bluuebunny/crossref_metadata_2025 huggingface dataset:
Chronic modafinil therapy ameliorates depressive-like behavior, spatial memory and hippocampal plasticity impairments, and sleep-wake changes in a surgical mouse model of menopause
Authors: Yan Yu-Dong , Chen Yu-Qing , Wang Chen-Yao , Ye Chen-Bo , Hu Zhen-Zhen , Behnisch Thomas , Huang Zhi-Li , Yang Su-Rong
Published: February 2021

Depression, cognitive deficits, and sleep disturbances are common and often severe in menopausal women. Hormone replacement cannot effectively alleviate these symptoms and sometimes elicits life-threatening adverse reactions. Exploring effective therapies to target psychological problems is urgently needed. In this work, we developed a mouse model of menopause by bilateral ovariectomies (OVXs) and investigated whether menopausal mental symptoms can be ameliorated by psychostimulant modafinil (MOD) as well as explored the underlying mechanisms. At ~3 weeks after OVXs, mice got daily intraperitoneal administrations of MOD at the beginning of the active phase. Several behavioral tests and electroencephalogram (EEG) recordings were conducted. Electrophysiological and immunohistochemical experiments were carried out to evaluate the synaptic plasticity and neurogenesis, respectively. We found that chronic MOD administration in OVX mice significantly decreased immobility time. The spatial memory performance of OVX mice improved significantly in response to MOD administration in the Morris water-maze test. The OVX mice were characterized by an attenuation of hippocampal synaptic transmission and synaptic long-term potentiation and had fewer 5-ethynyl-2′-deoxyuridine-labeled cells in the dentate gyrus, which were restored after MOD administration. Antagonists of dopamine D1 and D2 receptors and GABAA receptor agonists were involved in MOD-exerted anti-depressant actions and augments of hippocampal neurogenesis in OVX mice. Moreover, night-dosed MOD therapy significantly promoted the night-time delta-band EEG power during wakefulness and the day-time rapid eye movement sleep amount, which were significantly reduced by OVXs. Collectively, these findings suggest that MOD is a promising therapeutic candidate for menopausal women.
Phase 1 open-label study of panobinostat, lenalidomide, bortezomib + dexamethasone in relapsed and relapsed/refractory multiple myeloma
Authors: Laubach Jacob P. , Tuchman Sascha A. , Rosenblatt Jacalyn M. , Mitsiades Constantine S. , Colson Kathleen , Masone Kelly , Warren Diane , Redd Robert A. , Grayson Dena , Richardson Paul G.
Published: February 2021

Additional therapeutic options are needed for relapsed and refractory multiple myeloma (RRMM). We present data from a phase 1b, open-label, dose-escalation study (NCT01965353) of 20 patients with RRMM (median age: 63 years [range: 50–77]) and a median of four prior regimens (range: 2–14); 85% had refractory disease (lenalidomide [80%]; bortezomib [75%]; lenalidomide and bortezomib [50%]). Patients received a median of six cycles (range: 1–74) of panobinostat (10 or 15 mg), lenalidomide 15 mg, bortezomib 1 mg/m2, and dexamethasone 20 mg (pano-RVd). Median follow-up was ~14 months. Six dose-limiting toxicities were reported (mostly hematological); maximum tolerated dose of panobinostat (primary endpoint) was 10 mg. Most common adverse events (AEs) were diarrhea (60%) and peripheral neuropathy (60%); all grade 1/2. Grade 3/4 AEs occurred in 80% of patients and included decreased neutrophil (45%), platelet (25%) and white blood cell (25%) counts, anemia (25%) and hypophosphatemia (25%). No treatment-related discontinuations or mortality occurred. In evaluable patients (n = 18), overall response rate was 44%, and clinical benefit rate was 61%. Median duration of response was 9.2 months; progression-free survival was 7.4 months; overall survival was not reached. Pano-RVd proved generally well-tolerated and demonstrated potential to overcome lenalidomide and/or bortezomib resistance.
Changes in patient-reported outcomes in light chain amyloidosis in the first year after diagnosis and relationship to NT-proBNP change
Authors: D’Souza Anita , Brazauskas Ruta , Dispenzieri Angela , Panepinto Julie , Flynn Kathryn E.
Published: February 2021

We conducted a prospective cohort study in newly diagnosed systemic light chain (AL) amyloidosis patients (N = 59) to study patient-reported outcomes (PROs) through the first year. The median age was 68 years with 42% female, 8% Black, and 78% lambda subtype. Organ involvement was cardiac in 66%, renal in 58%, with 25% having 3 or greater organs involved. Between baseline and 3 months, all PROMIS®-29 domain scores worsened by 0.4–4.1 points except anxiety which improved by 2.1 points. By 1 year, scores improved compared to the greatest decline at 3 months, most statistically significant for global physical health, physical function, and fatigue. On stage-adjusted survival analysis, in addition to baseline global physical and mental health, domains measuring physical function, fatigue, anxiety, depression, and social roles were associated with 1-year survival. At 1 year, PROMIS measures were associated with NT-proBNP changes and hematologic response. Among patients with an NT-proBNP response, the improvement was seen in physical function, social roles, global mental health, and anxiety. Among patients with an NT-proBNP progression, worsening was seen with anxiety, depression, sleep, and global mental health. Measuring and tracking PROs in patients with AL amyloidosis is important and these important outcomes can be used as correlative endpoints in clinical care/research.
A clinical perspective on plasma cell leukemia; current status and future directions
Authors: Tuazon Sherilyn A. , Holmberg Leona A. , Nadeem Omar , Richardson Paul G.
Published: February 2021

Primary plasma cell leukemia (pPCL) is an aggressive plasma cell disorder with a guarded prognosis. The diagnosis is confirmed when peripheral blood plasma cells (PCs) exceed 20% of white blood cells or 2000/μL. Emerging data demonstrates that patients with lower levels of circulating (PCs) have the same adverse prognosis, challenging the clinical disease definition, but supporting the adverse impact of circulating PCs. The cornerstone of treatment consists of combination therapy incorporating a proteasome inhibitor, an immunomodulatory agent, steroids, and/or anthracyclines and alkylators as part of more-intensive chemotherapy, followed by consolidative autologous hematopoietic cell transplantation in eligible patients and then maintenance therapy. Monoclonal antibodies are also currently being evaluated in this setting with a strong rationale for their use based on their activity in multiple myeloma (MM). Due to limited therapeutic studies specifically evaluating pPCL, patients with pPCL should be considered for clinical trials. In contrast to MM, the outcomes of patients with pPCL have only modestly improved with novel therapies, and secondary PCL arising from MM in particular is associated with a dismal outlook. Newer drug combinations, immunotherapy, and cellular therapy are under investigation, and these approaches hopefully will demonstrate efficacy to improve the prognosis of pPCL.
Outcomes following hematopoietic stem cell transplantation in patients treated with standard chemotherapy with or without gemtuzumab ozogamicin for acute myeloid leukemia
Authors: Pautas Cécile , Raffoux Emmanuel , Lambert Juliette , Legrand Ollivier , Chantepie Sylvain , Gastaud Lauris , Marolleau Jean-Pierre , Thomas Xavier , Turlure Pascal , Benner Rebecca J. , Vandendries Erik , Gogat Karïn , Dombret Hervé , Castaigne Sylvie
Published: February 2021

The phase 3 ALFA-0701 trial demonstrated improved outcomes with fractionated-dose gemtuzumab ozogamicin (GO) combined with standard chemotherapy vs. standard chemotherapy alone in adults with de novo acute myeloid leukemia (AML). We examined post-transplant outcomes and occurrence of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in patients who received hematopoietic stem cell transplantation (HSCT) as follow-up therapy in ALFA-0701. Patients aged 50–70 years were randomized to standard chemotherapy with or without GO (3 mg/m2 on days 1, 4, and 7 of induction and day 1 on each of two consolidation courses). Allogeneic HSCT was recommended for patients in first complete remission with matched (related or unrelated) donor, except those with core-binding factor AML or normal karyotype and either NPM1+/FLT3-ITDwt or CEBPA+ AML. Eighty-five patients (GO: n = 32; control: n = 53) received HSCT in first complete remission or after relapse/primary induction failure. Three patients (GO: n = 2; control: n = 1 [received GO as follow-up therapy]) developed VOD/SOS after HSCT or conditioning. Post-transplant survival, non-relapse mortality, and relapse were not different between arms. Results indicate fractionated-dose GO as part of induction and consolidation chemotherapy for AML does not induce excess post-transplant VOD/SOS or mortality and thus does not preclude the use of HSCT as consolidation treatment.
Pharmaceutical immunoglobulin G impairs anti-carcinoma activity of oxaliplatin in colon cancer cells
Authors: Shang Yuru , Zhang Xianbin , Lu Lili , Jiang Ke , Krohn Mathias , Matschos Stephanie , Mullins Christina Susanne , Vollmar Brigitte , Zechner Dietmar , Gong Peng , Linnebacher Michael
Published: February 2021

Background

Recent evidence proves that intravenous human immunoglobulin G (IgG) can impair cancer cell viability. However, no study evaluated whether IgG application benefits cancer patients receiving chemotherapeutics.

Methods

Influence of pharmaceutical-grade human IgG on the viability of a series of patient-derived colon cancer cell lines with and without chemotherapeutic intervention was determined. Cell death was analysed flow cytometrically. In addition, the influence of oxaliplatin and IgG on the ERK1/2-signalling pathway was evaluated by western blots.

Results

We evaluated the effects of pharmaceutical IgG, such as PRIVIGEN® IgG and Tonglu® IgG, in combination with chemotherapeutics. We did not observe any significant effects of IgG on tumour cell viability directly; however, human IgG significantly impaired the anti-tumoral effects of oxaliplatin. Primary cancer cell lines express IgG receptors and accumulate human IgG intracellularly. Moreover, while oxaliplatin induced the activation of ERK1/2, the pharmaceutical IgG inhibited ERK1/2 activity.

Conclusions

The present study demonstrates that pharmaceutical IgG, such as PRIVIGEN® IgG and Tonglu® IgG, can impair the anti-carcinoma activity of oxaliplatin. These data strongly suggest that therapeutic IgG as co-medication might have harmful side effects in cancer patients. The clinical significance of these preclinical observations absolutely advises further preclinical, as well as epidemiological and clinical research.
A genome-wide association study for gut metagenome in Chinese adults illuminates complex diseases
Authors: Liu Xiaomin , Tang Shanmei , Zhong Huanzi , Tong Xin , Jie Zhuye , Ding Qiuxia , Wang Dan , Guo Ruidong , Xiao Liang , Xu Xun , Yang Huanming , Wang Jian , Zong Yang , Liu Weibin , Liu Xiao , Zhang Yong , Brix Susanne , Kristiansen Karsten , Hou Yong , Jia Huijue , Zhang Tao
Published: February 2021

The gut microbiome has been established as a key environmental factor to health. Genetic influences on the gut microbiome have been reported, yet, doubts remain as to the significance of genetic associations. Here, we provide shotgun data for whole genome and whole metagenome from a Chinese cohort, identifying no <20% genetic contribution to the gut microbiota. Using common variants-, rare variants-, and copy number variations-based association analyses, we identified abundant signals associated with the gut microbiome especially in metabolic, neurological, and immunological functions. The controversial concept of enterotypes may have a genetic attribute, with the top two loci explaining 11% of the Prevotella–Bacteroides variances. Stratification according to gender led to the identification of differential associations in males and females. Our two-stage metagenome genome-wide association studies on a total of 1295 individuals unequivocally illustrates that neither microbiome nor GWAS studies could overlook one another in our quest for a better understanding of human health and diseases.
Highly efficient neuronal gene knockout in vivo by CRISPR-Cas9 via neonatal intracerebroventricular injection of AAV in mice
Authors: Hana Sam , Peterson Michael , McLaughlin Helen , Marshall Eric , Fabian Attila J. , McKissick Olivia , Koszka Kathryn , Marsh Galina , Craft Michael , Xu Shanqin , Sorets Alexander , Torregrosa Tess , Sun Chao , Henderson Chris E. , Lo Shih-Ching
Published: February 2021

CRISPR-Cas systems have emerged as a powerful tool to generate genetic models for studying normal and diseased central nervous system (CNS). Targeted gene disruption at specific loci has been demonstrated successfully in non-dividing neurons. Despite its simplicity, high specificity and low cost, the efficiency of CRISPR-mediated knockout in vivo can be substantially impacted by many parameters. Here, we used CRISPR-Cas9 to disrupt the neuronal-specific gene, NeuN, and optimized key parameters to achieve effective gene knockout broadly in the CNS in postnatal mice. Three cell lines and two primary neuron cultures were used to validate the disruption of NeuN by single-guide RNAs (sgRNA) harboring distinct spacers and scaffold sequences. This triage identified an optimal sgRNA design with the highest NeuN disruption in in vitro and in vivo systems. To enhance CRISPR efficiency, AAV-PHP.B, a vector with superior neuronal transduction, was used to deliver this sgRNA in Cas9 mice via neonatal intracerebroventricular (ICV) injection. This approach resulted in 99.4% biallelic indels rate in the transduced cells, leading to greater than 70% reduction of total NeuN proteins in the cortex, hippocampus and spinal cord. This work contributes to the optimization of CRISPR-mediated knockout and will be beneficial for fundamental and preclinical research.
The effects of drift and selection on latitudinal genetic variation in Scandinavian common toads (Bufo bufo) following postglacial recolonisation
Authors: Thörn Filip , Rödin-Mörch Patrik , Cortazar-Chinarro Maria , Richter-Boix Alex , Laurila Anssi , Höglund Jacob
Published: February 2021

Clinal variation is paramount for understanding the factors shaping genetic diversity in space and time. During the last glacial maximum, northern Europe was covered by glacial ice that rendered the region uninhabitable for most taxa. Different evolutionary processes during and after the recolonisation of this area from different glacial refugia have affected the genetic landscape of the present day European flora and fauna. In this study, we focus on the common toad (Bufo bufo) in Sweden and present evidence suggesting that these processes have resulted in two separate lineages of common toad, which colonised Sweden from two directions. Using ddRAD sequencing data for demographic modelling, structure analyses, and analysis of molecular variance (AMOVA), we provide evidence of a contact zone located between Uppland and Västerbotten in central Sweden. Genetic diversity was significantly higher in southern Sweden compared to the north, in accordance with a pattern of decreased genetic diversity with increasing distance from glacial refugia. Candidate genes under putative selection are identified through outlier detection and gene–environment association methods. We provide evidence of divergent selection related to stress response and developmental processes in these candidate genes. The colonisation of Sweden by two separate lineages may have implications for how future conservation efforts should be directed by identifying management units and putative local adaptations.
Germline mutational spectrum in Armenian breast cancer patients suspected of hereditary breast and ovarian cancer
Authors: Moradian Mike M. , Babikyan Davit T. , Markarian Sione , Petrosyan Jonny G. , Avanesian Nare , Arutunyan Tereza , Sarkisian Tamara F.
Published: February 2021

Hereditary breast and ovarian cancer (HBOC) can be identified by genetic testing of cancer-causing genes. In this study, we identified a spectrum of genetic variations among 76 individuals of Armenian descent either with a family history of cancer or breast cancer before the age of 40. We screened 76 suspected HBOC patients and family members as well as four healthy controls using a targeted and hereditary comprehensive cancer panel (127 genes). We found 26 pathogenic (path) and 6 likely pathogenic (LPath)variants in 6 genes in 44 patients (58%); these variants were found in BRCA1 (17), BRCA2 (19), CHEK2 (4), PALB2 (2), and NBN (1). A few different variants were found in unrelated individuals; most notably, variant p.Trp1815Ter in the BRCA1 gene occurred in four unrelated patients. We did not find any known significant variants in five patients. Comprehensive cancer panel testing revealed pathogenic variants in cancer genes other than BRCA1 and BRCA2, suggesting that testing only BRCA1 and BRCA2 would have missed 8 out of 44 suspected HBOC patients (18%). These data also confirm that a comprehensive cancer panel testing approach could be an appropriate way to identify most of the variants associated with hereditary breast cancer.
CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy
Authors: Rodriguez-Garcia Alba , Lynn Rachel C. , Poussin Mathilde , Eiva Monika A. , Shaw Lauren C. , O’Connor Roddy S. , Minutolo Nicholas G. , Casado-Medrano Victoria , Lopez Gonzalo , Matsuyama Takami , Powell Daniel J.
Published: February 2021

The immunosuppressive tumor microenvironment (TME) represents a major barrier for effective immunotherapy. Tumor-associated macrophages (TAMs) are highly heterogeneous and plastic cell components of the TME which can either promote tumor progression (M2-like) or boost antitumor immunity (M1-like). Here, we demonstrate that a subset of TAMs that express folate receptor β (FRβ) possess an immunosuppressive M2-like profile. In syngeneic tumor mouse models, chimeric antigen receptor (CAR)-T cell-mediated selective elimination of FRβ+TAMs in the TME results in an enrichment of pro-inflammatory monocytes, an influx of endogenous tumor-specific CD8+T cells, delayed tumor progression, and prolonged survival. Preconditioning of the TME with FRβ-specific CAR-T cells also improves the effectiveness of tumor-directed anti-mesothelin CAR-T cells, while simultaneous co-administration of both CAR products does not. These results highlight the pro-tumor role of FRβ+TAMs in the TME and the therapeutic implications of TAM-depleting agents as preparative adjuncts to conventional immunotherapies that directly target tumor antigens.
Reward-related choices determine information timing and flow across macaque lateral prefrontal cortex
Authors: Tang Hua , Bartolo Ramon , Averbeck Bruno B.
Published: February 2021

Prefrontal cortex is critical for cognition. Although much is known about the representation of cognitive variables in the prefrontal cortex, much less is known about the spatio-temporal neural dynamics that underlie cognitive operations. In the present study, we examined information timing and flow across the lateral prefrontal cortex (LPFC), while monkeys carried out a two-armed bandit reinforcement learning task in which they had to learn to select rewarding actions or rewarding objects. When we analyzed signals independently within subregions of the LPFC, we found a task-specific, caudo-rostral gradient in the strength and timing of signals related to chosen objects and chosen actions. In addition, when we characterized information flow among subregions, we found that information flow from action to object representations was stronger from the dorsal to ventral LPFC, and information flow from object to action representations was stronger from the ventral to dorsal LPFC. The object to action effects were more pronounced in object blocks, and also reflected learning specifically in these blocks. These results suggest anatomical segregation followed by the rapid integration of information within the LPFC.
Evidence for SARS-CoV-2 related coronaviruses circulating in bats and pangolins in Southeast Asia
Authors: Wacharapluesadee Supaporn , Tan Chee Wah , Maneeorn Patarapol , Duengkae Prateep , Zhu Feng , Joyjinda Yutthana , Kaewpom Thongchai , Chia Wan Ni , Ampoot Weenassarin , Lim Beng Lee , Worachotsueptrakun Kanthita , Chen Vivian Chih-Wei , Sirichan Nutthinee , Ruchisrisarod Chanida , Rodpan Apaporn , Noradechanon Kirana , Phaichana Thanawadee , Jantarat Niran , Thongnumchaima Boonchu , Tu Changchun , Crameri Gary , Stokes Martha M. , Hemachudha Thiravat , Wang Lin-Fa
Published: February 2021

Among the many questions unanswered for the COVID-19 pandemic are the origin of SARS-CoV-2 and the potential role of intermediate animal host(s) in the early animal-to-human transmission. The discovery of RaTG13 bat coronavirus in China suggested a high probability of a bat origin. Here we report molecular and serological evidence of SARS-CoV-2 related coronaviruses (SC2r-CoVs) actively circulating in bats in Southeast Asia. Whole genome sequences were obtained from five independent bats (Rhinolophus acuminatus) in a Thai cave yielding a single isolate (named RacCS203) which is most related to the RmYN02 isolate found in Rhinolophus malayanus in Yunnan, China. SARS-CoV-2 neutralizing antibodies were also detected in bats of the same colony and in a pangolin at a wildlife checkpoint in Southern Thailand. Antisera raised against the receptor binding domain (RBD) of RmYN02 was able to cross-neutralize SARS-CoV-2 despite the fact that the RBD of RacCS203 or RmYN02 failed to bind ACE2. Although the origin of the virus remains unresolved, our study extended the geographic distribution of genetically diverse SC2r-CoVs from Japan and China to Thailand over a 4800-km range. Cross-border surveillance is urgently needed to find the immediate progenitor virus of SARS-CoV-2.
LC-MS based plant metabolic profiles of thirteen grassland species grown in diverse neighbourhoods
Authors: Marr Sue , Hageman Jos A. , Wehrens Ron , van Dam Nicole M. , Bruelheide Helge , Neumann Steffen
Published: February 2021

In plants, secondary metabolite profiles provide a unique opportunity to explore seasonal variation and responses to the environment. These include both abiotic and biotic factors. In field experiments, such stress factors occur in combination. This variation alters the plant metabolic profiles in yet uninvestigated ways. This data set contains trait and mass spectrometry data of thirteen grassland species collected at four time points in the growing season in 2017. We collected above-ground vegetative material of seven grass and six herb species that were grown in plant communities with different levels of diversity in the Jena Experiment. For each sample, we recorded visible traits and acquired shoot metabolic profiles on a UPLC-ESI-Qq-TOF-MS. We performed the raw data pre-processing in Galaxy-W4M and prepared the data for statistical analysis in R by applying missing data imputation, batch correction, and validity checks on the features. This comprehensive data set provides the opportunity to investigate environmental dynamics across diverse neighbourhoods that are reflected in the metabolomic profile.
Developmental transcriptome profiling uncovered carbon signaling genes associated with almond fruit drop
Authors: Guo Chunmiao , Wei Yu , Yang Bo , Ayup Mubarek , Li Ning , Liu Jun , Liao Kang , Wang Huan
Published: February 2021

Almond is one of the most featured nut crops owing to its high nutritional value. However, due to three different waves of flower and fruitlet drop, fruit drop is a major concern for growers. In this study, we carried out a time-course transcriptome analysis to investigate gene expression differences between normal and abnormal fruitlet development. By de novo assembly analysis, we identified 33,577 unigenes and provided their functional annotations. In total, we identified 7,469 differentially expressed genes and observed the most apparent difference between normal and abnormal fruits at 12 and 17 days after flowering. Their biological functions were enriched in carbon metabolism, carbon fixation in photosynthetic organisms and plant hormone signal transduction. RT-qPCR validated the expression pattern of 14 representative genes, includingglycosyltransferase like family 2,MYB39,IAA13,gibberellin-regulated protein 11-likeandPOD44, which confirmed the reliability of our transcriptome data. This study provides an insight into the association between abnormal fruit development and carbohydrate signaling from the early developmental stages and could be served as useful information for understanding the regulatory mechanisms related to almond fruit drop.
Novel urinary glycan profiling by lectin array serves as the biomarkers for predicting renal prognosis in patients with IgA nephropathy
Authors: Kawakita Chieko , Mise Koki , Onishi Yasuhiro , Sugiyama Hitoshi , Yoshida Michihiro , Yamada Masao , Wada Jun
Published: February 2021

In IgA nephropathy (IgAN), IgA1 molecules are characterized by galactose deficiency in O-glycans. Here, we investigated the association between urinary glycosylation profile measured by 45 lectins at baseline and renal prognosis in 142 patients with IgAN. The primary outcome was estimated glomerular filtration rate (eGFR) decline (> 4 mL/min/1.73 m2/year), or eGFR ≥ 30% decline from baseline, or initiation of renal replacement therapies within 3 years. During follow-up (3.4 years, median), 26 patients reached the renal outcome (Group P), while 116 patients were with good renal outcome (Group G). Multivariate logistic regression analyses revealed that lectin binding signals of Erythrina cristagalli lectin (ECA) (odds ratio [OR] 2.84, 95% confidence interval [CI] 1.11–7.28) and Narcissus pseudonarcissus lectin (NPA) (OR 2.32, 95% CI 1.11–4.85) adjusted by age, sex, eGFR, and urinary protein were significantly associated with the outcome, and they recognize Gal(β1-4)GlcNAc and high-mannose including Man(α1-6)Man, respectively. The addition of two lectin-binding glycan signals to the interstitial fibrosis/tubular atrophy score further improved the model fitness (Akaike’s information criterion) and incremental predictive abilities (c-index, net reclassification improvement, and integrated discrimination improvement). Urinary N-glycan profiling by lectin array is useful in the prediction of IgAN prognosis, since ECA and NPA recognize the intermediate glycans during N-glycosylation of various glycoproteins.
Improved 7 Tesla transmit field homogeneity with reduced electromagnetic power deposition using coupled Tic Tac Toe antennas
Authors: Santini Tales , Wood Sossena , Krishnamurthy Narayanan , Martins Tiago , Aizenstein Howard J. , Ibrahim Tamer S.
Published: February 2021

Recently cleared by the FDA, 7 Tesla (7 T) MRI is a rapidly growing technology that can provide higher resolution and enhanced contrast in human MRI images. However, the increased operational frequency (~ 297 MHz) hinders its full potential since it causes inhomogeneities in the images and increases the power deposition in the tissues. This work describes the optimization of an innovative radiofrequency (RF) head coil coupled design, named Tic Tac Toe, currently used in large scale human MRI scanning at 7 T; to date, this device was used in more than 1,300 neuro 7 T MRI scans. Electromagnetic simulations of the coil were performed using the finite-difference time-domain method. Numerical optimizations were used to combine the calculated electromagnetic fields produced by these antennas, based on the superposition principle, resulting in homogeneous magnetic field distributions at low levels of power deposition in the tissues. The simulations were validated in-vivo using the Tic Tac Toe RF head coil system on a 7 T MRI scanner.
Global chromatin organizer SATB1 acts as a context-dependent regulator of the Wnt/Wg target genes
Authors: Ramanujam Praveena L. , Mehrotra Sonam , Kumar Ram Parikshan , Verma Shreekant , Deshpande Girish , Mishra Rakesh K. , Galande Sanjeev
Published: February 2021

Special AT-rich binding protein-1 (SATB1) integrates higher-order chromatin architecture with gene regulation, thereby regulating multiple signaling pathways. In mammalian cells SATB1 directly interacts with β-catenin and regulates the expression of Wnt targets by binding to their promoters. Whether SATB1 regulates Wnt/wg signaling by recruitment of β-catenin and/or its interactions with other components remains elusive. Since Wnt/Wg signaling is conserved from invertebrates to humans, we investigated SATB1 functions in regulation of Wnt/Wg signaling by using mammalian cell-lines and Drosophila. Here, we present evidence that in mammalian cells, SATB1 interacts with Dishevelled, an upstream component of the Wnt/Wg pathway. Conversely, ectopic expression of full-length human SATB1 but not that of its N- or C-terminal domains in the eye imaginal discs and salivary glands of third instar Drosophila larvae increased the expression of Wnt/Wg pathway antagonists and suppressed phenotypes associated with activated Wnt/Wg pathway. These data argue that ectopically-provided SATB1 presumably modulates Wnt/Wg signaling by acting as negative regulator in Drosophila. Interestingly, comparison of SATB1 with PDZ- and homeo-domain containing Drosophila protein Defective Proventriculus suggests that both proteins exhibit limited functional similarity in the regulation of Wnt/Wg signaling in Drosophila. Collectively, these findings indicate that regulation of Wnt/Wg pathway by SATB1 is context-dependent.
Baseline microvessel density predicts response to neoadjuvant bevacizumab treatment of locally advanced breast cancer
Authors: Krüger Kristi , Silwal-Pandit Laxmi , Wik Elisabeth , Straume Oddbjørn , Stefansson Ingunn M. , Borgen Elin , Garred Øystein , Naume Bjørn , Engebraaten Olav , Akslen Lars A.
Published: February 2021

A subset of breast cancer patients benefits from preoperative bevacizumab and chemotherapy, but validated predictive biomarkers are lacking. Here, we aimed to evaluate tissue-based angiogenesis markers for potential predictive value regarding response to neoadjuvant bevacizumab treatment in breast cancer. In this randomized 1:1 phase II clinical trial, 132 patients with large or locally advanced HER2-negative tumors received chemotherapy ± bevacizumab. Dual Factor VIII/Ki-67 immunohistochemical staining was performed on core needle biopsies at baseline and week 12. Microvessel density (MVD), proliferative microvessel density (pMVD; Factor VIII/Ki-67 co-expression), glomeruloid microvascular proliferation (GMP), and a gene expression angiogenesis signature score, were studied in relation to pathologic complete response (pCR), clinico-pathologic features and intrinsic molecular subtype. We found that high baseline MVD (by median) significantly predicted pCR in the bevacizumab-arm (odds ratio 4.9, P = 0.012). High pMVD, presence of GMP, and the angiogenesis signature score did not predict pCR, but were associated with basal-like (P ≤ 0.009) and triple negative phenotypes (P ≤ 0.041). pMVD and GMP did also associate with high-grade tumors (P ≤ 0.048). To conclude, high baseline MVD significantly predicted response to bevacizumab treatment. In contrast, pMVD, GMP, and the angiogenesis signature score, did not predict response, but associated with aggressive tumor features, including basal-like and triple-negative phenotypes.
Physiological and molecular responses of lobe coral indicate nearshore adaptations to anthropogenic stressors
Authors: Tisthammer Kaho H. , Timmins-Schiffman Emma , Seneca Francois O. , Nunn Brook L. , Richmond Robert H.
Published: February 2021

Corals in nearshore marine environments are increasingly exposed to reduced water quality, which is the primary local threat to Hawaiian coral reefs. It is unclear if corals surviving in such conditions have adapted to withstand sedimentation, pollutants, and other environmental stressors. Lobe coral populations from Maunalua Bay, Hawaii showed clear genetic differentiation between the 'polluted, high-stress' nearshore site and the 'less polluted, lower-stress' offshore site. To understand the driving force of the observed genetic partitioning, reciprocal transplant and common-garden experiments were conducted to assess phenotypic differences between these two populations. Physiological responses differed significantly between the populations, revealing more stress-resilient traits in the nearshore corals. Changes in protein profiles highlighted the inherent differences in the cellular metabolic processes and activities between the two; nearshore corals did not significantly alter their proteome between the sites, while offshore corals responded to nearshore transplantation with increased abundances of proteins associated with detoxification, antioxidant defense, and regulation of cellular metabolic processes. The response differences across multiple phenotypes between the populations suggest local adaptation of nearshore corals to reduced water quality. Our results provide insight into coral’s adaptive potential and its underlying processes, and reveal potential protein biomarkers that could be used to predict resiliency.
Voluntary intake of psychoactive substances is regulated by the dopamine receptor Dop1R1 in Drosophila
Authors: Kanno Mai , Hiramatsu Shun , Kondo Shu , Tanimoto Hiromu , Ichinose Toshiharu
Published: February 2021

Dysregulated motivation to consume psychoactive substances leads to addictive behaviors that often result in serious health consequences. Understanding the neuronal mechanisms that drive drug consumption is crucial for developing new therapeutic strategies. The fruit fly Drosophila melanogaster offers a unique opportunity to approach this problem with a battery of sophisticated neurogenetic tools available, but how they consume these drugs remains largely unknown. Here, we examined drug self-administration behavior of Drosophila and the underlying neuronal mechanisms. We measured the preference of flies for five different psychoactive substances using a two-choice feeding assay and monitored its long-term changes. We found that flies show acute preference for ethanol and methamphetamine, but not for cocaine, caffeine or morphine. Repeated intake of ethanol, but not methamphetamine, increased over time. Preference for methamphetamine and the long-term escalation of ethanol preference required the dopamine receptor Dop1R1 in the mushroom body. The protein level of Dop1R1 increased after repeated intake of ethanol, but not methamphetamine, which correlates with the acquired preference. Genetic overexpression of Dop1R1 enhanced ethanol preference. These results reveal a striking diversity of response to individual drugs in the fly and the role of dopamine signaling and its plastic changes in controlling voluntary intake of drugs.
Effect of tamoxifen with or without gonadotropin-releasing hormone analog on DXA values in women with breast cancer
Authors: Kim Eun Heui , Jeon Yun Kyung , Pak Kyoungjune , Kang Taewoo , Kim Kyung-Eun , Kim Seong-Jang , Kim In-Joo , Kim Keunyoung
Published: February 2021

The purpose of this study was to compare the changes in DXA values including trabecular bone score (TBS) and bone mineral density (BMD) of lumbar spine (LS) and femur according to the hormone therapies including tamoxifen (TMXF) treatment with or without gonadotropin releasing hormone analog (GnRH analog) in women with breast cancer. We enrolled 119 women with breast cancer who had undergone breast-conserving surgery or mastectomy followed by TMXF treatment for postmenopausal women (TMXF group, n = 63, 52.9%) or by combination therapy of TMXF combined with GnRH analog for premenopausal women (TMXF + GnRH group, n = 56, 47.1%) from December 2013 to December 2017. The median follow-up period was 13 months (interquartile range [IQR], 12.0–14.75) for TMXF group and 13.5 months (IQR, 12.00–16.00) for TMXF + GnRH group, respectively. Patients did not receive bone-modifying therapy. The baseline dual-energy X-ray absorptiometry (DXA) scan before breast cancer surgery and follow-up DXA during hormone therapy. Comparing the first and follow-up DXA results, BMD in LS were significantly decreased in both TMXF (P < 0.001, mean difference: − 0.06) and TMXF + GnRH (P < 0.001, mean difference: − 0.09) groups. BMD values of femoral neck (P = 0.0011, mean difference: − 0.01) and total femur (P < 0.001, mean difference: − 0.03) was significantly changed between the baseline and follow-up DXA in TMXF + RnRH group. In the TMX group, a significant changed occurred in the BMD in total femur (P < 0.001, mean difference: − 0.030) but not the BMD of femoral neck (P = 0.095, mean difference: − 0.007). Regarding TBS, no significant change was found in the TMXF (P = 0.574, mean difference: − 0.004) group, whereas there was a significant decrease in TBS in the TMXF + GnRH (P < 0.001, mean difference: − 0.02) group during follow-up. TBS is more sensitive in reflecting the bone microarchitecture changes by TMXF or GnRH agonist in breast cancer patients than BMD. This finding demonstrates that TBS can be a useful parameter to detect bone microarchitectural changes in clinical applications.
Automated diagnostic support system with deep learning algorithms for distinction of Philadelphia chromosome-negative myeloproliferative neoplasms using peripheral blood specimen
Authors: Kimura Konobu , Ai Tomohiko , Horiuchi Yuki , Matsuzaki Akihiko , Nishibe Kumiko , Marutani Setsuko , Saito Kaori , Kaniyu Kimiko , Takehara Ikki , Uchihashi Kinya , Ohsaka Akimichi , Tabe Yoko
Published: February 2021

Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-negative MPNs) such as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis are characterized by abnormal proliferation of mature bone marrow cell lineages. Since various non-hematologic disorders can also cause leukocytosis, thrombocytosis and polycythemia, the detection of abnormal peripheral blood cells is essential for the diagnostic screening of Ph-negative MPNs. We sought to develop an automated diagnostic support system of Ph-negative MPNs. Our strategy was to combine the complete blood cell count and research parameters obtained by an automated hematology analyzer (Sysmex XN-9000) with morphological parameters that were extracted using a convolutional neural network deep learning system equipped with an Extreme Gradient Boosting (XGBoost)-based decision-making algorithm. The developed system showed promising performance in the differentiation of PV, ET, and MF with high accuracy when compared with those of the human diagnoses, namely: > 90% sensitivity and > 90% specificity. The calculated area under the curve of the ROC curves were 0.990, 0.967, and 0.974 for PV, ET, MF, respectively. This study is a step toward establishing a universal automated diagnostic system for all types of hematology disorders.
Dependence of the damage in optical metal/dielectric coatings on the energy of ions in irradiation experiments for space qualification
Authors: Pelizzo Maria G. , Corso Alain J. , Santi Giovanni , Hübner René , Garoli Denis , Doyle Dominic , Lubin Philip , Cohen Alexander N. , Erlikhman Jacob , Favaro Giulio , Bazzan Marco , Drobny Jon , Curreli Davide , Umansky Maxim
Published: February 2021

Terrestrial accelerator facilities can generate ion beams which enable the testing of the resistance of materials and thin film coatings to be used in the space environment. In this work, a $$\hbox {TiO}_2$$

TiO
2

/Al bi-layer coating has been irradiated with a $$\hbox {He}^+$$

He
+

beam at three different energies. The same flux and dose have been used in order to investigate the damage dependence on the energy. The energies were selected to be in the range 4–100 keV, in order to consider those associated to the quiet solar wind and to the particles present in the near-Earth space environment. The optical, morphological and structural modifications have been investigated by using various techniques. Surprisingly, the most damaged sample is the one irradiated at the intermediate energy, which, on the other hand, corresponds to the case in which the interface between the two layers is more stressed. Results demonstrate that ion energies for irradiation tests must be carefully selected to properly qualify space components.
Observation of terahertz coherent edge radiation amplified by infrared free-electron laser oscillations
Authors: Sei Norihiro , Sakai Takeshi , Hayakawa Yasushi , Sumitomo Yoske , Nogami Kyoko , Tanaka Toshinari , Hayakawa Ken
Published: February 2021

A coupling device, which can extract coherent edge radiation (CER) from an optical cavity for a free-electron laser (FEL) without damaging the FEL due to diffraction loss, was developed at Nihon University. We successfully observed the CER beam with a power of 1 mW or more in the terahertz range during FEL oscillation. It is revealed that the CER power changed with the detuning of the optical cavity and the dependence of the CER power on the detuning length differs from that of the FEL power. The measured CER spectra indicate that the longitudinal electron distribution in a bunch is modulated by the FEL oscillation with a period corresponding to the FEL slippage length. We herein report the characteristics of the CER with FEL oscillation in detail. These results demonstrate that the CER is excellent tool to reveal the overall effect of FEL interaction on electron distribution in a bunch.
Rapid profiling of drug-resistant bacteria using DNA-binding dyes and a nanopore-based DNA sequencer
Authors: Ohno Ayumu , Umezawa Kazuo , Asai Satomi , Kryukov Kirill , Nakagawa So , Miyachi Hayato , Imanishi Tadashi
Published: February 2021

Spread of drug-resistant bacteria is a serious problem worldwide. We thus designed a new sequence-based protocol that can quickly identify bacterial compositions of clinical samples and their drug-resistance profiles simultaneously. Here we utilized propidium monoazide (PMA) that prohibits DNA amplifications from dead bacteria, and subjected the original and antibiotics-treated samples to 16S rRNA metagenome sequencing. We tested our protocol on bacterial mixtures, and observed that sequencing reads derived from drug-resistant bacteria were significantly increased compared with those from drug-sensitive bacteria when samples were treated by antibiotics. Our protocol is scalable and will be useful for quickly profiling drug-resistant bacteria.
A general framework for automatic closed-loop control of bladder voiding induced by intraspinal microstimulation in rats
Authors: Yousefpour Abolhasan , Erfanian Abbas
Published: February 2021

Individuals with spinal cord injury or neurological disorders have problems in voiding function due to the dyssynergic contraction of the urethral sphincter. Here, we introduce a closed-loop control of intraspinal microstimulation (ISMS) for efficient bladder voiding. The strategy is based on asynchronous two-electrode ISMS with combined pulse-amplitude and pulse-frequency modulation without requiring rhizotomy, neurotomy, or high-frequency blocking. Intermittent stimulation is alternately applied to the two electrodes that are implanted in the S2 lateral ventral horn and S1 dorsal gray commissure, to excite the bladder motoneurons and to inhibit the urethral sphincter motoneurons. Asynchronous stimulation would lead to reduce the net electric field and to maximize the selective stimulation. The proposed closed-loop system attains a highly voiding efficiency of 77.2–100%, with an average of 91.28 ± 8.4%. This work represents a promising approach to the development of a natural and robust motor neuroprosthesis device for restoring bladder functions.
Selective endocytosis of recombinant human BMPs through cell surface heparan sulfate proteoglycans in CHO cells: BMP-2 and BMP-7
Authors: Kim Mi Gyeom , Kim Che Lin , Kim Young Sik , Jang Ju Woong , Lee Gyun Min
Published: February 2021

Cell surface heparan sulfate proteoglycan (HSPG)-mediated endocytosis results in poor yields of recombinant human bone morphogenetic proteins (rhBMPs) from CHO cell cultures. Upon incubation of rhBMP-2 and rhBMP-7 with CHO cells at 37 °C, both rhBMP-2 and rhBMP-7 bound to the cell surface HSPGs in CHO cells, but only rhBMP-2 was actively internalized into CHO cells. Cell surface HSPGs were found to serve as the main receptor for rhBMP-2 internalization. It was also found that the cell surface HSPG-mediated endocytosis of rhBMP-2 occurred through both the clathrin- and caveolin-dependent pathways. Blockage of rhBMP-2 internalization by the addition of structural analogs of HSPGs such as dextran sulfate (DS) and heparin dramatically increased rhBMP-2 production in recombinant CHO (rCHO) cell cultures. Compared to the control cultures, addition of DS (1.0 g/L) and heparin (0.2 g/L) resulted in a 22.0- and 19.0-fold increase in the maximum rhBMP-2 concentration, respectively. In contrast, the production of rhBMP-7, which was not internalized into the rCHO cells, did not dramatically increase upon addition of DS and heparin. Taken together, rhBMPs have a different fate in terms of HSPG-mediated internalization in CHO cells. HSPG-mediated endocytosis of each rhBMP should be understood individually to increase the rhBMP yield in rCHO cell cultures.
Describing variability in pig genes involved in coronavirus infections for a One Health perspective in conservation of animal genetic resources
Authors: Bovo Samuele , Schiavo Giuseppina , Ribani Anisa , Utzeri Valerio J. , Taurisano Valeria , Ballan Mohamad , Muñoz Maria , Alves Estefania , Araujo Jose P. , Bozzi Riccardo , Charneca Rui , Di Palma Federica , Djurkin Kušec Ivona , Etherington Graham , Fernandez Ana I. , García Fabián , García-Casco Juan , Karolyi Danijel , Gallo Maurizio , Martins José Manuel , Mercat Marie-José , Núñez Yolanda , Quintanilla Raquel , Radović Čedomir , Razmaite Violeta , Riquet Juliette , Savić Radomir , Škrlep Martin , Usai Graziano , Zimmer Christoph , Ovilo Cristina , Fontanesi Luca
Published: February 2021

Coronaviruses silently circulate in human and animal populations, causing mild to severe diseases. Therefore, livestock are important components of a “One Health” perspective aimed to control these viral infections. However, at present there is no example that considers pig genetic resources in this context. In this study, we investigated the variability of four genes (ACE2, ANPEP and DPP4 encoding for host receptors of the viral spike proteins and TMPRSS2 encoding for a host proteinase) in 23 European (19 autochthonous and three commercial breeds and one wild boar population) and two Asian Sus scrofa populations. A total of 2229 variants were identified in the four candidate genes: 26% of them were not previously described; 29 variants affected the protein sequence and might potentially interact with the infection mechanisms. The results coming from this work are a first step towards a “One Health” perspective that should consider conservation programs of pig genetic resources with twofold objectives: (i) genetic resources could be reservoirs of host gene variability useful to design selection programs to increase resistance to coronaviruses; (ii) the described variability in genes involved in coronavirus infections across many different pig populations might be part of a risk assessment including pig genetic resources.