabetic rats produced a 2.5- and 4-5-fold increase in NAD in the SMG and ileal mesenteric nerves, respectively, in comparison to untreated diabetics. Although SDI-711 treatment of non-diabetic control rat ganglia increased ganglionic sorbitol 40-fold (a value 8-fold higher than untreated diabetics), the frequency of NAD remained at control levels. Levels of ganglionic sorbitol pathway intermediates in STZ-treated rats (a model of type 1 diabetes) and Zucker Diabetic Fatty rats (ZDF, a genetic model of type 2 diabetes) were comparable, although STZ-diabetic rats develop NAD and ZDF-diabetic rats do not. SDI failed to increase diabetes-related ganglionic NGF above levels seen in untreated diabetics. Initiation of Sorbinil treatment for the last 4 months of a 9 month course of diabetes, substantially reversed the frequency of established NAD in the diabetic rat SMG without affecting the metabolic severity of diabetes. These findings indicate that sorbitol pathway-linked metabolic alterations play an important role in the development of NAD, but sorbitol pathway activity, not absolute levels of sorbitol or fructose per se, may be most critical to its pathogenesis.