Retrospective Observational Study of Patients With Subdural Hematoma Treated With Idarucizumab.

Use of anticoagulants is increasing with the aging of societies. The safe first-line drug is likely to be a direct oral anticoagulant (DOAC), but outcomes of treatment of traumatic brain injury (TBI) with anticoagulants are uncertain. Therefore, we examined the clinical effect of idarucizumab as reversal therapy in elderly patients with TBI who were treated with dabigatran. A retrospective multi-center observational study was performed in patients ≥65 years of age who developed acute traumatic subdural hematoma during treatment with dabigatran and underwent reversal therapy with idarucizumab. The items examined included patient background, neurological and imaging findings at arrival, course after admission, complications, and outcomes. A total of 23 patients were enrolled in the study. The patients had a mean age of 78.9 years. Cause of TBI was fall in 60.9% of the subjects. Mean Glasgow Coma Scale score at arrival was 8.7; anisocoria was present in 31.8% of cases. Exacerbation of consciousness was found in 30.4%, but only in 13.3% of subjects treated with idarucizumab before consciousness and imaging findings worsened. Dabigatran was discontinued in 81.8% of cases after hematoma development, with a mean withdrawal period of 12.1 days. The favorable outcome rate was 21.7%, and mortality was 39.1%. In multi-variate analysis, timing of idarucizumab administration was associated with a favorable outcome. There were ischemic complications in 3 cases (13.1%), and all three events occurred ≥7 days after administration of idarucizumab. These findings suggest that in cases that develop hematoma during treatment with dabigatran, it is important to administer idarucizumab early and restart dabigatran after conditions stabilize.

The liver-to-spleen ratio is a risk factor predicting oxygen demand in COVID-19 patients.

Background: We aimed to investigate risk factors predicting oxygen demand in COVID-19 patients. Methods: Patients admitted to Shizuoka General Hospital with COVID-19 from August 2020 to August 2021 were included. First, we divided patients into groups with and without oxygen demand. Then, we compared patients' clinical characteristics and laboratory and radiological findings to determine factors predicting oxygen demand. Results: One hundred seventy patients with COVID-19 (aged 58±15 years, 57 females) were enrolled. Common comorbidities were cardiovascular diseases (47.6%), diabetes mellitus (28.8%), and dyslipidemia (26.5%). Elder age, higher body mass index, cardiovascular diseases, diabetes mellitus, lower lymphocyte count, albumin, hepatic attenuation value, and the liver-to-spleen ratio (L/S), higher D-dimer, aspartate aminotransferase, lactate dehydrogenase, troponin-T, C-reactive protein, KL-6, chest and abdominal circumference, and visceral fat were found in patients with oxygen demand. According to the multivariate logistic regression analysis, L/S, lymphocyte count, D-dimer, and abdominal circumference under the diaphragm were independent risk factors predicting oxygen demand in COVID-19 patients. Conclusions: On admission, L/S, lymphocyte count, D-dimer, and abdominal circumference were predictive factors for oxygen demand. These factors may help in the appropriate triage of COVID-19 patients in the decision to admit them to the hospital.

New designs for HIV-1 integrase inhibitors: a patent review (2018-present).

INTRODUCTION: Combination antiretroviral therapy (cART) has dramatically reduced morbidity and mortality of HIV-1-infected patients. Integrase strand transfer inhibitors (INSTIs) play an important role as a key drug in cART. The second-generation INSTIs are very potent, but due to the emergence of highly resistant viruses and the demand for more conveniently usable drugs, the development of 'third-generation' INSTIs and mechanistically different inhibitors is actively being pursued. AREAS COVERED: This article reviews the patents (from 2018 to the present) for two classes of HIV-1 integrase inhibitors of INSTIs and integrase-LEDGF/p75 allosteric inhibitors (INLAIs). EXPERT OPINION: Since the approval of the second-generation INSTI dolutegravir, the design of new INSTIs has been mostly focused on its scaffold, carbamoylpyridone (CAP). This CAP scaffold is used not only for HIV-1 INSTIs but also for drug discoveries targeting other viral enzymes. With the approval of cabotegravir as a regimen of long-acting injection in combination with rilpivirine, there is a growing need for longer-acting agents. INLAIs have been intensely studied by many groups but have yet to reach the market. However, INLAIs have recently been reported to also function as a latency promoting agent (LPA), indicating further development possibilities.

Microbial Diversity in the Phyllosphere and Rhizosphere of an Apple Orchard Managed under Prolonged "Natural Farming" Practices.

Microbial diversity in an apple orchard cultivated with natural farming practices for over 30 years was compared with conventionally farmed orchards to analyze differences in disease suppression. In this long-term naturally farmed orchard, major apple diseases were more severe than in conventional orchards but milder than in a short-term natural farming orchard. Among major fungal species in the phyllosphere, we found that Aureobasidium pullulans and Cryptococcus victoriae were significantly less abundant in long-term natural farming, while Cladosporium tenuissimum predominated. However, diversity of fungal species in the phyllosphere was not necessarily the main determinant in the disease suppression observed in natural farming; instead, the maintenance of a balanced, constant selection of fungal species under a suitable predominant species such as C. tenuissimum seemed to be the important factors. Analysis of bacteria in the phyllosphere revealed Pseudomonas graminis, a potential inducer of plant defenses, predominated in long-term natural farming in August. Rhizosphere metagenome analysis showed that Cordyceps and Arthrobotrys, fungal genera are known to include insect- or nematode-infecting species, were found only in long-term natural farming. Among soil bacteria, the genus Nitrospira was most abundant, and its level in long-term natural farming was more than double that in the conventionally farmed orchard.

Inheritance of heat tolerance in perennial ryegrass (Lolium perenne, Poaceae): evidence from progeny array analysis.

BACKGROUND: Heat stress is considered one of the most important environmental factors influencing plant physiology, growth, development, and reproductive output. The occurrence and damage caused by heat stress will likely increase with global climate change. Thus, there is an urgent need to better understand the genetic basis of heat tolerance, especially in cool season plants. MATERIALS AND METHODS: In this study, we assessed the inheritance of heat tolerance in perennial ryegrass (Lolium perenne L. subspecies perenne) , a cool season grass, through a comparison of two parental cultivars with their offspring. We crossed plants of a heat tolerant cultivar (Kangaroo Valley) with plants of a heat sensitive cultivar (Norlea), to generate 72 F1 hybrid progeny arrays. Both parents and their progeny were then exposed to heat stress for 40 days, and their photosynthetic performance (Fv/Fm values) and leaf H2O2 content were measured. RESULTS: As expected, Kangaroo Valley had significantly higher Fv/Fm values and significantly lower H2O2 concentrations than Norlea. For the F1 progeny arrays, values of Fv/Fm decreased gradually with increasing exposure to heat stress, while the content of H2O 2 increased. The progeny had a wide distribution of Fv/Fm and H 2O2 values at 40 days of heat stress. Approximately 95% of the 72 F1 progeny arrays had Fv/Fm values that were equal to or intermediate to the values of the two parental cultivars and 68% of the progeny arrays had H2O2 concentrations equal to or intermediate to their two parents. CONCLUSION: Results of this study indicate considerable additive genetic variation for heat tolerance among the 72 progeny arrays generated from these crosses, and such diversity can be used to improve heat tolerance in perennial ryegrass cultivars. Our findings point to the benefits of combining physiological measurements within a genetic framework to assess the inheritance of heat tolerance, a complex plant response.

Discovery of novel HIV-1 integrase-LEDGF/p75 allosteric inhibitors based on a pyridine scaffold forming an intramolecular hydrogen bond.

We have discovered HIV-1 novel integrase-LEDGF/p75 allosteric inhibitors (INLAIs) based on a pyridine scaffold forming an intramolecular hydrogen bond. Scaffolds containing a pyridine moiety have been studied extensively and we have already reported that substituents extending from the C1 position contributed to the antiviral potency. In this study, we designed a new pyridine scaffold 2 with a substituent at the C1 position. Interestingly, during attempts at optimization, we found that the direction of the C1 substituents with an intramolecular hydrogen bond contributed to the antiviral potency. Compound 34f exhibited better antiviral potency against WT and the T174I mutant (EC50 (WT) = 6.6 nM, EC50 (T174I) = 270 nM) than BI 224436 (EC50 (WT) = 22 nM, EC50 (T174I) > 5000 nM).

Phylogenetic signal of host plants in the bacterial and fungal root microbiomes of cultivated angiosperms.

Root microbiomes are established through selective recruitment by host plants from pools of potential partners. However, the assembly rules of root microbiomes remain unclear. To elucidate (i) the effects of host plant phylogeny on root microbiome assembly and (ii) which microbial groups affect differences in root microbiome assemblies, the structures of bacterial and fungal root microbiomes from 20 cultivated angiosperms were compared. Surface-sterilized seeds from each species were sown in identical soil, and DNA was extracted from the plant roots after 7-8 weeks. The bacterial (16S rRNA) and fungal (ITS) communities were then examined using Illumina MiSeq. The phylogenetic distances of host plants and assembly dissimilarities of bacterial microbiomes, but not of fungal ones, were significantly correlated, as were the topologies of the host plant phylogenetic tree and the community dissimilarity tree, thereby confirming the phylogenetic conservation of bacterial root microbiomes. Furthermore, host plant phylogeny mainly affected only a few specific bacterial lineages, including the Betaproteobacteria, Gammaproteobacteria, and Chloroflexi. Burkholderia (Betaproteobacteria) taxa were more abundant in monocots than in dicots, whereas Streptomyces (Actinobacteria) taxa were less abundant. These findings suggest that bacterial root microbiomes have significantly contributed to the functional divergence of angiosperms at higher taxonomic levels.

Discovery of novel integrase-LEDGF/p75 allosteric inhibitors based on a benzene scaffold.

We report herein the discovery of novel integrase-LEDGF/p75 allosteric inhibitors (INLAIs) based on a benzene scaffold 3. This scaffold can extend substituents from the C1 position unlike the common pyridine scaffolds 2. Structure-activity relationship studies showed that the sulfonamide linker at the C1 position was important for the antiviral activity. Interaction between sulfonamide and Q95 was observed by X-ray crystallography. Compound 31h showed more potent antiviral activity (EC50 (NL432) = 3.9 nM) than BI-224436 (EC50 (NL432) = 56 nM), suggesting the potential of the newly designed scaffold 3.

Soil productivity and structure of bacterial and fungal communities in unfertilized arable soil.

Soil productivity is strongly influenced by the activities of microbial communities. However, it is not well understood how community structure, including its richness, mass, and composition, influences soil functions. We investigated the relationships between soil productivity and microbial communities in unfertilized arable soils extending over 1000 km in eastern Japan. Soil properties, including C turnover rate, N mineralization rate, microbial C, and various soil chemical properties, were measured. Soil bacterial and fungal communities were analyzed by Illumina's MiSeq using 16S rRNA and ITS regions. In addition, root microbial communities from maize grown in each soil were also investigated. Soil bacterial communities shared many operational taxonomic units (OTUs) among farms. An ordination plot based on correspondence analysis revealed convergent distribution of soil bacterial communities across the farms, which seemed to be a result of similar agricultural management practices. Although fungal communities showed lower richness and a lower proportion of shared OTUs than bacterial communities, community structure between the farms tended to be convergent. On the other hand, root communities had lower richness and a higher abundance of specific taxa than the soil communities. Two soil functions, decomposition activity and soil productivity, were extracted by principal component analysis (PCA) based on eight soil properties. Soil productivity correlated with N mineralization rate, P2O5, and maize growth, but not with decomposition activity, which is characterized by C turnover rate, soil organic C, and microbial mass. Soil productivity showed a significant association with community composition, but not with richness and mass of soil microbial communities. Soil productivity also correlated with the abundance of several specific taxa, both in bacteria and fungi. Root communities did not show any clear correlations with soil productivity. These results demonstrate that community composition and abundance of soil microbial communities play important roles in determining soil productivity.

Response to Comment on "Worldwide evidence of a unimodal relationship between productivity and plant species richness".

Tredennick et al. criticize one of our statistical analyses and emphasize the low explanatory power of models relating productivity to diversity. These criticisms do not detract from our key findings, including evidence consistent with the unimodal constraint relationship predicted by the humped-back model and evidence of scale sensitivities in the form and strength of the relationship.

Microbial community composition controls the effects of climate change on methane emission from rice paddies.

Rice paddies are one of the most important sources of CH4 emission from the terrestrial ecosystem. A Free-air CO2 Enrichment (FACE) experiment, which included a soil warming treatment, was conducted in a rice paddy at Shizukuishi, Japan. In this study, the changes in CH4 emission from a rice paddy, caused by global climate change, were explored in relation to the structural changes that have occurred in the methanogenic archaeal communities found in the soil and roots. The composition of the archaeal community was examined by terminal restriction fragment length polymorphism (T-RFLP) using the 16S rRNA gene, while its abundance was measured by real-time PCR using the methyl coenzyme M reductase (mcrA) gene. The archaeal community in the roots showed considerable change, characterized by the dominance of hydrogenotrophic methanogens and a corresponding decrease in acetoclastic methanogens. Seasonal changes in CH4 flux were closely related to the changes in methanogen abundance in the roots. Elevated CO2 caused an increase in root mass, which increased the abundance of methanogens leading to a rise in CH4 emissions. However, soil warming stimulated CH4 emissions by increasing CH4 production per individual methanogen. These results demonstrated that climate warming stimulates CH4 emission in a rice paddy by altering the abundance and activity of methanogenic archaea in the roots.

How meristem plasticity in response to soil nutrients and light affects plant growth in four Festuca grass species.

Investigation of responses of meristems to environmental conditions is important for understanding the mechanisms and consequences of plant phenotypic plasticity. Here, we examined how meristem plasticity to light and soil nutrients affected leaf growth and relative growth rate (RGR) in fast- and slow-growing Festuca grass species. Activity in shoot apical meristems was measured by leaf appearance rate, and that in leaf meristems by the duration and rate of cell production, which was further divided into single cell cycle time and the number of dividing cells. Light and soil nutrients affected activity in shoot apical meristems similarly. The high nutrient supply increased the number of dividing cells, which was responsible for enhancement of cell production rate; shaded conditions extended the duration of cell production. As a result, leaf length increased under high nutrient and shaded conditions. The RGR was correlated positively with the total meristem size of the shoot under a low nutrient supply, implying inhibition of RGR by cell production under nutrient-limited conditions. Fast-growing species were more plastic for cell production rate and specific leaf area (SLA) but less plastic for RGR than slow-growing species. This study demonstrates that meristem plasticity plays key roles in characterizing environmental responses of plant species.

Polyploidy and cellular mechanisms changing leaf size: comparison of diploid and autotetraploid populations in two species of Lolium.

BACKGROUND AND AIMS: Growth and development of plant organs, including leaves, depend on cell division and expansion. Leaf size is increased by greater cell ploidy, but the mechanism of this effect is poorly understood. Therefore, in this study, the role of cell division and expansion in the increase of leaf size caused by polyploidy was examined by comparing various cell parameters of the mesophyll layer of developing leaves of diploid and autotetraploid cultivars of two grass species, Lolium perenne and L. multiflorum. METHODS: Three cultivars of each ploidy level of both species were grown under pot conditions in a controlled growth chamber, and leaf elongation rate and the cell length profile at the leaf base were measured on six plants in each cultivar. Cell parameters related to division and elongation activities were calculated by a kinematic method. KEY RESULTS: Tetraploid cultivars had faster leaf elongation rates than did diploid cultivars in both species, resulting in longer leaves, mainly due to their longer mature cells. Epidermal and mesophyll cells differed 20-fold in length, but were both greater in the tetraploid cultivars of both species. The increase in cell length of the tetraploid cultivars was caused by a faster cell elongation rate, not by a longer period of cell elongation. There were no significant differences between cell division parameters, such as cell production rate and cell cycle time, in the diploid and tetraploid cultivars. CONCLUSION: The results demonstrated clearly that polyploidy increases leaf size mainly by increasing the cell elongation rate, but not the duration of the period of elongation, and thus increases final cell size.