Progressive Cactus is a multiple-genome aligner for the thousand-genome era.

New genome assemblies have been arriving at a rapidly increasing pace, thanks to decreases in sequencing costs and improvements in third-generation sequencing technologies1-3. For example, the number of vertebrate genome assemblies currently in the NCBI (National Center for Biotechnology Information) database4 increased by more than 50% to 1,485 assemblies in the year from July 2018 to July 2019. In addition to this influx of assemblies from different species, new human de novo assemblies5 are being produced, which enable the analysis of not only small polymorphisms, but also complex, large-scale structural differences between human individuals and haplotypes. This coming era and its unprecedented amount of data offer the opportunity to uncover many insights into genome evolution but also present challenges in how to adapt current analysis methods to meet the increased scale. Cactus6, a reference-free multiple genome alignment program, has been shown to be highly accurate, but the existing implementation scales poorly with increasing numbers of genomes, and struggles in regions of highly duplicated sequences. Here we describe progressive extensions to Cactus to create Progressive Cactus, which enables the reference-free alignment of tens to thousands of large vertebrate genomes while maintaining high alignment quality. We describe results from an alignment of more than 600 amniote genomes, which is to our knowledge the largest multiple vertebrate genome alignment created so far.

Evolution of the ancestral mammalian karyotype and syntenic regions.

Decrypting the rearrangements that drive mammalian chromosome evolution is critical to understanding the molecular bases of speciation, adaptation, and disease susceptibility. Using 8 scaffolded and 26 chromosome-scale genome assemblies representing 23/26 mammal orders, we computationally reconstructed ancestral karyotypes and syntenic relationships at 16 nodes along the mammalian phylogeny. Three different reference genomes (human, sloth, and cattle) representing phylogenetically distinct mammalian superorders were used to assess reference bias in the reconstructed ancestral karyotypes and to expand the number of clades with reconstructed genomes. The mammalian ancestor likely had 19 pairs of autosomes, with nine of the smallest chromosomes shared with the common ancestor of all amniotes (three still conserved in extant mammals), demonstrating a striking conservation of synteny for ∼320 My of vertebrate evolution. The numbers and types of chromosome rearrangements were classified for transitions between the ancestral mammalian karyotype, descendent ancestors, and extant species. For example, 94 inversions, 16 fissions, and 14 fusions that occurred over 53 My differentiated the therian from the descendent eutherian ancestor. The highest breakpoint rate was observed between the mammalian and therian ancestors (3.9 breakpoints/My). Reconstructed mammalian ancestor chromosomes were found to have distinct evolutionary histories reflected in their rates and types of rearrangements. The distributions of genes, repetitive elements, topologically associating domains, and actively transcribed regions in multispecies homologous synteny blocks and evolutionary breakpoint regions indicate that purifying selection acted over millions of years of vertebrate evolution to maintain syntenic relationships of developmentally important genes and regulatory landscapes of gene-dense chromosomes.

Binary reversals: a diagnostic sign in primary progressive aphasia.

BACKGROUND: Binary reversals (exemplified by 'yes'/'no' confusions) have been described in patients with primary progressive aphasia (PPA) but their diagnostic value and phenotypic correlates have not been defined. METHODS: We conducted a retrospective cohort study analysing demographic, clinical, neuropsychological, linguistic and behavioural data from patients representing all major PPA syndromes (non-fluent/agrammatic variant, nfvPPA; logopenic variant, lvPPA; semantic variant, svPPA) and behavioural variant frontotemporal dementia (bvFTD). The prevalence of binary reversals and behavioural abnormalities, illness duration, parkinsonian features and neuropsychological test scores were compared between neurodegenerative syndromes, and the diagnostic predictive value of binary reversals was assessed using logistic regression. RESULTS: Data were obtained for 83 patients (21 nfvPPA, 13 lvPPA, 22 svPPA, 27 bvFTD). Binary reversals occurred in all patients with nfvPPA, but significantly less frequently and later in lvPPA (54%), svPPA (9%) and bvFTD (44%). Patients with bvFTD with binary reversals had significantly more severe language (but not general executive or behavioural) deficits than those without reversals. Controlling for potentially confounding variables, binary reversals strongly predicted a diagnosis of nfvPPA over other syndromes. CONCLUSIONS: Binary reversals are a sensitive (though not specific) neurolinguistic feature of nfvPPA, and should suggest this diagnosis if present as a prominent early symptom.

Comprehension of acoustically degraded speech in Alzheimer's disease and primary progressive aphasia.

Successful communication in daily life depends on accurate decoding of speech signals that are acoustically degraded by challenging listening conditions. This process presents the brain with a demanding computational task that is vulnerable to neurodegenerative pathologies. However, despite recent intense interest in the link between hearing impairment and dementia, comprehension of acoustically degraded speech in these diseases has been little studied. Here we addressed this issue in a cohort of 19 patients with typical Alzheimer's disease and 30 patients representing the three canonical syndromes of primary progressive aphasia (non-fluent/agrammatic variant primary progressive aphasia; semantic variant primary progressive aphasia; logopenic variant primary progressive aphasia), compared to 25 healthy age-matched controls. As a paradigm for the acoustically degraded speech signals of daily life, we used noise-vocoding: synthetic division of the speech signal into frequency channels constituted from amplitude-modulated white noise, such that fewer channels convey less spectrotemporal detail thereby reducing intelligibility. We investigated the impact of noise-vocoding on recognition of spoken three-digit numbers and used psychometric modelling to ascertain the threshold number of noise-vocoding channels required for 50% intelligibility by each participant. Associations of noise-vocoded speech intelligibility threshold with general demographic, clinical and neuropsychological characteristics and regional grey matter volume (defined by voxel-based morphometry of patients' brain images) were also assessed. Mean noise-vocoded speech intelligibility threshold was significantly higher in all patient groups than healthy controls, and significantly higher in Alzheimer's disease and logopenic variant primary progressive aphasia than semantic variant primary progressive aphasia (all P < 0.05). In a receiver operating characteristic analysis, vocoded intelligibility threshold discriminated Alzheimer's disease, non-fluent variant and logopenic variant primary progressive aphasia patients very well from healthy controls. Further, this central hearing measure correlated with overall disease severity but not with peripheral hearing or clear speech perception. Neuroanatomically, after correcting for multiple voxel-wise comparisons in predefined regions of interest, impaired noise-vocoded speech comprehension across syndromes was significantly associated (P < 0.05) with atrophy of left planum temporale, angular gyrus and anterior cingulate gyrus: a cortical network that has previously been widely implicated in processing degraded speech signals. Our findings suggest that the comprehension of acoustically altered speech captures an auditory brain process relevant to daily hearing and communication in major dementia syndromes, with novel diagnostic and therapeutic implications.

Widespread Production of Polyunsaturated Aldehydes by Benthic Diatoms of the North Pacific Ocean's Salish Sea.

Diatoms are key primary producers across marine, freshwater, and terrestrial ecosystems. They are responsible for photosynthesis and secondary production that, in part, support complex food webs. Diatoms can produce phytochemicals that have transtrophic ecological effects which increase their competitive fitness. Polyunsaturated aldehydes (PUAs) are one class of diatom-derived phytochemicals that are known to have allelopathic and anti-herbivory properties. The anti-herbivory capability of PUAs results from their negative effect on grazer fecundity. Since their discovery, research has focused on their production by pelagic marine diatoms, and their effects on copepod egg production, hatching success, and juvenile survival and development. Few investigations have explored PUA production by the prolific suite of benthic marine diatoms, despite their importance to coastal trophic systems. In this study, we tested eight species of benthic diatoms for the production of the bioactive PUAs 2,4-heptadienal, 2,4-octadienal, and 2,4-decadienal. Benthic diatom species were isolated from the Salish Sea, an inland sea within the North Pacific ecosystem. All species were found to be producers of at least two PUAs in detectable concentrations, with five species producing all three PUAs in quantifiable concentrations. Our results indicate that production of PUAs from Salish Sea benthic diatoms may be widespread, and thus these compounds may contribute to benthic coastal food web dynamics through heretofore unrecognized pathways. Future studies should expand the geographic scope of investigations into benthic diatom PUA production and explore the effects of benthic diatoms on benthic consumer fecundity.

Acetogenins from the Stem of Uvaria rufa and Their Cytotoxic Activity.

Four new adjacent bis-tetrahydrofuran acetogenins, bullacin C (7), uvarirufin (9), and uvariasolins III (12) and IV (13), along with 11 known acetogenins, were isolated from the stem of Uvaria rufa. Their structures were elucidated based on spectroscopic data analysis, including 1D and 2D NMR, HRESIMS, and MALDI-MS/MS of the lithium adducts. Absolute configurations were assigned using Mosher ester analysis and ECD measurements. Uvarirufin (9) possesses a unique C-39 skeleton among acetogenins. Most tested acetogenins exhibited cytotoxicity against human cancer cell lines (HCT 116, 22Rv1, MDA-MB-435, OVCAR3). Squamocin (8) and uvarirufin (9) were found to be the most potent, with an IC50 value of 1.2 µM for both in HCT 116 colon cancer cells. Additionally, a new application of Dragendorff's reagent is proposed herein for the TLC detection of acetogenins.

Pediatric Traumatic Lumbar Hernias and Associated Injuries: A Case Series.

OBJECTIVE: Traumatic lumbar hernias are a rare entity mostly seen with high-impact, blunt abdominal trauma. This injury occurs when there is disruption of the posterior musculature along with bony structures, allowing for herniation of abdominal contents. There are minimal cases of this entity reported in adults, but even fewer in the pediatric population. METHODS: We describe 3 cases of traumatic lumbar hernia at our institution as well as provide a review of the literature to elucidate the most common mechanisms, severity of injury, and associated injuries. RESULTS: Traumatic lumbar hernia is most commonly seen in restrained passengers involved in motor vehicle collisions. A majority of cases are diagnosed using computed tomography imaging and less frequently during primary surgical exploration. The most common associated injuries were mesenteric and bowel injuries, followed by spinal and chest trauma. Traumatic lumbar hernia often leads to prolonged hospital stays and increased need for posthospital rehabilitation because of associated traumatic comorbidities. CONCLUSIONS: Traumatic lumbar hernia is a rare entity in children, and early suspicion and identification of associated injuries is necessary in the management of these patients.

Characterizing the Stability of Angiotensin II in 0.9% Sodium Chloride Using High Performance Liquid Chromatography and Liquid Chromatography Tandem Mass Spectrometry.

Purpose: The purpose of this study was to evaluate the stability of angiotensin II in 0.9% sodium chloride for up to 5 days. Methods: We prepared angiotensin II dilutions, by aseptically diluting 2.5 mg (1 mL) in 249 mL 0.9% sodium chloride creating a solution of 10 000 ng/mL. Admixtures were stored under refrigeration (5 ± 3°C). Stability of the dilution was assessed by: preservation of clarity, consistency of pH, and retention of concentration. Solutions were sampled at times 0, 24, 48, 72, 96, 120 hours. Solutions were analyzed via High-Performance Liquid Chromatography (HPLC-UV) and Liquid Chromatography Mass Spectrometry (LC-MS/MS). Retention of concentration was set a priori at > 90% of initial concentration. Results: Clarity, color, and pH at all sample time points remained constant. Both methods of analysis confirmed similar results. When stored under refrigeration, the concentration of angiotensin II solution remained above 90% of initial concentration throughout the entire sampling period. Conclusions: Angiotensin II in 0.9% sodium chloride stored in infusion bags under refrigeration (5 ± 3°C) maintained at least 90% of their original concentrations for up to 5 days. Stability was also demonstrated based on turbidity, color, and pH assessment.

Characterization of organic crystals for second-harmonic generation.

Second-harmonic generation (SHG) is a common technique with many applications. Common inorganic single-crystalline materials used to produce SHG light are effective using short IR/visible wavelengths but generally do not perform well at longer, technologically relevant IR wavelengths such as 1300, 1550, and 2000 nm. Efficient SHG materials possess many of the same key material properties as terahertz (THz) generators, and certain single-crystalline organic THz generation materials have been reported to perform at longer IR wavelengths. Consequently, this work focuses on characterizing three efficient organic THz generators for SHG, namely, DAST (trans-4-[4-(dimethylamino)-N-methylstilbazolium] p-tosylate), DSTMS (4-N,N-dimethylamino-4'-N'-methylstilbazolium 2,4,6-trimethylbenzenesulfonate), and the recently discovered generator PNPA ((E)-4-((4-nitrobenzylidene)amino)-N-phenylaniline). All three of these crystals outperform the beta-barium borate (BBO), an inorganic material commonly used for SHG, using IR pump wavelengths (1200-2000 nm).

Benign mesenchymal tumours of the tongue: A report of adult-type rhabdomyoma and granular cell tumour with a review of the literature.

The cytomorphological features of benign mesenchymal tumours of the tongue have rarely been reported. Herein, we present the cytomorphological features of adult-type rhabdomyoma, which occurred in the tongue of a female patient, and granular cell tumour (GCT), which occurred in the tongue of a male patient; both patients were in their mid-50s. The cytological features of the adult-type rhabdomyoma case included large polygonal to ovoid cells with abundant and granular cytoplasm with predominantly peripherally located, uniform, round to oval nuclei and small nucleoli. Cross-striation and crystalline intracytoplasmic structures were not seen. The cytological features of the GCT case included large cells with abundant granular pale cytoplasm, small round nuclei and small distinct nucleoli. The cytological differential diagnoses of these tumours overlap; thus, the cytological findings of the different entities included in their differential diagnoses are discussed.

Tirzepatide: A Novel Glucose-Dependent Insulinotropic Polypeptide/Glucagon-Like Peptide 1 Receptor Agonist for the Treatment of Type 2 Diabetes: The First Twincretin.

Tirzepatide is a dual-action glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 (GLP-1) receptor agonist and the first drug in a new class known as twincretins. It is similar to GLP-1 receptor agonists but provides a synergistic enhancement of the incretin effect to control blood glucose levels and reduce weight. Across the SURPASS research program trials, tirzepatide lowered A1C by 1.7-2.4% from baseline. The proportion of patients using tirzepatide who achieved an A1C <7% ranged from 91 to 97%. Patients in the treatment groups averaged a weight loss of 5.44-11.34 kg (12-25 lb). Across all trials, patients on tirzepatide 15 mg lost 8.8-12.9 kg (19.4-28.44 lb) or 9.17-13.7% body weight. In the SURMOUNT-1 trial, maximum weight loss was 23.6 kg (52 lb) or 22.5% body weight. Tirzepatide is a potent new weapon in the arsenal against diabetes.

A quantitative framework for characterizing the evolutionary history of mammalian gene expression.

The evolutionary history of a gene helps predict its function and relationship to phenotypic traits. Although sequence conservation is commonly used to decipher gene function and assess medical relevance, methods for functional inference from comparative expression data are lacking. Here, we use RNA-seq across seven tissues from 17 mammalian species to show that expression evolution across mammals is accurately modeled by the Ornstein-Uhlenbeck process, a commonly proposed model of continuous trait evolution. We apply this model to identify expression pathways under neutral, stabilizing, and directional selection. We further demonstrate novel applications of this model to quantify the extent of stabilizing selection on a gene's expression, parameterize the distribution of each gene's optimal expression level, and detect deleterious expression levels in expression data from individual patients. Our work provides a statistical framework for interpreting expression data across species and in disease.

Custom terahertz waveforms using complementary organic nonlinear optical crystals.

Organic nonlinear optical (NLO) crystals are among the most efficient (>1%) terahertz (THz) radiation generators. However, one of the limitations of using organic NLO crystals is that the unique THz absorptions in each crystal make it difficult to obtain a strong, smooth, and broad emission spectrum. In this work, we combine THz pulses from two complementary crystals, DAST and PNPA, to effectively fill in spectral gaps, creating a smooth spectrum with frequencies out to 5 THz. The combination of pulses also increases the peak-to-peak field strength from 1 MV/cm to 1.9 MV/cm.

The purple mangosteen (Garcinia mangostana): Defining the anticancer potential of selected xanthones.

The purple mangosteen (Garcinia mangostana) is a popular Southeast Asian fruit that has been used traditionally for its health promoting benefits for years. Unique to the mangosteen are a class of phytochemicals known as xanthones that have been reported to display significant anti-cancer and anti-tumor activities, specifically through the promotion of apoptosis, targeting of specific cancer-related proteins, or modulation of cell signaling pathways. α-Mangostin, the most abundant xanthone isolated from the mangosteen, has received substantial attention as it has proven to be a potent phytochemical, specifically as an anticancer agent, in numerous different cancer cell studies and cancer animal models. While the mechanisms for these anticancer effects have been reported in many studies, lesser xanthones, including gartanin, ß-mangostin, γ-mangostin, garcinone C, and garcinone E, and mangosteen extracts from the pericarp, roots, rind, and stem show promise for their anticancer activity but their mechanisms of action are not as well developed and remain to be determined. Mangosteen products appear safe and have been well tolerated in human clinical trials where they show antioxidant activity, though their clinical anticancer activity has not yet been evaluated. This review summarizes the work that has been done to explore and explain the anticancer and antitumor activities of α-mangostin, lesser xanthones, and mangosteen extracts in vitro, in vivo, and in humans in various cancers.

Traumatic Pediatric Fatalities: Are They Preventable?

INTRODUCTION: Trauma related injury remains the leading cause of mortality in pediatric patients, many of which are preventable. The goal of our study was to identify the mechanism of injury (MOI) in pediatric trauma-related fatalities and determine if these injuries were preventable to direct future injury prevention efforts within trauma programs. METHODS: After IRB approval, a retrospective, single-institution review of pediatric (age ≤18) trauma fatalities from 2010 to 2019 was performed. MOI, use of protective devices, demographics, and whether the injury was preventable were collected. Patients were divided into five age cohorts, and frequencies and proportions were used to summarize data. Bivariate testing was done using Fisher's exact and Monte Carlo estimates for the exact test. RESULTS: MOI was found to vary by age with non-accidental trauma found to be the most common cause of trauma related deaths in children <1 (88.5%) and 1-4 (33.3%). MVC was the most common MOI in children >5 y, with 68.4% in the 5-9, 34.4% in the 10-14, and 45.8% in the 15-18 age group. The majority of fatalities resulted from a preventable injury (P < 0.0001) in the younger children with a negative association as age increased: 92.3% <1, 53.3% in 1-4, 36.8% in 5-9, 46.9% in 10-14 and 48.6% in 15-18. Of the preventable injuries, non-accidental trauma was the most common MOI in children <5, while GSW was the most common MOI in children >10. CONCLUSIONS: This study demonstrates many pediatric fatalities are the result of a preventable traumatic injury. This data can guide focused traumatic injury prevention efforts.

Hearing and dementia: from ears to brain.

The association between hearing impairment and dementia has emerged as a major public health challenge, with significant opportunities for earlier diagnosis, treatment and prevention. However, the nature of this association has not been defined. We hear with our brains, particularly within the complex soundscapes of everyday life: neurodegenerative pathologies target the auditory brain, and are therefore predicted to damage hearing function early and profoundly. Here we present evidence for this proposition, based on structural and functional features of auditory brain organization that confer vulnerability to neurodegeneration, the extensive, reciprocal interplay between 'peripheral' and 'central' hearing dysfunction, and recently characterized auditory signatures of canonical neurodegenerative dementias (Alzheimer's disease, Lewy body disease and frontotemporal dementia). Moving beyond any simple dichotomy of ear and brain, we argue for a reappraisal of the role of auditory cognitive dysfunction and the critical coupling of brain to peripheral organs of hearing in the dementias. We call for a clinical assessment of real-world hearing in these diseases that moves beyond pure tone perception to the development of novel auditory 'cognitive stress tests' and proximity markers for the early diagnosis of dementia and management strategies that harness retained auditory plasticity.

The prevalence of subthreshold psychiatric symptoms and associations with alcohol and substance use disorders: from a nationally representative survey of 36,309 adults.

BACKGROUND: Our aim was to describe a broad number of subthreshold psychiatric symptoms (SPS) in a nationally representative population and evaluate associations with substance use. SPS describe groups of symptoms with significant pathology, but that do not quite meet full psychiatric diagnostic criteria. They have been associated with significant impairment and cost. METHODS: The National Epidemiologic Survey on Alcohol and Related Conditions-III was a multistage, weighted, cross-sectional survey completed in the United States in 2013 comprising 36,309 noninstitutionalized adults. We report lifetime prevalence rates of 14 SPS related to mood, anxiety, trauma, eating, and personality disorders. We then evaluate associations with lifetime alcohol use disorders (AUD) and all substance use disorders (SUD) using logistic regression and adjusted odds ratios. SPS and psychiatric diagnoses were mutually exclusive (could not co-occur). RESULTS: Lifetime prevalence of having at least one of 14 SPS was 57% compared with 37% for the related psychiatric disorders. This was similar for males and females, in contrast to psychiatric disorders in which prevalence was 42% in females and 31% in males. Otherwise, overall SPS and disorders had similar prevalence patterns across sociodemographic characteristics. Subthreshold personality symptoms had the highest prevalence rates (schizotypal 21.3%, antisocial 18.3%, and borderline 17.6%), followed by posttraumatic stress (13.1%). Subthreshold bipolar and depression had lifetime prevalence rates of 2.7 and 8.5%, respectively. Prevalence rates of subthreshold anxiety symptoms ranged from 2.2% (agoraphobia) to 9.8% (specific phobia). Subthreshold eating disorder related symptoms had the lowest prevalence rates (anorexia 1.5% and bulimia 1.7%). Half (seven) of the SPS had significantly increased odds of lifetime AUD. This number increased to 12 for all SUD. Subthreshold antisocial personality symptoms had the highest odds of AUD (2.2; 95% CI 2.00-2.37) and SUD (3.5; 95% CI 3.22-3.81). CONCLUSIONS: We found high lifetime SPS prevalence rates and significant associations with AUD and SUD. To our knowledge, this is the first published study evaluating a broad number of SPS. This indicates possible opportunities for early intervention and prevention but requires additional research and development of infrastructure and guidelines to better understand and manage patients who experience SPS.

Comparative Association Mapping Reveals Conservation of Major Gene Resistance to White Pine Blister Rust in Southwestern White Pine (Pinus strobiformis) and Limber Pine (P. flexilis).

All native North American white pines are highly susceptible to white pine blister rust (WPBR) caused by Cronartium ribicola. Understanding genomic diversity and molecular mechanisms underlying genetic resistance to WPBR remains one of the great challenges in improvement of white pines. To compare major gene resistance (MGR) present in two species, southwestern white pine (Pinus strobiformis) Cr3 and limber pine (P. flexilis) Cr4, we performed association analyses of Cr3-controlled resistant traits using single nucleotide polymorphism (SNP) assays designed with Cr4-linked polymorphic genes. We found that ∼70% of P. flexilis SNPs were transferable to P. strobiformis. Furthermore, several Cr4-linked SNPs were significantly associated with the Cr3-controlled traits in P. strobiformis families. The most significantly associated SNP (M326511_1126R) almost colocalized with Cr4 on the Pinus consensus linkage group 8, suggesting that Cr3 and Cr4 might be the same R locus, or have localizations very close to each other in the syntenic region of the P. strobiformis and P. flexilis genomes. M326511_1126R was identified as a nonsynonymous SNP, causing amino acid change (Val376Ile) in a putative pectin acetylesterase, with coding sequences identical between the two species. Moreover, top Cr3-associated SNPs were further developed as TaqMan genotyping assays, suggesting their usefulness as marker-assisted selection (MAS) tools to distinguish genotypes between quantitative resistance and MGR. This work demonstrates the successful transferability of SNP markers between two closely related white pine species in the hybrid zone, and the possibility for deployment of MAS tools to facilitate long-term WPBR management in P. strobiformis breeding and conservation.

Solenodon genome reveals convergent evolution of venom in eulipotyphlan mammals.

Venom systems are key adaptations that have evolved throughout the tree of life and typically facilitate predation or defense. Despite venoms being model systems for studying a variety of evolutionary and physiological processes, many taxonomic groups remain understudied, including venomous mammals. Within the order Eulipotyphla, multiple shrew species and solenodons have oral venom systems. Despite morphological variation of their delivery systems, it remains unclear whether venom represents the ancestral state in this group or is the result of multiple independent origins. We investigated the origin and evolution of venom in eulipotyphlans by characterizing the venom system of the endangered Hispaniolan solenodon (Solenodon paradoxus). We constructed a genome to underpin proteomic identifications of solenodon venom toxins, before undertaking evolutionary analyses of those constituents, and functional assessments of the secreted venom. Our findings show that solenodon venom consists of multiple paralogous kallikrein 1 (KLK1) serine proteases, which cause hypotensive effects in vivo, and seem likely to have evolved to facilitate vertebrate prey capture. Comparative analyses provide convincing evidence that the oral venom systems of solenodons and shrews have evolved convergently, with the 4 independent origins of venom in eulipotyphlans outnumbering all other venom origins in mammals. We find that KLK1s have been independently coopted into the venom of shrews and solenodons following their divergence during the late Cretaceous, suggesting that evolutionary constraints may be acting on these genes. Consequently, our findings represent a striking example of convergent molecular evolution and demonstrate that distinct structural backgrounds can yield equivalent functions.

Covalent Modification of Proteins by Plant-Derived Natural Products: Proteomic Approaches and Biological Impacts.

Plant-derived natural products (NPs) with electrophilic functional groups engage various subsets of the proteome via covalent modification of nucleophilic cysteine residues. This electrophile-nucleophile interaction can change protein conformation, alter protein function, and modulate their biological action. The biological significance of these covalent protein modifications in health and disease is increasingly recognized. One way to understand covalent NP-protein interactions is to utilize traditional proteomics and modern mass spectrometry (MS)-based proteomic strategies. These strategies have proven effective in uncovering specific NP protein targets and are critical first steps that allow for a much deeper understanding of the ability of NPs to modulate cellular processes. Here, plant-derived NPs that covalently modify proteins are reviewed, the biological significance of these covalent modifications, and the different proteomic strategies that have been employed to study these NP-protein interactions.