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Introduction: Previous studies have established a link between gut microbiota and polycystic ovary syndrome (PCOS), but little is known about their precise causal relationship. Therefore, this study aims to explore whether there are precise causal relationships between gut microbiota and PCOS., Material and Methods: We performed a bidirectional two-sample Mendelian randomization (MR) analysis. Datasets were from the largest published meta-analysis on gut microbiota composition and the FinnGen cohort of the IEU Open Genome-Wide Association Study Project database. Inverse variance weighted (IVW), MR-Egger, constrained maximum likelihood-based Mendelian randomization, weighted median, weighted mode, and simple mode were used. Cochran's Q and MR-Egger intercept tests were employed to measure the heterogeneity., Results: A total of 211 gut microbiota taxa were identified in MR analysis. Nine taxa of bacteria, including Alphaproteobacteria (0.55, 0.30-0.99, p = 0.04), Bacilli (1.76, 1.07-2.91, p = 0.03), Bilophila (0.42, 0.23-0.77, p < 0.01), Blautia (0.16, 0.03-0.79, p = 0.02), Burkholderiales (2.37, 1.22-4.62, p = 0.01), Candidatus Soleaferrea (0.65, 0.43-0.98, p = 0.04), Cyanobacteria (0.51, 0.31-0.83, p = 0.01), Holdemania (0.53, 0.35-0.81, p < 0.01), and Lachnospiraceae (1.86, 1.04-3.35, p = 0.03), were found to be associated with PCOS in the above MR methods included at least IVW method. Cochran's Q statistics and MR-Egger intercept test suggested no significant heterogeneity. In addition, 69 taxa were shown significant for at least the IVW method in reverse MR analysis, of these, 25 had a positive correlation, and 37 had a negative correlation. Additionally, Alphaproteobacteria and Lachnospiraceae (0.95, 0.91-0.98, p < 0.01; 0.97, 0.94-0.99, p = 0.02, respectively) were shown a bidirected causally association with PCOS., Conclusions: Our study provides evidence of the bidirectional causal association between gut microbiota and PCOS from a genetic perspective., (© 2024 The Author(s). Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Objective: To investigate the effects of carbon black and cadmium (Cd) combined exposure on autophagy and inflammatory response mediated by protein kinase R-like endoplasmic reticulum kinase (PERK) pathway in human bronchial epithelial (16HBE) cells. Methods: In January 2022, human bronchial epithelial (16HBE) cells were resuscitated and cultured. Carbon black nanoparticles (CBNPs) were oxidized to adsorb Cd ions to construct "CBNPs-Cd" complexes. CCK-8 assay was used to detect the effects of different concentrations and time combinations of CBNPs and Cd on the viability of 16HBE cells. The subsequent dose groups were exposed to 2 μg/ml Cd, 100 μg/ml CBNPs, 100 μg/ml CBNPs+2 μg/ml Cd for 24 h. The number of autophagosomes and autolysosomes was detected by transmission electron microscopy. Western blotting was used to detect the protein expressions of PERK, eukaryotic initiation factor 2α (eIf2α), activating transcription factor 4 (ATF4), sequestosome 1 (SQSTM1/P62), and microtubule-associated protein 1 light chain 3 (LC3). After PERK gene was silenced by siRNA technology, the changes of autophagy marker proteins P62 and LC3 were detected, and the expressions of inflammatory factors interleukin-6 (IL6) and interleukin-8 (IL8) were detected by fluorescence quantitative PCR technique. One-way ANOVA analysis was used to compare three groups or more. LSD test was used for comparison between two groups. Factorial analysis was used for multivariate component analysis. Results: There was no significant change in cell viability of 16HBE after 24 h exposure to CBNPs and Cd alone or combined ( P >0.05). Compared with the control group, the expressions of P62 and LC3 in 16HBE cells were significantly increased in the CBNPs and Cd alone/combined exposure group ( P <0.05), and the number of autophagosomes and autophagolysosomes in the combined exposure group was increased compared with other groups. Compared with the control group, CBNPs and Cd alone exposure group had no significant effects on p-PERK/PERK and p-eIf2α/eIf2α protein expression ( P >0.05). However, the protein expressions of p-PERK/PERK and p-eIf2α/eIf2α and ATF4 were all increased in the combined exposure group ( P <0.05), and the levels of IL6 and IL8 in 16HBE cells in the combined exposure group of CBNPs and Cd were significantly higher than those in the control group ( P <0.05). The levels of LC3 protein, IL6 and IL8 were decreased in the CBNPs-Cd combined exposure group after knockdown of PERK gene ( P <0.05). The results of factorial analysis showed that exposure to CBNPs and Cd had significant effects on the expression of P62, LC3 and IL6 ( P <0.05), but the interaction between the two chemicals had no statistical significance ( P >0.05) . Conclusion: CBNPs-Cd combined exposure may inhibit autophagy and increase inflammation in human bronchial epithelial cells through activation of PERK-eIf2α-ATF4 pathway.

After first episodes of venous thromboembolism (VTE), patients are at increased risk of recurrent VTE and arterial thrombotic events (ATE) compared with the general population, two disorders that are influenced by anticoagulation. However, risk factors of these conditions occurring during and after anticoagulation are little described. Using cause-specific hazard regression models, we aimed to determine risk factors of the composite outcome recurrent VTE/ATE, and separately recurrent VTE or ATE, during and after anticoagulation in patients with first episodes of VTE from a prospective cohort. Hazard ratios (HRs) are given with 95% confidence intervals (CIs). A total of 2,011 patients treated for at least 3 months were included. A total of 647 patients had recurrent VTE/ATE (incidence: 4.69% per patient-years) during overall follow-up (median: 92 months). Of these events, 173 occurred during anticoagulation (incidence: 3.67% per patient-years). Among patients free of events at the end of anticoagulation, 801 had a post-anticoagulation follow-up ≥3 months; and 95 had recurrent VTE/ATE (incidence: 1.27% per patient-years). After adjustment for confounders, cancer-associated VTE (HR: 2.64, 95% CI: 1.70-4.11) and unprovoked VTE (HR: 1.95, 95% CI: 1.35-2.81) were the identified risk factors of recurrent VTE/ATE during anticoagulation (vs. transient risk factor-related VTE). Risk factors of recurrent VTE/ATE after anticoagulation included 50 to 65 years of age (vs. < 50, HR: 1.99, 95% CI: 1.04-3.81), older than 65 years (vs. < 50, HR: 5.28, 95% CI: 3.03-9.21), and unprovoked VTE (vs. transient risk factor-related VTE, HR: 2.06, 95% CI: 1.27-3.34). Cancer-associated VTE and unprovoked VTE are the main risk factors of recurrent VTE/ATE during anticoagulation, while older age and unprovoked VTE mainly predict the risk of these events after anticoagulation., Competing Interests: F.C. reports having received research grant support from Pfizer and fees for board memberships or symposia from Bayer and Astra Zeneca and having received travel support from Bayer, Daiichi Sankyo, Leo Pharma, InterMune, and Actelion. All other authors declare that they have no competing interests related to this study., (Thieme. All rights reserved.)

Background:  Previous studies have reported inconsistent findings regarding the association between obstructive sleep apnea (OSA) and incident venous thromboembolism (VTE). More specifically, the association between OSA and unprovoked VTE was barely evaluated. We aimed to evaluate whether apnea hypopnea index (AHI) and nocturnal hypoxemia markers were associated with unprovoked VTE incidence in patients investigated for OSA., Material and Methods:  Data from the Pays de la Loire Sleep Cohort were linked to the French health administrative data to identify incident unprovoked VTE in patients suspected for OSA and no previous VTE disease. Cox proportional hazards models were used to evaluate the association of unprovoked VTE incidence with AHI and nocturnal hypoxemia markers including the time spent under 90% of saturation (T90), oxygen desaturation index, and hypoxic burden (HB), a more specific marker of respiratory events related to hypoxia. The impact of continuous positive airway pressure (CPAP) was evaluated in the subgroup of patients who were proposed the treatment., Results:  After a median [interquartile range] follow-up of 6.3 [4.3-9.0] years, 104 of 7,355 patients developed unprovoked VTE, for an incidence rate of 10.8 per 1,000 patient-years. In a univariate analysis, T90 and HB predicted incident VTE. In the fully adjusted model, T90 was the only independent predictor (hazard ratio: 1.06; 95% confidence interval: [1.01-1.02]; p  = 0.02). The CPAP treatment has no significant impact on VTE incidence., Conclusion:  Patients with more severe nocturnal hypoxia are more likely to have incident unprovoked VTE., Competing Interests: W.T. reports support for attending meetings by ASTEN SANTE. C.G.-P. has nothing to disclose. B.H. has nothing to disclose. M.B. has nothing to disclose. N.M. reports support for attending meetings by ASTEN SANTE. M.J. has nothing to disclose. S.K. has nothing to disclose. R.L.M. received support for attending meetings by Astra Zeneca, GSK and Orkyn, and consulting fees from Astra Zeneca and GSK, outside the submitted work. E.M. has nothing to disclose. J.-L.R. has nothing to disclose. A.S. has nothing to disclose. J.T. received fees from Laboratoire Pierre Fabres, outside the submitted work. F.C. received consulting fees from Bayer, Pfizer, Astra, MSD, GSK, Leopharma, outside the submitted work. F.G. received support for attending meetings by ASTEN SANTE and ACTELION and consulting fees from NYXOAH, SEFAM, RESMED, CIDELEC, ASTEN SANTE, and BOEHRINGER INGELHEIM, outside the submitted work., (Thieme. All rights reserved.)

Identifying cold-related genes can provide insights into the cold adaptation mechanism of weeping forsythia. In this study, we compared the changes in gene expressions and physiological and biochemical indices under short-term cold stimulation with the changes in gene sequences under a long-term heterogeneous environment to investigate the cold adaptation mechanism in weeping forsythia. The data of adaptive gene sequence changes, e.g., single nucleotide polymorphisms, were obtained from previous landscape genomics studies. The physiological and biochemical indicators and transcriptome results showed that weeping forsythia initiated a series of programs, including increasing cell osmotic pressures, scavenging ROS, activating the defense mechanism that crosses with pathogen infection, and upregulating CBF/DREB1 transcription factor 1, to cope with short-term cold stress. A reanalysis of landscape genomic data suggested that weeping forsythia responded to long-term heterogeneous cold stress by the differentiation of genes related to synthesis of aromatic substances and adenosine triphosphate. Our results supported the hypothesis that the adaptation mechanisms of species to short-term environmental stimulation and long-term stress in heterogeneous environments are different. The differences in cold tolerance among populations are not necessarily obtained by changing cold-responsive gene sequences. This study provides new insights into the cold adaptation mechanisms of plants., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective:  D-dimer measurement is a safe tool to exclude pulmonary embolism (PE), but its specificity decreases in coronavirus disease 2019 (COVID-19) patients. Our aim was to derive a new algorithm with a specific D-dimer threshold for COVID-19 patients., Methods:  We conducted a French multicenter, retrospective cohort study among 774 COVID-19 patients with suspected PE. D-dimer threshold adjusted to extent of lung damage found on computed tomography (CT) was derived in a patient set ( n  = 337), and its safety assessed in an independent validation set ( n  = 337)., Results:  According to receiver operating characteristic curves, in the derivation set, D-dimer safely excluded PE, with one false negative, when using a 900 ng/mL threshold when lung damage extent was <50% and 1,700 ng/mL when lung damage extent was ≥50%. In the derivation set, the algorithm sensitivity was 98.2% (95% confidence interval [CI]: 94.7-100.0) and its specificity 28.4% (95% CI: 24.1-32.3). The negative likelihood ratio (NLR) was 0.06 (95% CI: 0.01-0.44) and the area under the curve (AUC) was 0.63 (95% CI: 0.60-0.67). In the validation set, sensitivity and specificity were 96.7% (95% CI: 88.7-99.6) and 39.2% (95% CI: 32.2-46.1), respectively. The NLR was 0.08 (95% CI; 0.02-0.33), and the AUC did not differ from that of the derivation set (0.68, 95% CI: 0.64-0.72, p  = 0.097). Using the Co-LEAD algorithm, 76 among 250 (30.4%) COVID-19 patients with suspected PE could have been managed without CT pulmonary angiography (CTPA) and 88 patients would have required two CTs., Conclusion:  The Co-LEAD algorithm could safely exclude PE, and could reduce the use of CTPA in COVID-19 patients. Further prospective studies need to validate this strategy., Competing Interests: T.M. reports personal fees and nonfinancial support from Bayer Healthcare SAS, personal fees and nonfinancial support from Incyte Biosciences, France, nonfinancial support from Alexion Pharma, France, nonfinancial support from Abbott, France, nonfinancial support from Amgen SAS, nonfinancial support from Boehringer Ingelheim, France, nonfinancial support from Bristol-Myers Squibb, no-financial support from MSD France, outside the submitted work; F.C. reports grants from Pfizer, personal fees from Bayer, other from Boehringer; grants, personal fees, and other from BMS; personal fees and other from Astra-Zeneca, other from GSK, personal fees from LEO-Pharma, other from Actelion, outside the submitted work; S.S. reports grants from LEO-Pharma, personal fees from Bayer, personal fees from BMS Pfizer, outside the submitted work; N.G. reports personal fees and nonfinancial support from Boehringer Ingelheim, personal fees and nonfinancial support from Bayer, personal fees from Bristol-Myers Squibb/Pfizer, personal fees from LEO-Pharma, personal fees from Aspen, outside the submitted work; O.S. reports grants, personal fees, and nonfinancial support from Bayer; grants, personal fees, and nonfinancial support from BMS; personal fees and nonfinancial support from Sanofi Aventis; personal fees and nonfinancial support from Boston Scientifics; personal fees from Pfizer; grants, personal fees, and nonfinancial support from MSD; grants and personal fees from Boehringer Ingelheim; grants from Daiichi Sankyo; personal fees from Chiesi; personal fees and nonfinancial support from BTG, outside the submitted work; L.K. reports personal fees from Bristol-Myers Squibb/Pfizer, outside the submitted work; M.A.S. reports personal fees and nonfinancial support from Bristol-Myers Squibb/Pfizer, personal fees and nonfinancial support from Bayer SA, grants, personal fees, and nonfinancial support from Leo-Pharma, personal fees from Aspen, outside the submitted work; R.C. reports personal fees from Aspen, outside the submitted work; D.M.S. reports grants from Boehringer Ingelheim, personal fees from Bayer, personal fees from Bristol-Myers Squibb/Pfizer, personal fees from Leo-Pharma, personal fees from Aspen, personal fees from Carmat, outside the submitted work; E.M. reports personal fees and nonfinancial support from Bayer, personal fees from Bristol-Myers Squibb/Pfizer, personal fees from Novartis, outside the submitted work; . N.M. reports grants and personal fees from Bayer Healthcare, grants and personal fees from BMS Pfizer, personal fees from Astra-Zeneca, personal fees from Terumo, grants and personal fees from Abbott, outside the submitted work; L.F. reports personal fees from Janssen, personal fees from Sanofi, personal fees from General Electrics, nonfinancial support from Guerbet, grants from Invectys, nonfinancial support from Philips, nonfinancial support from Ariana Pharma, nonfinancial support from Evolucare, outside the submitted work. All the other authors have nothing to declare., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background:  Cardiovascular deaths (CVDTs) are more frequent in patients with venous thromboembolism (VTE) than in the general population; however, risk factors associated with this increased risk of CVDT in patients with VTE are not described., Methods:  To determine the risk factors of CVDT in patients with VTE from a multicenter prospective cohort study, Fine and Gray subdistribution hazard models were conducted., Results:  Of the 3,988 included patients, 426 (10.7%) died of CVDT during a median follow-up of 5 years. The risk factors of CVDT after multivariate analyses were: age of 50 to 65 years (vs. <50 years, hazard ratio [HR]: 3.22, 95% confidence interval [CI]: 1.67-6.62), age >65 years (vs. <50 years, HR: 7.60, 95% CI: 3.73-15.52), cancer-associated VTE (vs. transient risk factor-related VTE, HR: 1.73, 95% CI: 1.15-2.61), unprovoked VTE (vs. transient risk factor-related VTE, HR: 1.42, 95% CI: 1.02-2.00), past tobacco use (vs. never, HR: 1.43, 95% CI: 1.06-1.94), current tobacco use (vs. never, HR: 1.87, 95% CI: 1.15-3.01), hypertension (HR: 2.11, 95% CI: 1.51-2.96), chronic heart failure (HR: 2.28, 95% CI: 1.37-3.79), chronic respiratory failure (HR: 1.72, 95% CI: 1.02-2.89), and atrial fibrillation (HR: 1.67, 95% CI: 1.06-2.60). The risk of CVDT was significantly reduced with direct oral anticoagulants (vs. vitamin-K antagonists) and with longer duration of treatment (>3 months)., Conclusion:  Risk factors of CVDT after VTE include some traditional cardiovascular risk factors and other risk factors that are related to characteristics of VTE, and patients' comorbidities., Competing Interests: F.C. reports having received research grant support from Pfizer and fees for board memberships or symposia from Bayer and Astra-Zeneca and having received travel support from Bayer, Daiichi Sankyo, Leo Pharma, InterMune, and Actelion. All other authors declare that they have no competing interests related to this study., (Thieme. All rights reserved.)

Background:  There is an increased risk of arterial events including major adverse cardiovascular events (MACE) and major adverse limb events (MALE) after venous thromboembolism (VTE). However, their risk factors remain little explored., Methods:  We aimed to determine the risk factors for MACE (acute coronary syndrome/stroke/cardiovascular death) and MALE (limb ischemia/critical limb ischemia/non-traumatic amputation/any limb revascularization) after VTE. Competing risk models (Fine-Gray) were used in a multicenter prospective cohort of 4,940 patients (mean age: 64.6 years and median follow-up: 64 months)., Results:  MACE occurred in 17.3% of participants (2.35% per patient-years) and MALE in 1.7% (0.27% per patient-years). In multivariable analysis, the identified risk factors for MACE were the age of 50 to 65 years (vs. <50 years, hazard ratio [HR]: 2.00, 95% confidence interval [CI]: 1.38-2.91), age >65 years (vs. <50 years, HR 4.85, 95% CI: 3.35-7.02), pulmonary embolism + deep vein thrombosis (DVT) (vs. isolated-DVT, HR: 1.25, 95% CI: 1.02-1.55), unprovoked-VTE (vs. transient risk factor associated-VTE, HR: 1.29, 95% CI: 1.04-1.59), current tobacco use (vs. never, HR: 1.45, 95% CI: 1.07-1.98), hypertension (HR: 1.61, 95% CI: 1.30-1.98), past history of symptomatic atherosclerosis (HR: 1.52, 95% CI: 1.17-1.98), heart failure (HR: 1.71, 95% CI: 1.21-2.42), atrial fibrillation (HR: 1.55, 95% CI: 1.15-2.08), and vena cava filter insertion (HR: 1.46, 95% CI: 1.03-2.08). The identified risk factors for MALE were the age of 50-65 years (vs. <50 years, HR: 3.49, 95% CI: 1.26-9.65) and atrial fibrillation (HR: 2.37, 95% CI: 1.15-4.89)., Conclusions:  Risk factors for MACE and MALE after VTE included some traditional cardiovascular risk factors, patient's comorbidities, and some characteristics of VTE., Competing Interests: None declared., (Thieme. All rights reserved.)

Alzheimer's disease (AD) is a chronic neurodegenerative disease that mainly causes dementia. It is a serious threat to the health of the global elderly population. Considerable money and effort has been invested in the development of drug therapy for AD worldwide. Many drug therapies are currently under development or in clinical trials, based on two known mechanisms of AD, namely, Aβ toxicity and the abnormal Tau hyperphosphorylation. Numerous drugs are also being developed for other AD associated mechanisms such as neuroinflammation, neurotransmitter imbalance, oxidative damage and mitochondrial dysfunction, neuron loss and degeneration. Even so, the number of drugs that can successfully improve symptoms or delay the progression of the disease remains very limited. However, multi-drug combinations may provide a new avenue for drug therapy for AD. In addition, early diagnosis of AD and timely initiation of treatment may allow drugs that act on the early pathological processes of AD to help improve the symptoms and prevent the progression of the condition.

Background: Mounting evidence, consistent with our previous study, showed that γ-aminobutyric acid type A receptor (GABAAR) played an indispensable role in airway inflammation and mucus hypersecretion in asthma. Monocyte chemotactic protein-inducing protein 1 (MCPIP1) was a key negative regulator of inflammation. Recent studies showed that inflammation was largely suppressed by enhanced MCPIP1 expression in many inflammatory diseases. However, the role and potential mechanism of MCPIP1 in airway inflammation and mucus hypersecretion in asthma were still not well studied. This study was to explore the role of MCPIP1 in asthmatic airway inflammation and mucus hypersecretion in both mice and BEAS-2B cells, and its potential mechanism., Methods: In vivo, mice were sensitized and challenged by ovalbumin (OVA) to induce asthma. Airway inflammation and mucus secretion were analyzed. In vitro, BEAS-2B cells were chosen. Interleukin (IL)-13 was used to stimulate inflammation and mucus hypersecretion in cells. MCPIP1 Lentiviral vector (LA-MCPIP1) and plasmid-MCPIP1 were used to up-regulate MCPIP1 in lung and cells, respectively. MCP-1, thymic stromal lymphopoietin (TSLP), mucin 5AC (MUC5AC), MCPIP1, and GABAARβ2 expressions were measured in both lung and BEAS-2B cells. Immunofluorescence staining was performed to observe the expression of GABAARβ2 in cells., Results: MCPIP1 was up-regulated by LA-MCPIP1 (P < 0.001) and plasmid-MCPIP1 (P < 0.001) in lung and cells, respectively. OVA-induced airway inflammation and mucus hypersecretion, OVA-enhanced MCP-1, TSLP, MUC5AC, and GABAARβ2 expressions, and OVA-reduced MCPIP1 were significantly blunted by LA-MCPIP1 in mice (all P < 0.001). IL-13-enhanced MCP-1, TSLP, MUC5AC, and GABAARβ2 expressions, and IL-13-reduced MCPIP1 were markedly abrogated by plasmid-MCPIP1 in BEAS-2B cells (all P < 0.001)., Conclusion: The results of this study suggested that OVA and IL-13-induced airway inflammation and mucus hypersecretion were negatively regulated by MCPIP1 in both lung and BEAS-2B cells, involving GABAAR signaling pathway., (Copyright © 2020 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Patients with two unprovoked venous thromboembolism (VTE) events could be at high risk for cancer diagnosis and may therefore benefit from extended cancer screening strategies. However, accurate data on the incidence of cancer in this population is lacking. In a prospective cohort study, we followed-up with all patients who experienced two unprovoked symptomatic VTE events that occurred in less than 2 years apart. We estimated the 1-year incidence rate of cancer following the second unprovoked VTE event using the Kaplan-Meier method. Potential predictors for cancer diagnosis were assessed using a Cox proportional hazard regression model. Between May 2000 and December 2013, we included 197 patients with two episodes of symptomatic unprovoked VTE that occurred in less than 2 years apart. Their mean age was 66.2 ± 16.3 years, and 122 (51.8%) were male. Seventeen patients were diagnosed with cancer during the year following the second episode of unprovoked VTE, corresponding to a cumulative incidence rate of 9.19% (95% confidence interval [CI]: 5.81-14.37). The 1-year cumulative incidence rate of cancer was 35.88% (95% CI: 19.75-59.25) in patients with VTE recurrence on anticoagulation, 5.51% (95% CI: 2.9-10.32) among patients with a second episode of unprovoked VTE occurring after stopping anticoagulation and 1.15% (95% CI: 0.16-7.88) when time elapsed between the first and recurrent VTE was > 1 year. Our study suggests that the incidence of cancer in patients with a second episode of unprovoked VTE that occurs off anticoagulation, or > 1 year after the first event, is similar to that of patients with a first unprovoked VTE event., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Landscape genomics is a relatively new discipline that aims to reveal the relationship between adaptive genetic imprints in genomes and environmental heterogeneity among natural populations. Although the interest in landscape genomics has increased since this term was coined, studies on this topic remain scarce. Landscape genomics has become a powerful method to scan and determine the genes responsible for the complex adaptive evolution of species at population (mostly) and individual (more rarely) level. This review outlines the sampling strategies, molecular marker types and research categories in 37 articles published during the first 10 years of this field (i.e., 2007-2016). We also address major challenges and future directions for landscape genomics. This review aims to promote interest in conducting additional studies in landscape genomics.

Background: The adaptive evolution of species response to environment are the key issues in molecular ecology and evolutionary biology. The direction of adaptive differentiation of species in regions lacking strong selection pressure is usually diverse. However, the driving mechanism of the diverse adaptive differentiation for regional species is still undetermined to date. In this study, we used landscape genomics modelling to infer the adaptive evolution of Cotinus coggygria in China's warm-temperate zone., Results: Using fifteen natural populations and nine start codon targeted (SCoT) markers, a total of 1131 unambiguous loci were yielded. Our results showed two genetic groups existed in the fifteen natural populations of C. coggygria, which is due to the divergent selection driven by six environmental factors. Environmental association analyses revealed the environmental variables related to precipitation were associated with high numbers of environment-associated loci., Conclusions: Our results indicated that the ecological characters of C. coggygria, i.e. avoiding wetness and tolerating drought, determine its adaptive evolution. This study provides a reference that ecological character determines the adaptive evolution of species in regions lacking strong selection pressure.

Understanding the genetic mechanisms of adaptation to environmental variables is a key concern in molecular ecology and evolutionary biology. Determining the adaptive evolutionary direction and evaluating the adaptation status of species can improve our understanding of these mechanisms. In this study, we sampled 20 populations of Forsythia suspensa to infer the relationship between environmental variables and adaptive genetic variations. Population structure analysis revealed that four genetic groups of F. suspensa exist resulting from divergent selection driven by seven environmental variables. A total of 26 outlier loci were identified by both BayeScan and FDIST2, 23 of which were environment-associated loci (EAL). Environmental association analysis revealed that the environmental variables related to the ecological habitats of F. suspensa are associated with high numbers of EAL. Results of EAL characterization in F. suspensa are consistent with the hypothesis that ecological habitats determine the adaptive evolution of this species. Moreover, a model of species adaptation to environmental variables was proposed in this study. The adaptation model was used to further evaluate the adaptation status of F. suspensa to environmental variables. This study will be useful to help us in understanding the adaptive evolution of species in regions lacking strong selection pressure.

Deep phylogenetic relationships of the largest salamander family Plethodontidae have been difficult to resolve, probably reflecting a rapid diversification early in their evolutionary history. Here, data from 50 independent nuclear markers (total 48,582 bp) are used to reconstruct the phylogeny and divergence times for plethodontid salamanders, using both concatenation and coalescence-based species tree analyses. Our results robustly resolve the position of the enigmatic eastern North American four-toed salamander (Hemidactylium) as the sister taxon of Batrachoseps + Tribe Bolitoglossini, thus settling a long-standing question. Furthermore, we statistically reject sister taxon status of Karsenia and Hydromantes, the only plethodontids to occur outside the Americas, leading us to new biogeographic hypotheses. Contrary to previous long-standing arguments that plethodontid salamanders are an old lineage originating in the Cretaceous (more than 90 Ma), our analyses lead to the hypothesis that these salamanders are much younger, arising close to the K-T boundary (~66 Ma). These time estimates are highly stable using alternative calibration schemes and dating methods. Our data simulation highlights the potential risk of making strong arguments about phylogenetic timing based on inferences from a handful of nuclear genes, a common practice. Based on the newly obtained timetree and ancestral area reconstruction results, we argue that (i) the classic "Out of Appalachia" hypothesis of plethodontid origins is problematic; (ii) the common ancestor of extant plethodontids may have originated in northwestern North America in the early Paleocene; (iii) origins of Eurasian plethodontids likely result from two separate dispersal events from western North America via Beringia in the late Eocene (~42 Ma) and the early Miocene (~23 Ma), respectively., (© The Author(s) 2015. Published by Oxford University Press, on behalf of the Society of Systematic Biologists. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Although several recent studies have investigated the major phylogenetic relationships within Hynobiidae, their evolutionary history remains partially resolved and the phylogenetic positions of some genera, particularly Pachyhynobius and Salamandrella are still disputed. Notably, previous studies relied primarily on mitochondrial DNA data and concatenated analyses; thus, a new investigation based on multiple nuclear genes and species-tree inference is needed. Here, we provide an in-depth phylogenetic analysis, based on 29 nuclear genes comprising 29,232bp of data from a comprehensive taxonomic sampling (24 hynobiids and 7 outgroups), using both concatenated and species-tree methods. Our results robustly resolved most genus-level relationships within Hynobiidae, including the placement of Salamandrella as the sister group to a clade containing Batrachuperus, Liua and Pseudohynobius, and the placement of Pachyhynobius as the sister group to a clade containing all hynobiids excluding Onychodactylus, Paradactylodon and Ranodon. Time estimates based on our data suggest that the major group of living hynobiids (excluding Onychodactylus) originated approximately 40Ma, ∼50% younger than estimates from mtDNA data (62.5Ma) but 10% older than estimates from three nuclear genes (36Ma). Our results highlight the benefits of using a large number of nuclear loci to infer both phylogeny and time for relatively old lineages., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Anura (frogs and toads) constitute over 88% of living amphibian diversity but many important questions about their phylogeny and evolution remain unresolved. For this study, we developed an efficient method for sequencing anuran mitochondrial DNAs (mtDNAs) by amplifying the mitochondrial genome in 12 overlapping fragments using frog-specific universal primer sets. Based on this method, we generated 47 nearly complete, new anuran mitochondrial genomes and discovered nine novel gene arrangements. By combining the new data and published anuran mitochondrial genomes, we assembled a large mitogenomic data set (11,007 nt) including 90 frog species, representing 39 of 53 recognized anuran families, to investigate their phylogenetic relationships and evolutionary history. The resulting tree strongly supported a paraphyletic arrangement of archaeobatrachian (=nonneobatrachian) frogs, with Leiopelmatoidea branching first, followed by Discoglossoidea, Pipoidea, and Pelobatoidea. Within Neobatrachia, the South African Heleophrynidae is the sister-taxon to all other neobatrachian frogs and the Seychelles-endemic Sooglossidae is recovered as the sister-taxon to Ranoidea. These phylogenetic relationships agree with many nuclear gene studies. The chronogram derived from two Bayesian relaxed clock methods (MultiDivTime and BEAST) suggests that modern frogs (Anura) originated in the early Triassic about 244 Ma and the appearance of Neobatrachia took place in the late Jurassic about 163 Ma. The initial diversifications of two species-rich superfamilies Hyloidea and Ranoidea commenced 110 and 133 Ma, respectively. These times are older than some other estimates by approximately 30-40 My. Compared with nuclear data, mtDNA produces compatible time estimates for deep nodes (>150 Ma), but apparently older estimates for more shallow nodes. Our study shows that, although it evolves relatively rapidly and behaves much as a single locus, mtDNA performs well for both phylogenetic and divergence time inferences and will provide important reference hypotheses for the phylogeny and evolution of frogs.

The petrous apex is a complex area surrounded by the cavernous sinus, Dorello's canal and Meckel's cave. The petrosphenoidal ligament (PSL) and the petrolingual ligament (PLL) are important structures located in the region. These two ligaments were examined under a surgical microscope in 10 specimens of five adult cadaveric heads fixed in formalin. They were found to span from the petrous apex to the posterior clinoid process, and the lingula of the sphenoid bone, respectively. The dural sleeve of the abducens nerve, the dorsal meningeal artery or its medial branch, and the venous blood space were located below the PSL in all specimens, and the petrous or sphenoidal insertion of the PSL varied in five specimens. The PLL invariably surrounded part of the dorsal and lateral walls of the lacerum segment of the internal carotid artery (ICA), just under the anteroinferior portion of the anteromedial wall of Meckel's cave in all specimens. The PSL and PLL are valuable anatomical landmarks for identifying the ICA and the nerves in this region. A thorough understanding of the relationship of the two ligaments with neurovascular structures is a prerequisite for surgery in and around the petrous apex., ((c) 2009 Wiley-Liss, Inc.)

Background: Brain stem tumors in adults are infrequent. Most reports of surgical treatment for these tumors involve partial tumor removal in highly selected patients. A more aggressive approach for removing tumors, especially solid and intrinsic ones, has been controversial., Methods: Twenty-two adult patients with brain stem tumors were surgically treated. Surgical techniques, potential risks, and selection of appropriate treatment were evaluated., Results: Tumors were totally or subtotally removed in 20 patients and only partially removed in two patients. Serious complications such as respiratory disturbances and circulatory dysfunction occurred in 10 patients. Eight patients with these complications recovered after appropriate treatments. Upon discharge, most signs and symptoms improved in 17 patients., Conclusion: Most brain stem tumors, except for malignant gliomas and small ventral tumors, are amenable to an aggressive surgical approach. Exophytic medullary tumors that present dorsally comprise the most benign subgroup of brain stem tumors. Total removal can enhance survival, improve the patient's quality of life, and offer a favorable long-term prognosis. Appropriate management of postoperative complications is essential for good results.

Background: Intramedullary tumors of the cervical spinal cord are common and many believe they are amenable to an aggressive approach. However, surgical removal of intramedullary tumors of the cervical spinal cord is still controversial because of the great risk of respiratory dysfunction or quadriplegia or both upon resection of the tumor., Methods: We present a consecutive series of 58 patients who underwent surgical treatment for intramedullary tumors of the cervical spinal cord. Surgical results are analyzed to refine our indications for surgery and its timing. The roles of preoperative radiotherapy and posttherapeutic cord appearance and function are discussed., Results: Tumors were totally resected in 50 (86.2%), subtotally in seven and partially in one patient. Forty-five (77.6%) patients had improved neurologic status postoperatively. Intramedullary tumors in the cervical area have better results from surgery than intramedullary tumors in other levels of the spine. Patients with moderate neurologic deficits can recover remarkably well after total tumor removal. Laser surgery is especially helpful for lipoma. Preoperative radiotherapy should be avoided because it is associated with difficult surgery and poor clinical outcome. The thin spinal cord can function surprisingly well., Conclusions: We conclude that intramedullary tumors of the cervical spinal cord are amenable to total surgical removal. Surgery is suitable when a patient presents with a moderate neurologic deficit. Proficient surgical technique for total tumor resection is necessary for good results. Preoperative radiotherapy contributes to difficult surgery and poor prognosis, and is not recommended.

Thirteen cases of intramedullary hemangioblastoma of the spinal cord are reported. The tumors were diagnosed with radiological studies, especially magnetic resonance imaging. Microsurgery was used to achieve gross total removal of the tumors in all cases. Signs and symptoms improved in 84.6% of the patients after surgery. The authors describe the diagnosis and microsurgical techniques for the excision of intramedullary hemangioblastoma of the spinal cord. This disease should be differentiated from hydromyelia, intramedullary ependymoma, and vascular malformation of the spinal cord. Total removal of the tumor is recommended.