bluuebunny/crossref_metadata_2025 huggingface dataset:
A transcriptomic investigation of heat-induced transgenerational plasticity in beetles
Authors: Ledón-Rettig Cristina C
Published: February 2023

In response to environmental stressors, parents can shape the developmental outcomes of their offspring by contributing non-genetic but heritable factors. The transmission of such factors can potentially allow offspring, from the beginning of their lives, to express phenotypes that match their anticipated environments. In this study, I ask whether enhanced growth in larvae of Onthophagus taurus (the bull-headed dung beetle) is modified by parental exposure to heat or by exposure of the offspring to heat during early life. I find that, irrespective of the early environment of the offspring, individuals produced by parents exposed to heat grow larger. Furthermore, taking a transcriptomic approach, I find that ecdysone signalling might mediate the transgenerational effect and that increased insulin signalling or reduced production of heat shock proteins might be responsible for the enhanced growth in larvae derived from parents exposed to heat. Together, my results provide evidence for a thermally induced transgenerational effect and a foundation for functional testing of candidate mechanisms mediating the effect.
Implementation and validation of a novel instrument for the grading of unexpected events in paediatric surgery: Clavien–Madadi classification
Authors: Madadi-Sanjani Omid , Kuebler Joachim F , Brendel Julia , Wiesner Soeren , Mutanen Annika , Eaton Simon , Domenghino Anja , Clavien Pierre-Alain , Ure Benno M
Published: February 2023

Background

Inconsistent definitions of complications and unexpected events have limited accurate analysis of surgical outcomes. Perioperative outcome classifications currently used for adult patients have limitations when used for children.

Methods

A multidisciplinary group of experts modified the Clavien–Dindo classification to increase its utility and accuracy in paediatric surgery cohorts. Organizational and management errors were considered in the novel Clavien–Madadi classification, which focuses on procedural invasiveness rather than anaesthetic management. Unexpected events were prospectively documented in a paediatric surgery cohort. Results of the Clavien–Dindo and Clavien–Madadi classifications were compared and correlated with procedure complexity.

Results

Unexpected events were prospectively documented in a cohort of 17 502 children undergoing surgery between 2017 and 2021. The results of both classifications were highly correlated (ρ = 0.95), although the novel Clavien–Madadi classification identified 449 additional events (organizational and management errors) over the Clavien–Dindo classification, increasing the total number of events by 38 per cent (1605 versus 1158 events). The results of the novel system correlated significantly with the complexity of procedures in children (ρ = 0.756). Furthermore, grading of events > grade III according to the Clavien–Madadi classification showed a higher correlation with procedure complexity (ρ = 0.658) than the Clavien–Dindo classification (ρ = 0.198).

Conclusion

The Clavien–Madadi classification is a tool for the detection of surgical and non-medical errors in paediatric surgery populations. Further validation in paediatric surgery populations is required before widespread use.
An extreme environment drives local adaptation ofGenista tinctoria(Fabaceae) from the Mefite (Ansanto Valley, southern Italy)
Authors: Di Iorio Emanuela , Menale Bruno , Innangi Michele , Santangelo Annalisa , Strumia Sandro , De Castro Olga
Published: February 2023

The Mefite in the Ansanto Valley is one of the largest and oldest cold natural carbon dioxide springs (CNCDS) known in the world. This site is characterized by toxic concentrations of CO2 and other harmful gases, and few plant species can survive in this environment. Among these plants, there is an aberrant Genista tinctoria population previously described as G. anxantica. This study aims to advance understanding of evolution over small geographical scales in an extreme environment using G. tinctoria populations from low and high CO2 environments. To investigate differentiation of the Mefite population, we analysed plastid sequences and microsatellite data for populations in the surrounding area. Considering the genetic results, it is evident that the population of the Mefite has an exclusive genetic pattern from both plastid and nuclear points of view with the presence of significant genetic barriers for both genomes analysed, which would point to the isolation of this population from neighbouring G. tinctoria populations. The population of G. tinctoria from the Mefite shows evidence of genetic differentiation from the nearby populations and the genetic indices show discrete variation. Recruitment was confirmed in the Mefite population, an indication that fitness is maintained despite the extreme local conditions. Our results indicate that the potent selection pressure imposed by the Mefite atmosphere has driven genetic differentiation of the local population from nearby G. tinctoria populations. A correct taxonomic rank evaluation and some conservation remarks are also proposed. Our study demonstrates that CO2 concentrations can influence population differentiation and adaptation in plants in a similar way to atmospheric sulphur, herbicides or edaphic conditions.
Severity of prematurity and age impact early postnatal development of GABA and glutamate systems
Authors: Basu Sudeepta K , Pradhan Subechhya , Sharker Yushuf M , Kapse Kushal J , Murnick Jonathan , Chang Taeun , Lopez Catherine A , Andescavage Nickie , duPlessis Adre J , Limperopoulos Catherine
Published: February 2023

Gamma-aminobutyric acid (GABA) and glutamatergic system perturbations following premature birth may explain neurodevelopmental deficits in the absence of structural brain injury. Using GABA-edited spectroscopy (MEscher-GArwood Point Resolved Spectroscopy [MEGA-PRESS] on 3 T MRI), we have described in-vivo brain GABA+ (+macromolecules) and Glx (glutamate + glutamine) concentrations in term-born infants. We report previously unavailable comparative data on in-vivo GABA+ and Glx concentrations in the cerebellum, the right basal ganglia, and the right frontal lobe of preterm-born infants without structural brain injury. Seventy-five preterm-born (gestational age 27.8 ± 2.9 weeks) and 48 term-born (39.6 ± 0.9 weeks) infants yielded reliable MEGA-PRESS spectra acquired at post-menstrual age (PMA) of 40.2 ± 2.3 and 43.0 ± 2 weeks, respectively. GABA+ (median 2.44 institutional units [i.u.]) concentrations were highest in the cerebellum and Glx higher in the cerebellum (5.73 i.u.) and basal ganglia (5.16 i.u.), with lowest concentrations in the frontal lobe. Metabolite concentrations correlated positively with advancing PMA and postnatal age at MRI (Spearman’s rho 0.2–0.6). Basal ganglia Glx and NAA, and frontal GABA+ and NAA concentrations were lower in preterm compared with term infants. Moderate preterm infants had lower metabolite concentrations than term and extreme preterm infants. Our findings emphasize the impact of premature extra-uterine stimuli on GABA–glutamate system development and may serve as early biomarkers of neurodevelopmental deficits.
Predacious Natural Enemies Associated With Suppression of Onion Thrips, Thrips tabaci (Thysanoptera: Thripidae), in Intercropped Onion-Barley Agroecosystems
Authors: Uesugi Ryuji , Konishi-Furihata Ryoko , Tabuchi Ken , Yoshimura Hideto , Shimoda Takeshi
Published: February 2023

The effects of two possible factors, prevention of pest immigration and enhancement of natural enemies, in suppressing onion thrips, Thrips tabaci L., were estimated in a small-scale experimental system of spring-planted onions intercropped with barley. The population dynamics of the thrips and their potential predatory natural enemies were investigated in four treatments: control (bare ground), insect net barrier, and onion-barley intercropping with or without trimming. We found that intercropping significantly suppressed onion thrips. It is unlikely that this effect was due to the prevention of thrip immigration because they seemed to move over the camouflage and/or physical barriers of the barley and the net barrier surrounding the onions easily. Intercropping with barley significantly increased hoverfly (Syrphidae) larvae numbers on onion leaves, and that of some groups of ground-dwelling predators such as large carnivorous ground beetles (Carabidae), ants (Formicidae), and wolf spiders (Lycosidae). We conclude that the suppression of thrips in this system was associated with the enhancement of hoverfly larvae abundance, mainly Sphaerophoria macrogaster (Thomson) (Syrphidae: Diptera) because they were observed together with thrips on onions and have been reported to predate thrips as well as aphids. Some hoverfly larvae on barley might move to nearby onions to search for new food sources and attack thrips.
Rescue balloon pulmonary angioplasty for worsening chronic thromboembolic pulmonary hypertension with essential thrombocythaemia and theJAK2-V617F mutation: a case report
Authors: Tamura Hiroto , Hosokawa Shinobu , Yuba Kenichiro , Kishi Koichi
Published: February 2023

Background

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare thromboembolic disease, with occasional critical consequences. Essential thrombocythaemia (ET) is associated with an increased incidence of venous and arterial thrombotic events. In addition, the JAK2-V617F mutation increases the risk of thrombosis. Few reports have evaluated the utility of balloon pulmonary angioplasty (BPA) for worsening CTEPH with ET and the JAK2-V617F mutation.

Case Summary

A 76-year-old woman, diagnosed with ET and the JAK2-V617F mutation, presented with dyspnoea. Echocardiography showed severe tricuspid regurgitation with a flattened interventricular septum. Contrast-enhanced computed tomography showed an eccentric thrombus in the right main pulmonary artery (PA) and thrombi in bilateral peripheral PAs. Acute pulmonary embolism (PE) was initially diagnosed, and heparinization was initiated; however, her oxygen saturation gradually worsened despite continued anticoagulation therapy. Her oxygen saturation level decreased to 90% (under a reservoir mask of 10 L). Her haemodynamics suggested CTEPH comorbidity. We decided to perform emergency right heart catheterization (RHC) and pulmonary angiography (PAG). RHC showed severe pulmonary hypertension. PAG showed fresh and organized thrombi and web regions in several segmental PAs. These findings indicated a combination of acute PE and CTEPH. Rescue BPA was performed on the right A1, A3, A8, and A9 segments. After BPA, the patient’s oxygen saturation showed marked improvement. The patient was discharged 18 days after hospitalization without complications.

Discussion

Rescue BPA could be an effective treatment for worsening CTEPH in severely impaired conditions, even with ET and the JAK2-V617F mutation.
Think outside the box: a case report of utilization of an excimer laser sheath as an intracardiac bioptome
Authors: Schenker Niklas , Kaiser Lukas , Bohnen Sebastian , Hakmi Samer
Published: February 2023

Background

Malignant cardiac tumours are rare entities that cause severe morbidity and mortality. Possible treatment options vary between surgical removement, (immuno-) chemotherapy, and palliative care, whilst diagnostic workup comprises of imaging and histopathology analysis. Excimer laser sheaths are a new possibility to extract significant tissue samples to offer adequate treatment.

Case summary

A 67-year-old Caucasian female presented with progressive shortness of breath, new onset of fevers, weight loss, and recurrent night sweats. She showed signs of upper venous stasis.

Cardiac imaging revealed an obstructive, hypoperfused right atrial mass superior to the tricuspid valve and a sessile structure at the mitral valve. Guideline-directed therapy for endocarditis was started subsequently.

A conventional intracardiac biopsy of the tumour was unsuccessful, but an off-label approach using an excimer laser sheath as bioptome leads to the diagnosis of a diffuse large B-cell lymphoma. Immuno-chemotherapy was commenced, leading to reduction in tumour size and rapid improvement in the quality of life.

Discussion

Intracardiac biopsies are an important piece of the puzzle in the diagnostic workup of cardiac neoplasms. This case report is the first description of the utilization of a laser lead extraction tool as a bioptome for intracardiac tumours. Two imaging modalities (echocardiogram, fluoroscopy), as well as the precise technique of the excimer laser, ensured safety for the patient. Clinical studies are paramount to further evaluate the laser sheath as a possible new instrument in the toolbox of an interventional cardiologist.
Surgical outcomes of thoracic endovascular aortic repair for retrograde Stanford type a dissection
Authors: Koizumi Shigeki , Inoue Yosuke , Shinzato Kento , Yokawa Koki , Kasai Mio , Masada Kenta , Seike Yoshimasa , Sasaki Hiroaki , Matsuda Hitoshi
Published: February 2023

OBJECTIVES

The optimal indications and contraindications for thoracic endovascular aortic repair of retrograde Stanford type A acute aortic dissection (R-AAAD) are not well known. The goal of this study was to determine the outcomes of thoracic endovascular aortic repair for R-AAAD at our institution and to discuss optimal indications.

METHODS

The medical records of 359 patients admitted to our institution for R-AAAD between December 2016 and December 2022 were reviewed, and 83 patients were finally diagnosed with R-AAAD. We selected thoracic endovascular aortic repair as an alternative, considering the anatomy of aortic dissection and the risk to patients undergoing open surgery.

RESULTS

Nineteen patients underwent thoracic endovascular aortic repair for R-AAAD. No in-hospital deaths or neurologic complications occurred. A type Ia endoleak was detected in 1 patient. All other primary entries were successfully closed. All dissection-related complications, such as cardiac tamponade, malperfusion distal to the primary entry and abdominal aortic rupture, were resolved. One patient required open conversion for intimal injury at the proximal edge of the stent graft; all other ascending false lumens were completely thrombosed and contracted at discharge. During the follow-up period, no aortic-related deaths or aortic events proximal to the stent graft occurred.

CONCLUSIONS

The indications for thoracic endovascular aortic repair were expanded to low-risk and emergency cases at our institution. The early- and midterm outcomes of thoracic endovascular aortic repair for R-AAAD were acceptable. Further long-term follow-up is required.
Resection of thymic carcinoma after induction therapy and reconstruction of right ventricular outflow tract with pulmonary homograft
Authors: Cafarotti Stefano , Torre Tiziano M , Patella Miriam , Demertzis Stefanos
Published: February 2023

Treatment of malignant epithelial thymic tumours, including thymoma and thymic carcinoma, is based on surgical resection, whenever possible. Mainstay of surgical treatment is complete resection with clear margins. This may require resection of adjacent structures, even major vessels. We describe a case of resection of the main pulmonary artery trunk and reconstruction with cadaveric homograft after induction chemo-radiotherapy for a locally advanced thymic carcinoma. Written informed consent was obtained from the patient.
Veneto Region dementia-related mortality during the COVID-19 pandemic: multiple causes of death and time series analysis
Authors: Basso Cristina , Barbiellini Amidei Claudio , Casotto Veronica , Schievano Elena , Dotto Matilde , Tiozzo Netti Silvia , Zorzi Manuel , Fedeli Ugo
Published: February 2023

Background

Older individuals with dementia have been severely affected by the COVID-19 pandemic. There is a lack of in-depth evaluation of mortality trends using both the underlying cause of death (UCOD) and the multiple causes of death (MCOD) approaches. The objective of this study was to determine the impact of the COVID-19 pandemic on dementia-related deaths considering comorbidities and the place of death.

Methods

This retrospective, population-based study was conducted in Veneto, Italy. All the death certificates of individuals aged ≥65 years issued from 2008 to 2020 were analyzed for dementia-related mortality using age-standardized sex-stratified rates of dementia as UCOD and MCOD. Excess in monthly dementia-related mortality in 2020 was estimated by applying Seasonal Autoregressive Integrated Moving Average (SARIMA) model.

Results

Overall, 70 301 death certificates reported dementia (MCOD proportional mortality: 12.9%), and 37 604 cases identified it as UCOD (proportional mortality: 6.9%). In 2020, the MCOD proportional mortality increased to 14.3% whereas that of UCOD remained static (7.0%). Compared to the SARIMA prediction, MCOD increased by 15.5% in males and 18.3% in females in 2020. Compared to the 2018–19 average, deaths in nursing homes increased by 32% in 2020, at home by 26% and in hospitals by 12%.

Conclusions

An increase in dementia-related mortality during the first months of the COVID-19 pandemic could only be detected using the MCOD approach. MCOD proved to be more robust, and hence, should be included in future analyses. Nursing homes appeared to be the most critical setting which should guide establishing protective measures for similar situations.
The potential of entomopathogenic nematodes of the genera Steinernema and Heterorhabditis for biological control of the pine lappet moth Dendrolimus pini L. (Lepidoptera: Lasiocampidae) in Scots pine stands
Authors: Tumialis Dorota , Mazurkiewicz Anna , Florczak Lidia , Skrzecz Iwona
Published: February 2023

Protecting stands of Scots pine (Pinus sylvestris) from the larvae of the pine lappet moth (Dendrolimus pini) has been a problem for many years in Central Europe. The feeding habits of the larvae of D. pini often result in more than 50 per cent defoliation, which weakens trees and increases their susceptibility to unfavourable environmental conditions. The aim of this study was to evaluate the effectiveness of native isolates of the entomopathogenic nematodes Steinernema feltiae (Filipjev, 1934) and Heterorhabditis megidis (Poinar, Jackson and Klein, 1987), as well as of the commercial preparations Nemamax (Heterorhabditis downesi) (Stock, Griffin and Burnell), Entonem (S. feltiae) and E-nema GmbH (S. carpocapsae) in greenhouse experiments and field trials. The highest extensity of infection (>80 per cent) of the pine lappet moth with nematodes in the greenhouse experiments studies was found for the strain S. feltiae ZAG15. In field trials, a greater effectiveness was obtained using commercial preparations of S. feltiae (Entonem), which led to approximately a twofold reduction in the number of wintering D. pini larvae. The results of this study indicate that entomopathogenic nematodes can be considered a potential biological control agent for reducing the damage caused by D. pini larvae.
Genetic association models are robust to common population kinship estimation biases
Authors: Hou Zhuoran , Ochoa Alejandro
Published: February 2023

Common genetic association models for structured populations, including principal component analysis (PCA) and linear mixed-effects models (LMMs), model the correlation structure between individuals using population kinship matrices, also known as genetic relatedness matrices. However, the most common kinship estimators can have severe biases that were only recently determined. Here we characterize the effect of these kinship biases on genetic association. We employ a large simulated admixed family and genotypes from the 1000 Genomes Project, both with simulated traits, to evaluate key kinship estimators. Remarkably, we find practically invariant association statistics for kinship matrices of different bias types (matching all other features). We then prove using statistical theory and linear algebra that LMM association tests are invariant to these kinship biases, and PCA approximately so. Our proof shows that the intercept and relatedness effect coefficients compensate for the kinship bias, an argument that extends to generalized linear models. As a corollary, association testing is also invariant to changing the reference ancestral population of the kinship matrix. Lastly, we observed that all kinship estimators, except for popkin ratio-of-means, can give improper non-positive semidefinite matrices, which can be problematic although some LMMs handle them surprisingly well, and condition numbers can be used to choose kinship estimators. Overall, we find that existing association studies are robust to kinship estimation bias, and our calculations may help improve association methods by taking advantage of this unexpected robustness, as well as help determine the effects of kinship bias in related problems.
Maternal infections and medications in pregnancy: how does self-report compare to medical records in childhood cancer case–control studies?
Authors: Bonaventure Audrey , Kane Eleanor , Simpson Jill , Roman Eve
Published: February 2023

Background

Studies examining the potential impact of mothers’ health during pregnancy on the health of their offspring often rely on self-reported information gathered several years later. To assess the validity of this approach, we analysed data from a national case–control study of childhood cancer (diagnosed <15 years) that collected health information from both interviews and medical records.

Methods

Mothers’ interview reports of infections and medications in pregnancy were compared with primary care records. Taking clinical diagnoses and prescriptions as the reference, sensitivity and specificity of maternal recall along with kappa coefficients of agreement were calculated. Differences in the odd ratios estimated using logistic regression for each information source were assessed using the proportional change in the odds ratio (OR).

Results

Mothers of 1624 cases and 2524 controls were interviewed ∼6 years (range 0–18 years) after their child’s birth. Most drugs and infections were underreported; in general practitioner records, antibiotic prescriptions were nearly three times higher and infections >40% higher. Decreasing with increasing time since pregnancy, sensitivity was ⩽40% for most infections and all drugs except ‘anti-epileptics and barbiturates’ (sensitivity 80% among controls). ORs associated with individual drug/disease categories that were based on self-reported data varied from 26% lower to 26% higher than those based on medical records; reporting differences between mothers of cases and controls were not systematically in the same direction.

Conclusions

The findings highlight the scale of under-reporting and poor validity of questionnaire-based studies conducted several years after pregnancy. Future research using prospectively collected data should be encouraged to minimize measurement errors.
Community pantries: a health service of great quality for the most affected ones
Authors: Cordero Dalmacito A
Published: February 2023

The COVID-19 pandemic has continuously caused many people to suffer worldwide. The Philippine government had imposed a series of lockdowns that caused many citizens to be unemployed and hungry. As the crisis continues, ordinary citizens from different religious communities and non-governmental organizations willed to establish community pantries to aid their hungry and helpless neighbors. The spirit of volunteerism was also awakened for those who desired to serve and shared their time and effort.
Forced Degradation and Stability-Indicating Study for the Binary Mixture of Allopurinol and Thioctic Acid Using Validated HPLC-DAD Method
Authors: El-Kafrawy Dina S , Abdelhamid Ahmed G , Abdel-Khalek Magdi M , Belal Tarek S
Published: February 2023

Background

Careful review of the scientific databases revealed that no stability-indicating analytical method is available for the binary mixture of allopurinol (ALO) and thioctic acid (THA).

Objective

A comprehensive stability-indicating HPLC-DAD procedure has been executed for concurrent analysis of ALO and THA.

Method

Successful chromatographic separation of the cited drugs was reached using a Durashell C18 column (4.6 × 250 mm, 5 µm particle size). The mobile phase consisted of a mixture of acidified water (pH 4.0) using phosphoric acid and acetonitrile pumped in gradient elution mode. For quantification of ALO and THA, their respective peak areas were recorded at 249 and 210 nm. A systematic validation of analytical performance was investigated in terms of system suitability, linearity, ranges, precision, accuracy, specificity, robustness, detection, and quantification limits.

Results

ALO and THA peaks emerged at retention times 4.26 and 8.15 min, respectively. Linear ranges for ALO and THA were 5–100 and 10–400 µg/mL, respectively, with correlation coefficient values exceeding 0.9999. Both drugs were exposed to conditions of neutral, acidic, and alkaline hydrolysis, oxidation, and thermal decomposition. Stability-indicating features have been demonstrated by resolution of the drugs from their forced degradation peaks. For verification of peak identity and purity, the diode-array detector (DAD) was used. In addition, degradation pathways for the cited drugs were postulated. Furthermore, separation of both analytes from about 13 medicinal compounds of different therapeutic classes disclosed optimum specificity of the proposed method.

Conclusions

Advantageous application of the validated HPLC method for the concurrent analysis of ALO/THA in their tablet dosage form was accomplished.

Highlights

So far, the described HPLC-DAD method is considered the first detailed stability-indicating analytical study for this pharmaceutical mixture.
Characteristics of the complete mitochondrial genome of Douhua chicken (Gallus gallus) and phylogenetic considerations
Authors: Jin Sihua , Jia Yuqing , Jiang Lijun , Cao Chengcheng , Ding Yunfei , Zhang Taikang , Liu Xuling , Li Yongsheng , Geng Zhaoyu
Published: February 2023

Douhua chicken is a unique local breed from Anhui Province, China. This study aimed to illustrate the Douhua chicken mitogenome and clarify its phylogenetic status by sequencing and annotating the complete mitochondrial genome using high-throughput sequencing and primer walking. Phylogenetic analysis through the Kimura 2-parameter model indicated the maternal origin of Douhua chicken. The results revealed that the mitochondrial genome is a closed circular molecule (16,785 bp) that consists of 13 protein-coding genes, 22 transfer RNA (tRNA) coding genes, two ribosomal RNA (rRNA) coding genes, and a control region. The base composition of the Douhua chicken mitogenome contains 30.3% A, 23.7% T, 32.5% C, and 13.5% G, and the haplotype and nucleotide diversity values are 0.829 (Hd) and 0.00441 (Pi), respectively. Furthermore, 10 haplotypes of D-loop sequences among 60 Douhua chickens were identified and distributed into four haplogroups (A, C, D, and E). Overall, the result of the present study indicates that Douhua chicken may have originated from Gallus gallus, and this process was influenced by Gallus gallus spadiceus, Gallus gallus murghi, and Gallus gallus bankiva. This study provides novel mitogenome data to support further phylogenetic and taxonomic studies on Douhua chicken. Additionally, the findings of this study will provide deeper insights for identifying the genetic relationships among populations and tracing maternal origins based on phylogenetic considerations for use in studies on the geographic conservation, utilization, and molecular genetics of poultry species.
Neuropathological features of SARS-CoV-2 delta and omicron variants
Authors: Normandin Erica , Valizadeh Navid , Rudmann Emily A , Uddin Rockib , Dobbins Sabrina T , MacInnis Bronwyn L , Padera Robert F , Siddle Katherine J , Lemieux Jacob E , Sabeti Pardis C , Mukerji Shibani S , Solomon Isaac H
Published: February 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continually evolving resulting in variants with increased transmissibility, more severe disease, reduced effectiveness of treatments or vaccines, or diagnostic detection failure. The SARS-CoV-2 Delta variant (B.1.617.2 and AY lineages) was the dominant circulating strain in the United States from July to mid-December 2021, followed by the Omicron variant (B.1.1.529 and BA lineages). Coronavirus disease 2019 (COVID-19) has been associated with neurological sequelae including loss of taste/smell, headache, encephalopathy, and stroke, yet little is known about the impact of viral strain on neuropathogenesis. Detailed postmortem brain evaluations were performed for 22 patients from Massachusetts, including 12 who died following infection with Delta variant and 5 with Omicron variant, compared to 5 patients who died earlier in the pandemic. Diffuse hypoxic injury, occasional microinfarcts and hemorrhage, perivascular fibrinogen, and rare lymphocytes were observed across the 3 groups. SARS-CoV-2 protein and RNA were not detected in any brain samples by immunohistochemistry, in situ hybridization, or real-time quantitative PCR. These results, although preliminary, demonstrate that, among a subset of severely ill patients, similar neuropathological features are present in Delta, Omicron, and non-Delta/non-Omicron variant patients, suggesting that SARS-CoV-2 variants are likely to affect the brain by common neuropathogenic mechanisms.
Population pharmacokinetic/pharmacodynamic evaluations of amikacin dosing in critically ill patients undergoing continuous venovenous hemodiafiltration
Authors: Li Sanwang , Zhu Sucui , Xie Feifan
Published: February 2023

Objectives

The pharmacokinetics/pharmacodynamics (PK/PD) of amikacin in critically ill patients undergoing continuous venovenous hemodiafiltration (CVVHDF) are poorly described, and appropriate dosing is unclear in this patient population. This study aimed to develop a population PK model of amikacin and to provide systemic PK/PD evaluations for different dosing regimens in CVVHDF patients.

Methods

One hundred and sixty-one amikacin concentration observations from thirty-three CVVHDF patients were pooled to develop the population PK model. Monte Carlo simulations were performed to assess the PK/PD index-based efficacy (Cmax/minimal inhibitory concentration (MIC) > 8 and AUC/MIC > 58.3), nonrisk of drug resistance (T>MIC > 60%) and risk of toxicity (trough concentration > 5 mg/l) for different dosing regimens.

Key findings

A two-compartment model adequately described the concentration data of amikacin. A loading dose of at least 25 mg/kg amikacin is needed to reach the efficacy targets in CVVHDF patients for an MIC of 4 mg/l, and the studied doses could not provide adequate drug exposure and T>MIC > 60% for an MIC ≥ 8 mg/l. The risk of toxicity for amikacin was unacceptably high for the patient population with low clearance.

Conclusions

Our study demonstrated that a loading dose of 25–30 mg/kg amikacin is needed to provide adequate PK/PD target attainment in CVVHDF patients for an MIC ≤ 4 mg/l.
A network pharmacology-based approach to explore the active ingredients and molecular mechanism of Shen-Kui-Tong-Mai granules on a rat model with chronic heart failure
Authors: Huang Hong , Xu Junyao , Zhang Siqi , Zhao Jing , Liu Shun , Tian Lei , Wang Haidan , Geng Zhirong , Yan Shihai
Published: February 2023

Objectives

This study aimed to comprehensively investigate the potential active components and therapeutic mechanisms of Shen-Kui-Tong-Mai granule (SKTMG) in the treatment of heart failure.

Methods

Network pharmacology combined with ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC–MS/MS), molecular docking, and in vivo validation was performed to identify the active components and the potential targets for SKTMG to improve chronic heart failure (CHF).

Key findings

The network pharmacology identified 192 active compounds and 307 potential consensus targets for SKTMG. On the other hand, network analysis discovered 10 core target genes related to the MAPK signal pathway. These genes include AKT1, STAT3, MAPK1, P53, SRC, JUN, TNF, APP, MAPK8 and IL6. The molecular docking results revealed that the SKTMG components were luteolin, quercetin, astragaloside IV and kaempferol, which could bind AKT1, MAPK1, P53, JUN, TNF and MAPK8. Additionally, SKTMG inhibited phosphorylation of AKT, P38, P53 and c-JUN, and reduced TNF-α expression in CHF rats.

Conclusions

The present results demonstrated that network pharmacology combined with UHPLC–MS/MS, molecular docking and in vivo validation can facilitate the identification of active components and the potential targets for SKTMG to improve CHF.
Acinar cystic transformation of the pancreas—a rare case in a young patient
Authors: Steinkraus Kira Carlotta , Mühlberger Michael , Schmidt Stefan Andreas , Kornmann Marko
Published: February 2023

Acinar cystic transformation (ACT) is a very rare transformation of the pancreas and has been described in less than 100 cases since its first report in 2002. The aim of this case report is to get a better understanding of this pancreatic transformation, which to date appears to be non-malignant. However, radical surgery was performed in most cases due to misinterpreting the initial diagnosis. ACT may be misdiagnosed for intraductal papillary mucinous neoplasms and is currently not included as a potential differential diagnosis for cystic lesions of the pancreas. ACT belongs to the benign cystic alterations of the pancreas. Despite its rarity, it should be considered as a potential differential diagnosis with regard to cystic lesions in the pancreas, especially in order to avoid unnecessary surgery.
Grafting in plants: recent discoveries and new applications
Authors: Loupit Grégoire , Brocard Lysiane , Ollat Nathalie , Cookson Sarah Jane
Published: February 2023

Grafting is a traditional horticultural technique that makes use of plant wound healing mechanisms to join two different genotypes together to form one plant. In many agricultural systems, grafting with rootstocks controls the vigour of the scion and/or provides tolerance to deleterious soil conditions such as the presence of soil pests or pathogens or limited or excessive water or mineral nutrient supply. Much of our knowledge about the limits to grafting different genotypes together comes from empirical knowledge of horticulturalists. Until recently, researchers believed that grafting monocotyledonous plants was impossible, because they lack a vascular cambium, and that graft compatibility between different scion/rootstock combinations was restricted to closely related genotypes. Recent studies have overturned these ideas and open up the possibility of new research directions and applications for grafting in agriculture. The objective of this review is to describe and assess these recent advances in the field of grafting and, in particular, the molecular mechanisms underlining graft union formation and graft compatibility between different genotypes. The challenges of characterizing the different stages of graft union formation and phenotyping graft compatibility are examined.
Assembly, transfer, and fate of mitochondrial iron–sulfur clusters
Authors: Pedroletti Luca , Moseler Anna , Meyer Andreas J
Published: February 2023

Since the discovery of an autonomous iron–sulfur cluster (Fe–S) assembly machinery in mitochondria, significant efforts to examine the nature of this process have been made. The assembly of Fe–S clusters occurs in two distinct steps with the initial synthesis of [2Fe–2S] clusters by a first machinery followed by a subsequent assembly into [4Fe–4S] clusters by a second machinery. Despite this knowledge, we still have only a rudimentary understanding of how Fe–S clusters are transferred and distributed among their respective apoproteins. In particular, demand created by continuous protein turnover and the sacrificial destruction of clusters for synthesis of biotin and lipoic acid reveal possible bottlenecks in the supply chain of Fe–S clusters. Taking available information from other species into consideration, this review explores the mitochondrial assembly machinery of Arabidopsis and provides current knowledge about the respective transfer steps to apoproteins. Furthermore, this review highlights biotin synthase and lipoyl synthase, which both utilize Fe–S clusters as a sulfur source. After extraction of sulfur atoms from these clusters, the remains of the clusters probably fall apart, releasing sulfide as a highly toxic by-product. Immediate refixation through local cysteine biosynthesis is therefore an essential salvage pathway and emphasizes the physiological need for cysteine biosynthesis in plant mitochondria.
Endoplasmic reticulum membrane contact sites: cross-talk between membrane-bound organelles in plant cells
Authors: Bian Jiahui , Su Xiao , Yuan Xiaoyan , Zhang Yuan , Lin Jinxing , Li Xiaojuan
Published: February 2023

Eukaryotic cells contain organelles surrounded by monolayer or bilayer membranes. Organelles take part in highly dynamic and organized interactions at membrane contact sites, which play vital roles during development and response to stress. The endoplasmic reticulum extends throughout the cell and acts as an architectural scaffold to maintain the spatial distribution of other membrane-bound organelles. In this review, we highlight the structural organization, dynamics, and physiological functions of membrane contact sites between the endoplasmic reticulum and various membrane-bound organelles, especially recent advances in plants. We briefly introduce how the combined use of dynamic and static imaging techniques can enable monitoring of the cross-talk between organelles via membrane contact sites. Finally, we discuss future directions for research fields related to membrane contact.
Fitness and Functional Landscapes of theE. coliRNase III Genernc
Authors: Weeks Ryan , Ostermeier Marc
Published: February 2023

How protein properties such as protein activity and protein essentiality affect the distribution of fitness effects (DFE) of mutations are important questions in protein evolution. Deep mutational scanning studies typically measure the effects of a comprehensive set of mutations on either protein activity or fitness. Our understanding of the underpinnings of the DFE would be enhanced by a comprehensive study of both for the same gene. Here, we compared the fitness effects and in vivo protein activity effects of ∼4,500 missense mutations in the E. coli rnc gene. This gene encodes RNase III, a global regulator enzyme that cleaves diverse RNA substrates including precursor ribosomal RNA and various mRNAs including its own 5′ untranslated region (5′UTR). We find that RNase III's ability to cleave dsRNA is the most important determinant of the fitness effects of rnc mutations. The DFE of RNase III was bimodal, with mutations centered around neutral and deleterious effects, consistent with previously reported DFE's of enzymes with a singular physiological role. Fitness was buffered to small effects on RNase III activity. The enzyme's RNase III domain, which contains the RNase III signature motif and all active site residues, was more sensitive to mutation than its dsRNA binding domain, which is responsible for recognition and binding to dsRNA. Differential effects on fitness and functional scores for mutations at highly conserved residues G97, G99, and F188 suggest that these positions may be important for RNase III cleavage specificity.
Diagnosis and management of complications from the treatment of primary central nervous system tumors in adults
Authors: Weller Michael , Le Rhun Emilie , Van den Bent Martin , Chang Susan M , Cloughesy Timothy F , Goldbrunner Roland , Hong Yong-Kil , Jalali Rakesh , Jenkinson Michael D , Minniti Giuseppe , Nagane Motoo , Razis Evangelia , Roth Patrick , Rudà Roberta , Tabatabai Ghazaleh , Wen Patrick Y , Short Susan C , Preusser Matthias
Published: February 2023

Central nervous system (CNS) tumor patients commonly undergo multimodality treatment in the course of their disease. Adverse effects and complications from these interventions have not been systematically studied, but pose significant challenges in clinical practice and impact function and quality of life, especially in the management of long-term brain tumor survivors. Here, the European Association of Neuro-Oncology (EANO) has developed recommendations to prevent, diagnose, and manage adverse effects and complications in the adult primary brain CNS tumor (except lymphomas) patient population with a specific focus on surgery, radiotherapy, and pharmacotherapy. Specifically, we also provide recommendations for dose adaptations, interruptions, and reexposure for pharmacotherapy that may serve as a reference for the management of standard of care in clinical trials. We also summarize which interventions are unnecessary, inactive or contraindicated. This consensus paper should serve as a reference for the conduct of standard therapy within and outside of clinical trials.
Extracellular Vesicles Derived From Neural Stem Cells, Astrocytes, and Microglia as Therapeutics for Easing TBI-Induced Brain Dysfunction
Authors: Hering Catherine , Shetty Ashok K
Published: February 2023

Extracellular vesicles (EVs) derived from neural stem cells (NSC-EVs), astrocytes (ADEVs), and microglia (MDEVs) have neuroregenerative properties. This review discusses the therapeutic efficacy of NSC-EVs, ADEVs, and MDEVs in traumatic brain injury (TBI) models. The translational value and future directions for such EV therapy are also deliberated. Studies have demonstrated that NSC-EV or ADEV therapy can mediate neuroprotective effects and improve motor and cognitive function after TBI. Furthermore, NSC-EVs or ADEVs generated after priming parental cells with growth factors or brain-injury extracts can mediate improved therapeutic benefits. However, the therapeutic effects of naïve MDEVs are yet to be tested rigorously in TBI models. Studies using activated MDEVs have reported both adverse and beneficial effects. NSC-EV, ADEV, or MDEV therapy for TBI is not ready for clinical translation. Rigorous testing of their efficacy for preventing chronic neuroinflammatory cascades and enduring motor and cognitive impairments after treatment in the acute phase of TBI, an exhaustive evaluation of their miRNA or protein cargo, and the effects of delayed EV administration post-TBI for reversing chronic neuroinflammation and enduring brain impairments, are needed. Moreover, the most beneficial route of administration for targeting EVs into different neural cells in the brain after TBI and the efficacy of well-characterized EVs from NSCs, astrocytes, or microglia derived from human pluripotent stem cells need to be evaluated. EV isolation methods for generating clinical-grade EVs must also be developed. Overall, NSC-EVs and ADEVs promise to mitigate TBI-induced brain dysfunction, but additional preclinical studies are needed before their clinical translation.
Computational study of novel natural inhibitors targeting Kirsten rat sarcoma viral oncogene homolog G12C
Authors: Yang Wenzhuo , Ge Junliang , Yuan Meng , Li Jialin , Pan Lin , Ren Junan , Dou Gaojing , Yang Laiyu , Zhou Yang , Xie Haoqun , Wang Xinhui , Hu Hongrong
Published: February 2023

Lung adenocarcinoma is one of the most aggressive and rapidly fatal types of malignant lung tumor. Molecular docking and virtual screening were effectively and systematically used to identify specific targets in malignant tumors and screen potential drugs. Here, we screen perfect leading compounds from a medicate library (ZINC15 database) and analyze their properties (conveyance, absorption, metabolism, excretion, and harmless forecasts) with potential inhibition of Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) G12C. Further results demonstrated that ZINC000013817014 and ZINC000004098458 were screened out from the ZINC15 database and were identified to have a much better binding affinity and more favorable interaction vitality binding with KRAS G12C and less rat carcinogenicity, Ames mutagenicity, way better dissolvability in water and noninhibition with cytochrome P-450 2D6. Molecular dynamics simulation analysis indicated that the binding capacity of these two compounds and KRAS G12C, ZINC000013817014-KRAS G12C, and ZINC000004098458-KRAS G12C is stable in the natural environment. Our findings reveal that ZINC000013817014 and ZINC000004098458 were perfect leading compounds to be inhibitors binding with KRAS G12C, which were selected as safe drug candidates and a cornerstone for KRAS G12C-related medicine plan and improvement. What is more, we have conducted a Cell Counting Kit-8 to verify the exactly inhibitory effects of the two selected drugs on Lung adenocarcinoma. This study establishes a solid framework for systematic anticancer medication research and development.
RIDR-PI-103, ROS-activated prodrug PI3K inhibitor inhibits cell growth and impairs the PI3K/Akt pathway in BRAF and MEK inhibitor-resistant BRAF-mutant melanoma cells
Authors: Patel Hima , Mishra Rosalin , Wier Adam , Mokhtarpour Nazanin , Merino Edward J. , Garrett Joan T.
Published: February 2023

Reactive oxygen species (ROS) levels are elevated after acquisition of resistance to v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors including dabrafenib and MEK inhibitors such as trametinib in BRAF-mutant melanoma. To circumvent toxicity to PI-103 (a pan PI3K inhibitor), we utilized a novel ROS-induced drug release (RIDR)-PI-103, with a self-cyclizing moiety linked to PI-103. Under high ROS conditions, RIDR-PI-103 releases PI-103, which inhibits conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3). Previous findings demonstrate that trametinib and dabrafenib-resistant (TDR) cells maintain p-Akt levels compared to parental counterparts and have significantly higher ROS. This is a rationale to explore the efficacy RIDR-PI-103 in TDR cells. We tested the effect of RIDR-PI-103 on melanocytes and TDR cells. RIDR-PI-103 exhibited less toxicity compared to PI-103 at 5 µM in melanocytes. RIDR-PI-103 significantly inhibited TDR cell proliferation at 5 and 10 µM. Twenty-four hour treatment with RIDR-PI-103 inhibited p-Akt, p-S6 (Ser240/244) and p-S6 (Ser235/236). We assessed the mechanism of activation of RIDR-PI-103, using glutathione or t-butyl hydrogen peroxide (TBHP) on the TDR cells in the presence or absence of RIDR-PI-103. Addition of the ROS scavenger glutathione to RIDR-PI-103 significantly rescued the cell proliferation in TDR cell lines while addition of the ROS inducer TBHP and RIDR-PI-103 inhibited cell proliferation in WM115 and WM983B TDR cell lines. Examining the efficacy of RIDR-PI-103 on BRAF and MEK inhibitor-resistant cells will expand possible treatment options and open avenues for the development of new ROS-based treatment therapies for BRAF-mutant melanoma patients.
Ellagic acid inhibits human colon cancer HCT-116 cells by regulating long noncoding RNAs
Authors: Zhao Jinlu , Li Guodong , Ren Yi , Zhang Zhicheng , Chen Hongsheng , Zhang Haopeng , Zhao Xingyu , Li Wang , Jia Yucheng , Guan Xue , Liu Ming
Published: February 2023

The natural phenolic compound ellagic acid exerts anti-cancer effects, including activity against colorectal cancer (CRC). Previously, we reported that ellagic acid can inhibit the proliferation of CRC, and can induce cell cycle arrest and apoptosis. This study investigated ellagic acid-mediated anticancer effects using the human colon cancer HCT-116 cell line. After 72 h of ellagic acid treatment, a total of 206 long noncoding RNAs (lncRNAs) with differential expression greater than 1.5-fold were identified (115 down-regulated and 91 up-regulated). Furthermore, the co-expression network analysis of differentially expressed lncRNA and mRNA showed that differential expressed lncRNA might be the target of ellagic acid activity in inhibiting CRC.