bluuebunny/crossref_metadata_2025 huggingface dataset:
Biochemical Characterization of Two Rhamnogalacturonan Lyases From Bacteroides ovatus ATCC 8483 With Preference for RG-I Substrates
Authors: Wang Weiyang , Wang Yibing , Yi Haoting , Liu Yang , Zhang Guojing , Zhang Le , Mayo Kevin H. , Yuan Ye , Zhou Yifa
Published: January 2022

Rhamnogalacturonan lyase (RGL) cleaves backbone α-1,4 glycosidic bonds between L-rhamnose and D-galacturonic acid residues in type I rhamnogalacturonan (RG-I) by β-elimination to generate RG oligosaccharides with various degrees of polymerization. Here, we cloned, expressed, purified and biochemically characterized two RGLs (Bo3128 and Bo4416) in the PL11 family from Bacteroides ovatus ATCC 8483. Bo3128 and Bo4416 displayed maximal activity at pH 9.5 and pH 6.5, respectively. Whereas the activity of Bo3128 could be increased 1.5 fold in the presence of 5 mM Ca2+, Bo4416 required divalent metal ions to show any enzymatic activity. Both of RGLs showed a substrate preference for RG-I compared to other pectin domains. Bo4416 and Bo3128 primarily yielded unsaturated RG oligosaccharides, with Bo3128 also producing them with short side chains, with yields of 32.4 and 62.4%, respectively. Characterization of both RGLs contribute to the preparation of rhamnogalacturonan oligosaccharides, as well as for the analysis of the fine structure of RG-I pectins.
The Activated Macrophage – A Tough Fortress for Virus Invasion: How Viruses Strike Back
Authors: Banete Andra , Barilo Julia , Whittaker Reese , Basta Sameh
Published: January 2022

Macrophages (Mφ) are innate immune cells with a variety of functional phenotypes depending on the cytokine microenvironment they reside in. Mφ exhibit distinct activation patterns that are found within a wide array of activation states ranging from the originally discovered classical pro-inflammatory (M1) to the anti-inflammatory (M2) with their multi-facades. M1 cells are induced by IFNγ + LPS, while M2 are further subdivided into M2a (IL-4), M2b (Immune Complex) and M2c (IL-10) based on their inducing stimuli. Not surprisingly, Mφ activation influences the outcome of viral infections as they produce cytokines that in turn activate cells of the adaptive immune system. Generally, activated M1 cells tend to restrict viral replication, however, influenza and HIV exploit inflammation to support their replication. Moreover, M2a polarization inhibits HIV replication at the post-integration level, while HCMV encoded hrIL-10 suppresses inflammatory reactions by facilitating M2c formation. Additionally, viruses such as LCMV and Lassa Virus directly suppress Mφ activation leading to viral chronicity. Here we review how Mφ activation affects viral infection and the strategies by which viruses manipulate Mφ polarization to benefit their own fitness. An understanding of these mechanisms is important for the development of novel immunotherapies that can sway Mφ phenotype to inhibit viral replication.
The Occurrence of Malignancy in Trypanosoma brucei brucei by Rapid Passage in Mice
Authors: Cai Xiao-Li , Li Su-Jin , Zhang Peng , Li Ziyin , Hide Geoff , Lai De-Hua , Lun Zhao-Rong
Published: January 2022

Pleomorphic Trypanosoma brucei are best known for their tightly controlled cell growth and developmental program, which ensures their transmissibility and host fitness between the mammalian host and insect vector. However, after long-term adaptation in the laboratory or by natural evolution, monomorphic parasites can be derived. The origin of these monomorphic forms is currently unclear. Here, we produced a series of monomorphic trypanosome stocks by artificially syringe-passage in mice, creating snapshots of the transition from pleomorphism to monomorphism. We then compared these artificial monomorphic trypanosomes, alongside several naturally monomorphic T. evansi and T. equiperdum strains, with the pleomorphic T. brucei. In addition to failing to generate stumpy forms in animal bloodstream, we found that monomorphic trypanosomes from laboratory and nature exhibited distinct differentiation patterns, which are reflected by their distinct differentiation potential and transcriptional changes. Lab-adapted monomorphic trypanosomes could still be induced to differentiate, and showed only minor transcriptional differences to that of the pleomorphic slender forms but some accumulated differences were observed as the passages progress. All naturally monomorphic strains completely fail to differentiate, corresponding to their impaired differentiation regulation. We propose that the natural phenomenon of trypanosomal monomorphism is actually a malignant manifestation of protozoal cells. From a disease epidemiological and evolutionary perspective, our results provide evidence for a new way of thinking about the origin of these naturally monomorphic strains, the malignant evolution of trypanosomes may raise some concerns. Additionally, these monomorphic trypanosomes may reflect the quantitative and qualitative changes in the malignant evolution of T. brucei, suggesting that single-celled protozoa may also provide the most primitive model of cellular malignancy, which could be a primitive and inherent biological phenomenon of eukaryotic organisms from protozoans to mammals.
Tau Knockout and α-Synuclein A53T Synergy Modulated Parvalbumin-Positive Neurons Degeneration Staging in Substantia Nigra Pars Reticulata of Parkinson’s Disease-Liked Model
Authors: Zheng Meige , Liu Yanchang , Xiao Zhaoming , Jiao Luyan , Lin Xian
Published: January 2022

The loss of parvalbumin-positive (PV+) neurons in the substantia nigra pars reticulata (SNR) was observed in patients with end-stage Parkinson’s disease (PD) and our previously constructed old-aged Pitx3-A53Tα-Syn × Tau–/– triple transgenic mice model of PD. The aim of this study was to examine the progress of PV+ neurons loss. We demonstrated that, as compared with non-transgenic (nTg) mice, the accumulation of α-synuclein in the SNR of aged Pitx3-A53Tα-Syn × Tau–/– mice was increased obviously, which was accompanied by the considerable degeneration of PV+ neurons and the massive generation of apoptotic NeuN+TUNEL+ co-staining neurons. Interestingly, PV was not costained with TUNEL, a marker of apoptosis. PV+ neurons in the SNR may undergo a transitional stage from decreased expression of PV to increased expression of NeuN and then to TUNEL expression. In addition, the degeneration of PV+ neurons and the expression of NeuN were rarely observed in the SNR of nTg and the other triple transgenic mice. Hence, we propose that Tau knockout and α-syn A53T synergy modulate PV+ neurons degeneration staging in the SNR of aged PD-liked mice model, and NeuN may be suited for an indicator that suggests degeneration of SNR PV+ neurons. However, the molecular mechanism needs to be further investigated.
Associations Between Cognitive Function, Depression, and Olfactory Function in Elderly People With Dementia in Korea
Authors: Cha Hyegyeong , Kim Sisook , Son Yedong
Published: January 2022

Early detection is important for delaying or preventing cognitive impairment. Since olfactory dysfunction and depression are common symptoms of cognitive dysfunction, they may serve as measurable risk indicators. This study was designed to identify the relationship between olfaction, depression, and each domain of cognitive function in elderly dementia patients in South Korea. Study participants were 108 patients who visited the outpatient clinic between March and September 2019. More significant impairment of olfactory function was found in those with mild (7.48 ± 1.28) or moderate (7.37 ± 2.22) test scores of the Expanded Clinical Dementia Rating (CDR) scale than in those with questionable scores (20.58 ± 6.18). The language domain of cognitive function, age, and education level showed 39.2% explanatory power for olfactory function (F = 5.591, p < 0.001). It is expected that assessment of olfactory function in elderly people can lead to the early detection, diagnosis, and treatment of dementia. Furthermore, it is important for future studies to confirm the relationship between each domain of cognitive function and olfactory function according to the type of dementia and to establish criteria for screening dementia in order to utilize olfactory function as a clinical marker.
Identification of Mineralocorticoid Receptors, Aldosterone, and Its Processing Enzyme CYP11B2 on Parasympathetic and Sympathetic Neurons in Rat Intracardiac Ganglia
Authors: Dehe Lukas , Mousa Shaaban A. , Aboryag Noureddin , Shaqura Mohammed , Beyer Antje , Schäfer Michael , Treskatsch Sascha
Published: January 2022

Recent interest has focused on the mineralocorticoid receptor (MR) and its impact on the myocardium and the performance of the heart. However, there is a lack of evidence about MR expression and its endogenous ligand aldosterone synthesis with specific regard to the intrinsic cardiac nervous system. Therefore, we looked for evidence of MR and aldosterone in sympathetic and parasympathetic neurons of intracardiac ganglia. Tissue samples from rat heart atria were subjected to conventional reverse-transcriptase polymerase chain reaction (PCR), Western blot, and double immunofluorescence confocal analysis of MR, corticosterone-inactivating enzyme 11β-hydroxysteroid-dehydrogenase-2 (11β-HSD2), aldosterone, and its processing enzyme CYP11B2 together with the neuronal markers vesicular acetylcholine transporter (VAChT) and tyrosine hydroxylase (TH). Our results demonstrated MR, 11β-HSD2, and CYP11B2 specific mRNA and protein bands in rat heart atria. Double immunofluorescence labeling revealed coexpression of MR immunoreactivity with VAChT in large diameter parasympathetic principal neurons. In addition, MR immunoreactivity was identified in TH-immunoreactive small intensely fluorescent (SIF) cells and in nearby VAChT- and TH-immunoreactive nerve terminals. Interestingly, the aldosterone and its synthesizing enzyme CYP11B2 and 11β-HSD2 colocalized in MR– immunoreactive neurons of intracardiac ganglia. Overall, this study provides first evidence for the existence of not only local expression of MR, but also of 11β-HSD2 and aldosterone with its processing enzyme CYP11B2 in the neurons of the cardiac autonomic nervous system, suggesting a possible modulatory role of the mineralocorticoid system on the endogenous neuronal activity on heart performance.
Maturation of Social-Vocal Communication in Prairie Vole (Microtus ochrogaster) Pups
Authors: Warren Megan R. , Campbell Drayson , Borie Amélie M. , Ford Charles L. , Dharani Ammar M. , Young Larry J. , Liu Robert C.
Published: January 2022

Impairments in social communication are common among neurodevelopmental disorders. While traditional animal models have advanced our understanding of the physiological and pathological development of social behavior, they do not recapitulate some aspects where social communication is essential, such as biparental care and the ability to form long-lasting social bonds. Prairie voles (Microtus ochrogaster) have emerged as a valuable rodent model in social neuroscience because they naturally display these behaviors. Nonetheless, the role of vocalizations in prairie vole social communication remains unclear. Here, we studied the ontogeny [from postnatal days (P) 8–16] of prairie vole pup ultrasonic vocalizations (USVs), both when isolated and when the mother was present but physically unattainable. In contrast to other similarly sized rodents such as mice, prairie vole pups of all ages produced isolation USVs with a relatively low fundamental frequency between 22 and 50 kHz, often with strong harmonic structure. Males consistently emitted vocalizations with a lower frequency than females. With age, pups vocalized less, and the acoustic features of vocalizations (e.g., duration and bandwidth) became more stereotyped. Manipulating an isolated pup's social environment by introducing its mother significantly increased vocal production at older (P12–16) but not younger ages, when pups were likely unable to hear or see her. Our data provide the first indication of a maturation in social context-dependent vocal emission, which may facilitate more active acoustic communication. These results help lay a foundation for the use of prairie voles as a model organism to probe the role of early life experience in the development of social-vocal communication.
Synergistic Effects of Combined Nurr1 Overexpression and Natural Inducers on the More Efficient Production of Dopaminergic Neuron-Like Cells From Stem Cells
Authors: Beiki Reyhaneh , Khaghani Mahsa , Esmaeili Fariba , Dehghanian Fariba
Published: January 2022

The development of dopaminergic (DA) neurons is a very complex process, and a combination of extrinsic and intrinsic factors involves their differentiation. Transcription factor, Nurr1 plays an essential role in the differentiation and maintenance of midbrain DA neurons. Nurr1-based therapies may restore DA function in Parkinson's disease (PD) by replacing damaged cells with differentiated cells derived from stem cells. Providing tissue-specific microenvironments such as brain extract can effectively induce dopaminergic gene expression in stem cells. The present study aimed to investigate the combined effects of Nurr1 gene overexpression and a neonatal rat brain extract (NRBE) induction on dopaminergic differentiation of P19 stem cells. In order to neural differentiation induction, stably Nurr1-transfected cells were treated with 100 μg/ml of NRBE. The differentiation potential of the cells was then evaluated during a period of 1–3 weeks via various methods. The initial evaluation of the cells by direct observation under a light microscope and cresyl violet specific staining, confirmed neuron-like morphology in the differentiated cells. In addition, different molecular and cellular techniques, including real-time PCR, immunofluorescence, and flow cytometry, demonstrated that the treated cells expressed pan-neuronal and dopaminergic markers. In all experimental groups, neuronal phenotype with dopaminergic neuron-like cells characteristics mainly appeared in the second week of the differentiation protocol. Overall, the results of the present study revealed for the first time the synergistic effects of Nurr1 gene overexpression and possible soluble factors that existed in NRBE on the differentiation of P19 stem cells into dopaminergic neuron-like cells.
High-Frequency Repetitive Transcranial Magnetic Stimulation Over the Left Dorsolateral Prefrontal Cortex Shortly Alleviates Fatigue in Patients With Multiple System Atrophy: A Randomized Controlled Trial
Authors: Pan Jing , Mi Tao-Mian , Ma Jing-Hong , Sun Hong , Chan Piu
Published: January 2022

Background: Fatigue is a common symptom in patients with Multiple system atrophy (MSA), but effective treatments remain elusive. The present study aims to investigate whether high-frequency repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) could relieve fatigue in patients with MSA.

Methods: This is a single-center, randomized and double-blind trial. Twenty-two patients with MSA and fatigue were randomly allocated to receive 10 sessions of either active (N = 11) or sham (N = 11) 10 Hz rTMS over the left DLPFC. The participants were assessed at baseline (T0), after the last session of treatment (T1), and at 2-week (T2), and 4-week (T3) follow-up timepoints. The primary outcomes were Fatigue Severity Scale-9 (FSS-9) scores, with Unified Multiple System Atrophy Rating Scale (UMSARS), 17-item Hamilton Depression Scale (HAMD-17), and Hamilton Anxiety Scale (HAMA) as secondary outcomes.

Results: Two-way repeated ANOVAs revealed significant group × time interactions for FSS-9 scores (p < 0.001), HAMD-17 scores (p = 0.01), HAMA scores (p = 0.01), and UMRSA part II (p = 0.05). Post-hoc analyses showed that compared to T0, the active group exhibited remarkable improvements in FSS-9 and UMRSA part II scores at T1 and T2, but not at T3, and also in HAMD-17 and HAMA scores at T1, T2, and T3. No significant improvement was found in the sham group.

Conclusion: High-frequency rTMS over the left DLPFC could provide short-term improvements for alleviating fatigue in patients with MSA, but the beneficial effects last no more than 4 weeks.
Evaluation and Prediction of Post-stroke Cerebral Edema Based on Neuroimaging
Authors: Zhang Xiaocheng , Huang Peiyu , Zhang Ruiting
Published: January 2022

Cerebral edema is a common complication of acute ischemic stroke that leads to poorer functional outcomes and substantially increases the mortality rate. Given that its negative effects can be reduced by more intensive monitoring and evidence-based interventions, the early identification of patients with a high risk of severe edema is crucial. Neuroimaging is essential for the assessment and prediction of edema. Simple markers, such as midline shift and hypodensity volume on computed tomography, have been used to evaluate edema in clinical trials; however, advanced techniques can be applied to examine the underlying mechanisms. In this study, we aimed to review current imaging tools in the assessment and prediction of cerebral edema to provide guidance for using these methods in clinical practice.
Current Knowledge of Microglia in Traumatic Spinal Cord Injury
Authors: Xu Lintao , Wang Jingyu , Ding Yueming , Wang Linlin , Zhu Yong-Jian
Published: January 2022

Microglia are the resident immune cells in the central nervous system (CNS). After traumatic spinal cord injury (SCI), microglia undergo activation, proliferation, and changes in gene and protein expression and morphology, with detrimental and beneficial effects. Activated microglia cause secondary neuronal injuryviathe production of proinflammatory cytokines, reactive oxygen species, and proteases. However, activated microglia also promote neuronal repair through the secretion of anti-inflammatory growth factors and cytokines. Proinflammatory cytokines increase endothelial permeability, promote A1 astrocyte activation and axonal demyelination, and reduce neural stem/progenitor cells (NSPCs), leading to the exacerbation of neuronal injury. In contrast, anti-inflammatory factors facilitate angiogenesis, reduce reactive astrocytes, and promote axonal remyelination and the propagation of NSPCs, contributing to tissue repair and locomotor recovery. Due to its limited regenerative capacity, the CNS requires beneficial microglia for continuous protection against injury. Understanding and regulating microglial activation status are beneficial to reducing detrimental effects and promoting repair behaviors and to obtain more information on efficient therapies for traumatic SCI. This review discusses microglial activation and the differences between microglia and similar immune cells, microglial interactions with other cells in the spinal cord, and the progress in the development of therapies targeting microglia in SCI.
Social Isolation and Associated Factors in Chinese Adults With Epilepsy: A Cross-Sectional Study
Authors: Zhong Rui , Zhang Hanyu , Chen Qingling , Guo Xin , Han Yujian , Lin Weihong
Published: January 2022

Objective: We aimed to determine the prevalence of social isolation and associated factors among adults with epilepsy in northeast China.

Methods: A cohort of consecutive patients with epilepsy (PWE) from the First Hospital of Jilin University (Changchun, China) was recruited. Demographic and clinical data for each patient were collected during a face-to-face interview. Social isolation was measured using the Berkman-Syme Social Network Index (SNI), and the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) and Quality of Life in Epilepsy Inventory (QOLIE-31) were also administered. Multivariate logistic regression analyses were used to determine the factors associated with social isolation in PWE.

Results: A total of 165 patients were included in the final analysis. The mean SNI score was 2.56 (SD: 1.19), and 35 patients (21.2%) were socially isolated. In multivariate logistic regression analysis, higher depressive symptom levels (OR = 1.15, 95% CI: 1.003–1.318, P = 0.045) and poorer quality of life (OR = 0.967, 95% CI: 0.935–0.999, P = 0.047) emerged as independent factors associated with social isolation in PWE.

Conclusion: Social isolation is common and occurs in approximately one-fifth of PWE. Social isolation is significantly associated with depressive symptoms and poor quality of life in PWE. Patients need to be encouraged to actively integrate with others and reduce social isolation, which may help improve their quality of life.
Frontal-Sensory Cortical Projections Become Dispensable for Attentional Performance Upon a Reduction of Task Demand in Mice
Authors: Norman Kevin J. , Bateh Julia , Maccario Priscilla , Cho Christina , Caro Keaven , Nishioka Tadaaki , Koike Hiroyuki , Morishita Hirofumi
Published: January 2022

Top-down attention is a dynamic cognitive process that facilitates the detection of the task-relevant stimuli from our complex sensory environment. A neural mechanism capable of deployment under specific task-demand conditions would be crucial to efficiently control attentional processes and improve promote goal-directed attention performance during fluctuating attentional demand. Previous studies have shown that frontal top-down neurons projecting from the anterior cingulate area (ACA) to the visual cortex (VIS; ACAVIS) are required for visual attentional behavior during the 5-choice serial reaction time task (5CSRTT) in mice. However, it is unknown whether the contribution of these projecting neurons is dependent on the extent of task demand. Here, we first examined how behavior outcomes depend on the number of locations for mice to pay attention and touch for successful performance, and found that the 2-choice serial reaction time task (2CSRTT) is less task demanding than the 5CSRTT. We then employed optogenetics to demonstrate that suppression ACAVIS projections immediately before stimulus presentation has no effect during the 2CSRTT in contrast to the impaired performance during the 5CSRTT. These results suggest that ACAVIS projections are necessary when task demand is high, but once a task demand is lowered, ACAVIS neuron activity becomes dispensable to adjust attentional performance. These findings support a model that the frontal-sensory ACAVIS projection regulates visual attention behavior during specific high task demand conditions, pointing to a flexible circuit-based mechanism for promoting attentional behavior.
Walking Football During Ramadan Fasting for Cardiometabolic and Psychological Health Benefits to the Physically Challenged and Aged Populations
Authors: Zainudin Sueziani Binte , Salle Dee Dee A. , Aziz Abdul Rashid
Published: January 2022

Concurrent exercise and intermittent fasting regimens for long periods have been shown to enhance cardiometabolic health in healthy individuals. As exercise and fasting confer health benefits independently, we propose that Muslims who are fasting, especially those experiencing health and clinical challenges, continually engage in physical activity during the Ramadan month. In this opinion piece, we recommend walking football (WF) as the exercise of choice among Muslims who are fasting. WF can be played by any individual regardless of the level of fitness, skills, and age. WF has been shown to elicit cardiovascular and metabolic stress responses, which are suitable for populations with low fitness levels. Most importantly, WF has the inherent characteristics of being a fun team activity requiring social interactions among participants and, hence, likely to encourage long-term consistent and sustainable participation.
Mechanisms for Improving Hepatic Glucolipid Metabolism by Cinnamic Acid and Cinnamic Aldehyde: An Insight Provided by Multi-Omics
Authors: Wu You , Wang Ming-hui , Yang Tao , Qin Tian-yu , Qin Ling-ling , Hu Yao-mu , Zhang Cheng-fei , Sun Bo-ju , Ding Lei , Wu Li-li , Liu Tong-hua
Published: January 2022

Cinnamic acid (AC) and cinnamic aldehyde (AL) are two chemicals enriched in cinnamon and have been previously proved to improve glucolipid metabolism, thus ameliorating metabolic disorders. In this study, we employed transcriptomes and proteomes on AC and AL treated db/db mice in order to explore the underlying mechanisms for their effects. Db/db mice were divided into three groups: the control group, AC group and AL group. Gender- and age-matched wt/wt mice were used as a normal group. After 4 weeks of treatments, mice were sacrificed, and liver tissues were used for further analyses. Functional enrichment of differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) were performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. DEPs were further verified by parallel reaction monitoring (PRM). The results suggested that AC and AL share similar mechanisms, and they may improve glucolipid metabolism by improving mitochondrial functions, decreasing serotonin contents and upregulating autophagy mediated lipid clearance. This study provides an insight into the molecular mechanisms of AC and AL on hepatic transcriptomes and proteomes in disrupted metabolic situations and lays a foundation for future experiments.
Identifying Molecular Changes in Early Cervical Cancer Samples of Patients That Developed Metastasis
Authors: de Geus Vera , Ewing-Graham Patricia C. , de Koning Willem , de Koning Maurits N. C. , van den Bosch Thierry P. P. , Nigg Alex L. , van Eijck Casper H. J. , Jozwiak Marta , van Beekhuizen Heleen J. , Mustafa Dana A. M.
Published: January 2022

Cervical cancer is one of the most common cancers in women worldwide. Patients diagnosed with early-stage cervical cancer have a good prognosis, however, 10-20% suffer from local or distant recurrent disease after primary treatment. Treatment options for recurrent cervical cancer are limited. Therefore, it is crucial to identify factors that can predict patients with an increased risk of recurrence to optimize treatment to prevent the recurrence of cervical cancer. We aimed to identify biomarkers in early-stage primary cervical cancer which recurred after surgery. Formalin-Fixed, Paraffin-Embedded surgical specimens of 34 patients with early-stage cervical cancer (FIGO 2009 stage 1B1) and 7 healthy controls were analyzed. Targeted gene expression profiling using the PanCancer IO 360 panel of NanoString Technology was performed. The findings were confirmed by performing immunohistochemistry stainings. Various genes, namely GLS, CD36, WNT5a, HRAS, DDB2, PIK3R2, and CDH2 were found to be differentially highly expressed in primary cervical cancer samples of patients who developed distant recurrence. In addition, The relative infiltration score of CD8+ T cells, CD80+CD86+ macrophages, CD163+MRC1+ macrophages, and FOXP3+IL2RA+ regulatory T cells were significantly higher in this group of samples. In contrast, no significant differences in gene expression and relative immune infiltration were found in samples of patients who developed local recurrence. The infiltration of CD8 and FOXP3 cells were validated by immunohistochemistry using all samples included in the study. We identified molecular alterations in primary cervical cancer samples from patients who developed recurrent disease. These findings can be utilized towards developing a molecular signature for the early detection of patients with a high risk to develop metastasis.
Determinants of Drug Resistance in B-Cell Non-Hodgkin Lymphomas: The Case of Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia
Authors: Piazza Francesco , Di Paolo Veronica , Scapinello Greta , Manni Sabrina , Trentin Livio , Quintieri Luigi
Published: January 2022

Lymphoplasmacytic lymphoma (LPL) is a rare subtype of B cell-derived non-Hodgkin lymphoma characterized by the abnormal growth of transformed clonal lymphoplasmacytes and plasma cells. This tumor almost always displays the capability of secreting large amounts of monoclonal immunoglobulins (Ig) of the M class (Waldenström Macroglobulinemia, WM). The clinical manifestations of WM/LPL may range from an asymptomatic condition to a lymphoma-type disease or may be dominated by IgM paraprotein-related symptoms. Despite the substantial progresses achieved over the last years in the therapy of LPL/WM, this lymphoma is still almost invariably incurable and exhibits a propensity towards development of refractoriness to therapy. Patients who have progressive disease are often of difficult clinical management and novel effective treatments are eagerly awaited. In this review, we will describe the essential clinical and pathobiological features of LPL/WM. We will also analyze some key aspects about the current knowledge on the mechanisms of drug resistance in this disease, by concisely focusing on conventional drugs, monoclonal antibodies and novel agents, chiefly Bruton’s Tyrosine Kinase (BTK) inhibitors. The implications of molecular lesions as predictors of response or as a warning for the development of therapy resistance will be highlighted.
Haematopoietic Stem Cell Transplantation in Adolescents and Young Adults With Acute Lymphoblastic Leukaemia: Special Considerations and Challenges
Authors: Calvo Charlotte , Ronceray Leila , Dhédin Nathalie , Buechner Jochen , Troeger Anja , Dalle Jean-Hugues
Published: January 2022

Adolescents and young adults (AYAs) represent a challenging group of acute lymphoblastic leukaemia (ALL) patients with specific needs. While there is growing evidence from comparative studies that this age group profits from intensified paediatric-based chemotherapy, the impact and optimal implementation of haematopoietic stem cell transplantation (HSCT) in the overall treatment strategy is less clear. Over recent years, improved survival rates after myeloablative allogeneic HSCT for ALL have been reported similarly for AYAs and children despite differences in transplantation practise. Still, AYAs appear to have inferior outcomes and an increased risk of treatment-related morbidity and mortality in comparison with children. To further improve HSCT outcomes and reduce toxicities in AYAs, accurate stratification and evaluation of additional or alternative targeted treatment options are crucial, based on specific molecular and immunological characterisation of ALL and minimal residual disease (MRD) assessment during therapy. Age-specific factors such as increased acute toxicities and poorer adherence to treatment as well as late sequelae might influence treatment decisions. In addition, educational, social, work, emotional, and sexual aspects during this very crucial period of life need to be considered. In this review, we summarise the key findings of recent studies on treatment approach and outcomes in this vulnerable patient group after HSCT, turning our attention to the different approaches applied in paediatric and adult centres. We focus on the specific needs of AYAs with ALL regarding social aspects and supportive care to handle complications as well as fertility issues. Finally, we comment on potential areas of future research and concisely debate the capacity of currently available immunotherapies to reduce toxicity and further improve survival in this challenging patient group.
Aprepitant Inhibits JNK and p38/MAPK to Attenuate Inflammation and Suppresses Inflammatory Pain
Authors: Yang Yang , Zhou Wei , Xu Xiuqi , Ge Xianxiu , Wang Fei , Zhang Guang-Qin , Miao Lin , Deng Xueting
Published: January 2022

Substance P contributes to the pathogenesis of pain by acting on NK-1R, specialized sensory neurons that detect noxious stimuli. Aprepitant, an antagonist of NK-1R, is widely used to treat chemotherapy-induced nausea and vomiting. In this study, we used LPS-stimulated BV-2 microglia cell line and animal models of inflammatory pain to explore the analgesic effect of aprepitant on inflammatory pain and its underlying mechanism. The excitability of DRG neurons were measured using whole-cell patch-clamp recordings. The behavioral tests were measured and the morphological changes on inflamed paw sections were determined by HE staining. Changes in the expressions of cytokine were measured by using real-time quantitative PCR analysis and ELISA method. Immunofluorescence and western blotting were used to detect the microglia activation and MAPK. Aprepitant treatment significantly inhibited the excitability of DRG neurons. The pain behavior and the paw tissues inflammatory damage were significantly relived after the administration of aprepitant compared to formalin group. Aprepitant significantly suppressed the activation of microglia, phosphorylation of JNK and p38 MAPK, as well as the mRNA and protein expressions of MCP-1, TNF-α, IL-6, and IL-1β, in vivo and in vitro. The LPS-induced over-translocation into nucleus of NF-κBp65 was down-regulated following aprepitant treatment in BV-2 cells. The present study suggests that aprepitant attenuates inflammatory pain in mice via suppressing the phosphorylation of JNK and p38, and inhibiting the NF-κB signaling pathway.
Investigating the Efficacy and Safety of Thalidomide for Treating Patients With ß-Thalassemia: A Meta-Analysis
Authors: Lu Yanfei , Wei Zhenbin , Yang Gaohui , Lai Yongrong , Liu Rongrong
Published: January 2022

At present, the main therapies for ß-thalassemia patients include regular blood transfusion and iron chelation, associating with a number of limitations. Thalidomide, a fetal hemoglobin (HbF) inducer that promotes γ-globin gene expression, has been reported to be effective for ß-thalassemia. Thus, this meta-analysis was conducted to assess the efficacy and safety of thalidomide for treating patients with ß-thalassemia. We searched the related studies from eight databases published from inception until December 1, 2021. The R 4.0.5 language programming was used to perform meta-analysis. After screening of retrieved articles, 12 articles were included that enrolled a total of 451 patients. The Cochrane Collaboration risk assessment tool was used to evaluate the quality and the bias risk of the randomized controlled trials (RCTs), and non randomized trials were assessed using Newcastle-Ottawa Scale (NOS). After treatment with thalidomide, the pooled overall response rate (ORR) was 85% (95% confidence interval (CI): 80–90%), and the pooled complete response rate (CRR) was 54% (95% confidence interval: 31–76%). Compared with the placebo group, the thalidomide group had higher odds of overall response rate (odds ratio = 20.4; 95% CI: 6.75–61.64) and complete response rate (odds ratio = 20.4; 95% CI: 6.75–61.64). A statistically significant increase in hemoglobin level and HbF level after treatment, while there was no statistically significant difference in adult hemoglobin (HbA) level, spleen size, and serum ferritin. According to the results of ORR and CRR, transfusion-dependent thalassemia (TDT) patients showed remarkable efficacy of thalidomide, 83 and 52% respectively. So we analyzed 30 transfusion-dependent thalassemia patients from three studies and found that the most frequent ß-globin gene mutations were CD41-42 (-TCTT), while response to thalidomide did not show any statistically significant relationship with XmnI polymorphism or CD41-42 (-TCTT) mutation. About 30% of patients experienced mild adverse effects of thalidomide. Collectively, thalidomide is a relatively safe and effective therapy to reduce the blood transfusion requirements and to increase Hb level in patients with ß-thalassemia.
Topological One-Way Edge States in an Air-Hole Honeycomb Gyromagnetic Photonic Crystal
Authors: Peng Chaoqun , Chen Jianfeng , Qin Qiumeng , Li Zhi-Yuan
Published: January 2022

Topological one-way edge states have attracted increasing attention because of their intriguing fundamental physics and potential applications, particularly in the realm of photonics. In this paper, we present a theoretical and numerical demonstration of topological one-way edge states in an air-hole honeycomb gyromagnetic photonic crystal biased by an external magnetic field. Localized horizontally to the edge and confined in vertical direction by two parallel metallic plates, these unique states possess robust one-way propagation characteristics. They are strongly robust against various types of defects, imperfections and sharp corners on the path, and even can unidirectionally transport along the irregular edges of arbitrary geometries. We further utilize the one-way property of edge states to overcome entirely the issue of back-reflections and show the design of topological leaky wave antennas. Our results open a new door towards the observation of nontrivial edge states in air-hole topological photonic crystal systems, and offer useful prototype of robust topological photonic devices, such as geometry-independent topological energy flux loops and topological leaky wave antennas.
Patterned Illumination Techniques in Optogenetics: An Insight Into Decelerating Murine Hearts
Authors: Diaz-Maue Laura , Steinebach Janna , Richter Claudia
Published: January 2022

Much has been reported about optogenetic based cardiac arrhythmia treatment and the corresponding characterization of photostimulation parameters, but still, our capacity to interact with the underlying spatiotemporal excitation patterns relies mainly on electrical and/or pharmacological approaches. However, these well-established treatments have always been an object of somehow heated discussions. Though being acutely life-saving, they often come with potential side-effects leading to a decreased functionality of the complex cardiac system. Recent optogenetic studies showed the feasibility of the usage of photostimulation as a defibrillation method with comparatively high success rates. Although, these studies mainly concentrated on the description as well as on the comparison of single photodefibrillation approaches, such as locally focused light application and global illumination, less effort was spent on the description of excitation patterns during actual photostimulation. In this study, the authors implemented a multi-site photodefibrillation technique in combination with Multi-Lead electrocardiograms (ECGs). The technical connection of real-time heart rhythm measurements and the arrhythmia counteracting light control provides a further step toward automated arrhythmia classification, which can lead to adaptive photodefibrillation methods. In order to show the power effectiveness of the new approach, transgenic murine hearts expressing channelrhodopsin-2 ex vivo were investigated using circumferential micro-LED and ECG arrays. Thus, combining the best of two methods by giving the possibility to illuminate either locally or globally with differing pulse parameters. The optical technique presented here addresses a number of challenges of technical cardiac optogenetics and is discussed in the context of arrhythmic development during photostimulation.
Differential Effects of One Meal per Day in the Evening on Metabolic Health and Physical Performance in Lean Individuals
Authors: Meessen Emma C. E. , Andresen Håvard , van Barneveld Thomas , van Riel Anne , Johansen Egil I. , Kolnes Anders J. , Kemper E. Marleen , Olde Damink Steven W. M. , Schaap Frank G. , Romijn Johannes A. , Jensen Jørgen , Soeters Maarten R.
Published: January 2022

Background: Generally, food intake occurs in a three-meal per 24 h fashion with in-between meal snacking. As such, most humans spend more than ∼ 12–16 h per day in the postprandial state. It may be reasoned from an evolutionary point of view, that the human body is physiologically habituated to less frequent meals. Metabolic flexibility (i.e., reciprocal changes in carbohydrate and fatty acid oxidation) is a characteristic of metabolic health and is reduced by semi-continuous feeding. The effects of time-restricted feeding (TRF) on metabolic parameters and physical performance in humans are equivocal.

Methods: To investigate the effect of TRF on metabolism and physical performance in free-living healthy lean individuals, we compared the effects of eucaloric feeding provided by a single meal (22/2) vs. three meals per day in a randomized crossover study. We included 13 participants of which 11 (5 males/6 females) completed the study: age 31.0 ± 1.7 years, BMI 24.0 ± 0.6 kg/m2 and fat mass (%) 24.0 ± 0.6 (mean ± SEM). Participants consumed all the calories needed for a stable weight in either three meals (breakfast, lunch and dinner) or one meal per day between 17:00 and 19:00 for 11 days per study period.

Results: Eucaloric meal reduction to a single meal per day lowered total body mass (3 meals/day –0.5 ± 0.3 vs. 1 meal/day –1.4 ± 0.3 kg, p = 0.03), fat mass (3 meals/day –0.1 ± 0.2 vs. 1 meal/day –0.7 ± 0.2, p = 0.049) and increased exercise fatty acid oxidation (p < 0.001) without impairment of aerobic capacity or strength (p > 0.05). Furthermore, we found lower plasma glucose concentrations during the second half of the day during the one meal per day intervention (p < 0.05).

Conclusion: A single meal per day in the evening lowers body weight and adapts metabolic flexibility during exercise via increased fat oxidation whereas physical performance was not affected.
Left Ventricular Ejection Time Measured by Echocardiography Differentiates Neurobehavioral Resilience and Vulnerability to Sleep Loss and Stress
Authors: Yamazaki Erika M. , Rosendahl-Garcia Kathleen M. , Casale Courtney E. , MacMullen Laura E. , Ecker Adrian J. , Kirkpatrick James N. , Goel Namni
Published: January 2022

There are substantial individual differences (resilience and vulnerability) in performance resulting from sleep loss and psychosocial stress, but predictive potential biomarkers remain elusive. Similarly, marked changes in the cardiovascular system from sleep loss and stress include an increased risk for cardiovascular disease. It remains unknown whether key hemodynamic markers, including left ventricular ejection time (LVET), stroke volume (SV), heart rate (HR), cardiac index (CI), blood pressure (BP), and systemic vascular resistance index (SVRI), differ in resilient vs. vulnerable individuals and predict differential performance resilience with sleep loss and stress. We investigated for the first time whether the combination of total sleep deprivation (TSD) and psychological stress affected a comprehensive set of hemodynamic measures in healthy adults, and whether these measures differentiated neurobehavioral performance in resilient and vulnerable individuals. Thirty-two healthy adults (ages 27–53; 14 females) participated in a 5-day experiment in the Human Exploration Research Analog (HERA), a high-fidelity National Aeronautics and Space Administration (NASA) space analog isolation facility, consisting of two baseline nights, 39 h TSD, and two recovery nights. A modified Trier Social Stress Test induced psychological stress during TSD. Cardiovascular measure collection [SV, HR, CI, LVET, BP, and SVRI] and neurobehavioral performance testing (including a behavioral attention task and a rating of subjective sleepiness) occurred at six and 11 timepoints, respectively. Individuals with longer pre-study LVET (determined by a median split on pre-study LVET) tended to have poorer performance during TSD and stress. Resilient and vulnerable groups (determined by a median split on average TSD performance) showed significantly different profiles of SV, HR, CI, and LVET. Importantly, LVET at pre-study, but not other hemodynamic measures, reliably differentiated neurobehavioral performance during TSD and stress, and therefore may be a biomarker. Future studies should investigate whether the non-invasive marker, LVET, determines risk for adverse health outcomes.
Selection and Validation of Reference Genes for RT-qPCR Normalization in Bradysia odoriphaga (Diptera: Sciaridae) Under Insecticides Stress
Authors: Fu Haiyan , Huang Tubiao , Yin Cheng , Xu Zhenhua , Li Chao , Liu Chunguang , Wu Tong , Song Fuqiang , Feng Fujuan , Yang Fengshan
Published: January 2022

Bradysia odoriphaga (Diptera: Sciaridae) is the most serious root maggot pest which causes substantial damage to the Chinese chive. Organophosphate (OP) and neonicotinoid insecticides are widely used chemical pesticides and play important roles in controlling B. odoriphaga. However, a strong selection pressure following repeated pesticide applications has led to the development of resistant populations of this insect. To understand the insecticide resistance mechanism in B. odoriphaga, gene expression analysis might be required. Appropriate reference gene selection is a critical prerequisite for gene expression studies, as the expression stability of reference genes can be affected by experimental conditions, resulting in biased or erroneous results. The present study shows the expression profile of nine commonly used reference genes [elongation factor 1α (EF-1α), actin2 (ACT), elongation factor 2α (EF-2α), glucose-6-phosphate dehydrogenase (G6PDH), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), ribosomal protein L10 (RPL10), ribosomal protein S3 (RPS3), ubiquitin-conjugating enzyme (UBC), and α-tubulin (TUB)] was systematically analyzed under insecticide stress. Moreover, we also evaluated their expression stability in other experimental conditions, including developmental stages, sexes, and tissues. Five programs (NormFinder, geNorm, BestKeeper, RefFinder, and ΔCt) were used to validate the suitability of candidate reference genes. The results revealed that the most appropriate sets of reference genes were RPL10 and ACT across phoxim; ACT and TUB across chlorpyrifos and chlorfluazuron; EF1α and TUB across imidacloprid; EF1α and EF2α across developmental stages; RPL10 and TUB across larvae; EF1α and ACT across tissues, and ACT and G6PDH across sex. These results will facilitate the standardization of RT-qPCR and contribute to further research on B. odoriphaga gene function under insecticides stress.
Response to Early Generation Genomic Selection for Yield in Wheat
Authors: Bonnett David , Li Yongle , Crossa Jose , Dreisigacker Susanne , Basnet Bhoja , Pérez-Rodríguez Paulino , Alvarado G. , Jannink J. L. , Poland Jesse , Sorrells Mark
Published: January 2022

We investigated increasing genetic gain for grain yield using early generation genomic selection (GS). A training set of 1,334 elite wheat breeding lines tested over three field seasons was used to generate Genomic Estimated Breeding Values (GEBVs) for grain yield under irrigated conditions applying markers and three different prediction methods: (1) Genomic Best Linear Unbiased Predictor (GBLUP), (2) GBLUP with the imputation of missing genotypic data by Ridge Regression BLUP (rrGBLUP_imp), and (3) Reproducing Kernel Hilbert Space (RKHS) a.k.a. Gaussian Kernel (GK). F2 GEBVs were generated for 1,924 individuals from 38 biparental cross populations between 21 parents selected from the training set. Results showed that F2 GEBVs from the different methods were not correlated. Experiment 1 consisted of selecting F2s with the highest average GEBVs and advancing them to form genomically selected bulks and make intercross populations aiming to combine favorable alleles for yield. F4:6 lines were derived from genomically selected bulks, intercrosses, and conventional breeding methods with similar numbers from each. Results of field-testing for Experiment 1 did not find any difference in yield with genomic compared to conventional selection. Experiment 2 compared the predictive ability of the different GEBV calculation methods in F2 using a set of single plant-derived F2:4 lines from randomly selected F2 plants. Grain yield results from Experiment 2 showed a significant positive correlation between observed yields of F2:4 lines and predicted yield GEBVs of F2 single plants from GK (the predictive ability of 0.248,P< 0.001) and GBLUP (0.195,P< 0.01) but no correlation with rrGBLUP_imp. Results demonstrate the potential for the application of GS in early generations of wheat breeding and the importance of using the appropriate statistical model for GEBV calculation, which may not be the same as the best model for inbreds.