bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetic–pharmacodynamic guided optimisation of dose and schedule of CGM097, an HDM2 inhibitor, in preclinical and clinical studies
Authors: Bauer Sebastian , Demetri George D. , Halilovic Ensar , Dummer Reinhard , Meille Christophe , Tan Daniel S. W. , Guerreiro Nelson , Jullion Astrid , Ferretti Stephane , Jeay Sebastien , Van Bree Laurence , Hourcade-Potelleret Florence , Wuerthner Jens U. , Fabre Claire , Cassier Philippe A.
Published: June 2021

Background

CGM097 inhibits the p53-HDM2 interaction leading to downstream p53 activation. Preclinical in vivo studies support clinical exploration while providing preliminary evidence for dosing regimens. This first-in-human phase I study aimed at assessing the safety, MTD, PK/PD and preliminary antitumor activity of CGM097 in advanced solid tumour patients (NCT01760525).

Methods

Fifty-one patients received oral treatment with CGM097 10–400 mg 3qw (n = 31) or 300–700 mg 3qw 2 weeks on/1 week off (n = 20). Choice of dose regimen was guided by PD biomarkers, and quantitative models describing the effect of CGM097 on circulating platelet and PD kinetics.

Results

No dose-limiting toxicities were reported in any regimens. The most common treatment-related grade 3/4 AEs were haematologic events. PK/PD models well described the time course of platelet and serum GDF-15 changes, providing a tool to predict response to CGM097 for dose-limiting thrombocytopenia and GDF-15 biomarker. The disease control rate was 39%, including one partial response and 19 patients in stable disease. Twenty patients had a cumulative treatment duration of >16 weeks, with eight patients on treatment for >32 weeks. The MTD was not determined.

Conclusions

Despite delayed-onset thrombocytopenia frequently observed, the tolerability of CGM097 appears manageable. This study provided insights on dosing optimisation for next-generation HDM2 inhibitors.

Translational relevance

Haematologic toxicity with delayed thrombocytopenia is a well-known on-target effect of HDM2 inhibitors. Here we have developed a PK/PD guided approach to optimise the dose and schedule of CGM097, a novel HDM2 inhibitor, using exposure, platelets and GDF-15, a known p53 downstream target to predict patients at higher risk to develop thrombocytopenia. While CGM097 had shown limited activity, with disease control rate of 39% and only one patient in partial response, the preliminary data from the first-in-human escalation study together with the PK/PD modeling provide important insights on how to optimize dosing of next generation HDM2 inhibitors to mitigate hematologic toxicity.
Sulfiredoxin-1 attenuates injury and inflammation in acute pancreatitis through the ROS/ER stress/Cathepsin B axis
Authors: He Jun , Ma Miaomiao , Li Daming , Wang Kunpeng , Wang Qiuguo , Li Qiuguo , He Hongye , Zhou Yan , Li Qinglong , Hou Xuyang , Yang Leping
Published: June 2021

Acinar cell injury and the inflammatory response are critical bioprocesses of acute pancreatitis (AP). We investigated the role and underlying mechanism of sulfiredoxin-1 (Srxn1) in AP. Mild AP was induced by intraperitoneal injection of cerulein and severe AP was induced by partial duct ligation with cerulein stimulation or intraperitoneal injection of L-arginine in mice. Acinar cells, neutrophils, and macrophages were isolated. The pancreas was analyzed by histology, immunochemistry staining, and TUNEL assays, and the expression of certain proteins and RNAs, cytokine levels, trypsin activity, and reactive oxygen species (ROS) levels were determined. Srxn1 was inhibited by J14 or silenced by siRNA, and overexpression was introduced by a lentiviral vector. Transcriptomic analysis was used to explore the mechanism of Srxn1-mediated effects. We also evaluated the effect of adeno-associated virus (AAV)-mediated overexpression of Srxn1 by intraductal administration and the protection of AP. We found that Srxn1 expression was upregulated in mild AP but decreased in severe AP. Inhibition of Srxn1 increased ROS, histological score, the release of trypsin, and inflammatory responses in mice. Inhibition of Srxn1 expression promoted the production of ROS and induced apoptosis, while overexpression of Srxn1 led to the opposite results in acinar cells. Furthermore, inhibition of Srxn1 expression promoted the inflammatory response by accumulating and activating M1 phenotype macrophages and neutrophils in AP. Mechanistically, ROS-induced ER stress and activation of Cathepsin B, which converts trypsinogen to trypsin, were responsible for the Srxn1 inhibition-mediated effects on AP. Importantly, we demonstrated that AAV-mediated overexpression of Srxn1 attenuated AP in mice. Taken together, these results showed that Srxn1 is a protective target for AP by attenuating acinar injury and inflammation through the ROS/ER stress/Cathepsin B axis.
Revisiting species and areas of interest for conserving global mammalian phylogenetic diversity
Authors: Robuchon Marine , Pavoine Sandrine , Véron Simon , Delli Giacomo , Faith Daniel P. , Mandrici Andrea , Pellens Roseli , Dubois Grégoire , Leroy Boris
Published: June 2021

Various prioritisation strategies have been developed to cope with accelerating biodiversity loss and limited conservation resources. These strategies could become more engaging for decision-makers if they reflected the positive effects conservation can have on future projected biodiversity, by targeting net positive outcomes in future projected biodiversity, rather than reflecting the negative consequences of further biodiversity losses only. Hoping to inform the post-2020 biodiversity framework, we here apply this approach of targeting net positive outcomes in future projected biodiversity to phylogenetic diversity (PD) to re-identify species and areas of interest for conserving global mammalian PD. We identify priority species/areas as those whose protection would maximise gains in future projected PD. We also identify loss-significant species/areas as those whose/where extinction(s) would maximise losses in future projected PD. We show that our priority species/areas differ from loss-significant species/areas. While our priority species are mostly similar to those identified by the EDGE of Existence Programme, our priority areas generally differ from previously-identified ones for global mammal conservation. We further highlight that these newly-identified species/areas of interest currently lack protection and offer some guidance for their future management.
Dendritic calcium signals in rhesus macaque motor cortex drive an optical brain-computer interface
Authors: Trautmann Eric M. , O’Shea Daniel J. , Sun Xulu , Marshel James H. , Crow Ailey , Hsueh Brian , Vesuna Sam , Cofer Lucas , Bohner Gergő , Allen Will , Kauvar Isaac , Quirin Sean , MacDougall Matthew , Chen Yuzhi , Whitmire Matthew P. , Ramakrishnan Charu , Sahani Maneesh , Seidemann Eyal , Ryu Stephen I. , Deisseroth Karl , Shenoy Krishna V.
Published: June 2021

Calcium imaging is a powerful tool for recording from large populations of neurons in vivo. Imaging in rhesus macaque motor cortex can enable the discovery of fundamental principles of motor cortical function and can inform the design of next generation brain-computer interfaces (BCIs). Surface two-photon imaging, however, cannot presently access somatic calcium signals of neurons from all layers of macaque motor cortex due to photon scattering. Here, we demonstrate an implant and imaging system capable of chronic, motion-stabilized two-photon imaging of neuronal calcium signals from macaques engaged in a motor task. By imaging apical dendrites, we achieved optical access to large populations of deep and superficial cortical neurons across dorsal premotor (PMd) and gyral primary motor (M1) cortices. Dendritic signals from individual neurons displayed tuning for different directions of arm movement. Combining several technical advances, we developed an optical BCI (oBCI) driven by these dendritic signalswhich successfully decoded movement direction online. By fusing two-photon functional imaging with CLARITY volumetric imaging, we verified that many imaged dendrites which contributed to oBCI decoding originated from layer 5 output neurons, including a putative Betz cell. This approach establishes new opportunities for studying motor control and designing BCIs via two photon imaging.
Identification of optimal dosing schedules of dacomitinib and osimertinib for a phase I/II trial in advanced EGFR-mutant non-small cell lung cancer
Authors: Poels Kamrine E. , Schoenfeld Adam J. , Makhnin Alex , Tobi Yosef , Wang Yuli , Frisco-Cabanos Heidie , Chakrabarti Shaon , Shi Manli , Napoli Chelsi , McDonald Thomas O. , Tan Weiwei , Hata Aaron , Weinrich Scott L. , Yu Helena A. , Michor Franziska
Published: June 2021

Despite the clinical success of the third-generation EGFR inhibitor osimertinib as a first-line treatment of EGFR-mutant non-small cell lung cancer (NSCLC), resistance arises due to the acquisition of EGFR second-site mutations and other mechanisms, which necessitates alternative therapies. Dacomitinib, a pan-HER inhibitor, is approved for first-line treatment and results in different acquired EGFR mutations than osimertinib that mediate on-target resistance. A combination of osimertinib and dacomitinib could therefore induce more durable responses by preventing the emergence of resistance. Here we present an integrated computational modeling and experimental approach to identify an optimal dosing schedule for osimertinib and dacomitinib combination therapy. We developed a predictive model that encompasses tumor heterogeneity and inter-subject pharmacokinetic variability to predict tumor evolution under different dosing schedules, parameterized using in vitro dose-response data. This model was validated using cell line data and used to identify an optimal combination dosing schedule. Our schedule was subsequently confirmed tolerable in an ongoing dose-escalation phase I clinical trial (NCT03810807), with some dose modifications, demonstrating that our rational modeling approach can be used to identify appropriate dosing for combination therapy in the clinical setting.
Single-cell RNA sequencing shows the immunosuppressive landscape and tumor heterogeneity of HBV-associated hepatocellular carcinoma
Authors: Ho Daniel Wai-Hung , Tsui Yu-Man , Chan Lo-Kong , Sze Karen Man-Fong , Zhang Xin , Cheu Jacinth Wing-Sum , Chiu Yung-Tuen , Lee Joyce Man-Fong , Chan Albert Chi-Yan , Cheung Elaine Tin-Yan , Yau Derek Tsz-Wai , Chia Nam-Hung , Lo Irene Lai-Oi , Sham Pak-Chung , Cheung Tan-To , Wong Carmen Chak-Lui , Ng Irene Oi-Lin
Published: June 2021

Interaction between tumor cells and immune cells in the tumor microenvironment is important in cancer development. Immune cells interact with the tumor cells to shape this process. Here, we use single-cell RNA sequencing analysis to delineate the immune landscape and tumor heterogeneity in a cohort of patients with HBV-associated human hepatocellular carcinoma (HCC). We found that tumor-associated macrophages suppress tumor T cell infiltration and TIGIT-NECTIN2 interaction regulates the immunosuppressive environment. The cell state transition of immune cells towards a more immunosuppressive and exhaustive status exemplifies the overall cancer-promoting immunocellular landscape. Furthermore, the heterogeneity of global molecular profiles reveals co-existence of intra-tumoral and inter-tumoral heterogeneity, but is more apparent in the latter. This analysis of the immunosuppressive landscape and intercellular interactions provides mechanistic information for the design of efficacious immune-oncology treatments in hepatocellular carcinoma.
Hypoxia-induced SETX links replication stress with the unfolded protein response
Authors: Ramachandran Shaliny , Ma Tiffany S. , Griffin Jon , Ng Natalie , Foskolou Iosifina P. , Hwang Ming-Shih , Victori Pedro , Cheng Wei-Chen , Buffa Francesca M. , Leszczynska Katarzyna B. , El-Khamisy Sherif F. , Gromak Natalia , Hammond Ester M.
Published: June 2021

Tumour hypoxia is associated with poor patient prognosis and therapy resistance. A unique transcriptional response is initiated by hypoxia which includes the rapid activation of numerous transcription factors in a background of reduced global transcription. Here, we show that the biological response to hypoxia includes the accumulation of R-loops and the induction of the RNA/DNA helicase SETX. In the absence of hypoxia-induced SETX, R-loop levels increase, DNA damage accumulates, and DNA replication rates decrease. Therefore, suggesting that, SETX plays a role in protecting cells from DNA damage induced during transcription in hypoxia. Importantly, we propose that the mechanism of SETX induction in hypoxia is reliant on the PERK/ATF4 arm of the unfolded protein response. These data not only highlight the unique cellular response to hypoxia, which includes both a replication stress-dependent DNA damage response and an unfolded protein response but uncover a novel link between these two distinct pathways.
Longevity and germination of Juniperus communis L. pollen after storage
Authors: Kormuťák Andrej , Bolecek Peter , Galgóci Martin , Gömöry Dušan
Published: June 2021

Pollen storage belongs among the most important activities associated with pollen handling. It overcomes the differences in pollen shedding and ovule receptivity during controlled pollination experiments. It is especially important for species like common juniper (Juniperus communis L.) with an extremely low quality of seeds due to pollination failure. Additionally, it is a substantial part of germplasm preservation programmes in pollen banks. In the present paper, the effect of short-term storage of pollen was studied using pollen samples from five shrubs in an in vitro germination test. Two temperature regimes were tested. The pollen viability of freshly collected pollen varied considerably between individual shrubs, exhibiting 67.3–88.6% germination rate and 248.0–367.3 µm of pollen tubes. Storage at + 4 °C for four months was accompanied by a profound decline in pollen viability. The germination percentage was reduced to 49.2–75.2% and the pollen tube length to 32.5–69.0%, depending on individual shrubs. The corresponding decline in pollen viability characteristics during storage at − 20 °C was only negligible in two of the tested shrubs. In the remaining three shrub samples, an increase in germination percentage was observed. Pollen tube growth responded more sensitively to freezing, but, on average, the decrease in length was lower than that at + 4 °C. The rate of reduction in pollen tube length varied between 11.5 and 45.4%. Cytological events accompanying in vitro germination of freezer-stored pollen exhibited some delay in releasing the exine from pollen grains during the early stages of germination as compared with freshly collected pollen. In conclusion, short-term storage of the common juniper pollen in a freezer is better for the preservation of its viability than storage at + 4 °C.
Persistent symptoms and lab abnormalities in patients who recovered from COVID-19
Authors: Varghese Julian , Sandmann Sarah , Ochs Kevin , Schrempf Inga-Marie , Frömmel Christopher , Dugas Martin , Schmidt Hartmut H. , Vollenberg Richard , Tepasse Phil-Robin
Published: June 2021

With increasing numbers of patients recovering from COVID-19, there is increasing evidence for persistent symptoms and the need for follow-up studies. This retrospective study included patients without comorbidities, who recovered from COVID-19 and attended an outpatient clinic at a university hospital for follow-up care and potential convalescent plasma donation. Network analysis was applied to visualize symptom combinations and persistent symptoms. Comprehensive lab-testing was ascertained at each follow-up to analyze differences regarding patients with vs without persistent symptoms. 116 patients were included, age range was 18–69 years (median: 41) with follow-ups ranging from 22 to 102 days. The three most frequent persistent symptoms were Fatigue (54%), Dyspnea (29%) and Anosmia (25%). Lymphopenia was present in 13 of 112 (12%) cases. Five of 35 cases (14%) had Lymphopenia in the later follow-up range of 80–102 days. Serum IgA concentration was the only lab parameter with significant difference between patients with vs without persistent symptoms with reduced serum IgA concentrations in the patient cohort of persistent symptoms (p = 0.0219). Moreover, subgroup analyses showed that patients with lymphopenia experienced more frequently persistent symptoms. In conclusion, lymphopenia persisted in a noticeable percentage of recovered patients. Patients with persistent symptoms had significantly lower serum IgA levels. Furthermore, our data provides evidence that lymphopenia is associated with persistence of COVID-19 symptoms.
Ginsenoside Rg1 can restore hematopoietic function by inhibiting Bax translocation-mediated mitochondrial apoptosis in aplastic anemia
Authors: Cao Huiqin , Wei Wei , Xu Ruirong , Cui Xing
Published: June 2021

The present study investigated, the anti-apoptotic activity of Ginsenoside Rg1 (Rg1) via inhibition of Bax translocation and the subsequent recovery of hematopoietic function. Mitochondrial apoptosis in bone marrow mononuclear cells (BMNCs) was observed in aplastic anemia (AA) patients. To establish a mouse model of AA, BALB/c mice were transplanted with lymph node cells from DBA/2 donor mice via vein injection after treatment with Co60 γ-radiation. After treatment with Rg1 for 14 days, the peripheral blood and Lin–Sca-1 + c-Kit + (LSK) cell counts of the treated group were increased compared with those of the untreated model mice. In in vivo and in vitro tests of LSKs, Rg1 was found to increase mitochondrial number and the ratio of Bcl-2/Bax and to decrease damage to the mitochondrial inner and outer membranes, the mitochondrial Bax level and the protein levels of mitochondrial apoptosis-related proteins AIF and Cyt-C by decreasing the ROS level. Rg1 also improved the concentration–time curve of MAO and COX and levels of ATP, ADP and AMP in an in vitro test. In addition, high levels of Bax mitochondrial translocation could be corrected by Rg1 treatment. Levels of markers of mitochondrial apoptosis in the Rg1-treated group were significantly better than those in the AA model group, implying that Rg1 might improve hematopoietic stem cells and thereby restore hematopoietic function in AA by suppressing the mitochondrial apoptosis mediated by Bax translocation.
Photoperiodically driven transcriptome-wide changes in the hypothalamus reveal transcriptional differences between physiologically contrasting seasonal life-history states in migratory songbirds
Authors: Sharma Aakansha , Das Subhajit , Sur Sayantan , Tiwari Jyoti , Chaturvedi Khushboo , Agarwal Neha , Malik Shalie , Rani Sangeeta , Kumar Vinod
Published: June 2021

We investigated time course of photoperiodically driven transcriptional responses in physiologically contrasting seasonal life-history states in migratory blackheaded buntings. Birds exhibiting unstimulated winter phenotype (photosensitive state; responsive to photostimulation) under 6-h short days, and regressed summer phenotype (photorefractory state; unresponsiveness to photostimulation) under 16-h long days, were released into an extended light period up to 22 h of the day. Increased tshβ and dio2, and decreased dio3 mRNA levels in hypothalamus, and low prdx4 and high il1β mRNA levels in blood confirmed photoperiodic induction by hour 18 in photosensitive birds. Further, at hours 10, 14, 18 and 22 of light exposure, the comparison of hypothalamus RNA-Seq results revealed transcriptional differences within and between states. Particularly, we found reduced expression at hour 14 of transthyretin and proopiomelanocortin receptor, and increased expression at hour 18 of apolipoprotein A1 and carbon metabolism related genes in the photosensitive state. Similarly, valine, leucine and isoleucine degradation pathway genes and superoxide dismutase 1 were upregulated, and cocaine- and amphetamine-regulated transcript and gastrin-releasing peptide were downregulated in the photosensitive state. These results show life-history-dependent activation of hypothalamic molecular pathways involved in initiation and maintenance of key biological processes as early as on the first long day.
OpiumPlex is a novel microsatellite system for profiling opium poppy (Papaver somniferum L.)
Authors: Vašek Jakub , Čílová Daniela , Melounová Martina , Svoboda Pavel , Zdeňková Kamila , Čermáková Eliška , Ovesná Jaroslava
Published: June 2021

Opium poppy (Papaver somniferum L.) is a versatile plant exploited by the pharmaceutical and food industries. Unfortunately, it is also infamously known as a source of highly addictive narcotics, primarily heroin. Drug abuse has devastating consequences for users and also has many direct or indirect negative impacts on human society as a whole. Therefore, developing a molecular genetic tool for the individualization of opium poppy, raw opium or heroin samples could help in the fight against the drug trade by retrieving more information about the source of narcotics and linking isolated criminal cases. Bioinformatic analysis provided insight into the distribution, density and other characteristics of roughly 150 thousand microsatellite loci within the poppy genome and indicated underrepresentation of microsatellites with the desired attributes. Despite this fact, 27 polymorphic STR markers, divided into three multiplexed assays, were developed in this work. Internal validation confirmed species-specific amplification, showed that the optimal amount of DNA is within the range of 0.625–1.25 ng per reaction, and indicate relatively well balanced assays according to the metrics used. Moreover, the stutter ratio (mean + 3 SD 2.28–15.59%) and allele-specific stutters were described. The analysis of 187 individual samples led to the identification of 158 alleles in total, with a mean of 5.85 alleles and a range of 3–14 alleles per locus. Most of the alleles (151) were sequenced by the Sanger method, which enabled us to propose standardized nomenclature and create three allelic ladders. The OpiumPlex system discriminates most of the varieties from each other and pharmaceutical varieties from the others (culinary, dual and ornamental).
Identification of antigenic domains and peptides from VP15 of white spot syndrome virus and their antiviral effects in Marsupenaeus japonicus
Authors: Boonyakida Jirayu , Xu Jian , Satoh Jun , Nakanishi Takafumi , Mekata Tohru , Kato Tatsuya , Park Enoch Y.
Published: June 2021

White spot syndrome virus (WSSV) is one of the most devastating pathogens in penaeid shrimp and can cause massive damage in shrimp aquaculture industries. Previously, the WSSV structural protein VP15 was identified as an antigenic reagent against WSSV infections. In this study, we truncated this protein into VP15(1–25), VP15(26–57), VP15(58–80), and VP15(1–25,58–80). The purified proteins from theE. coliexpression system were assayed as potential protective agents in Kuruma shrimp (Marsupenaeus japonicus) using the prime-and-boost strategy. Among the four truncated constructs, VP15(26–57)provided a significant improvement in the shrimp survival rate after 20 days of viral infection. Subsequently, four peptides (KR11, SR11, SK10, and KK13) from VP15(26–57)were synthesized and applied in an in vivo assay. Our results showed that SR11 could significantly enhance the shrimp survival rate, as determined from the accumulated survival rate. Moreover, a multiligand binding protein with a role in the host immune response and a possible VP15-binding partner, MjgC1qR, from the hostM. japonicuswere employed to test its binding with the VP15 protein. GST pull-down assays revealed that MjgC1qR binds with VP15, VP15(26–57), and SR11. Taken together, we conclude that SR11 is a determinant antigenic peptide of VP15 conferring antiviral activity against WSSV.
An estimation on the mechanical stabilities of SAMs by low energy Ar+ cluster ion collision
Authors: Tong Y. , Berdiyorov G. R. , Sinopoli A. , Madjet M. E. , Esaulov V. A. , Hamoudi H.
Published: June 2021

The stability of the molecular self-assembled monolayers (SAMs) is of vital importance to the performance of the molecular electronics and their integration to the future electronics devices. Here we study the effect of electron irradiation-induced cross-linking on the stability of self-assembled monolayer of aromatic 5,5′-bis(mercaptomethyl)-2,2′-bipyridine [BPD; HS-CH2-(C5H3N)2-CH2-SH] on Au (111) single crystal surface. As a refence, we also study the properties of SAMs of electron saturated 1-dodecanethiol [C12; CH3-(CH2)11-SH] molecules. The stability of the considered SAMs before and after electron-irradiation is studied using low energy Ar+ cluster depth profiling monitored by recording the X-ray photoelectron spectroscopy (XPS) core level spectra and the UV-photoelectron spectroscopy (UPS) in the valance band range. The results indicate a stronger mechanical stability of BPD SAMs than the C12 SAMs. The stability of BPD SAMs enhances further after electron irradiation due to intermolecular cross-linking, whereas the electron irradiation results in deterioration of C12 molecules due to the saturated nature of the molecules. The depth profiling time of the cross-linked BPD SAM is more than 4 and 8 times longer than the profiling time obtained for pristine and BPD and C12 SAMs, respectively. The UPS results are supported by density functional theory calculations, which show qualitative agreement with the experiment and enable us to interpret the features in the XPS spectra during the etching process for structural characterization. The obtained results offer helpful options to estimate the structural stability of SAMs which is a key factor for the fabrication of molecular devices.
DCBLD1 is associated with the integrin signaling pathway and has prognostic value in non-small cell lung and invasive breast carcinoma
Authors: Cardin Guillaume B. , Bernard Monique , Rodier Francis , Christopoulos Apostolos
Published: June 2021

Germline single nucleotide polymorphisms in the promoter region of the DCBLD1 gene are associated with non-smoking cases of both non-small cell lung carcinoma (NSCLC) and human papillomavirus-negative head and neck cancer. However the clinical relevance and function of DCBLD1 remain unclear. This multicenter retrospective study was designed to evaluate the prognostic value and function of DCBLD1 in the four main solid cancers: NSCLC, invasive breast carcinoma, colorectal adenocarcinoma and prostate adenocarcinoma. We included the following cohorts: GSE81089 NSCLC, METABRIC invasive breast carcinoma, GSE14333 colorectal adenocarcinoma, GSE70770 prostate adenocarcinoma and The Cancer Genome Atlas (TCGA) Firehose Legacy cohorts of all four cancers. DCBLD1 gene expression was associated with a worse overall survival in multivariate analyses for both NSCLC cohorts (TCGA: P = 0.03 and GSE81089: P = 0.04) and both invasive breast carcinoma cohorts (TCGA: P = 0.02 and METABRIC: P < 0.001). Patients with high DCBLD1 expression showed an upregulation of the integrin signaling pathway in comparison to those with low DCBLD1 expression in the TCGA NSCLC cohort (FDR = 5.16 × 10–14) and TCGA invasive breast carcinoma cohort (FDR = 1.94 × 10–05).
Cardiorespiratory responses to exercise related to post-stroke fatigue severity
Authors: Oyake Kazuaki , Baba Yasuto , Suda Yuki , Murayama Jun , Mochida Ayumi , Ito Yuki , Abe Honoka , Kondo Kunitsugu , Otaka Yohei , Momose Kimito
Published: June 2021

Physical deconditioning after stroke may induce post-stroke fatigue. However, research on this association is limited. Our primary objective was to investigate the associations of post-stroke fatigue severity with oxygen uptake ($$\dot{\mathrm{V}}$$

V
˙

O2) at peak exercise and the time constant of $$\dot{\mathrm{V}}$$

V
˙

O2 kinetics (τ$$\dot{\mathrm{V}}$$

V
˙

O2) at exercise onset. The secondary objective was to examine the associations between fatigue and cardiorespiratory variables potentially affecting $$\dot{\mathrm{V}}$$

V
˙

O2 during exercise. Twenty-three inpatients from a subacute rehabilitation ward were enrolled in this study. The median (interquartile range) Fatigue Severity Scale (FSS) score, as a measure of fatigue, was 32 (range 27–42) points. The FSS score was not associated with $$\dot{\mathrm{V}}$$

V
˙

O2 at peak exercise during a symptom-limited graded exercise test (rho = − 0.264; p = 0.224), whereas it was significantly associated with τ$$\dot{\mathrm{V}}$$

V
˙

O2 during a submaximal constant-load exercise test (rho = 0.530; p = 0.009). A higher FSS score also significantly correlated with a longer time constant of cardiac output (CO) kinetics (rho = 0.476; p = 0.022). Our findings suggest that severe post-stroke fatigue is associated with delayed increases in $$\dot{\mathrm{V}}$$

V
˙

O2 and CO at the onset of exercise. Our findings can contribute to the development of an appropriate rehabilitation programme for individuals with post-stroke fatigue.
Sea level rise outpaced by vertical dune toe translation on prograding coasts
Authors: van IJzendoorn Christa O. , de Vries Sierd , Hallin Caroline , Hesp Patrick A.
Published: June 2021

Sea level is rising due to climate change and is expected to influence the development and dynamics of coastal dunes. However, the anticipated changes to coastal dunes have not yet been demonstrated using field data. Here, we provide evidence of dune translation that is characterized by a linear increase of the dune toe elevation on the order of 13–15 mm/year during recent decades along the Dutch coast. This rate of increase is a remarkable 7–8 times greater than the measured sea level rise. The observed vertical dune toe translation coincides with seaward movement of the dune toe (i.e., progradation), which shows similarities to prograding coasts in the Holocene both along the Dutch coast and elsewhere. Thus, we suspect that other locations besides the Dutch coast might also show such large ratios between sea level rise and dune toe elevation increase. This phenomenon might significantly influence the expected impact of sea level rise and climate change adaptation measures.
A methodology for an acute exercise clinical trial called dementia risk and dynamic response to exercise
Authors: White Dreu , John Casey S. , Kucera Ashley , Truver Bryce , Lepping Rebecca J. , Kueck Paul J. , Lee Phil , Martin Laura , Billinger Sandra A. , Burns Jeffrey M. , Morris Jill K. , Vidoni Eric D.
Published: June 2021

Exercise likely has numerous benefits for brain and cognition. However, those benefits and their causes remain imprecisely defined. If the brain does benefit from exercise it does so primarily through cumulative brief, “acute” exposures over a lifetime. The Dementia Risk and Dynamic Response to Exercise (DYNAMIC) clinical trial seeks to characterize the acute exercise response in cerebral perfusion, and circulating neurotrophic factors in older adults with and without the apolipoprotein e4 genotype (APOE4), the strongest genetic predictor of sporadic, late onset Alzheimer’s disease. DYNAMIC will enroll 60 older adults into a single moderate intensity bout of exercise intervention, measuring pre- and post-exercise cerebral blood flow (CBF) using arterial spin labeling, and neurotrophic factors. We expect that APOE4 carriers will have poor CBF regulation, i.e. slower return to baseline perfusion after exercise, and will demonstrate blunted neurotrophic response to exercise, with concentrations of neurotrophic factors positively correlating with CBF regulation. Preliminary findings on 7 older adults and 9 younger adults demonstrate that the experimental method can capture CBF and neurotrophic response over a time course. This methodology will provide important insight into acute exercise response and potential directions for clinical trial outcomes.

ClinicalTrials.gov NCT04009629, Registered 05/07/2019.
Maturation of the preterm gastrointestinal tract can be defined by host and microbial markers for digestion and barrier defense
Authors: Henderickx Jannie G. E. , Zwittink Romy D. , Renes Ingrid B. , van Lingen Richard A. , van Zoeren-Grobben Diny , Jebbink Liesbeth J. Groot , Boeren Sjef , van Elburg Ruurd M. , Knol Jan , Belzer Clara
Published: June 2021

Functionality of the gastrointestinal tract is essential for growth and development of newborns. Preterm infants have an immature gastrointestinal tract, which is a major challenge in neonatal care. This study aims to improve the understanding of gastrointestinal functionality and maturation during the early life of preterm infants by means of gastrointestinal enzyme activity assays and metaproteomics. In this single-center, observational study, preterm infants born between 24 and 33 weeks (n = 40) and term infants born between 37 and 42 weeks (n = 3), who were admitted to Isala (Zwolle, the Netherlands), were studied. Enzyme activity analyses identified active proteases in gastric aspirates of preterm infants. Metaproteomics revealed human milk, digestive and immunological proteins in gastric aspirates of preterm infants and feces of preterm and term infants. The fecal proteome of preterm infants was deprived of gastrointestinal barrier-related proteins during the first six postnatal weeks compared to term infants. In preterm infants, bacterial oxidative stress proteins were increased compared to term infants and higher birth weight correlated to higher relative abundance of bifidobacterial proteins in postnatal week 3 to 6. Our findings indicate that gastrointestinal and beneficial microbial proteins involved in gastrointestinal maturity are associated with gestational and postnatal age.
In search of the spectral composition of an effective light trap for the mushroom pest Lycoriella ingenua (Diptera: Sciaridae)
Authors: Kecskeméti Sándor , Geösel András , Fail József , Egri Ádám
Published: June 2021

Certain fungus gnats, like Lycoriella ingenua are notorious pests in agriculture, especially in mushroom production. While larvae cause mainly direct crop damage, adults are vectors of several dangerous fungal pathogens. To promote the development of pesticide-free management methods, such as light trapping, we measured the spectral sensitivity of L. ingenua compound eyes with electroretinography and performed two different behavioural experiments to reveal the wavelength dependence of phototaxis in this species. The spectral sensitivity of the compound eyes is bimodal with peaks at 370 nm (UV) and 526 nm (green). Behavioural experiments showed that attraction to light as a function of wavelength depends on light intensity. In our first experiment, where the minimal photon flux (105–109 photons/cm2/s) needed for eliciting a phototactic response was determined wavelength by wavelength, phototaxis was strongest in the green spectral range (~526 nm). In the other behavioural experiment, where wavelength preference was tested under a higher but constant light intensity (~1013 photons/cm2/s), the highest attraction was elicited by UV wavelengths (398 nm). Our results suggest that both UV and green are important spectral regions for L. ingenua thus we recommend to use both UV (~370-398 nm) and green (~526 nm) for trapping these insects.
Global land cover trajectories and transitions
Authors: Radwan Taher M. , Blackburn G. Alan , Whyatt J. Duncan , Atkinson Peter M.
Published: June 2021

Global land cover (LC) changes threaten sustainability and yet we lack a comprehensive understanding of the gains and losses of LC types, including the magnitudes, locations and timings of transitions. We used a novel, fine-resolution and temporally consistent satellite-derived dataset covering the entire Earth annually from 1992 to 2018 to quantify LC changes across a range of scales. At global and continental scales, the observed trajectories of change for most LC types were fairly smooth and consistent in direction through time. We show these observed trajectories in the context of error margins produced by extrapolating previously published accuracy metrics associated with the LC dataset. For many LC classes the observed changes were found to be within the error margins. However, an important exception was the increase in urban land, which was consistently larger than the error margins, and for which the LC transition was unidirectional. An advantage of analysing the global, fine spatial resolution LC time-series dataset is the ability to identify where and when LC changes have taken place on the Earth. We present LC change maps and trajectories that identify locations with high dynamism, and which pose significant sustainability challenges. We focused on forest loss and urban growth at the national scale, identifying the top 10 countries with the largest percentages of forest loss and urban growth globally. Crucially, we found that most of these ‘worst-case’ countries have stabilized their forest losses, although urban expansion was monotonic in all cases. These findings provide crucial information to support progress towards the UN’s SDGs.
A novel model of ischemia in rats with middle cerebral artery occlusion using a microcatheter and zirconia ball under fluoroscopy
Authors: Komatsu Teppei , Ohta Hiroki , Motegi Haruhiko , Hata Junichi , Terawaki Koshiro , Koizumi Makoto , Muta Kanako , Okano Hirotaka James , Iguchi Yasuyuki
Published: June 2021

The failure of neuroprotective treatment-related clinical trials may be partially caused by unestablished animal models. Existing animal models are less likely to provide occlusion confined to the middle cerebral artery (MCA), making transarterial intervention difficult. We aimed to develop a novel focal stroke model using a microcatheter and zirconium dioxide that is non-magnetic under fluoroscopic guidance, which can monitor MCA occlusion and can improve hemorrhagic complications. Using male Sprague Dawley rats (n = 10), a microcatheter was navigated from the caudal ventral artery to the left internal carotid artery using an X-ray fluoroscopy to establish local occlusion. All rat cerebral angiographies were successful. No rats had hemorrhagic complications. Eight (80%) rats underwent occlusion of the MCA bifurcation by zirconium dioxide. Accidentally, the left posterior cerebral artery was failure embolized in 2 rats (20%). The median operating time was 8 min. All rats of occlusion MCA revealed an incomplete hemiparesis on the right side with neurological deficit score ranging from 1 to 3 (median 1, interquartile range 1–3) at 24 h after the induction of ischemia. Moreover, 2% 2,3,5-triphenyl tetrazolium chloride staining showed that the median infarct volume (mm3) was 280 (interquartile range 267–333) 24 h after the left MCA bifurcation occlusion. We present a novel rat model for focal stroke using a microcatheter and zirconium dioxide which does not affect the MRI. The model is predictable which is well confined within the territory supplied by the MCA, and reproducibility of this model is 80%. Fluoroscopy was able to identify which the MCA occlusion and model success while creating the model. It permitted exclusion of animals with complications from the experiment.
Multipolar-sensitive engineering of magnetic dipole spontaneous emission with a dielectric nanoresonator antenna
Authors: Habil Mojtaba Karimi , Zapata–Rodríguez Carlos J. , Cuevas Mauro , Entezar Samad Roshan
Published: June 2021

We propose an axisymmetric silicon nanoresonator with designed tapered angle well for the extraordinary enhancement of the decay rate of magnetic dipole (MD) emitters. Due to the resonant coupling of a MD emitter and the MD mode of the subwavelength resonator, the Purcell factor (PF) can easily reach 500, which is significantly higher than the PF when using a silicon nanosphere of the same size. The PF and the resonance frequency are conveniently tuned through the resonator diameter and the taper angle of the blind hole. When supported by a metallic substrate, further enhancement ($$>10^3$$

>

10
3

) of the MD spontaneous emission is triggered by an image-induced quadrupolar high-Q mode of the nanoantenna. For the sake of comparison we include a critical analysis of the canonical problem that considers a Si spherical shell. Our results might facilitate a novel strategy for promising realizations of chip-scale nanophotonic applications.
The application of principal component analysis to characterize gait and its association with falls in multiple sclerosis
Authors: Monaghan Andrew S. , Huisinga Jessie M. , Peterson Daniel S.
Published: June 2021

People with multiple sclerosis (PwMS) demonstrate gait impairments that are related to falls. However, redundancy exists when reporting gait outcomes. This study aimed to develop an MS-specific model of gait and examine differences between fallers and non-fallers. 122 people with relapsing–remitting MS and 45 controls performed 3 timed up-and-go trials wearing inertial sensors. 21 gait parameters were entered into a principal component analysis (PCA). The PCA-derived gait domains were compared between MS fallers (MS-F) and MS non-fallers (MS-NF) and correlated to cognitive, clinical, and quality-of-life outcomes. Six distinct gait domains were identified: pace, rhythm, variability, asymmetry, anterior–posterior dynamic stability, and medial–lateral dynamic stability, explaining 79.15% of gait variance. PwMS exhibited a slower pace, larger variability, and increased medial–lateral trunk motion compared to controls (p < 0.05). The pace and asymmetry domains were significantly worse (i.e., slower and asymmetrical) in MS-F than MS-NF (p < 0.001 and p = 0.03, respectively). Fear of falling, cognitive performance, and functional mobility were associated with a slower gait (p < 0.05). This study identified a six-component, MS-specific gait model, demonstrating that PwMS, particularly fallers, exhibit deficits in pace and asymmetry. Findings may help reduce redundancy when reporting gait outcomes and inform interventions targeting specific gait domains.
NMR Studies of Oxide-type Solid State Electrolytes in All Solid State Batteries
Authors: Liang Ziteng , Xiang Yuxuan , Wang Dawei , Fu Riqiang , Yang Yong
Published: June 2021

Oxide-type solid state electrolytes are considered to be a promising solid state electrolyte in all solid state batteries due to their relatively high ionic conductivity, wide potential window, and excellent thermal stability. However, many issues associated with their practical applications in all solid state batteries have yet to be solved, and their underlying mechanisms have not been fully understood. Thus, advanced techniques are called on to analyse these issues. Solid state nuclear magnetic resonance (ssNMR), with its ability to probe local structure, to track ionic motion in different length/time scales, to study lithium/sodium dendrites, and to investigate interfacial issues, has unique advantages in characterizing such oxide-type solid state batteries. In this chapter, we first summarize the state-of-the art applications of ssNMR in the oxide-type solid state batteries mainly including garnet-type and NASICON-type. After that, we also present some perspectives on the employment of ssNMR in oxide-type solid state batteries.
Ni/NiO/Ni–B/graphene heterostructure-modified electrodes and their electrochemical activities towards acetaminophen
Authors: Ipekci Hasan Huseyin , Ozcan Merve , Turkyilmaz Busra Gizem , Uzunoglu Aytekin
Published: June 2021

Schematic representation of the sensor fabrication process.
An exosome-mimicking membrane hybrid nanoplatform for targeted treatment toward Kras-mutant pancreatic carcinoma
Authors: Deng Lang , Zhang Hanming , Zhang Yu , Luo Shi , Du Zhengwu , Lin Qing , Zhang Zhirong , Zhang Ling
Published: June 2021

Schematic of the preparation of M-LIP-CLT.
Hierarchy of π-stacking determines the conformational preferences of bis-squaramates
Authors: Singh Abhishek , Singh Reman Kumar , Patwari G. Naresh
Published: June 2021

Orientation of squaramate dimers in crystal structures is tuned by varying the degree of cooperativity between hydrogen bonding and π-stacking.
Electronic and thermal transport in novel carbon-based bilayer with tetragonal rings: a combined study using first-principles and machine learning approach
Authors: Ghosal Supriya , Chowdhury Suman , Jana Debnarayan
Published: June 2021

The structural, electronic and thermal transport characteristics of novel carbon-based bilayer tetragonal graphene are systematically explored with a combination of first-principles calculations and machine-learning interatomic potential approaches.
Unusual binary aggregates of perylene bisimide revealed by their electronic transitions in helium nanodroplets and DFT calculations
Authors: Izadnia S. , LaForge A. C. , Stienkemeier F. , Cheeseman James R. , Bloino Julien , Cheramy J. , Jäger Wolfgang , Xu Yunjie
Published: June 2021

The superfluid helium nanodroplet environment produces some uncharacteristic perylene bisimide dimer geometries which feature discrete red-shifted vibronic bands, in contrast to the usual π-stacked dimers observed in solution.
The effect of Mg3As2 alloying on the thermoelectric properties of n-type Mg3(Sb, Bi)2
Authors: Imasato Kazuki , Anand Shashwat , Gurunathan Ramya , Snyder G. Jeffrey
Published: June 2021

The effect of Mg3As2 alloying on thermoelectric properties of Mg3(Sb, Bi)2 has been investigated. While the crystal structure of pure Mg3As2 is different from Mg3(Sb, Bi)2, at least 15% arsenic solubility on anion site is confirmed.
Solar denitrification coupled with in situ water splitting
Authors: Lee Shinbi , Kim Suhyeon , Park Cheolwoo , Kim Wooyul , Ryu Sunmin , Choi Wonyong
Published: June 2021

A photoconversion system that couples solar water splitting with denitrification (without chemical reductants) is proposed for controlling nitrate by developing a ternary composite composed of TiO2, Cu–Pd bimetals, and reduced graphene oxide.
Copper on charcoal: Cu0 nanoparticle catalysed aerobic oxidation of α-diazo esters
Authors: Zhao Rong , Teng Jiangge , Wang Zhiwei , Dong Wenwen , Lin Jia , Chu Changhu
Published: June 2021

Highly efficient Cu0 nanoparticle catalysed aerobic oxidation of α-diazo esters with molecular oxygen as the terminal oxidant.
A bias-free CuBi2O4–CuWO4 tandem cell for solar-driven water splitting
Authors: Zhang Yuwei , Wang Lina , Xu Xiaoxiang
Published: June 2021

An all-copper-based oxide tandem cell based on CuBi2O4 and CuWO4 films has been fabricated which shows promising water splitting photocurrents under simulated solar insolation without an external bias.
Revised structural assignment of azalomycins based on genomic and chemical analysis
Authors: Lee Seoung Rak , Guo Huijuan , Yu Jae Sik , Park Minji , Dahse Hans-Martin , Jung Won Hee , Beemelmanns Christine , Kim Ki Hyun
Published: June 2021

We clarified structural inconsistencies of four azalomycin derivatives (F4a, F4b, F5a and F5b) from Streptomyces sp. M56 by nuclear magnetic resonance, J-based configuration analyses, electronic circular dichroism and in silico genome studies.
Pressure-driven electronic phase transition in the high-pressure phase of nitrogen-rich 1H-tetrazoles
Authors: Liu Ying , Du Huifang , Fang Leiming , Sun Fei , Su Haipeng , Ge Zhongxue , Guo Wei , Zhu Jinlong
Published: June 2021

Combined high pressure in situ spectra with first-principles calculations, a possible hydrogen-bond assisted phase transition was proposed in tetrazole.
Stability of neutral molecular polynitrogens: energy content and decomposition mechanisms
Authors: Gomes A. C. R. , Silva M. X. , Galvão B. R. L.
Published: June 2021

All-nitrogen molecules may provide green energy sources, releasing large amounts of energy without polluting byproducts. Here we predict the stability towards unimolecular decomposition of several structures and discuss their unusual chemistry.
Development of pyrazoline-based derivatives as aminopeptidase N inhibitors to overcome cancer invasion and metastasis
Authors: Cao Jiangying , Zhao Chunlong , Dong Hang , Xu Qifu , Zhang Yingjie
Published: June 2021

Compound 2k exhibited promising in vitro anti-invasion and in vivo anti-metastasis potencies, suggesting its prospect as an anti-invasion and anti-metastasis lead.