Chromosome-level genome assembly of a cliff plant Taihangia rupestris var. ciliata provides insights into its adaptation and demographic history.

BACKGROUND: Cliffs are recognized as one of the most challenging environments for plants, characterized by harsh conditions such as drought, infertile soil, and steep terrain. However, they surprisingly host ancient and diverse plant communities and play a crucial role in protecting biodiversity. The Taihang Mountains, which act as a natural boundary in eastern China, support a rich variety of plant species, including many unique to cliff habitats. However, it is little known how cliff plants adapt to harsh habitats and the demographic history in this region. RESULTS: To better understand the demographic history and adaptation of cliff plants in this area, we analyzed the chromosome-level genome of a representative cliff plant, T. rupestris var. ciliata, which has a genome size of 769.5 Mb, with a scaffold N50 of 104.92 Mb. The rapid expansion of transposable elements may have contributed to the increasing genome and its ability to adapt to unique and challenging cliff habitats. Comparative analysis of the genome evolution between Taihangia and non-cliff plants in Rosaceae revealed a significant expansion of gene families associated with oxidative phosphorylation, which is likely a response to the abiotic stresses faced by cliff plants. This expansion may explain the long-term adaptation of Taihangia to harsh cliff environments. The effective population size of the two varieties has continuously decreased due to climatic fluctuations during the Quaternary period. Furthermore, significant differences in gene expression between the two varieties may explain the varied leaf phenotypes and adaptations to harsh conditions in different natural distributions. CONCLUSION: Our study highlights the extraordinary adaptation of T. rupestris var. ciliata, shedding light on the evolution of cliff plants worldwide.

Effects of the Medicaid coverage cliff on low-income elderly Medicare beneficiaries.

The Medicaid coverage "cliff" occurs when Medicare beneficiaries with household income exceeding 100% of the federal poverty level lose eligibility for supplemental Medicaid coverage. Using a regression discontinuity design with data from Medical Expenditure Panel Survey and National Health and Nutrition Examination Survey for 2007-2019, we demonstrate that the cliff increases out-of-pocket spending by 25% and the probability of experiencing problems paying medical bills by 44.4% without decreases in overall health care spending. However, there is evidence that near-poor Medicare beneficiaries changed behavior in response to the cliff, increasing the use of high-value diagnostic and preventive testing by 8.8% and enrollment in a more affordable plan by 12.2%. The cliff does not encourage healthy behavior.

Modified Uni-Traveling-Carrier Photodetector with Its Optimized Cliff Layer.

We have designed the MUTC-PD with an optimized thickness of cliff layer to pre-distort the electric field at the front side of the collection layer. With the optimized MUTC-PD design, the collapse of the electric field will be greatly suppressed, and the electrons in its collection layer will gradually reach their peak velocity with the growing incident light power. Moreover, as the incident light intensity increases, the differential capacitance also declines, thus the total bandwidth grows. It will make the MUTC-PD achieve high-speed and high-power response performance simultaneously. Based on simulation, for 16µm MUTC-PD with a 70 nm cliff layer, the maximum 3 dB bandwidth at -5 V is 137 GHz, compared with 64 GHz for the MUTC-PD with a 30 nm cliff layer. The saturation RF output power is 27.4 dBm at 60 GHz.

Effect of baby swimming lessons on infants' avoidance of bodies of water.

Despite the popularity of infant swimming programs, no evidence exists to determine whether they influence infants' judgments and behavior when confronted with bodies of water. We conducted two separate studies examining if the total number of swimming sessions an infant participated in predicted whether they avoided a body of water they could enter via an edge (Study 1-Water Cliff: n = 101 infants) or a slope (Study 2-Water Slope: n = 77 infants). The results revealed a significant interaction between number of sessions and type of entry into the water. Infants who participated in 10 or more sessions were more likely to avoid falling on the edge leading into the water but entered the water significantly more if they could access it via a slope. These findings suggest that while experience in baby swimming programs can promoted more adaptive behaviors on drop-offs leading into bodies of water, sloped entries may heighten drowning risks for young children with greater familiarity with water. Because we tested the two groups of infants in different countries, further research is warranted to determine if cultural differences in child rearing practices or variations in the content and/or teaching of the swimming programs might explain these intriguing findings.

System-Wide Change Is Essential to Value the Contributions of Women in Medicine and Science.

The persistent and pervasive gender gap in health care is a fact backed by data, science, and evidence. This editorial aims to describe some of the challenges that continue to persist. Many of the strategies outlined can be implemented both locally and nationally to effect meaningful change and work toward closing the existing gender gap in health care.

New Insights on the Activity and Selectivity of MAO-B Inhibitors through In Silico Methods.

To facilitate the identification of novel MAO-B inhibitors, we elaborated a consolidated computational approach, including a pharmacophoric atom-based 3D quantitative structure-activity relationship (QSAR) model, activity cliffs, fingerprint, and molecular docking analysis on a dataset of 126 molecules. An AAHR.2 hypothesis with two hydrogen bond acceptors (A), one hydrophobic (H), and one aromatic ring (R) supplied a statistically significant 3D QSAR model reflected by the parameters: R2 = 0.900 (training set); Q2 = 0.774 and Pearson's R = 0.884 (test set), stability s = 0.736. Hydrophobic and electron-withdrawing fields portrayed the relationships between structural characteristics and inhibitory activity. The quinolin-2-one scaffold has a key role in selectivity towards MAO-B with an AUC of 0.962, as retrieved by ECFP4 analysis. Two activity cliffs showing meaningful potency variation in the MAO-B chemical space were observed. The docking study revealed interactions with crucial residues TYR:435, TYR:326, CYS:172, and GLN:206 responsible for MAO-B activity. Molecular docking is in consensus with and complementary to pharmacophoric 3D QSAR, ECFP4, and MM-GBSA analysis. The computational scenario provided here will assist chemists in quickly designing and predicting new potent and selective candidates as MAO-B inhibitors for MAO-B-driven diseases. This approach can also be used to identify MAO-B inhibitors from other libraries or screen top molecules for other targets involved in suitable diseases.

In Silico Tools to Extract the Drug Design Information Content of Degradation Data: The Case of PROTACs Targeting the Androgen Receptor.

Proteolysis-Targeting Chimeras (PROTACs) have recently emerged as a promising technology in the drug discovery landscape. Large interest in the degradation of the androgen receptor (AR) as a new anti-prostatic cancer strategy has resulted in several papers focusing on PROTACs against AR. This study explores the potential of a few in silico tools to extract drug design information from AR degradation data in the format often reported in the literature. After setting up a dataset of 92 PROTACs with consistent AR degradation values, we employed the Bemis-Murcko method for their classification. The resulting clusters were not informative in terms of structure-degradation relationship. Subsequently, we performed Degradation Cliff analysis and identified some key aspects conferring a positive contribution to activity, as well as some methodological limits when applying this approach to PROTACs. Linker structure degradation relationships were also investigated. Then, we built and characterized ternary complexes to validate previous results. Finally, we implemented machine learning classification models and showed that AR degradation for VHL-based but not CRBN-based PROTACs can be predicted from simple permeability-related 2D molecular descriptors.

Persistent white matter vulnerability in a mouse model of mild traumatic brain injury.

BACKGROUND: Following one mild traumatic brain injury (mTBI), there is a window of vulnerability during which subsequent mTBIs can cause substantially exacerbated impairments. Currently, there are no known methods to monitor, shorten or mitigate this window. METHODS: To characterize a preclinical model of this window of vulnerability, we first gave male and female mice one or two high-depth or low-depth mTBIs separated by 1, 7, or 14 days. We assessed brain white matter integrity using silver staining within the corpus callosum and optic tracts, as well as behavioural performance on the Y-maze test and visual cliff test. RESULTS: The injuries resulted in windows of white matter vulnerability longer than 2 weeks but produced no behavioural impairments. Notably, this window duration is substantially longer than those reported in any previous preclinical vulnerability study, despite our injury model likely being milder than the ones used in those studies. We also found that sex and impact depth differentially influenced white matter integrity in different white matter regions. CONCLUSIONS: These results suggest that the experimental window of vulnerability following mTBI may be longer than previously reported. Additionally, this work highlights the value of including white matter damage, sex, and replicable injury models for the study of post-mTBI vulnerability and establishes important groundwork for the investigation of potential vulnerability mechanisms, biomarkers, and therapies.

Molecular modeling of a series of dehydroquinate dehydratase type II inhibitors of Mycobacterium tuberculosis and design of new binders.

Tuberculosis, caused by Mycobacterium tuberculosis (M. tuberculosis), is still responsible for a large number of fatal cases, especially in developing countries with alarming rates of incidence and prevalence worldwide. Mycobacterium tuberculosis has a remarkable ability to develop new resistance mechanisms to the conventional antimicrobials treatment. Because of this, there is an urgent need for novel bioactive compounds for its treatment. The dehydroquinate dehydratase II (DHQase II) is considered a key enzyme of shikimate pathway, and it can be used as a promising target for the design of new bioactive compounds with antibacterial action. The aim of this work was the construction of QSAR models to aid the design of new potential DHQase II inhibitors. For that purpose, various molecular modeling approaches, such as activity cliff, QSAR models and computer-aided ligand design were utilized. A predictive in silico 4D-QSAR model was built using a database comprising 86 inhibitors of DHQase II, and the model was used to predict the activity of the designed ligands. The obtained model proved to predict well the DHQase II inhibition for an external validation dataset ([Formula: see text] = 0.72). Also, the Activity Cliff analysis shed light on important structural features applied to the ligand design.

Do infants avoid a traversable slope leading into deep water?

Ramps used to access swimming pools are designed with a shallow slope that affords easy access for all including infants. Locomotor experience has been linked to infants' avoidance of falling into the water from drop-offs; however, the effect of such experience on infants' behavior when a slope is offered to access the water has not been addressed. Forty-three crawling infants (Mage  = 10.63 ± 1.91 months; Mcrawling  = 2.38 ± 1.77 months) and 34 walking infants (Mage  = 14.90 ± 2.18 months; Mwalking  = 2.59 ± 1.56 months) were tested on a new Water Slope paradigm, a sloped surface (10°) leading to deep water. No association between infants' avoidance of submersion and locomotor experience was found. Comparison with the results of infants' behavior on the water cliff revealed that a greater proportion of infants reached the submersion point on the water slope than fell into the water cliff. Collectively, these results indicate a high degree of specificity in which locomotor experience teaches infants about risky situations. Importantly, sloped access to deep water appears to increase the risk of infants moving into the water thereby making them more vulnerable to drowning.

Interpretation of Ligand-Based Activity Cliff Prediction Models Using the Matched Molecular Pair Kernel.

Activity cliffs (ACs) are formed by two structurally similar compounds with a large difference in potency. Accurate AC prediction is expected to help researchers' decisions in the early stages of drug discovery. Previously, predictive models based on matched molecular pair (MMP) cliffs have been proposed. However, the proposed methods face a challenge of interpretability due to the black-box character of the predictive models. In this study, we developed interpretable MMP fingerprints and modified a model-specific interpretation approach for models based on a support vector machine (SVM) and MMP kernel. We compared important features highlighted by this SVM-based interpretation approach and the SHapley Additive exPlanations (SHAP) as a major model-independent approach. The model-specific approach could capture the difference between AC and non-AC, while SHAP assigned high weights to the features not present in the test instances. For specific MMPs, the feature weights mapped by the SVM-based interpretation method were in agreement with the previously confirmed binding knowledge from X-ray co-crystal structures, indicating that this method is able to interpret the AC prediction model in a chemically intuitive manner.

Evolution of the human pelvis and obstructed labor: new explanations of an old obstetrical dilemma.

Without cesarean delivery, obstructed labor can result in maternal and fetal injuries or even death given a disproportion in size between the fetus and the maternal birth canal. The precise frequency of obstructed labor is difficult to estimate because of the widespread use of cesarean delivery for indications other than proven cephalopelvic disproportion, but it has been estimated that at least 1 million mothers per year are affected by this disorder worldwide. Why is the fit between the fetus and the maternal pelvis so tight? Why did evolution not lead to a greater safety margin, as in other primates? Here we review current research and suggest new hypotheses on the evolution of human childbirth and pelvic morphology. In 1960, Washburn suggested that this obstetrical dilemma arose because the human pelvis is an evolutionary compromise between two functions, bipedal gait and childbirth. However, recent biomechanical and kinematic studies indicate that pelvic width does not considerably affect the efficiency of bipedal gait and thus is unlikely to have constrained the evolution of a wider birth canal. Instead, bipedalism may have primarily constrained the flexibility of the pubic symphysis during pregnancy, which opens much wider in most mammals with large fetuses than in humans. We argue that the birth canal is mainly constrained by the trade-off between 2 pregnancy-related functions: while a narrow pelvis is disadvantageous for childbirth, it offers better support for the weight exerted by the viscera and the large human fetus during the long gestation period. We discuss the implications of this hypothesis for understanding pelvic floor dysfunction. Furthermore, we propose that selection for a narrow pelvis has also acted in males because of the role of pelvic floor musculature in erectile function. Finally, we review the cliff-edge model of obstetric selection to explain why evolution cannot completely eliminate cephalopelvic disproportion. This model also predicts that the regular application of life-saving cesarean delivery has evolutionarily increased rates of cephalopelvic disproportion already. We address how evolutionary models contribute to understanding and decision making in obstetrics and gynecology as well as in devising health care policies.

Advances in exploring activity cliffs.

The activity cliff (AC) concept is of comparable relevance for medicinal chemistry and chemoinformatics. An AC is defined as a pair of structurally similar compounds with a large potency difference against a given target. In medicinal chemistry, ACs are of interest because they reveal small chemical changes with large potency effects, a concept referred to as structure-activity relationship (SAR) discontinuity. Computationally, ACs can be systematically identified, going far beyond individual compound series considered during lead optimization. Large-scale analysis of ACs has revealed characteristic features across many different compound activity classes. The way in which the molecular similarity and potency difference criteria have been addressed for defining ACs distinguishes between different generations of ACs and mirrors the evolution of the AC concept. We discuss different stages of this evolutionary path and highlight recent advances in AC research.

Simplified activity cliff network representations with high interpretability and immediate access to SAR information.

Activity cliffs (ACs) consist of structurally similar compounds with a large difference in potency against their target. Accordingly, ACs introduce discontinuity in structure-activity relationships (SARs) and are a prime source of SAR information. In compound data sets, the vast majority of ACs are formed by differently sized groups of structurally similar compounds with large potency variations. As a consequence, many of these compounds participate in multiple ACs. This coordinated formation of ACs increases their SAR information content compared to ACs considered as individual compound pairs, but complicates AC analysis. In network representations, coordinated ACs give rise to clusters of varying size and topology, which can be interactively and computationally analyzed. While AC networks are indispensable tools to study coordinated ACs, they become difficult to navigate and interpret in the presence of clusters of increasing size and complex topologies. Herein, we introduce reduced network representations that transform AC networks into an easily interpretable format from which SAR information in the form of R-group tables can be readily obtained. The simplified network variant greatly improves the interpretability of large and complex AC networks and substantially supports SAR exploration.

Wilderness Falls: An Analysis and Comparison of Rock Climbers and Nonclimbers.

BACKGROUND: Wilderness travel and rock climbing are increasingly popular. Urban falls from height have been reported from trauma centers; however, there have been no trauma center reports of rock climbing or wilderness falls (WFs) in the United States. We sought to describe the injury pattern of WF and to determine whether rock climbers represent a distinct pattern of injury. MATERIALS AND METHODS: The trauma database from our level 1 trauma center was queried from 1/1/06 to 12/31/16 for the diagnosis of "fall from cliff" (ICD9: e884.1, ICD10: w15.xx). Demographics, injury characteristics, and trauma center care were analyzed. Data were analyzed using two sample unequal variance T-tests, two sample Z-tests for proportions, and Fisher's exact tests. RESULTS: One hundred fifty-one falls were analyzed (40 climbers, 111 nonclimbers). WF victims were predominantly male (79%), moderately injured (mean injury severity score = 13.2), frequently intoxicated (34%), and fell from an average of 43 feet (7-200 ft). The most frequent injures were soft tissue (55%), spine (50%), head (43%), lower extremity (38%), and chest (39%). Climbers were younger, more often sustained upper extremity and soft tissue injuries, more often flown from the scene, injured during daytime, and were better insured. Helmet use was rare (one climber and one nonclimber). There were 3 (2%) deaths, including one climber. CONCLUSIONS: WFs have a distinct injury pattern and demographic and occur from a height greater than twice those reported in urban falls. Rock climbing falls involve another distinct demographic and pattern of injury. Injury prevention strategies may include helmet use and avoiding nighttime wilderness travel and drug/alcohol use.

Systematic computational identification of promiscuity cliff pathways formed by inhibitors of the human kinome.

The ability of a small molecule to interact with multiple target proteins provides the molecular basis of polypharmacology. So-defined compound promiscuity is intensely investigated in drug discovery. For example, for kinase inhibitors, the interplay between target selectivity and promiscuity plays a decisive role for different therapeutic applications. The "promiscuity cliff" (PC) concept was introduced previously to aid in promiscuity analysis. A PC is defined as a pair of structurally similar compounds with a large difference in promiscuity. Accordingly, PCs can reveal small structural modifications that might be responsible for selectivity or multi-target activity. In network representations, PCs form clusters of varying size and complexity that are difficult to analyze interactively. Herein, we introduce a computational method to systematically identify PC pathways, which are particularly rich in structure-promiscuity information, and extract them from PC clusters. PC pathways provide informative templates for experimental design. In a proof-of-concept investigation, we have applied the new computational approach to systematically identify pathways in more than 600 PC clusters formed by inhibitors of the human kinome, demonstrating the utility of the method and revealing many interesting promiscuity patterns.

Fluctuating survival selection explains variation in avian group size.

Most animal groups vary extensively in size. Because individuals in certain sizes of groups often have higher apparent fitness than those in other groups, why wide group size variation persists in most populations remains unexplained. We used a 30-y mark-recapture study of colonially breeding cliff swallows (Petrochelidon pyrrhonota) to show that the survival advantages of different colony sizes fluctuated among years. Colony size was under both stabilizing and directional selection in different years, and reversals in the sign of directional selection regularly occurred. Directional selection was predicted in part by drought conditions: birds in larger colonies tended to be favored in cooler and wetter years, and birds in smaller colonies in hotter and drier years. Oscillating selection on colony size likely reflected annual differences in food availability and the consequent importance of information transfer, and/or the level of ectoparasitism, with the net benefit of sociality varying under these different conditions. Averaged across years, there was no net directional change in selection on colony size. The wide range in cliff swallow group size is probably maintained by fluctuating survival selection and represents the first case, to our knowledge, in which fitness advantages of different group sizes regularly oscillate over time in a natural vertebrate population.

Parasites favour intermediate nestling mass and brood size in cliff swallows.

A challenge of life-history theory is to explain why animal body size does not continue to increase, given various advantages of larger size. In birds, body size of nestlings and the number of nestlings produced (brood size) have occasionally been shown to be constrained by higher predation on larger nestlings and those from larger broods. Parasites also are known to have strong effects on life-history traits in birds, but whether parasitism can be a driver for stabilizing selection on nestling body size or brood size is unknown. We studied patterns of first-year survival in cliff swallows (Petrochelidon pyrrhonota) in western Nebraska in relation to brood size and nestling body mass in nests under natural conditions and in those in which hematophagous ectoparasites had been removed by fumigation. Birds from parasitized nests showed highest first-year survival at the most common, intermediate brood-size and nestling-mass categories, but cliff swallows from nonparasitized nests had highest survival at the heaviest nestling masses and no relationship with brood size. A survival analysis suggested stabilizing selection on brood size and nestling mass in the presence (but not in the absence) of parasites. Parasites apparently favour intermediate offspring size and number in cliff swallows and produce the observed distributions of these traits, although the mechanisms are unclear. Our results emphasize the importance of parasites in life-history evolution.

Activity Landscape and Molecular Modeling to Explore the SAR of Dual Epigenetic Inhibitors: A Focus on G9a and DNMT1.

In this work we discuss the insights from activity landscape, docking and molecular dynamics towards the understanding of the structure-activity relationships of dual inhibitors of major epigenetic targets: lysine methyltransferase (G9a) and DNA methyltranferase 1 (DNMT1). The study was based on a novel data set of 50 published compounds with reported experimental activity for both targets. The activity landscape analysis revealed the presence of activity cliffs, e.g., pairs of compounds with high structure similarity but large activity differences. Activity cliffs were further rationalized at the molecular level by means of molecular docking and dynamics simulations that led to the identification of interactions with key residues involved in the dual activity or selectivity with the epigenetic targets.

Hematophagous Ectoparasites of Cliff Swallows Invade a Hospital and Feed on Humans.

We describe a hospital infestation by 2 hematophagous ectoparasites of cliff swallows that nested in the window eaves. Breaks in window seals allowed entry of swallow ticks and swallow bugs. These pests emerged in large numbers in patient rooms, hallways, and stairwells; 17% of the ticks fed on humans.