bluuebunny/crossref_metadata_2025 huggingface dataset:
Current Barriers to Clinical Liver Xenotransplantation
Authors: Cross-Najafi Arthur A. , Lopez Kevin , Isidan Abdulkadir , Park Yujin , Zhang Wenjun , Li Ping , Yilmaz Sezai , Akbulut Sami , Ekser Burcin
Published: February 2022

Preclinical trials of pig-to-nonhuman primate liver xenotransplantation have recently achieved longer survival times. However, life-threatening thrombocytopenia and coagulation dysregulation continue to limit preclinical liver xenograft survival times to less than one month despite various genetic modifications in pigs and intensive pharmacological support. Transfusion of human coagulation factors and complex immunosuppressive regimens have resulted in substantial improvements in recipient survival. The fundamental biological mechanisms of thrombocytopenia and coagulation dysregulation remain incompletely understood. Current studies demonstrate that porcine von Willebrand Factor binds more tightly to human platelet GPIb receptors due to increased O-linked glycosylation, resulting in increased human platelet activation. Porcine liver sinusoidal endothelial cells and Kupffer cells phagocytose human platelets in an asialoglycoprotein receptor 1-dependent and CD40/CD154-dependent manner, respectively. Porcine Kupffer cells phagocytose human platelets via a species-incompatible SIRPα/CD47 axis. Key drivers of coagulation dysregulation include constitutive activation of the extrinsic clotting cascade due to failure of porcine tissue factor pathway inhibitor to repress recipient tissue factor. Additionally, porcine thrombomodulin fails to activate human protein C when bound by human thrombin, leading to a hypercoagulable state. Combined genetic modification of these key genes may mitigate liver xenotransplantation-induced thrombocytopenia and coagulation dysregulation, leading to greater recipient survival in pig-to-nonhuman primate liver xenotransplantation and, potentially, the first pig-to-human clinical trial.
Advances of DNA Damage Repair-Related Drugs and Combination With Immunotherapy in Tumor Treatment
Authors: Wang Yumin , Duan Meihan , Peng Zhouying , Fan Ruohao , He Yuxiang , Zhang Hua , Xiong Wei , Jiang Weihong
Published: February 2022

Cancer therapy has been an important and popular area in cancer research. With medical technology developing, the appearance of various targeted drugs and immunotherapy offer more choices to cancer treatment. With the increase in drug use, people have found more and more cases in which tumors are resistant to DNA damage repair (DDR)-based drugs. Recently, the concept of combination therapy has been brought up in cancer research. It takes advantages of combining two or more therapies with different mechanisms, aiming to benefit from the synergistic effects and finally rescue patients irresponsive to single therapies. Combination therapy has the potential to improve current treatment of refractory and drug-resistant tumors. Among the methods used in combination therapy, DDR is one of the most popular methods. Recent studies have shown that combined application of DDR-related drugs and immunotherapies significantly improve the therapeutic outcomes of malignant tumors, especially solid tumors.
Helium-Hydrogen Synergistic Effects in Structural Materials Under Fusion Neutron Irradiation
Authors: Huang Jia , Liu Haocheng , Gao Zhiying , Su Yue , Liu Qingyuan , Ge Wei , Luo Fengping , Xia Songqin , Cao Liuxuan , Xue Jianming , Wang Yugang , Wang Chenxu
Published: February 2022

In fusion reactors, 14 MeV high-energy neutron irradiation of structural materials will produce large amounts of helium and hydrogen simultaneously with displacement defects. These He and H atoms will interact with displacement defects, leading to He-H synergistic effects and aggravating the irradiation damage. Currently, there exist no available high-flux fusion neutron sources. Additionally, the neutron energy spectrum and the generation of He and H in fission reactors or spallation neutron sources greatly differ from those in fusion reactors. Multi-ion beam irradiation is a promising method to emulate the synergistic effects induced by fusion neutron irradiation. This review summarizes the experimental studies on the He-H synergistic effects, and analyzes the effects of He and H on cavity evolution and swelling under multi-ion beam irradiation. The roles of various experimental factors are also discussed. More systematically controlled experiments are suggested to develop a comprehensive understanding of He-H synergistic effects in structural materials.
Definition of Acute Respiratory Distress Syndrome on the Plateau of Xining, Qinghai: A Verification of the Berlin Definition Altitude-PaO2/FiO2-Corrected Criteria
Authors: Liu Xiaoqin , Pan Chun , Si Lining , Tong Shijun , Niu Yi , Qiu Haibo , Gan Guifen
Published: February 2022

Background

Acute respiratory distress syndrome (ARDS) is a common critical respiratory illness. Hypoxia at high altitude is a factor that influences the progression of ARDS. Currently, we lack clear diagnostic criteria for high-altitude ARDS. The purpose of this study was to determine the value of the application of the Berlin Definition altitude-PaO2/FiO2-corrected criteria for ARDS in Xining, Qinghai (2,261 m).

Methods

We retrospectively analyzed the clinical data of patients with ARDS admitted to the Department of Critical Care Medicine of the Affiliated Hospital of Qinghai University from January 2018 to December 2018. The severity of ARDS was categorized according to the Berlin Definition, Berlin Definition altitude-PaO2/FiO2-corrected criteria, and the diagnostic criteria for acute lung injury (ALI)/ARDS at high altitudes in Western China (Zhang criteria). In addition, the differences between the three criteria were compared.

Results

Among 1,221 patients, 512 were treated with mechanical ventilation. In addition, 253 met the Berlin Definition, including 49 (19.77%) with mild ARDS, 148 (58.50%) with moderate ARDS, and 56 (22.13%) with severe ARDS. A total of 229 patients met the altitude-PaO2/FiO2-corrected criteria, including 107 with mild ARDS (46.72%), 84 with moderate ARDS (36.68%), and 38 (16.59%) with severe ARDS. Intensive care unit (ICU) mortality increased with the severity of ARDS (mild, 17.76%; moderate, 21.43%; and severe, 47.37%). Twenty-eight-day mortality increased with worsening ARDS (mild 23.36% vs. moderate 44.05% vs. severe 63.16%) (p < 0.001). There were 204 patients who met the Zhang criteria, including 87 (42.65%) with acute lung injury and 117 (57.35%) with ARDS. The area under receiver operating characteristics (AUROCs) of the Berlin Definition, the altitude-P/F-corrected criteria, and the Zhang criteria were 0.6675 (95% CI 0.5866–0.7484), 0.6216 (95% CI 0.5317–0.7116), and 0.6050 (95% CI 0.5084–0.7016), respectively. There were no statistically significant differences between the three diagnostic criteria.

Conclusion

For Xining, Qinghai, the altitude-PaO2/FiO2-corrected criteria for ARDS can distinguish the severity of ARDS, but these results need to be confirmed in a larger sample and in multicenter clinical studies.

Clinical Trial Registration

ClinicalTrials.gov, identifier: NCT04199650.
Screening of Common Retinal Diseases Using Six-Category Models Based on EfficientNet
Authors: Zhu Shaojun , Lu Bing , Wang Chenghu , Wu Maonian , Zheng Bo , Jiang Qin , Wei Ruili , Cao Qixin , Yang Weihua
Published: February 2022

Purpose

A six-category model of common retinal diseases is proposed to help primary medical institutions in the preliminary screening of the five common retinal diseases.

Methods

A total of 2,400 fundus images of normal and five common retinal diseases were provided by a cooperative hospital. Two six-category deep learning models of common retinal diseases based on the EfficientNet-B4 and ResNet50 models were trained. The results from the six-category models in this study and the results from a five-category model in our previous study based on ResNet50 were compared. A total of 1,315 fundus images were used to test the models, the clinical diagnosis results and the diagnosis results of the two six-category models were compared. The main evaluation indicators were sensitivity, specificity, F1-score, area under the curve (AUC), 95% confidence interval, kappa and accuracy, and the receiver operator characteristic curves of the two six-category models were compared in the study.

Results

The diagnostic accuracy rate of EfficientNet-B4 model was 95.59%, the kappa value was 94.61%, and there was high diagnostic consistency. The AUC of the normal diagnosis and the five retinal diseases were all above 0.95. The sensitivity, specificity, and F1-score for the diagnosis of normal fundus images were 100, 99.9, and 99.83%, respectively. The specificity and F1-score for RVO diagnosis were 95.68, 98.61, and 93.09%, respectively. The sensitivity, specificity, and F1-score for high myopia diagnosis were 96.1, 99.6, and 97.37%, respectively. The sensitivity, specificity, and F1-score for glaucoma diagnosis were 97.62, 99.07, and 94.62%, respectively. The sensitivity, specificity, and F1-score for DR diagnosis were 90.76, 99.16, and 93.3%, respectively. The sensitivity, specificity, and F1-score for MD diagnosis were 92.27, 98.5, and 91.51%, respectively.

Conclusion

The EfficientNet-B4 model was used to design a six-category model of common retinal diseases. It can be used to diagnose the normal fundus and five common retinal diseases based on fundus images. It can help primary doctors in the screening for common retinal diseases, and give suitable suggestions and recommendations. Timely referral can improve the efficiency of diagnosis of eye diseases in rural areas and avoid delaying treatment.
Physiological Changes in Subjects Exposed to Accidental Hypothermia: An Update
Authors: Bjertnæs Lars J. , Næsheim Torvind O. , Reierth Eirik , Suborov Evgeny V. , Kirov Mikhail Y. , Lebedinskii Konstantin M. , Tveita Torkjel
Published: February 2022

Background

Accidental hypothermia (AH) is an unintended decrease in body core temperature (BCT) to below 35°C. We present an update on physiological/pathophysiological changes associated with AH and rewarming from hypothermic cardiac arrest (HCA).

Temperature Regulation and Metabolism

Triggered by falling skin temperature, Thyrotropin-Releasing Hormone (TRH) from hypothalamus induces release of Thyroid-Stimulating Hormone (TSH) and Prolactin from pituitary gland anterior lobe that stimulate thyroid generation of triiodothyronine and thyroxine (T4). The latter act together with noradrenaline to induce heat production by binding to adrenergic β3-receptors in fat cells. Exposed to cold, noradrenaline prompts degradation of triglycerides from brown adipose tissue (BAT) into free fatty acids that uncouple metabolism to heat production, rather than generating adenosine triphosphate. If BAT is lacking, AH occurs more readily.

Cardiac Output

Assuming a 7% drop in metabolism per °C, a BCT decrease of 10°C can reduce metabolism by 70% paralleled by a corresponding decline in CO. Consequently, it is possible to maintain adequate oxygen delivery provided correctly performed cardiopulmonary resuscitation (CPR), which might result in approximately 30% of CO generated at normal BCT.

Liver and Coagulation

AH promotes coagulation disturbances following trauma and acidosis by reducing coagulation and platelet functions. Mean prothrombin and partial thromboplastin times might increase by 40–60% in moderate hypothermia. Rewarming might release tissue factor from damaged tissues, that triggers disseminated intravascular coagulation. Hypothermia might inhibit platelet aggregation and coagulation.

Kidneys

Renal blood flow decreases due to vasoconstriction of afferent arterioles, electrolyte and fluid disturbances and increasing blood viscosity. Severely deranged renal function occurs particularly in the presence of rhabdomyolysis induced by severe AH combined with trauma.

Conclusion

Metabolism drops 7% per °C fall in BCT, reducing CO correspondingly. Therefore, it is possible to maintain adequate oxygen delivery after 10°C drop in BCT provided correctly performed CPR. Hypothermia may facilitate rhabdomyolysis in traumatized patients. Victims suspected of HCA should be rewarmed before being pronounced dead. Rewarming avalanche victims of HCA with serum potassium > 12 mmol/L and a burial time >30 min with no air pocket, most probably be futile.
Inhibitors of Bacterial Extracellular Vesicles
Authors: Chen Jianwei , Zhang Hongfang , Wang Siqi , Du Yujie , Wei Bin , Wu Qiang , Wang Hong
Published: February 2022

Both Gram-positive and Gram-negative bacteria can secrete extracellular vesicles (EVs), which contain numerous active substances. EVs mediate bacterial interactions with their hosts or other microbes. Bacterial EVs play a double-edged role in infections through various mechanisms, including the delivery of virulence factors, modulating immune responses, mediating antibiotic resistance, and inhibiting competitive microbes. The spread of antibiotic resistance continues to represent a difficult clinical challenge. Therefore, the investigation of novel therapeutics is a valuable research endeavor for targeting antibiotic-resistant bacterial infections. As a pathogenic substance of bacteria, bacterial EVs have gained increased attention. Thus, EV inhibitors are expected to function as novel antimicrobial agents. The inhibition of EV production, EV activity, and EV-stimulated inflammation are considered potential pathways. This review primarily introduces compounds that effectively inhibit bacterial EVs and evaluates the prospects of their application.
Optimal Experimental Design Based on Two-Dimensional Likelihood Profiles
Authors: Litwin Tim , Timmer Jens , Kreutz Clemens
Published: February 2022

Dynamic behavior of biological systems is commonly represented by non-linear models such as ordinary differential equations. A frequently encountered task in such systems is the estimation of model parameters based on measurement of biochemical compounds. Non-linear models require special techniques to estimate the uncertainty of the obtained model parameters and predictions, e.g. by exploiting the concept of the profile likelihood. Model parameters with significant uncertainty associated with their estimates hinder the interpretation of model results. Informing these model parameters by optimal experimental design minimizes the additional amount of data and therefore resources required in experiments. However, existing techniques of experimental design either require prior parameter distributions in Bayesian approaches or do not adequately deal with the non-linearity of the system in frequentist approaches. For identification of optimal experimental designs, we propose a two-dimensional profile likelihood approach, providing a design criterion which meaningfully represents the expected parameter uncertainty after measuring data for a specified experimental condition. The described approach is implemented into the open source toolbox Data2Dynamics in Matlab. The applicability of the method is demonstrated on an established systems biology model. For this demonstration, available data has been censored to simulate a setting in which parameters are not yet well determined. After determining the optimal experimental condition from the censored ones, a realistic evaluation was possible by re-introducing the censored data point corresponding to the optimal experimental condition. This provided a validation that our method is feasible in real-world applications. The approach applies to, but is not limited to, models in systems biology.
Clozapine Reverses Dysfunction of Glutamatergic Neurons Derived From Clozapine-Responsive Schizophrenia Patients
Authors: Hribkova Hana , Svoboda Ondrej , Bartecku Elis , Zelinkova Jana , Horinkova Jana , Lacinova Lubica , Piskacek Martin , Lipovy Bretislav , Provaznik Ivo , Glover Joel C. , Kasparek Tomas , Sun Yuh-Man
Published: February 2022

The cellular pathology of schizophrenia and the potential of antipsychotics to target underlying neuronal dysfunctions are still largely unknown. We employed glutamatergic neurons derived from induced pluripotent stem cells (iPSC) obtained from schizophrenia patients with known histories of response to clozapine and healthy controls to decipher the mechanisms of action of clozapine, spanning from molecular (transcriptomic profiling) and cellular (electrophysiology) levels to observed clinical effects in living patients. Glutamatergic neurons derived from schizophrenia patients exhibited deficits in intrinsic electrophysiological properties, synaptic function and network activity. Deficits in K+ and Na+ currents, network behavior, and glutamatergic synaptic signaling were restored by clozapine treatment, but only in neurons from clozapine-responsive patients. Moreover, neurons from clozapine-responsive patients exhibited a reciprocal dysregulation of gene expression, particularly related to glutamatergic and downstream signaling, which was reversed by clozapine treatment. Only neurons from clozapine responders showed return to normal function and transcriptomic profile. Our results underscore the importance of K+ and Na+ channels and glutamatergic synaptic signaling in the pathogenesis of schizophrenia and demonstrate that clozapine might act by normalizing perturbances in this signaling pathway. To our knowledge this is the first study to demonstrate that schizophrenia iPSC-derived neurons exhibit a response phenotype correlated with clinical response to an antipsychotic. This opens a new avenue in the search for an effective treatment agent tailored to the needs of individual patients.
Efficacy of LED Photobiomodulation for Functional and Axonal Regeneration After Facial Nerve Section-Suture
Authors: Er-Rouassi Hafsa , Benichou Luc , Lyoussi Badiaa , Vidal Catherine
Published: February 2022

Facial nerve damage can lead to partial or total facial nerve palsy. Photobiomodulation has been reported to improve and accelerate functional recovery following peripheral nerve lesion, depending on the type of lesion and the light exposure parameters used. The aim of this study was to investigate the effects of infrared exposure on functional and axonal regeneration after section-suture of the distal branches of the facial nerve: the buccal and marginal mandibular branches and the distal pes. The animals underwent surgery and were irradiated with infrared light at 850 nm twice daily from day 1 to day 16. The recovery of facial function was then studied at both the behavioral and morphological levels. Behavioral analyses were performed by videoscoring with a high-speed camera and using various devices to assess the recovery of whisker movement on the lesioned side from day 1 to day 30. We also assessed nasal deviation toward the intact side and the ability to close the ipsilateral eyelid completely from day 1 to day 38 and from day 1 to day 50, respectively. For morphological analyses, we assessed the re-establishment of facial motoneuron labeling with Fluorogold®, an immunofluorescent retrograde marker of axonal transport injected into the vibrissae, on D10, D14 and D30. We found that whisker movements recovery was significantly faster in treated than in control mice. A complete disappearance of nasal deviation was observed at 2 weeks in infrared-treated lesioned mice and at 5 weeks in controls. Complete eyelid closure was observed 3 weeks after surgery in treated animals and 6 weeks after surgery in controls. Finally, normal fluorogold labeling of the facial nuclei complex was restored 30 days after surgery in the treated animals, but no such restoration was ever observed in control animals. In conclusion, our data show that IR treatment at a distal site has a significant positive effect on facial nerve recovery. These findings pave the way for the clinical use of infrared photobiomodulation in patients with nerve lesions.
The Epidemiology and Phenotypes of Ocular Manifestations in Childhood and Juvenile Myasthenia Gravis: A Review
Authors: Heckmann Jeannine M. , Europa Tarin A. , Soni Aayesha J. , Nel Melissa
Published: February 2022

Myasthenia gravis (MG) appears to have a similar incidence among adult populations worldwide. However, epidemiological and phenotypic differences have been noted among children and juveniles with MG. We reviewed the literature on childhood- and juvenile-onset MG among different populations, with the focus on ocular involvement, antibody profiles, the genetic susceptibility to juvenile MG phenotypes, the use of immune treatments, and the reported responses of extraocular muscles to therapies. Although epidemiological studies used different methodologies, reports from Asia, compared to Europe, showed more than two-fold higher proportions of prepubertal onset (before 12 years) vs. postpubertal-onset juveniles with MG. Compared to European children, ocular MG was 4-fold more frequent among Asian children, and 2–3-fold more frequent among children with African ancestry both in prepubertal and postpubertal ages at onset. These results suggest genetic influences. In Asia, HLA-B*46 and DRB1*09 appeared overrepresented in children with ocular MG. In Europe, children with MG had a significantly higher rate of transforming from ocular to generalized disease and with an overrepresentation of HLADRB1*04. Although treatment regimens vary widely and the responses to immune therapies of the ocular muscles involved in MG were generally poorly described, there were indications that earlier use of steroid therapy may have better outcomes. Reports of treatment-resistant ophthalmoplegia may be more frequent in African and Asian juvenile MG cohorts compared to Europeans. Genetic and muscle gene expression studies point to dysregulated muscle atrophy signaling and mitochondrial metabolism pathways as pathogenetic mechanisms underpinning treatment-resistant ophthalmoplegia in susceptible individuals. In conclusion, phenotypic differences in juveniles with ocular manifestations of MG were evident in different populations suggesting pathogenetic influences. Treatment responses in MG-associated ocular disease should attract more careful descriptive reports. In MG, extraocular muscles may be vulnerable to critical periods of poor force generation and certain individuals may be particularly susceptible to developing treatment-resistant ophthalmoplegia. The development of prognostic biomarkers to identify these susceptible individuals is an unmet need.
Advanced Imaging Techniques for Newly Diagnosed and Recurrent Gliomas
Authors: Carrete Luis R. , Young Jacob S. , Cha Soonmee
Published: February 2022

Management of gliomas following initial diagnosis requires thoughtful presurgical planning followed by regular imaging to monitor treatment response and survey for new tumor growth. Traditional MR imaging modalities such as T1 post-contrast and T2-weighted sequences have long been a staple of tumor diagnosis, surgical planning, and post-treatment surveillance. While these sequences remain integral in the management of gliomas, advances in imaging techniques have allowed for a more detailed characterization of tumor characteristics. Advanced MR sequences such as perfusion, diffusion, and susceptibility weighted imaging, as well as PET scans have emerged as valuable tools to inform clinical decision making and provide a non-invasive way to help distinguish between tumor recurrence and pseudoprogression. Furthermore, these advances in imaging have extended to the operating room and assist in making surgical resections safer. Nevertheless, surgery, chemotherapy, and radiation treatment continue to make the interpretation of MR changes difficult for glioma patients. As analytics and machine learning techniques improve, radiomics offers the potential to be more quantitative and personalized in the interpretation of imaging data for gliomas. In this review, we describe the role of these newer imaging modalities during the different stages of management for patients with gliomas, focusing on the pre-operative, post-operative, and surveillance periods. Finally, we discuss radiomics as a means of promoting personalized patient care in the future.
A Ribosomal Perspective on Neuronal Local Protein Synthesis
Authors: Dastidar Sudhriti Ghosh , Nair Deepak
Published: February 2022

Continued mRNA translation and protein production are critical for various neuronal functions. In addition to the precise sorting of proteins from cell soma to distant locations, protein synthesis allows a dynamic remodeling of the local proteome in a spatially variable manner. This spatial heterogeneity of protein synthesis is shaped by several factors such as injury, guidance cues, developmental cues, neuromodulators, and synaptic activity. In matured neurons, thousands of synapses are non-uniformly distributed throughout the dendritic arbor. At any given moment, the activity of individual synapses varies over a wide range, giving rise to the variability in protein synthesis. While past studies have primarily focused on the translation factors or the identity of translated mRNAs to explain the source of this variation, the role of ribosomes in this regard continues to remain unclear. Here, we discuss how several stochastic mechanisms modulate ribosomal functions, contributing to the variability in neuronal protein expression. Also, we point out several underexplored factors such as local ion concentration, availability of tRNA or ATP during translation, and molecular composition and organization of a compartment that can influence protein synthesis and its variability in neurons.
Real-Time fMRI Neurofeedback Training Changes Brain Degree Centrality and Improves Sleep in Chronic Insomnia Disorder: A Resting-State fMRI Study
Authors: Li Xiaodong , Li Zhonglin , Zou Zhi , Wu Xiaolin , Gao Hui , Wang Caiyun , Zhou Jing , Qi Fei , Zhang Miao , He Junya , Qi Xin , Yan Fengshan , Dou Shewei , Zhang Hongju , Tong Li , Li Yongli
Published: February 2022

Background

Chronic insomnia disorder (CID) is considered a major public health problem worldwide. Therefore, innovative and effective technical methods for studying the pathogenesis and clinical comprehensive treatment of CID are urgently needed.

Methods

Real-time fMRI neurofeedback (rtfMRI-NF), a new intervention, was used to train 28 patients with CID to regulate their amygdala activity for three sessions in 6 weeks. Resting-state fMRI data were collected before and after training. Then, voxel-based degree centrality (DC) method was used to explore the effect of rtfMRI-NF training. For regions with altered DC, we determined the specific connections to other regions that most strongly contributed to altered functional networks based on DC. Furthermore, the relationships between the DC value of the altered regions and changes in clinical variables were determined.

Results

Patients with CID showed increased DC in the right postcentral gyrus, Rolandic operculum, insula, and superior parietal gyrus and decreased DC in the right supramarginal gyrus, inferior parietal gyrus, angular gyrus, middle occipital gyrus, and middle temporal gyrus. Seed-based functional connectivity analyses based on the altered DC regions showed more details about the altered functional networks. Clinical scores in Pittsburgh sleep quality index, insomnia severity index (ISI), Beck depression inventory, and Hamilton anxiety scale decreased. Furthermore, a remarkable positive correlation was found between the changed ISI score and DC values of the right insula.

Conclusions

This study confirmed that amygdala-based rtfMRI-NF training altered the intrinsic functional hubs, which reshaped the abnormal functional connections caused by insomnia and improved the sleep of patients with CID. These findings contribute to our understanding of the neurobiological mechanism of rtfMRI-NF in insomnia treatment. However, additional double-blinded controlled clinical trials with larger sample sizes need to be conducted to confirm the effect of rtfMRI-NF from this initial study.
Rediscovering the Potential of Multifaceted Orphan Legume Grasspea- a Sustainable Resource With High Nutritional Values
Authors: Ramya K. R. , Tripathi Kuldeep , Pandey Anjula , Barpete Surendra , Gore Padmavati G. , Raina Archana Peshin , Khawar Khalid Mahmood , Swain Nigamananda , Sarker Ashutosh
Published: February 2022

The genus Lathyrus consists of more than 184 herbaceous annual and perennial species suitable for multifaceted sustainable food and feed production system in the arid and semi-arid regions of the world. The grasspea is a promising source of protein nutrition. However, its potential is not being utilized fully due to the presence of neurotoxin content (β-N-oxalyl-l-α, β diaminopropionic acid, β-ODAP), a causal agent of non-reversible lower limbs paralysis. The high protein contents in seeds and leaves with ~90% digestibility make it sustainable super food to beat protein malnutrition in future. Therefore, it is desired to breed new grasspea cultivars with low β-ODAP contents. Limited research has been carried out to date about this feature. A draft genome sequence of grasspea has been recently published that is expected to play a vital role in breeding and identifying the genes responsible for biosynthesis pathway of β-ODAP contents in grasspea. Efforts to increase awareness about the importance of genus Lathyrus and detoxify β-ODAP in grasspea are desired and are in progress. Presently, in South Asia, systematic and dedicated efforts to support the farmers in the grasspea growing regions by disseminating low β-ODAP varieties has resulted in a considerable improvement in reducing the incidence of neurolathyrism. It is expected that the situation will improve further by mainstreaming grasspea cultivation by implementing different approaches such as the development and use of low β-ODAP varieties, strengthening government policies and improved detox methods. The present review provides insight into the multifaceted characteristics of sustainable nutritious grasspea in the global and Indian perspective.
Current Practice of Fluid Maintenance and Replacement Therapy in Mechanically Ventilated Critically Ill Children: A European Survey
Authors: Arrahmani Ismail , Ingelse Sarah A. , van Woensel Job B. M. , Bem Reinout A. , Lemson Joris
Published: February 2022

Appropriate fluid management in mechanically ventilated critically ill children remains an important challenge and topic of active discussion in pediatric intensive care medicine. An increasing number of studies show an association between a positive fluid balance or fluid overload and adverse outcomes. However, to date, no international consensus regarding fluid management or removal strategies exists. The aim of this study was to obtain more insight into the current clinical practice of fluid therapy in mechanically ventilated critically ill children. On behalf of the section of cardiovascular dynamics of the European Society of Pediatric and Neonatal Intensive Care (ESPNIC) we conducted an anonymous survey among pediatric intensive care unit (PICU) specialists in Europe regarding fluid overload and management. A total of 107 study participants responded to the survey. The vast majority of respondents considers fluid overload to be a common phenomenon in mechanically ventilated children and believes this complication is associated with adverse outcomes, such as mortality and duration of respiratory support. Yet, only 75% of the respondents administers a lower volume of fluids (reduction of 20% of normal intake) to mechanically ventilated critically ill children on admission. During PICU stay, a cumulative fluid balance of more than 5% is considered to be an indication to reduce fluid intake and start diuretic treatment in most respondents. Next to fluid balance calculation, the occurrence of peripheral and/or pulmonary edema (as assessed including by chest radiograph and lung ultrasound) was considered an important clinical sign of fluid overload entailing further therapeutic action. In conclusion, fluid overload in mechanically ventilated critically ill children is considered an important problem among PICU specialists, but there is great heterogeneity in the current clinical practice to avoid this complication. We identify a great need for further prospective and randomized investigation of the effects of (restrictive) fluid strategies in the PICU.
Decreased Risk of Anxiety in Diabetic Patients Receiving Glucagon-like Peptide-1 Receptor Agonist: A Nationwide, Population-Based Cohort Study
Authors: Tsai Wen-Hsuan , Sung Fung-Chang , Chiu Lu-Ting , Shih Ying-Hsiu , Tsai Ming-Chieh , Wu Shu-I
Published: February 2022

Background: Previous findings on using Glucagon-like peptide-1 receptor agonist (GLP1-RA) as an antidepressant were conflicting, lacking large-scale studies. We used population-based data to investigate depression and anxiety risk in diabetic patients receiving the medication.

Methods: From claims records of the National Health Insurance Research Database (NHIRD) of Taiwan, we identified cohorts of 10,690 GLP1-RA users and 42,766 propensity score-matched patients without GLP1-RA use from patients with diabetes mellitus (DM) diagnosed in 2011–2017, matched by age, gender, index year, occupation, urbanization, comorbidities, and medications. Incidence, hazard ratios (HR) and 95% confidence interval (CI) of depression and/or anxiety were estimated by the end of 2017.

Results: The overall combined incidence of anxiety and/or depression was lower in GLP1-RA users than in non-users (6.80 versus 9.36 per 1,000 person-years), with an adjusted HR adjusted hazard ratio (aHR) of 0.8 (95% CI: 0.67–0.95) after controlling for covariates. The absolute incidence reduction was greater in anxiety (2.13 per 1,000 person-years) than in depression (0.41 per 1,000 person-years). The treatment effectiveness was significant for women. Patients taking GLP1-RA for longer than 180 days had the incidence of anxiety reduced to 2.93 per 1,000 person-years, with an aHR of 0.41 (95%CI: 0.27–0.61), compared to non-users. Dulaglutide could significantly decrease risks of both anxiety and depression.

Conclusion: Patients with DM receiving GLP1-RA therapy have a greater reduction of the risk of anxiety than that of depression. Our findings strengthen previous research that advocated possible anti-depressant or anxiolytic effects of GLP1-RA and may lead to improved treatment adherence among patients with DM.
The Role of Trabectedin in Soft Tissue Sarcoma
Authors: Nakamura Tomoki , Sudo Akihiro
Published: February 2022

Background: Systemic chemotherapy for advanced disease is another therapeutic option in the management of metastases in soft tissue sarcoma (STS). Doxorubicin either alone or in combination with ifosfamide has been used as first-line chemotherapy. Furthermore, in the past decade, new drugs have been shown to be effective in the treatment of advanced STS after the failure of first-line anthracycline-based chemotherapy: trabectedin, pazopanib and eribulin. However, the appropriate usage of these agents has not been established.

Methods: We summarized clinical trials of trabectedin focusing on the efficacy and toxicity of trabectedin in the treatment of STS.

Results: Trabectedin can be administered safely and effectively to the patients with advanced STS at second line setting or later. Although trabectedin may be effective as first-line treatment in selected patients, anthracycline-based chemotherapy should be recommended because no regimen in addition to trabectedin has proved to be unequivocally superior to doxorubicin as the first-line treatment for locally advanced or metastatic STS. Nucleotide excision repair (NER) and homologous recombination (HRe) repair may be of particular importance as efficacy of trabectedin.

Conclusion: Trabectedin has shown a favorable toxicity profile and is an alternative therapeutic option in patients with advanced STS.
Long-Term Cultivation of Human Atrial Myocardium
Authors: Klumm Maximilian J. , Heim Christian , Fiegle Dominik J. , Weyand Michael , Volk Tilmann , Seidel Thomas
Published: February 2022

Organotypic culture of human ventricular myocardium is emerging in basic and translational cardiac research. However, few institutions have access to human ventricular tissue, whereas atrial tissue is more commonly available and important for studying atrial physiology. This study presents a method for long-term cultivation of beating human atrial myocardium. After written informed consent, tissues from the right-atrial appendage were obtained from patients with sinus rhythm undergoing open heart surgery with cardiopulmonary bypass. Trabeculae (pectinate muscles) prepared from the samples were installed into cultivation chambers at 37°C with a diastolic preload of 500 μN. After 2 days with 0.5 Hz pacing, stimulation frequency was set to 1 Hz. Contractile force was monitored continuously. Beta-adrenergic response, refractory period (RP) and maximum captured frequency (fmax) were assessed periodically. After cultivation, viability and electromechanical function were investigated, as well as the expression of several genes important for intracellular Ca2+ cycling and electrophysiology. Tissue microstructure was analyzed by confocal microscopy. We cultivated 19 constantly beating trabeculae from 8 patient samples for 12 days and 4 trabeculae from 3 specimen for 21 days. Functional parameters were compared directly after installation (0 d) with those after 12 d in culture. Contraction force was 384 ± 69 μN at 0 d and 255 ± 90 μN at 12 d (p = 0.8, n = 22), RP 480 ± 97 ms and 408 ± 78 ms (p = 0.3, n = 9), fmax 3.0 ± 0.5 Hz and 3.8 ± 0.5 Hz (p = 0.18, n = 9), respectively. Application of 100 nM isoprenaline to 11 trabeculae at 7 d increased contraction force from 168 ± 35 μN to 361 ± 60 μN (p < 0.01), fmax from 6.4 ± 0.6 Hz to 8.5 ± 0.4 Hz (p < 0.01) and lowered RP from 319 ± 22 ms to 223 ± 15 ms. CACNA1c (L-type Ca2+ channel subunit) and GJA1 (connexin-43) mRNA expressions were not significantly altered at 12 d vs 0 d, while ATP2A (SERCA) and KCNJ4 (Kir2.3) were downregulated, and KCNJ2 (Kir2.1) was upregulated. Simultaneous Ca2+ imaging and force recording showed preserved excitation-contraction coupling in cultivated trabeculae. Confocal microscopy indicated preserved cardiomyocyte structure, unaltered amounts of extracellular matrix and gap junctions. MTT assays confirmed viability at 12 d. We established a workflow that allows for stable cultivation and functional analysis of beating human atrial myocardium for up to 3 weeks. This method may lead to novel insights into the physiology and pathophysiology of human atrial myocardium.
Wheat Breeding, Transcription Factories, and Genetic Interactions: New Perspectives
Authors: Flavell Richard B.
Published: February 2022

Epistatic interactions and negative heterosis have been shown to be associated with interchromosomal interactions in wheat. Physical gene-gene interactions between co-regulated genes clustered in “transcription factories” have been documented, and a genome-wide atlas of functionally paired, interacting regulatory elements and genes of wheat recently produced. Integration of these new studies on gene and regulatory element interactions, co-regulation of gene expression in “transcription factories,” and epigenetics generates new perspectives for wheat breeding and trait enhancement.
Advances in the Understanding of Reactive Oxygen Species-Dependent Regulation on Seed Dormancy, Germination, and Deterioration in Crops
Authors: Li Wenjun , Niu Yongzhi , Zheng Yunye , Wang Zhoufei
Published: February 2022

Reactive oxygen species (ROS) play an essential role in the regulation of seed dormancy, germination, and deterioration in plants. The low level of ROS as signaling particles promotes dormancy release and triggers seed germination. Excessive ROS accumulation causes seed deterioration during seed storage. Maintaining ROS homeostasis plays a central role in the regulation of seed dormancy, germination, and deterioration in crops. This study highlights the current advances in the regulation of ROS homeostasis in dry and hydrated seeds of crops. The research progress in the crosstalk between ROS and hormones involved in the regulation of seed dormancy and germination in crops is mainly summarized. The current understandings of ROS-induced seed deterioration are reviewed. These understandings of ROS-dependent regulation on seed dormancy, germination, and deterioration contribute to the improvement of seed quality of crops in the future.
Phytochrome A Mediates the Disassembly of Processing Bodies in Far-Red Light
Authors: Schwenk Philipp , Hiltbrunner Andreas
Published: February 2022

Phytochromes are red- and far-red light receptors that control the growth and development of plants, enabling them to respond adequately to changing light conditions. It has been shown that halted mRNAs stored in RNA granules called processing bodies are released upon light perception and contribute to the adaptation to the light environment. However, the photophysiological background of this process is largely unknown. We found that light of different wavelengths can trigger the disassembly of processing bodies in a dose- and time-dependent manner. We show that phytochromes control this process in red- and far-red light and that cytoplasmic phytochrome A is sufficient and necessary for the far-red light-induced disassembly of processing bodies. This adds a novel, unexpected cytoplasmic function to the processes controlled by phytochrome A. Overall, our findings suggest a role of phytochromes in the control of translationally halted mRNAs that are stored in processing bodies. We expect our findings to facilitate understanding of how light and environmental cues control the assembly and disassembly of processing bodies, which could have broader implications for the regulation of non-membranous organelles in general.
Phytochrome B Positively Regulates Red Light-Mediated ER Stress Response in Arabidopsis
Authors: Ahn Gyeongik , Jung In Jung , Cha Joon-Yung , Jeong Song Yi , Shin Gyeong-Im , Ji Myung Geun , Kim Min Gab , Lee Sang Yeol , Kim Woe-Yeon
Published: February 2022

Light plays a crucial role in plant growth and development, and light signaling is integrated with various stress responses to adapt to different environmental changes. During this process, excessive protein synthesis overwhelms the protein-folding ability of the endoplasmic reticulum (ER), causing ER stress. Although crosstalk between light signaling and ER stress response has been reported in plants, the molecular mechanisms underlying this crosstalk are poorly understood. Here, we demonstrate that the photoreceptor phytochrome B (phyB) induces the expression of ER luminal protein chaperones as well as that of unfolded protein response (UPR) genes. The phyB-5 mutant was less sensitive to tunicamycin (TM)-induced ER stress than were the wild-type plants, whereas phyB-overexpressing plants displayed a more sensitive phenotype under white light conditions. ER stress response genes (BiP2 and BiP3), UPR-related bZIP transcription factors (bZIP17, bZIP28, and bZIP60), and programmed cell death (PCD)-associated genes (OXI1, NRP1, and MC8) were upregulated in phyB-overexpressing plants, but not in phyB-5, under ER stress conditions. The ER stress-sensitive phenotype of phyB-5 under red light conditions was eliminated with a reduction in photo-equilibrium by far-red light and darkness. The N-terminal domain of phyB is essential for signal transduction of the ER stress response in the nucleus, which is similar to light signaling. Taken together, our results suggest that phyB integrates light signaling with the UPR to relieve ER stress and maintain proper plant growth.
Controlling the Gate: The Functions of the Cytoskeleton in Stomatal Movement
Authors: Li Yihao , Zhang Xin , Zhang Yi , Ren Haiyun
Published: February 2022

Stomata are specialized epidermal structures composed of two guard cells and are involved in gas and water exchange between plants and the environment and pathogen entry into the plant interior. Stomatal movement is a response to many internal and external stimuli to increase adaptability to environmental change. The cytoskeleton, including actin filaments and microtubules, is highly dynamic in guard cells during stomatal movement, and the destruction of the cytoskeleton interferes with stomatal movement. In this review, we discuss recent progress on the organization and dynamics of actin filaments and microtubule network in guard cells, and we pay special attention to cytoskeletal-associated protein-mediated cytoskeletal rearrangements during stomatal movement. We also discuss the potential mechanisms of stomatal movement in relation to the cytoskeleton and attempt to provide a foundation for further research in this field.
Asymmetric Communication and Internal Exclusion in Everyday Political Talk
Authors: Schmitt-Beck Rüdiger
Published: February 2022

Citizens' everyday political talk is the foundation and mainspring of deliberative democracy. Accordingly, citizens' equal and inclusive participation in political discussions is deemed crucial for this “talk-centric” vision of normatively superior democratic will-formation. Yet, discussing politics is a quite demanding activity, and research has shown that de facto not everyone has equal access to this arena of political communication. Some citizens talk about public affairs almost constantly, others more sparingly, and yet others not at all. These inequalities reflect imbalances in structural and psychological resources. Little is known, however, about what happens once individuals have entered conversations about public affairs. The article breaks new ground by examining communicative asymmetries that ordinary people experience when talking about politics with members of their overall and core networks. By muting their voices they disadvantage certain citizens, thus impairing the discursive equality that is essential for deliberative democracy. Drawing on a unique high-quality survey conducted in Germany, the article finds such experiences to take different forms of which some are quite widespread. Many citizens resort to passive listening and contribute little to unfolding conversations. Smaller shares misrepresent their true standpoints, change subjects to avoid problematic topics, drop out of unpleasant conversations, or feel silenced by other interlocutors. The article contextualizes these communicative asymmetries in the broader theoretical framework of deliberative democrats' conception of discursive inequality. To examine how they come about it proposes and tests a model of internal exclusion that refers to social structural inequality, psychological dispositions, and attributes of the discussant networks within which political conversations take place. Social structural inequality is found to be of limited relevance. Individuals' communicative efficacy and orientations toward political conflict are more important predictors of their ability to cope with the challenges of political talk than aspects of general politicization like political interest, attitude strength and internal efficacy. Encountering political disagreement is normatively central for deliberative democracy, but empirically it stands out as a powerful social driver of asymmetric communication. Its impact is strongly conditioned by individuals' structural attributes and psychological dispositions.