Rationale, aims and objectives :Over the past decades, thrombophilia testing in patients with venous thrombo-embolism (VTE) has increased tremendously. However, the role of inherited thrombophilia (IT) in prediction the risk of recurrence remains controversial. Consequently, it is still unclear whether thrombophilia testing influences decisions regarding duration of anticoagulation in clinical practices. The aim of this study was to evaluate the impact if IT on VTE treatment decisions and on predicting the risk of recurrence. Methods : A retrospective longitudinal study (January 2011-Decembre 2016) including 190 patients with confirmed VTE referred from internal medicine department for inherited thrombophilia screening was carried out. Results : The mean age patients was 40.2 years and the sex ratio (M/F) was 0.78. IT was confirmed in 27.5% of patients. A long term anticoagulation was decided in 51.6% of patients with IT. There was no significant difference in the duration of anticoagulation between patients with or without IT. VTE recurrence was recorded in 26 (13.7 %) patients. The 24 years cumulative incidence of recurrence was 9% in patients with IT and 14% in those without. IT was not associated with increased risk of recurrence after treatment withdrawal (Hazard ratio=1.31 IC(0.47-3.63); p=0.6). Conclusion : In clinical practice, IT did not influence anticoagulation duration and was not associated with a higher VTE risk of recurrence. It seems to be less relevant for decision making than presumed.

Reviewers: Matthew Helm1 and Morgan E. Carter21.    USDA-ARS, Crop Protection and Pest Control Research Unit, West Lafayette, IN2.    Plant Pathology and Plant-Microbe Biology Section, School of Integrative Plant Science, Cornell University, Ithaca, NY SummaryThis is a review of Mazo-Molina and Mainiero, et al. bioRxiv (doi: https://doi.org/10.1101/2020.03.05.979484) posted on March 5, 2020. This study builds upon previous work that described the serendipitous discovery of a locus in the distantly related relative of tomato Solanum lycopersicoides, known as Pseudomonas tomato race 1 (Ptr1) (Mazo-Molina et al., (2019). Mazo-Molina and colleagues (2019) previously showed the Ptr1 locus confers resistance to several Pseudomonas syringae pv. tomato race 1 strains, but not the race 0 strain DC3000. Comparative genomic analysis of the effector repertoire between a race 1 strain of P. syringae pv. tomato, T1, and DC3000 identified AvrRpt2 as the cognate effector recognized by the Ptr1 locus. In Arabidopsis, AvrRpt2 is a cysteine protease that cleaves RIN4 and, upon cleavage, leads to activation of the Arabidopsis NLR protein RPS2. In this paper, Mazo-Molina and Mainiero et al. describe the identification and functional characterization of the Ptr1 gene. A single recombinant among 585 F2 S. lycopersicoides individuals segregating for the Ptr1 locus was identified that narrowed the Ptr1 candidate to eight NLR genes. By employing currently available gene models for S. lycopersicoides and 3’ RNA-seq data, Mazo-Molina and Mainiero et al. narrowed the list of Ptr1 candidates to three genes; A, B, and D. Candidate D was shown to be a pseudogene as it contained multiple mutations that disrupted the reading frame and was, therefore, not included in their functional analyses. Co-expression of candidate A with either AvrRpt2 or RipBN in N. glutinosa induced an HR-like cell death response. Candidate B, however, did not induce cell death by itself or when co-expressed with either AvrRpt2 or RipBN, and was thus not considered to be the Ptr1 gene. Taken together these experiments demonstrated that candidate A is the Ptr1 gene. Moreover, they show Ptr1 is conserved in many species within the Solanaceae family and that the Ptr1 ortholog from N. benthamiana and potato also mediate recognition of AvrRpt2 and RipBN. Lastly, phylogenetic analyses indicate that Ptr1, RPS2, and Mr5 (an NLR gene from apple whose protein product recognizes AvrRpt2) are not orthologous. The authors thus conclude the ability to recognize AvrRpt2 protease activity evolved convergently. CommentsResults section – LA4277 genome. In the first paragraph of the results section, the authors discuss NLR-encoding genes in the S. lycopersicoides genome sequence as well as in LA4277-R. Later, it was mentioned that the LA4277 genome was assembled as part of this paper. We suggest clarifying at the first introduction of the LA4277 genome features that this genome was sequenced in this study, for readers unfamiliar with available genomes. Results section—cell death assays. To test whether AvrRpt2 causes degradation of SlRin4 proteins resulting in activation of candidate A, the authors carried out cell death assays (Figure 2) by transiently co-expressing candidate A along with SlRin4-3 and AvrRpt2 or RipBN in N. glutinosa. However, in Figure 2A, they show transient co-expression of candidate A with either AvrRpt2 or RipBN is sufficient to induce an HR like cell death response, suggesting candidate A is guarding an endogenous RIN4-like protein in N. glutinosa. Did the authors try silencing the endogenous RIN4 protein in N. glutinosa and then co-express AvrRpt2/RipBN, candidate A, and SlRin4-3 to test whether SlRin4-3 has a role in AvrRpt2 recognition?  We would also suggest performing an electrolyte leakage assay to quantify the cell death responses in Figure 2C. Results section—Figure 2C. In the experiment depicted in Figure 2C, what was the rationale behind including only SlRin4-3 and not the other additional Rin4 proteins? Candidate B. Based on the immunoblot analysis in supplemental figure S2, candidate B protein expression is considerably weaker than that of candidate A protein expression (Figure 2D). Could it be a formal possibility that candidate B recognizes AvrRpt2 and RipBN, but because of the weak protein accumulation, there is no observable cell death in N. glutinosa? Discussion section.  As part of a very thorough discussion section, the second paragraph on page 10 covering RIN4 structure did not seem as relevant to the findings in this paper, as detailed analysis of Ptr1 detection of RIN4 cleavage was not experimentally investigated.

In this article, we provide advice and insights, based on our own experiences, for computational chemists who are beginning new tenure-track positions at primarily undergraduate institutions. We each followed different routes to obtain our tenure-track positions, but we all experienced similar challenges when getting started in our new position. In this article, we discuss our approaches to seven areas that we all found important for engaging undergraduate students in our computational chemistry research, including setting up computational resources, recruiting research students, training research students, designing student projects, managing the lab, mentoring students, and student conference participation. KEYWORDS — undergraduate research, computational chemistry, primarily undergraduate institution, tenure-track position, career pathways

Dear Editor,At 29th of February the World Health Organization (WHO) reported 85403 confirmed globally confirmed case of COVID-19 [1]. COVID-19 is dramatically increasing in Italy, the last report from the ministry of health on the 9th of march reported the presence of 9172 confirmed cases and 733 patients in intensive care unit (ICU) [2]. We agree with Chan et al that physicians managing airway procedures are at particularly high risk to contract the COVID-19 infection [3]. We support the authors that claimed for a full protective wearing including N95 respirator, gown, cap, eye protection, and gloves, during aerosol generating procedures (AGP) [3]. However, we’d like to focus the attention on the tracheostomy procedures in COVID-19 patients since otolaryngologists, anesthesiologists and intensive care physicians are at high risk of contracting the infection during tracheostomy [3]. Tracheostomy is required in case of prolonged mechanical ventilation and intensive care unit (ICU) stay [4]. Surgical tracheostomy is an AGP associated with an increased risk severe acute respiratory distress (SARS) infection [5]. Strict adherence to infection control guidelines in SARS is mandatory in performing tracheostomy in ICU or operating room [6].Few years ago, we proposed the double lumen endotracheal tube (DLET) for percutaneous tracheostomy in critically ill patients [7]. DLET was equipped with an upper channel that allows passage of a bronchoscope during the percutaneous tracheostomy and with a lower channel exclusively dedicated to patient ventilation [7]. The lower channel is equipped with a distal cuff positioned just above the carina that may allow a safe mechanical ventilation by keeping stable gas-exchange and limiting the spread of aerosol during the procedure [7]. During the percutaneous procedure, the puncture of the anterior tracheal wall, Seldinger insertion, dilatation, and cannula positioning were all performed with the DLET correctly placed in the trachea. The DLET was removed at the end of the tracheostomy when the cannula is inserted and correctly positioned with the FFB [7].Surgical tracheostomy in COVID-19 patients should be done with a close collaboration between otolaryngologists, preforming the surgical procedure, and anesthesiologists or intensive care physicians managing the general anesthesia and the airway.When a surgical tracheostomy is done under general anesthesia, just before the surgeon makes the tracheal stoma, the endotracheal tube is withdrawn, so that the cuff of the tube is not in the surgical field [8]. But when the surgeon makes the tracheal incision, ventilation is lost and the surgeon has to be quick enough to create the soma and insert the tracheostomy tube in a short time [8]. During this procedure a large spread of aerosol may occur. To avoid the aerosol, we suggest to push down the endotracheal tube beyond the site chosen for the tracheal stoma at the beginning of the procedure. The endotracheal tube should reach the tracheal carina so the cuff is surely distal to the tracheostomy site. By checking the airway pressure and the end-tidal CO2, on the mechanical ventilator we can realize if the endotracheal tube is still in the lower tract of the trachea or in the endobronchial tract. Our previous experience with the DLET demonstrated that the endotracheal tube and the tracheal cannula can be simultaneously inserted inside the trachea [7]. According to this, pushing down the endotracheal tube and cuffed it at the level of the carina may avoid the spread of aerosol and, then, may add an extra security for the medical staff during a procedure at high risk of generating aerosol.ReferencesCoronavirus disease 2019 (COVID-19) Situation Report – 40.https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200229-sitrep-40-covid-19.pdfItalian Minister of Health. COVID-19 Italian cases.http://www.salute.gov.it/portale/nuovocoronavirus/dettaglioContenutiNuovoCoronavirus.jsp?lingua=italiano&id=5351&area=nuovoCoronavirus&menu=vuotoChan YJK, Wong EWY, Lam W. Practical Aspects of Otolaryngologic Clinical Services During the 2019 Novel Coronavirus EpidemicAn Experience in Hong Kong. JAMA Otolaryngol Head Neck Surg. Published online March 20, 2020. doi:10.1001/jamaoto.2020.0488Vargas M, Sutherasan Y, Antonelli M, Brunetti I, Corcione A, Laffey JG, et al. Tracheostomy procedures in the intensive care unit: an international survey. Critical Care 2015;19:291-301Tran K, Cimon K, Severn M et al. Aerosol Generating Procedures and Risk of Transmission of Acute Respiratory Infections to Healthcare Workers: A Systematic Review. . PLoS ONE 2012; 7(4): e35797. doi:10.1371/journal.pone.0035797Chun-Wing A, Yin -Chun L, Kit-Ying L. Management of Critically Ill Patients with Severe Acute Respiratory Syndrome (SARS). Int. J. Med. Sci. 2004 1(1): 1-10Vargas M, Servillo G, Tessitore G, Aloj F, Brunetti I, Arditi E, et al. Percutaneous dilatational tracheostomy with a double-lumen endotracheal tube. A Comparison of Feasibility, Gas Exchange, and Airway Pressures. Chest 2015; 147:1267-74Walts PA, Sudish CM, DeCamp MM. Techniques of surgical tracheostomy. Clin Chest Med 24 (2003) 413 – 422

Background: The Coronavirus disease – 2019 (COVID-19) pandemic is a global health crisis and Otolaryngologists are at increased occupational risk of contracting COVID-19. There are currently no uniform best-practice recommendations for Otolaryngologic surgery in the setting of COVID-19.Methods: We reviewed relevant publications and position statements regarding the management of Otolaryngology patients in the setting of COVID-19. Recommendations regarding clinical practice during the Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) outbreaks were also reviewed.Results: Enhanced personal protective equipment (N95 respirator and face shield or powered air-purifying respirator, disposable cap and gown, gloves) is required for any Otolaryngology patient with unknown, suspected, or positive COVID-19 status. Elective procedures should be postponed indefinitely, and clinical practice should be limited to patients with urgent or emergent needs. Conclusion: We summarize current best-practice recommendations for Otolaryngologists to ensure safety for themselves, their clinical staff, and their patients.

The 2019 novel coronavirus disease (COVID-19) is a highly contagious zoonosis produced by SARS-CoV-2 that is spread human-to-human by respiratory secretions. It was declared by the WHO as a public health emergency. The most susceptible populations, needing mechanical ventilation, are the elderly and people with associated comorbidities.There is an important risk of contagion for anesthetists, dentists, head and neck surgeons, maxillofacial surgeons, ophthalmologists and otolaryngologists.  Health workers represent between 3.8% to 20% of the infected population; some 15% will develop severe complaints and among them, many will lose their lives. A large number of patients do not have overt signs and symptoms (fever/respiratory), yet pose a real risk to surgeons (who should know this fact and must therefore apply respiratory protective strategies for all patients they encounter).All interventions that have the potential to aerosolize aerodigestive secretions should be avoided or used only when mandatory. Health workers who are: pregnant, over 55-65 years of age, with a history of chronic diseases (uncontrolled hypertension, diabetes mellitus, chronic obstructive pulmonary diseases and all clinical scenarios where immunosuppression is feasible, including that induced to treat chronic inflammatory conditions and organ transplants) should avoid the clinical attention of a potentially infected patient. Healthcare facilities should prioritize urgent and emergency visits and procedures until the present condition stabilizes; truly elective care should cease and discussed on a case-by-case basis for cancer patients.For those who are working with COVID-19 infected patients’ isolation is compulsory in the following settings: a) unprotected close contact with COVID-19 pneumonia patients: b) onset of fever, cough, shortness of breath and other symptoms (gastrointestinal complaints, anosmia and dysgeusia have been reported in a minority of cases).For any care or intervention in the upper aerodigestive tract region, irrespective of the setting and a confirmed diagnosis (e.g.; rhinoscopy or flexible laryngoscopy in the outpatient setting and tracheostomy or rigid endoscopy under anesthesia) it is strongly recommended that all healthcare personnel wear personal protective equipment (PPE) such as N95, gown, cap, eye protection and gloves.The procedures described are essential in trying to maintain safety of healthcare workers during COVID-19 pandemic. In particular, otolaryngologists, head and neck, and maxillofacial surgeons are per se exposed to the greatest risk of infection while caring for COVID-19 positive subjects, and their protection should be considered a priority in the present circumstances.

Intravenous immunoglobulin (IVIGs) preparations, which are used in the treatment of many immune-based diseases, also have an important place in hematology practice. It is an important treatment option with many different immunoregulatory roles. There is a limitation of its use on adult patients due to the lack of retrospective data. In our study, the retrospective usage indications, responses and rates of IVIG preparations evaluated in our Hematology Clinic and used in various indications between January 2010 and January 2020 were attempted to be put forth. Our targets for treatment responses were as follows: For immune thrombocytopenia, the platelet count target was 30000 x 103/µL and above; no hospitalization need for secondary hypogammaglobulinemia; no replacement need for hemolytic anemia after IVIG and a hemoglobin level above 8 g/dl. When 166 patients were examined in total, 66 were diagnosed with immune thrombocytopenic purpura (ITP) (39.8%) . There were emergency indications for all patients with thrombocytopenia before getting a primary diagnosis. The number of patients who used IVIG before getting a primary diagnosis was 79 (47.6%), 41 of whom (51.9%) were diagnosed with immune thrombocytopenic purpura in follow up. The expected response was 36.1% with 60 patients within the entire patient group. With further examination performed after emergency usage, the diagnoses received by the patients were revealed. The response was 58.5% with 24 patients in whom IVIG was used under emergency conditions and deep thrombocytopenia before getting a primary diagnosis and were diagnosed with ITP after further examinations

Siberian larch (Larix Mill.) forests dominate vast areas of northern Russia and contribute important ecosystem services to the world. It is important to understand the past dynamics of larches, in order to predict their likely response to a changing climate in the future. Sedimentary ancient DNA extracted from lake sediment cores can serve as archives to study past vegetation. However, the traditional method of studying sedimentary ancient DNA – metabarcoding – focuses on small fragments which cannot resolve Larix to species level nor allow the detailed study of population dynamics. Here we use shotgun sequencing and hybridization capture with long-range PCR-generated baits covering the complete Larix chloroplast genome to study Larix populations from a sediment core reaching back up to 6700 years in age from the Taymyr region in northern Siberia. In comparison to shotgun sequencing, hybridization capture results in an increase of taxonomically classified reads by several orders of magnitude and the recovery of near-complete chloroplast genomes of Larix. Variation in the chloroplast reads corroborate an invasion of Larix gmelinii into the range of Larix sibirica before 6700 years ago. Since then, both species have been present at the site, although larch populations have decreased with only a few trees remaining in what was once a forested area. This study demonstrates for the first time that hybridization capture applied to ancient DNA from lake sediments can provide genome-scale information and is a viable tool for studying past changes of a specific taxon.

Due to its unique triacylglycerol composition, palm oil has the particularity of being semi-solid at room temperature. Major fatty acids are palmitic (P) and oleic (O) types, tripalmitin (P3), oleo-dipalmitin (P2O) and palmito-diolein (PO2) being the most abundant tri-saturated, mono-unsaturated and di-unsaturated triacylglycerols. Palm oil is also the most fractionated oil worldwide, mostly in multi-step operations. Dry fractionation is a process that combines crystallization and separation of partially crystallized oil; in the case of palm oil, the main triacylglycerols involved are obviously P3, P2O and PO2. Crude palm oil is made up of symmetrical and asymmetric isomers and, more particularly, contains POP and OPP in a fixed ratio. This ratio may sometimes be modified during the refining process. Adverse effects of excessive OPP content affect the dry fractionation process and are also reflected in the crystallization properties of the produced solid and liquid fractions. It is therefore fundamental to understand at a molecular level the interactions involved. This paper details and compares the binary phase diagrams of several systems: PPP-POP, PPP-OPP; PPP-POO, POP-POO, OPP-POO and POP-OPP, obtained by combining differential scanning calorimetry and variable temperature powder X-ray diffraction. Co-crystallization properties are analyzed in dynamic mode (heating after quenching) and after tempering (few months stabilization at room temperature). The ternary phase diagrams PPP/POP/POO and PPP/OPP/POO give a complementary representation in terms of isothermal melting lines. Better understanding of these molecular interactions is critical for perspicacious carrying out of the palm oil dry fractionation process.

Peanut was crushed by dry comminution and wet comminution, and effects of comminution on peanut particle size and yield of peanut oil and protein were analyzed. The properties (surface protein concentration, particle size, and ξ-potential) of emulsion were compared. Moreover, different demulsification methods were used to investigate the stability of the emulsion. Results showed that yield of peanut oil and protein reached highest (87.23% and 82.05%, respectively) at dry comminution 72 s. At wet comminution 120 s, yield of peanut oil and protein was 89.91% and 84.70%, respectively, which were both higher than that of dry comminution significantly (P < 0.05). The surface protein concentration and ξ-potential of emulsion made by dry comminution (DCE) was 7.02 mg/m2 and 12.08 mV, respectively, and that was 10.71 mg/m2 and 15.25 mV of emulsion made by wet comminution (WCE), which were significantly higher than that of DCE (P < 0.05). The volume average particle size (D(4,3)) of DCE was 3.41 µm, which was significantly higher than D(4,3) of WCE (3.18µm, P < 0.05). Collectively, results of emulsion properties indicated stability of WCE was higher than DCE. Further, demulsification rate of DCE was significantly higher than that of WCE treated by freeze-thawing, pH, Papain, and Phospholipase A2 (P < 0.05). Demulsification effect of Alcalase 2.4L was best in these five demulsification methods, and demulsification rate of DCE reached 92.77%, slightly higher than WCE (92.67%), further illustrated stability of WCE was higher than DCE.

A novel respiratory pathogen, SARS-CoV-2 has recently received worldwide attention and has been declared a public health emergency of global concern. Entry of SARS-CoV-2 is mediated through the viral spike glycoprotein (S2). Afterwards, the virus gets hold of the host cell machinery by employing the use of viral main protease 3CLpro and NSP15 endoribonuclease. In the present in silico study, active site mapping of the viral virulence factors was rendered by means of DoG Site Scorer. The possibility of repurposing of 2-deoxy-D-glucose (2-DG), a radio-chemo-modifier drug used for optimizing cancer therapy, and one of its derivative (1, 3, 4, 6-Tetra-O-acetyl-2-deoxy-D-glucopyranose, has been investigated by conducting ligand-receptor docking. Binding pose depictions of ligands and viral receptors were assessed by employing molecular dynamics analysis. Molinspiration and Toxicity Estimation Software tools were used to assess the drug likeliness, bioactivity indices and ADMETox values. 2-DG can dock efficiently with viral main protease 3CLpro as well as NSP15 endoribonuclease, thus efficiently inactivating these viral receptors leading to incapacitation of the SARS-CoV-2 virus. Such incapacitation was possible by means of formation of a hydrogen bond between 2-DG and proline residues of viral protease. The 2-DG derivative formed a hydrogen bond with the glutamine amino acid residues of the viral spike glycoprotein. The present in silico study supports the potential benefits of using 2-DG and its glucopyranose derivative as repurposed drugs/prodrugs for mitigating the novel COVID-19 infection. Since both these moieties present no signs of serious toxicity, further empirical studies on model systems and human clinical trials to ascertain effective dose-response are warranted and should be urgently initiated.

Behcet’s disease (BD) is a vasculitis of unknown aetiology that is reported to accompany autoimmune diseases. We report a rare case of BD, Addison’s disease, Hashimoto’s disease, and subclinical coeliac disease all occurring in one patient which has not previously been reported.

Eosinophilic gastroenteritis (EG) can easily be misdiagnosed. We present the case of a man with abdominal pain who was EG but misdiagnosed with cholelithiasis. This case highlights the need to consider EG in the differential diagnosis of abdominal pain since a favorable result can be achieved with timely treatment.

Chlamydia psittaci is an intracellular organism causing psittacosis which is found in psittacine birds and can be transmitted to humans by inhalation or direct contact. Here we present a case of human psittacosis mimicing acute monocytic leukemia which demonstrates an extraordinary clinical presentation of psittacosis.

What is precision medicine? No standard definition is found. Sometimes described as High Definition Medicine which is: “the dynamic assessment , management, and understanding of an individual’s health measured at (or near) its most basic units.” The impetus for this venture was advanced and stimulated by biogenetics, the study of how genes and their products affect health but also contribute to disease or resistance to cure. Medicine is an epistemology: a way of knowing, perceiving, remembering, finding out, proving, inferring, wondering, reflecting, a conceptual knowing relying upon observations fitted to disease concepts.

Mechanism of the oxidative nonpolar inversion reaction catalyzed by N-heterocyclic carbenes (NHCs) to achieve benzoxazoles was investigated in very details. The reaction was revealed to occur through five processes, and for oxidation in the second process, two successive tautomerizations followed by oxidation were demonstrated to be more energetically favorable than the other two pathways. The rate-determining step was disclosed to be the oxidation by 3,3’-5,5’-tetra-tert-butyl-4,4’-diphenoquinone (DQ). Afterwards, mechanism calculations to the non-catalyzed reaction was conducted and it was revealed that the excessive exothermic property of the initial step should be the main reason for the extremely high barrier in the following step. While with participation of NHC, this unfavorable transformation can be deftly prevented according to the specific sequence and amount of reagents addition, and therefore to enable the reaction to occur under mild conditions.

COVID-19 has emerged as a new viral illness with potential for significant morbidity and mortality. Pregnant women are high risk for contracting the virus or suffering from complications, however data regarding the effect of COVID-19 on pregnancy is limited to case reports from affected countries. The pathophysiology of COVID-19 infection may provide insights of the threat to mother and fetus. In this review we collate available evidence of harm caused by COVID-19 to mothers and their offspring in all trimesters. Obstetricians must understand the risks posed by this pandemic to effectively counsel women who are currently pregnant or planning conception.

Since end of December 2019, a cluster of patients with pneumonia of unknown origin was reported from Wuhan, Hubei province, China. They shared a connection with the Huanan South China Seafood Market in Wuhan, and now it has been confirmed that the disease is caused by a novel coronavirus (officially named COVID-19). According to real-time statistics from Johns Hopkins University in the United States, as of 5:30 on the 31st, Beijing time, the number of confirmed cases of COVID-19 pneumonia in the world has exceeded 770,000, reaching 777,286, and the number of deaths has reached 37,140. Currently, clinicians have found some atypical cases with positive chest CT findings may present with negative results of RT-PCR for COVID-19. The timely diagnosis, isolation and treatment of these patients will help control the further spread of COVID-19.

Leaf shape is a defining feature of how we recognise and classify plant species. Although there is extensive variation in leaf shape within many species, few studies have disentangled the underlying genetic architecture. We characterised the genetic architecture of leaf shape variation in Eurasian aspen (Populus tremula L.) by performing a genome wide association studies (GWAS) for physiognomy traits. To ascertain the roles of identified GWAS candidate genes within the leaf development transcriptional program, we performed gene co-expression network analyses from a developmental series, which is publicly available at http://aspleaf.plantgenie.org. We additionally used gene expression measurements across the population to analyse GWAS candidate genes in the context of a population-wide co-expression network and to identify genes that were differentially expressed between groups of individuals with contrasting leaf shapes. These data were integrated with expression GWAS (eQTL) results to define a set of candidate genes associated with leaf shape variation. Our results identified no clear adaptive link to leaf shape variation and indicate that leaf shape traits are genetically complex, likely determined by numerous small-effect variations in gene expression. Genes associated with shape variation were peripheral within the population-wide co-expression network, were not highly connected within the leaf development co-expression network and exhibited signatures of relaxed selection. As such, our results are consistent with the omnigenic model.

Background: Postpartum hemorrhage (PPH) was deadly prior to blood transfusions, and therefore either never existed or was eliminated by evolution millions of years ago. No animals hemorrhage. Human PPH appears to be a relatively recent occurrence, perhaps coinciding with the decrease in the use of squatting. The first documented case of human postpartum hemorrhage appears around 1400 AD. Regardless of which third stage protocol is used, 95% of low risk women do not hemorrhage, but about 5% do. A protocol called Judy’s 3,4,5 calls for squatting out the placenta between 3 and 5 minutes postpartum in order to lower the 5% PPH rate to the same rate as experienced by other mammals, i.e. zero. Methodology: A retrospective cohort study of 1,027 planned, attended low risk vaginal births in Israel using Judy’s 3,4,5 minute third stage protocol compared to 2,691 attended low risk vaginal births in British Columbia using various forms of active or expectant management of the third stage of labor. Results: Among similar groups of low risk births, active management, or expectant management resulted in 4% PPH over 1000 cc, whereas Judy’s 3,4,5 minute protocol resulted in 0% PPH over 500 cc. Conclusion: Judy’s 3,4,5 minute protocol is logical, using gravity to deliver the placenta expediently. It results in 0% postpartum hemorrhage over 500 cc and an average blood loss of 100 cc in the first hour after the birth of the newborn, which compares favorably to any other third stage protocol.

Background and Purpose Activation of Ca2+/calmodulin-dependent protein kinase (CaMKII) has been proved to play a vital role in cardiovascular diseases. Receptor-interaction protein kinase 3 (RIPK3)-mediated necroptosis is crucially participated in cardiac dysfunction. The study aimed to investigate the effect as well as mechanism of CaMKII activation and necroptosis on diabetic cardiomyopathy (DCM). Experimental Approach Primary cardiomyocytes were treated with AGEs (200 μg/mL) for 24 h. Cell injury, CaMKII activity and necroptosis were detected. Wild type (WT) and the RIPK3 gene knockout (RIPK3-/-) mice were intraperitoneally injected with 60 mg/kg/d streptozotocin (STZ) for 5 consecutive days. After 12 w feeding, 100 μL recombinant adenovirus solution carrying I1PP1 gene were injected into the caudal vein of mice. Echocardiography, myocardial injury, CaMKII activity, necroptosis, RIPK1 expression, MLKL phosphorylation, mitochondrial ultrastructure were measured. Key Results Cardiac dysfunction, CaMKII activation and necroptosis were aggravated in streptozotocin (STZ) stimulated mice, as well as in (Lepr) KO/KO (db/db) mice. RIPK3 deficiency alleviated cardiac dysfunction, CaMKII activation and necroptosis in DCM. Cell injury, CaMKII activation and necroptosis were augmented in advanced glcation endproducts (AGEs)-stimulated cardiomyocytes, which was attenuated after RIPK3 down-regulation. Furthermore, inhibitor 1 of protein phosphatase 1 (I1PP1) over-expression reversed cardiac dysfunction, myocardial injury and necroptosis augment, and CaMKII activity enhancement in WT mice with DCM, but not in RIPK3 knockout mice with DCM. Conclusion and Implications CaMKII activation and necroptosis augment in DCM via a RIPK3-dependent manner, which may provide therapeutic strategies for DCM.

BACKGROUND AND PURPOSE PP242, an inhibitor of mechanistic target of rapamycin (mTOR), displays potent anticancer effects against various types of cancer. However, the underlying metabolic mechanism associated with the PP242 effects is not clearly understood. In this study, comprehensive metabolomics and lipidomics investigations were performed in plasma and tumor tissue to reveal the metabolic mechanism of PP242 in an LS174T cell-induced colon cancer xenograft mouse model. EXPERIMENTAL APPROACH A colon cancer xenograft model was developed in BALB/c nude mice and then treated with PP242 for three weeks. After the final dose, blood, tumor, liver and kidney tissues were collected. Plasma and tumor samples were analyzed through untargeted metabolomics and lipidomics approaches using ultra-high-performance chromatography-Orbitrap-mass spectrometry (UHPLC-Orbitrap-MS). KEY RESULTS PP242 treatment reduces tumor size without any critical toxicities. According to results, metabolic changes due to the effects of PP242 were not significant in plasma. In contrast, metabolic changes in tumor tissues were very significant in the PP242-treated group compared to the xenograft control (XC) group, and revealed that energy and lipid metabolism were mainly altered by PP242 treatment like other cancer inhibitors. Additionally, it this study it was discovered that not only TCA cycle but also fatty acid β-oxidation (β-FAO) for energy metabolism was inhibited and clear reduction in glycerophospholipid was observed. CONCLUSIONS AND IMPLICATIONS The findings of this study reveal new insights into the underlying anticancer mechanism of the dual mTOR inhibitor PP242, and could help further facilitate the understanding of the effects PP242 in the course of clinical application.

The transformation mechanism and kinetics of 2-chloro-1,1,2-trifluoroethyl-difluoromethyl-ether (CTDE, CHF2OCF2CHFCl) triggered by OH radicals were researched by DFT methods and canonical variational transition state theory. The computational rate constant including small-curvature tunneling correction was in commendable agreement with the experimental data. Two hydrogen abstraction channels to form the alkyl radicals of C·F2OCF2CHFCl and CHF2OCF2C·FCl were observed, and the formation of CHF2OCF2C·FCl was more favorable than C·F2OCF2CHFCl in kinetics and thermodynamics. Subsequent evolution of CHF2OCF2C·FCl in the presence of NO and O2 indicated that the organic nitrate (CHF2OCF2CONO2FCl) was the stable product. The dechlorinate of alkoxy radical (CHF2OCF2C(O·)FCl) was the most favorable degradation channel and the estimated ozone depletion potential for CTDE relative to CFC-11 was 0.0204, which could lead to a consequence of ozone depletion. Computed atmospheric lifetime for CTDE was 3.69 years by considering the combined contributions from OH radicals and Cl atoms. The total radiative forcing and global warming potential of CTDE were respectively 0.547 W m-2 ppbv and 628.58 (100 years) at 298 K, suggesting that the contribution of CTDE to the greenhouse effect is moderate.

Background: The anti-inflammatory effect of the α7nAChR agonist, PNU-282987, has previously been explored in the context of inflammatory disease. However, the impact of PNU-282987 on type 2 innate lymphoid cells (ILC2s)-mediated allergic airway inflammation has not been established. Aims: To determine the effects of PNU-282987 on the function of ILC2s in the context of IL-33 or Alternaria Alternata (AA)-induced airway inflammation. Methods: PNU-282987 was administered to mice that received recombinant IL-33 or AA intranasal challenge. Whole lung was collected from mice for histological analysis, and ILC2 populations were quantified in the lungs and BALF of these mice. Additionally, ILC2s were isolated from murine lung tissue and cultured in vitro in the presence of IL-33, IL-2 and IL-7 with or without PNU-282987, and the expression of the transcription factors GATA3, IKK, and NF-κB was determined in these cells. Results: PNU-282987 significantly reduced airway goblet cell hyperplasia, eosinophil infiltration, and ILC2s numbers in BALF in response to IL-33 or AA. In vitro IL-33 stimulation of isolated lung ILC2s showed a reduction of GATA3 and Ki67 in response to PNU-282987 treatments. When compared to the established α7nAChR agonist, GTS-21, there was a notable reduction in IKK and NF-κB phosphorylation in the PNU-282987 treated group when compared to the GTS-21 treated ILC2s. Conclusion: PNU-282987 inhibits ILC2s-associated airway inflammation by inhibiting ILC2s cell proliferation and the initiation of inflammatory cascades.