bluuebunny/crossref_metadata_2025 huggingface dataset:
Getting the Teacher’s Attention: Parent-Teacher Contact and Teachers’ Behavior in the Classroom
Authors: Young Natalie A E
Published: January 2020

Studies suggest that both parental involvement and support from teachers matter for students’ academic success. Although cross-national research has revealed numerous ways in which parents shape the schooling process, less clear is whether parental involvement at school can influence teachers’ daily behavior toward students in class. In this study, I draw on data from the China Education Panel Survey (CEPS)—a nationally representative survey of Chinese middle-school students with unusually detailed information on parental involvement and teachers’ daily behaviors—to test a conceptual model that proposes a link between parent-teacher contact in China and attention students receive from teachers during daily lessons. In support of the conceptual model, I find that students whose parents cultivate relationships with teachers through frequent contact are more likely to be cold-called on and praised by teachers in class, even after controlling for family background, student academic performance, and student behavior. Moreover, I observe social class differences in parent-teacher contact, as well as some evidence that parent-teacher contact is linked to improved student performance through its impact on teachers’ attention. Overall, the findings point to a potential new pathway through which social class influences schooling by way of school-based parental involvement and in a broader set of contexts than previously imagined. I conclude with a discussion of implications for social reproduction theory, as well as challenges this situation presents for combatting educational inequality.
Effect of a mobile just-in-time implementation intention intervention on momentary smoking lapses in smoking cessation attempts among Asian American young adults
Authors: Huh Jimi , Cerrada Christian J , Dzubur Eldin , Dunton Genevieve F , Spruijt-Metz Donna , Leventhal Adam M
Published: January 2020

Identifying vulnerable windows for a given problematic behavior and providing timely and appropriate support are critical for building an effective just-in-time (JIT) intervention for behavioral change. We developed and evaluated an implementation intention (II) based, JIT cessation intervention prototype to support Asian American young adult smokers to prevent lapses in their cessation attempts in real-time. We examined how a JIT II reminder may prevent lapses during self-identified high-risk smoking situation (HRSS) as a microtemporal process. We also tested whether the effect of JIT reminder changes over the course of study and differed between those who used their own versus project loan phones. Asian American young adult smokers (N = 57) who were interested in quitting or reducing smoking participated in a 4 week, mobile-based, cessation study (MyQuit USC, MQU). MQU is a JIT mobile app that deploys a user-specified II reminder at user-specified HRSS and assesses momentary lapse status. Generalized mixed linear models were conducted to assess the effect of the JIT intervention on lapse prevention. We found a significant interaction effect (p = .03) such that receiving JIT reminder reduced the likelihood of lapses for participants using their own phones but not for the loaners. The results also showed that when participants enacted the suggested II, they were less likely to lapse (p < .001). The JIT effect did not change over time in study (p = .21). This study provides evidence that receiving a reminder of a smoker’s own plan just before a self-identified risky situation on a familiar device and successfully executing specified plans can be helpful in preventing lapses. Our results highlighted factors to consider when designing and refining a JIT intervention.
Identification of Reptarenaviruses, Hartmaniviruses and a Novel Chuvirus in Captive Brazilian Native Boa Constrictors with Boid Inclusion Body Disease
Authors: Argenta Fernando Froner , Hepojoki Jussi , Smura Teemu , Szirovicza Leonora , Hammerschmitt Márcia Elisa , Driemeier David , Kipar Anja , Hetzel Udo
Published: January 2020

Boid Inclusion Body Disease (BIBD) is a transmissible viral disease of captive snakes that causes severe losses in snake collections worldwide. It is caused by reptarenavirus infection, which can persist over several years without overt signs, but is generally associated with the eventual death of the affected snakes. Thus far, reports have confirmed existence of reptarenaviruses in captive snakes in North America, Europe, and Australia, but there is no evidence that it also occurs in wild snakes. BIBD affects both boas and pythons, the habitats of which do not naturally overlap. Herein, we studied Brazilian captive snakes with BIBD using a metatranscriptomic approach, and report the identification of novel reptarenaviruses, hartmaniviruses, and a new species in the familyChuviridae. The reptarenavirus L segments identified represent six novel species, while we only found a single novel reptarenavirus S segment. Until now, hartmaniviruses had been identified only in European captive boas with BIBD, and the present results increase the number of known hartmanivirus species from four to six. The newly identified chuvirus showed 38.4%, 40.9%, and 48.1% amino acid identity to the nucleoprotein, glycoprotein, and RNA-dependent RNA polymerase of its closest relative, Guangdong red-banded snake chuvirus-like virus. Although we cannot rule out the possibility that the found viruses originated from imported snakes, the results suggest that the viruses would circulate in indigenous snake populations.

IMPORTANCE

Boid Inclusion Body Disease (BIBD) caused by reptarenavirus infection affects captive snake populations worldwide, but the reservoir hosts of reptarenaviruses remain unknown. Herein, we report the identification of novel reptarenavirus and hartmanivirus species, and a chuvirus in captive Brazilian boas with BIBD. Three of the four snakes studied showed co-infection with all three viruses, and one of the snakes harbored three novel reptarenavirus L and one novel S segment. The samples originated from collections with Brazilian indigenous snakes only, which could indicate that these viruses circulate in wild snakes. The findings could further indicate that boid snakes are the natural reservoir of reptarena- and hartmaniviruses commonly found in captive snakes. The snakes infected with the novel chuvirus all suffered from BIBD; it is therefore not possible to comment on its potential pathogenicity and contribution to the observed changes in the present case material.
Improved Supra-Organization Is A Conformational And Functional Adaptation Of Respiratory Complexes
Authors: Rawat Shivali , Ghosh Suparna , Mondal Debodyuti , Anusha Valpadashi , Raychaudhuri Swasti
Published: January 2020

Multiple surveillance mechanisms accelerate proteasome mediated degradation of misfolded proteins to prevent protein aggregation inside and outside mitochondria. But how cells safeguard mitochondrial function despite increased protein aggregation during proteasome inactivation? Here, using two-dimensional complexome profiling, we extensively characterize the dynamic states of respiratory complexes (RCs) in proteasome-inhibited cells. We report that RC-subunits are increasingly integrated into supra-organizations to optimize catalytic activity simultaneous to their aggregation inside mitochondria. Complex-II (CII) and CV are incorporated into oligomers. CI, CIII, and CIV subcomplexes are associated into holocomplexes followed by integration into supercomplexes. Time-course experiments reveal that the core (CI+CIII2) stoichiometry of supercomplex (I+III2+IV) is preserved during early-stress while CIV composition varies. Simultaneously, increased CI-activity suggests conformational optimization of supercomplexes for better function. Re-establishment of steady-state stoichiometry and relative increase in supercomplex-quantity consolidates functional adaptation during prolonged proteasome-inhibition. Together, we name this pre-emptive adaptive mechanism as ‘improved Supra-organization of Respiratory Complexes’ (iSRC). We find that iSRC is active in multiple protein-unfolding stresses, in multiple cell-types that differ in proteostatic and metabolic demands, and reversible upon stress-withdrawal.
Consequences of combining sex-specific life-history traits
Authors: Venkateswaran Vandana Revathi , Roth Olivia , Gokhale Chaitanya S.
Published: January 2020

Males and females evolved distinct life-history strategies, reflected in diverse inter-linked life-history traits. The sex that allocates more resources towards offspring relies on an increased life span, and long life requires an efficient immune system. The other sex needs to attract mates and thus allocates its resources towards ornamentation, which may negatively correlate with investment into the immune defense. Such sex-specific resource allocation trade-offs are not always strictly female or male-specific but may depend on the overall resources allocated towards life-history traits. Informed by experimental data, we designed a theoretical framework that combines multiple life-history traits. We disentangled specific life-history strategies from particular sex, allowing us to include species with reversed sex-roles and male parental investment. We computed the lifetime reproductive success (combining fitness components from diverse sex-specific life-history traits) observing a strong bias in adult sex ratio depending on sex-specific resource allocation towards life-history traits. Overall, our work provides a generalized method to combine various life-history traits with sex-specific differences to calculate lifetime reproductive success. The results explain specific population-level empirical observations as a consequence of sexual dimorphism in life-history traits.
AnArabidopsisAT-hook motif nuclear protein mediates somatic embryogenesis and coinciding genome duplication
Authors: Karami Omid , Rahimi Arezoo , Mak Patrick , Horstman Anneke , Boutilier Kim , Compier Monique , van der Zaal Bert , Offringa Remko
Published: January 2020

Plant somatic cells can be reprogrammed to totipotent embryonic cells that are able to form differentiated embryos in a process called somatic embryogenesis (SE), by hormone treatment or through overexpression of certain transcription factor genes, such asBABY BOOM(BBM). Here we show that overexpression of theAT-HOOK MOTIF CONTAINING NUCLEAR LOCALIZED 15(AHL15) gene induces formation of somatic embryos onArabidopsis thalianaseedlings in the absence of hormone treatment. During zygotic embryogenesis,AHL15expression starts early in embryo development, andAH15and otherAHLgenes are required for proper embryo patterning and development beyond the heart stage. Moreover,AHL15and several of its homologs are upregulated and required for SE induction upon hormone treatment, and they are required for efficientBBM-induced SE as downstream targets of BBM. A significant number of plants derived fromAHL15overexpression-induced somatic embryos are polyploid. Polyploidisation occurs by endomitosis specifically during the initiation of SE, assumingly due to AHL15-mediated heterochromatin decondensation coinciding with the acquisition of embryonic competency in somatic plant cells.
The immediate early geneArcis not required for hippocampal long-term potentiation
Authors: Kyrke-Smith M. , Volk L.J. , Cooke S.F. , Bear M.F. , Huganir R.L. , Shepherd J.D
Published: January 2020

The immediate early geneArcis critical for maintenance of long-term memory. How Arc mediates this process remains unclear, but it has been proposed to sustain Hebbian synaptic potentiation, which is a key component of memory encoding. This form of plasticity is modelled experimentally by induction of long-term potentiation (LTP), which increases Arc mRNA and protein expression. However, mechanistic data implicates Arc in the endocytosis of AMPA-type glutamate receptors and the weakening of synapses. Here, we took a comprehensive approach to determine if Arc is necessary for hippocampal LTP. We find that Arc is not required for LTP maintenance and must regulate memory storage through alternative mechanisms.
Hypercholesterolemia Accelerates Both the Initiation and Progression of Angiotensin II-induced Abdominal Aortic Aneurysms
Authors: Liu Jing , Sawada Hisashi , Howatt Deborah A. , Moorleghen Jessica J. , Vsevolozhskaya Olga , Daugherty Alan , Lu Hong S.
Published: January 2020

Objective

This study determined whether hypercholesterolemia would contribute to both the initiation and progression of angiotensin (Ang)II-induced abdominal aortic aneurysms (AAAs) in mice.

Methods and Results

To determine whether hypercholesterolemia accelerates the initiation of AAAs, male low-density lipoprotein (LDL) receptor -/- mice were either fed one week of Western diet prior to starting AngII infusion or initiated Western diet one week after starting AngII infusion. During the first week of AngII infusion, mice fed normal diet had less luminal expansion of the suprarenal aorta compared to those initiated Western diet after the first week of AngII infusion. The two groups achieved comparable luminal dilation on week 2 through week 6 of AngII infusion as monitored by ultrasound. To determine whether hypercholesterolemia contributed to the progression of established AAAs, male LDL receptor -/- mice were fed Western diet and infused with AngII for 4 weeks. Mice with established AAAs were then stratified into two groups based on luminal diameters measured by ultrasound. While AngII infusion was continued for another 8 weeks in both groups, mice in one group were continuously fed Western diet, but diet in the other group was switched to normal laboratory diet. In the latter group, plasma cholesterol concentrations were reduced rapidly to approximately 500 mg/dl within one week after the diet was switched from Western diet to normal laboratory diet. Luminal expansion progressed constantly in mice continuously fed Western diet, whereas no continuous expansion was detected in mice that were switched to normal laboratory diet.

Conclusions

Hypercholesterolemia accelerates both the initiation of AAAs and progression of established AAAs in AngII-infused male LDL receptor -/- mice.

Clinical Relevance

Hypercholesterolemia is modestly associated with AAAs in observational or retrospective clinical studies. It is not feasible to study whether hypercholesterolemia contributes to the initiation of AAAs or progression of established AAAs in human. This study using AngII-induced AAA mouse model provides solid evidence that hypercholesterolemia contributes to both the initiation and progression of AAAs, supporting that statin therapy at any stage of AAA development may be beneficial to hypercholesterolemic patients with AAAs.
Interfering the mating ofChilo suppressalis(Walker): A new role of sex pheromones ((Z)-11-Octadecen-1-ol and (Z)-13-Octadecen-1-ol) fromCnaphalocrocis medinalisGuenée
Authors: Liang Yu-yong , Luo Mei , Fu Xiao-gang , Zheng Li-xia , Wei Hong-yi
Published: January 2020

The rice stem borer,Chilo suppressalis(Walker), and the rice leaf folder,Cnaphalocrocis medinalisGuenée are two of the most destructive lepidopteran pests in rice. Since these two lepidopteran insects show occurrence laps in rice paddy fields, farmers prefer to set the pheromone-baited traps ofC. suppressalisaccompany with the pheromone traps ofC. medinalisin the rice fields for convenient observation. However, our field observation demonstrated that no male of the rice stem borer was captured in the traps baited with commercialC. suppressalissex pheromone (CCS) combined with commercialC. medinalissex pheromone (CCM). To confirm theC. medinalissex pheromone component(s) to interfere with the attraction of males of the rice stem borers to their conspecific female moths, the single component ofC. medinalissex pheromone combined with CCS in traps were tested in the laboratory and in the rice paddy field. The results revealed the two alcohol components in CM, i.e., (Z)-11-octadecen-1-ol (Z11-18:OH) and (Z)-13-octadecen-1-ol (Z13-18:OH) may cause a significant reduction in the captures by CCS toC. suppressalismales. We recommend against using these sex pheromones together in the field and suggested that Z11-18:OH and Z13-18:OH could be potential inhibitors or antagonists ofC. suppressalissex pheromone to control the rice stem borer in practice.
cGAMP loading enhances the immunogenicity of VLP vaccines
Authors: Chauveau Lise , Bridgeman Anne , Tan Tiong Kit , Beveridge Ryan , Frost Joe , Pedroza-Pacheco Isabela , Partridge Thomas , Borrow Persephone , Drakesmith Hal , Townsend Alain , Rehwinkel Jan
Published: January 2020

Cyclic GMP-AMP (cGAMP) is an immunostimulatory second messenger produced by cGAS that activates STING. Soluble cGAMP acts as an adjuvant when administered with antigens. cGAMP is also incorporated into enveloped virus particles during budding. We hypothesised that inclusion of the adjuvant cGAMP within viral vaccine vectors would promote adaptive immunity against vector antigens. We immunised mice with virus-like particles (VLPs) containing the HIV-1 Gag protein and VSV-G. Inclusion of cGAMP within these VLPs augmented splenic VLP-specific CD4 and CD8 T cell responses. It also increased VLP- and VSV-G-specific serum antibody titres and enhancedin vitrovirus neutralisation. The superior antibody response was accompanied by increased numbers of T follicular helper cells in draining lymph nodes. Vaccination with cGAMP-loaded VLPs containing haemagglutinin induced high titres of influenza A virus neutralising antibodies and conferred protection following subsequent influenza A virus challenge. Together, these results show that incorporating cGAMP into VLPs enhances their immunogenicity, making cGAMP-VLPs an attractive platform for novel vaccination strategies.

Short summary

cGAMP is an innate immune signalling molecule that can be transmitted between cells by inclusion in enveloped virions. This study demonstrates enhanced immunogenicity of HIV-derived virus-like particles containing cGAMP. Viral vectors loaded with cGAMP may thus be potent vaccines.
BEE : a web service for biomedical entity exploration
Authors: Jung Jin-uk , Lim Jin-Muk , Joe Hyunwhan , Kim Hong-Gee
Published: January 2020

Recently there has been a trend in bioinformatics to produce and manage large quantities of data to better explain complex life phenomena through relationship and interactions among biomedical entities. This increase in data leads to a need for more efficient management and searching capabilities. As a result, Semantic Web technologies have been applied to biomedical data. To use these technologies, users have to learn a query language such as SPARQL in order to ask complex queries such as ‘What are the drugs associated with the disease breast carcinoma and Osteoporosis but not the gene ESR1’. BEE was developed to overcome the limitations and difficulties of learning such query languages. Our proposed system provides an intuitive and effective query interface based on natural language. Our system is a heterogeneous biomedical entity query system based on pathway, drug, microRNA, disease and gene datasets from DGIdb, Tarbase, Human Phenotype Ontology and Reactome, Gene Ontology, KEGG gene set of MSigDB. User queries can be joined with union, intersection and negation operators. The system also allows for selected results to be saved and later combined with newly created queries. To the best of our knowledge, BEE is the first system that supports condition search based on the relationship of heterogeneous biomedical entities and is expected to be used in various fields of bioinformatics such as in drug repositioning candidate selection as well as simple knowledge search.
Automatic building of protein atomic models from cryo-EM density maps using residue co-evolution
Authors: Bouvier Guillaume , Bardiaux Benjamin , Pellarin Riccardo , Rapisarda Chiara , Nilges Michael
Published: January 2020

Electron cryo-microscopy (cryo-EM) has emerged as a powerful method to obtain three-dimensional (3D) structures of macromolecular complexes at atomic or near-atomic resolution. However,de novobuilding of atomic models from near-atomic resolution (3-5 Å) cryo-EM density maps is a challenging task, in particular since poorly resolved side-chain densities hamper sequence assignment by automatic procedures at a lower resolution. Furthermore, segmentation of EM density maps into individual subunits remains a difficult problem when no three-dimensional structures of these subunits exist, or when significant conformational changes occur between the isolated and complexed form of the subunits. To tackle these issues, we have developed a graph-based method to thread most of the C-αtrace of the protein backbone into the EM density map. The EM density is described as a weighted graph such that the resulting minimum spanning tree encompasses the high-density regions of the map. A pruning algorithm cleans the tree and finds the most probable positions of the C-αatoms, using side-chain density when available, as a collection of C-αtrace fragments. By complementing experimental EM maps with contact predictions from sequence co-evolutionary information, we demonstrate that our approach can correctly segment EM maps into individual subunits and assign amino acids sequence to backbone traces to generate full-atom models.
Characterization of the Intestinal Absorption of Morroniside from Cornus officinalis Sieb. et Zucc via a Caco-2 Cell Monolayer Model
Authors: Xu Renjie , Zhu Hongdan , Hu Lingmin , Yu Beimeng , Zhan Xiaohua , Yuan Yichu , Zhou Ping
Published: January 2020

Morroniside is biologically active polyphenols found in Cornus officinalis Sieb. et Zucc (CO) which exhibits a broad spectrum of pharmacological activities, such as protecting nerves, preventing diabetic liver damageand renal damage. However, little data is available regarding its mechanism ofintestinal absorption. Here, ahuman intestinal epithelial cell model Caco-2 cell  in vitro cultured was applied to study on the absorption and transport of morroniside, the effects of time, donor concentration,pH, temperature and inhibitors,the absorption and transport of morroniside were investigated.The bidirectional permeability of morroniside from the apical (AP) to the basolateral (BL) side and in the revese direction was studied.  When administrated was setat three tested concentrations (5, 25 and 100μM), the P app value in AP-to-BL direction was ranged from 1.59 to 2.66×10 -6 cm/s. Inthe reverse direction, BL-to-AP, the value was ranged from 2.67to 4.10 ×10 -6 cm/s.The data indicated that morroniside transport was both pH- and temperature- dependent. The morroniside’s permeability process affected bytreatment with various inhibitors, such as the multidrug resistance protein inhibitors MK571 and benzbromarone, the breast cancer resistance protein inhibitor apigenin.It can be found that the mechanisms of intestinal absorption of morroniside may involve multiple transport pathways like passive diffusion as well as efflux protein-mediated active transportespecially the multidrug resistance protein2 and breast cancer resistance protein.After CO was added, P app AB increased significantly by about 125.26%, it can therefore be assumed that some ingredients in the crude material promote morroniside’s absorption in the small intestine.
A long tail of truth and beauty: A zigzag pattern of feather formation explains the symmetry, complexity, and beauty of the peacock’s tail
Authors: Singh Rama S. , Jagadeeshan Santosh
Published: January 2020

One hundred and fifty years after the publication of Darwin’s sexual selection theory, the problem of the peacock’s train remains unsolved. Darwin assumed that the peacock’s long train was maladaptive and was the indirect effect of selection by female mate choice based on the train’s beauty. While a relationship between the feathers’ elaborate features and mating success has been shown, the concept of eyespots as the basis of female choice remains controversial. We examined the anatomical plan underlying feather development using museum specimens and observed a zigzag pattern of feather follicles that determined both the number and the hexagonal arrangement of eyespots on the train as well as, strikingly, the individual eyespots’ color rings. While the zigzag pattern explains the symmetry, complexity, and structural beauty of the peacock’s train, it also precludes individual eyespot variation. The only available variation in eyespot number is expected to be due to annual addition of new rows of 10/11 feathers as a function of age, giving rise to an inherently determined eyespot number. New insights show that eyespot number and feather length are developmentally correlated and an asymptotic function of a male’s age, that their effects on female choice would be confounded and inseparable, and that male vigor would be a crucial factor affecting male fitness. Females may not always choose males with the largest number of eyespots, as older males may lack vigor. We propose a multimodal model of female choice based on male size, vigor, and beauty where females see eyespot and train size not as separate traits but as one complex trait combining both. The new model may be able to explain conflicting results and why eyespot number alone may not be sufficient to explain female choice.

Beauty is truth, truth beauty.

Keats
DNA damage induced during mitosis undergoes DNA repair synthesis
Authors: Godinez Veronica Gomez , Kabbara Sami , Sherman Adria , Wu Tao , Cohen Shirli , Kong Xiangduo , Maravillas-Montero Jose Luis , Shi Zhixia , Preece Daryl , Yokomori Kyoko , Berns Michael W.
Published: January 2020

Understanding the mitotic DNA damage response (DDR) is critical to our comprehension of cancer, premature aging and developmental disorders which are marked by DNA repair deficiencies. In this study we use a micro-focused-laser to induce DNA damage in selected mitotic chromosomes to study the subsequent repair response. Our findings demonstrate that (1) mitotic cells are capable of DNA repair as evidenced by DNA synthesis at damage sites, (2) Repair is attenuated when DNA-PKcs and ATM are simultaneously compromised, (3) Laser damage may permit the observation of previously undetected DDR proteins when damage is elicited by other methods in mitosis, and (4) Twenty five percent of mitotic DNA-damaged cells undergo a subsequent mitosis. Together these findings suggest that mitotic DDR is more complex than previously thought and may involve factors from multiple repair pathways that are better understood in interphase.
“Running with cancer”: a qualitative study to evaluate barriers and motivations in running for female oncological patients.
Authors: Avancini Alice , Skroce Kristina , Tregnago Daniela , Frada Paolo , Trestini Ilaria , Cercato Maria Cecilia , Bonaiuto Clelia , Tarperi Cantor , Schena Federico , Milella Michele , Pilotto Sara , Lanza Massimo
Published: January 2020

Nowadays, it is widely acknowledged that low physical activity levels are associated with an increase in terms of both disease recurrence and mortality in cancer survivors. In this light, deciphering those factors able to hamper or facilitate an active lifestyle is crucial in order to increase patients’ adherence to physical activity. The purpose of this study was to explore barriers and motivations in a sample of female oncological patients, practising running using the ecological model and compare them with healthy controls. Focus group interviews were conducted at Verona University. Participants were 12 female cancer survivors and 7 matched healthy controls who had participated at “Run for Science” project. The interviews were transcribed verbatim and analyzed using content analysis. Two main themes, motivations and barriers were found. About motivations, three sub-themes were identified: personal, interpersonal and environmental/organizational factors. Regarding barriers, another sub-theme was recognized: community/policy factors. Compare to healthy controls, survivors expressed motivations and barriers specifically related to their oncological disease. Running was a challenge with their cancer and a hope to give to other patients. Main barriers were represented by treatment-related side effects, inexperienced trainers and external factors, e.g. delivery of incorrect information. Running program dedicated to oncological patients should consider intrinsic obstacles, related to cancer and its treatment, offering a personalized intervention performed by qualified trainers, together with a motivational approach able to improve participants’ adherence to an active lifestyle.
Therapeutic Efficacy and Safety of Lenvatinib for Unresectable Hepatocellular Carcinoma Beyond Progression with Sorafenib
Authors: Tomonari Tetsu , Sato Yasushi , Tanaka Hironori , Tanaka Takahiro , Fujino Yasuteru , Mitsui Yasuhiro , Hirao Akihiro , Taniguchi Tatsuya , Sogabe Masahiro , Okamoto Koichi , Miyamoto Hiroshi , Muguruma Naoki , Kagiwada Harumi , Kitazawa Masashi , Fukui Kazuhiko , Horimoto Katsuhisa , Takayama Tetsuji
Published: January 2020

Background ? Aims The efficacy and safety of lenvatinib ( LEN ) as a second/third-line treatment for unresectable hepatocellular carcinoma (HCC) after sorafenib (SOR) therapy remains unknown. We evaluated the outcomes of second/third-line treatment of LEN, investigated the sensitivity of SOR-resistant HCC cell line (PLC/PRF5-R2) to LEN, and their signal transduction pathway by protein array analysis. Methods We retrospectively enrolled 57 unresectable HCC patients. Radiologic responses in 53 patients were evaluated by modified Response Evaluation Criteria in Solid Tumors. Active signal transduction pathways in cells were identified by protein array analysis, including 1205 proteins. Results Patients comprised 34 tyrosine kinase inhibitor (TKI)-naive (first-line), nine SOR-intolerant (second-line), and ten resistant to regorafenib (third-line). Objective response rates (ORRs) were 61.8% (21/34) in TKI-naive, 33.3% (3/9) in second-line, and 20.0% (2/10) in third-line groups. The overall survival (OS) and the progression free survival (PFS) in the first-line was significantly longer than those in third-line group ( p <0.05). Patients with better liver functional reserve (Child score, ALBI grade) exhibited higher ORR and longer OS. LEN was well-tolerated as second/third-line treatment. The IC 50 value of LEN against PLC/PRF5-R2 cells (30 μM) was significantly higher than that against PLC/PRF5 cells (6.4 μM). LEN inhibited significantly more signal transduction pathways related to FRS2, a crucial FGFR downstream molecule, in PLC/PRF5 than PLC/PRF5-R2 cells. Conclusions LEN was active and safe as a second/third-line treatment for unresectable HCC. LEN seems to be more effective for HCC patients with better hepatic reserve function or before TKI-resistance is acquired because of partial cross-resistance to SOR.
Cell-specific and targeted delivery of RNA moieties
Authors: Bhargava Aditi , Ohara Peter , Jasmin Luc
Published: January 2020

Delivery of therapeutic moieties to specific cell types, such as neurons remains a challenge. Genes present in neurons are also expressed in non-neuronal cell types such as glia where they mediate non-targeted related functions. Thus, non-specific targeting of these proteins/channels has numerous unwanted side effects, as is the case with current small molecules or drug therapies. Current methodologies that use nanoparticles, lipid-mediated uptake, or mannitol in conjunction with lipids to deliver double-stranded RNA (dsRNA) have yielded mixed and unreliable results. We used a neuroanatomical tracer (B subunit of Cholera Toxin (CTB)) that binds to the ganglioside receptors (GM1) expressed on cells, including primary sensory neurons to deliver encapsulated dsRNA. This approach greatly improved delivery of dsRNA to the desired cells by enhancing uptake, reducing vehicle-mediated toxicity and protecting nucleotides from degradation by endonucleases. The delivery complex is internalized, and once inside the cell, the dsRNA naturally dissociates itself from the carrier complex and is very effective in knocking down cognate targets, bothin vivoandin vitro. Past methods have used CTB-fusion proteins or chemically modified oligos or DNA moieties that have been covalently conjugated to CTB. Furthermore, CTB conjugated to an antigen, protein, or chemically modified nucleic acid is a potent activator of immune cell (T and B cells, macrophages) response, whereas CTB admixed with antigens or unmodified nucleic acids does not evoke this immune response. Importantly, in our method, the nucleic acids arenot covalently linkedto the carrier molecules. Thus, our method holds strong potential for targeted delivery of therapeutic moieties for cell types expressing GM1 receptors, including neuronal cell types.
PRIME: a probabilistic imputation method to reduce dropout effects in single cell RNA sequencing
Authors: Jeong Hyundoo , Liu Zhandong
Published: January 2020

Single-cell RNA sequencing technology provides a novel means to analyze the transcriptomic profiles of individual cells. The technique is vulnerable, however, to a type of noise called dropout effects, which lead to zero-inflated distributions in the transcriptome profile and reduce the reliability of the results. Single-cell RNA sequencing data therefore need to be carefully processed before in-depth analysis. Here we describe a novel imputation method that reduces dropout effects in single-cell sequencing. We construct a cell correspondence network and adjust gene expression estimates based on transcriptome profiles for the local community of cells of the same type. We comprehensively evaluated this method, called PRIME (PRobabilisticIMputation to reduce dropout effects inExpression profiles of single cell sequencing), on six datasets and verified that it improves the quality of visualization and accuracy of clustering analysis and can discover gene expression patterns hidden by noise.
The challenge of RNA branching prediction: a parametric analysis of multiloop initiation under thermodynamic optimization
Authors: Poznanović Svetlana , Barrera-Cruz Fidel , Kirkpatrick Anna , Ielusic Matthew , Heitsch Christine
Published: January 2020

Prediction of RNA base pairings yields insight into molecular structure, and therefore function. The most common methods predict an optimal structure under the standard thermodynamic model. One component of this model is the equation which governs the cost of branching, where three or more helical “arms” radiate out from a multiloop (also known as a junction). The multiloop initiation equation has three parameters; changing those values can significantly alter the predicted structure. We give a complete analysis of the prediction accuracy, stability, and robustness for all possible parameter combinations for a diverse set of tRNA sequences, and also for 5S rRNA. We find that the accuracy can often be substantially improved on a per sequence basis. However, simultaneous improvement within families, and most especially between families, remains a challenge.
Genetic underpinnings of host manipulation byOphiocordycepsas revealed by comparative transcriptomics
Authors: Will Ian , Das Biplabendu , Trinh Thienthanh , Brachmann Andreas , Ohm Robin , de Bekker Charissa
Published: January 2020

Abstract

The ant-infectingOphiocordycepsfungi are globally distributed, host manipulating, specialist parasites that drive aberrant behaviors in infected ants, at a lethal cost to the host. An apparent increase in activity and wandering behaviors precedes a final summiting and biting behavior on to vegetation, positioning the manipulated ant in a site beneficial for fungal growth and transmission. Notably, acrossOphiocordycepsspecies and other known host manipulators, the molecular mechanisms underlying behavioral changes remain largely unclear. We explored possible genetic underpinnings of host manipulation by: (i)producing a hybrid assembly of theOphiocordyceps camponoti-floridanigenome, (ii) conducting laboratory infections coupled with RNAseq of bothO. camponoti-floridaniand its host,Campontous floridanus, and (iii) using these data for a comparative analysis to similar work performed inOphiocordyceps kimflemingiaeandCamponotus castaneus. We propose differentially expressed genes tied to ant neurobiology, odor response, circadian rhythms, and foraging behavior may be the result of putative fungal effectors such as enterotoxins, aflatrem, and mechanisms disrupting nutrition-sensing or caste-identity pathways.
Active outer hair cell motility can suppress vibrations in the organ of Corti
Authors: Jabeen T. , Holt J. C. , Becker J. R. , Nam J.-H.
Published: January 2020

High sensitivity and selectivity of hearing require active cochlea. The cochlear sensory epithelium, the organ of Corti, vibrates due to external and internal excitations. The external stimulation is acoustic pressures mediated by the scala fluids, while the internal excitation is generated by a type of sensory receptor cells (the outer hair cells) in response to the acoustical vibrations. The outer hair cells are cellular actuators that are responsible for cochlear amplification. The organ of Corti is highly structured for transmitting vibrations originating from acoustic pressure and active outer hair cell force to the inner hair cells that synapse on afferent nerves. Understanding how the organ of Corti vibrates due to acoustic pressure and outer hair cell force is critical for explaining cochlear function. In this study, excised cochlear turns were freshly isolated from young gerbils. The organ of Corti in the excised cochlea was subjected to mechanical and electrical stimulation that are analogous to acoustical and cellular stimulation in the natural cochlea. Organ of Corti vibrations including those of individual outer hair cells were measured using optical coherence tomography. Respective vibration patterns due to mechanical and electrical stimulation were characterized. Interactions between the two vibration patterns were investigated by applying the two forms of stimulation simultaneously. Our results show that the interactions could be either constructive or destructive, which implies that the outer hair cells can either amplify or suppress vibrations in the organ of Corti. We discuss a potential consequence of the two interaction modes for cochlear frequency tuning.

Statement of Significance

The function of the mammalian cochlea is characterized by sharp tuning and high-level of amplification. Both tuning and amplification are achieved mechanically through the action of cellular actuators in the sensory epithelium. According to widely accepted theory, cochlear tuning is achieved by ‘selectively amplifying’ acoustic vibrations. This study presents a set of data suggesting that the cochlear actuators can both amplify and suppress vibrations to enhance cochlear tuning. Presented results will explain why the actuator cells in the cochlea spend energy in the locations where there is no need for amplification.
Bioengineering anin situovary (ISO) for fertility preservation
Authors: Buckenmeyer Michael J. , Sukhwani Meena , Iftikhar Aimon , Nolfi Alexis L. , Xian Ziyu , Dadi Srujan , Case Zachary W. , Steimer Sarah R. , D’Amore Antonio , Orwig Kyle E. , Brown Bryan N.
Published: January 2020

Female cancer patients who have undergone chemotherapy have an elevated risk of developing premature ovarian failure (POF) and infertility. Experimental approaches to treat iatrogenic infertility are evolving rapidly; however, there remain challenges and risks that have hindered clinical translation. To address these concerns, we developed an ovarian-specific extracellular matrix hydrogel to facilitate follicle delivery and establish anin situovary (ISO). We demonstrate sustainable engraftment, natural pregnancy and the birth of healthy pups after intraovarian microinjection of isolated exogenous follicles in a chemotherapy-induced POF mouse model. Our results suggest that the methods described could offer a minimally invasive alternative for the restoration of the ovarian reserve post-chemotherapy.
Investigating TNS4 in the Colorectal Tumour Microenvironment Using 3D Spheroid Models of Invasion
Authors: Raposo Teresa P. , Susanti Susanti , Ilyas Mohammad
Published: January 2020

TNS4 (Tensin 4 or Cten) is a putative oncogene in colorectal cancer (CRC) with a role in regulating cell adhesion, motility, invasion and epithelial to mesenchymal transition (EMT). Our objective was to study TNS4 role in CRC using more realistic models of the tumour microenvironment.

CRC cells expressing TdTomato protein and shTNS4/shLUC hairpin oligos were grown in 3D spheroids with and without cancer-associated fibroblasts (CAFs). Adhesiveness to collagen I and CAFs was assessed in 2D and cell proliferation, volume and invasion were assessed in 3D conditions. The role of TNS4 knockdown in Gefitinib chemosensitivity and EGFR and Ras protein levels were also tested.

In general, TNS4 knockdown increased cell proliferation in cell lines producing compact spheroids. The addition of CAFs in spheroids supported CRC cells proliferation, whereas CAFs themselves did not proliferate, but increased ECM degradation. TNS4 knockdown reduced adhesiveness and 3D invasion and disrupted EGFR signalling which resulted in increased sensitivity to Gefitinib.

In conclusion, in a 3D spheroid model, TNS4 inhibits cell proliferation and promotes cell invasion into the ECM, possibly by adhesion to the ECM and stromal cells. TNS4 knockdown enhances sensitivity to the EGFR inhibitor Gefitinib and may be helpful for KRAS mutant CRC patients.
Predicting long-term multicategory cause of death in patients with prostate cancer: random forest versus multinomial model
Authors: Wang Jianwei , Deng Fei , Zeng Fuqing , Shanahan Andrew J. , Li Wei V. , Zhang Lanjing
Published: January 2020

Patients with prostate cancer more likely die of non-cancer cause of death (COD) than prostate cancer. It is thus important to accurately predict multi-category COD in these patients. Random forest (RF), a popular machine learning model, has been shown useful for predicting binary cancer-specific deaths. However, its accuracy for predicting multi-category COD in cancer patients is unclear. We included patients in Surveillance, Epidemiology, and End Results-18 cancer registry-program with prostate cancer diagnosed in 2004 (followed-up through 2016). They were randomly divided into training and testing sets with equal sizes. We evaluated prediction accuracies of RF and conventional-statistical/multinomial models for 6-category COD by data-encoding types using the 2-fold cross-validation approach. Among 49,864 prostate cancer patients, 29,611 (59.4%) were alive at the end of follow-up, and 5,448 (10.9%) died of cardiovascular disease, 4,607 (9.2%) of prostate cancer, 3,681 (7.4%) of Non-Prostate cancer, 717 (1.4%) of infection, and 5,800 (11.6%) of other causes. We predicted 6-category COD among these patients with a mean accuracy of 59.1% (n=240, 95% CI, 58.7%-59.4%) in RF models with one-hot encoding, and 50.4% (95% CI, 49.7%-51.0%) in multinomial models. Tumor characteristics, prostate-specific antigen level, and diagnosis confirmation-method were important in RF and multinomial models. In RF models, no statistical differences were found between the accuracies of development versus cross validation phases, and those of categorical versus one-hot encoding. We here report a RF model that has an accuracy of 59.1% in predicting long-term 6-category COD among prostate cancer patients. It outperforms multinomial logistic models (absolute prediction-accuracy difference, 8.7%).
Cholesterol metabolism drives regulatory B cell function
Authors: Bibby Jack A. , Purvis Harriet A. , Hayday Thomas , Chandra Anita , Okkenhaug Klaus , Wood Michael , Lachmann Helen J. , Kemper Claudia , Cope Andrew P. , Perucha Esperanza
Published: January 2020

Regulatory B cells restrict immune and inflammatory responses across a number of contexts. This capacity is mediated primarily through the production of IL-10. Here we demonstrate that the induction of a regulatory program in human B cells is dependent on a metabolic priming event driven by cholesterol metabolism. Synthesis of the metabolic intermediate geranylgeranyl pyrophosphate (GGPP) was required to specifically drive IL-10 production, and to attenuate Th1 responses. Furthermore, GGPP-dependent protein modifications controlled signaling through PI3Kδ-AKT-GSK3, which in turn promoted BLIMP1-dependent IL-10 production. Inherited gene mutations in cholesterol metabolism result in a severe autoinflammatory syndrome, termed mevalonate kinase deficiency (MKD). Consistent with our findings, B cells from MKD patients induced poor IL-10 responses and were functionally impaired. Moreover, metabolic supplementation with GGPP was able to reverse this defect. Collectively, our data define cholesterol metabolism as an integral metabolic pathway for the optimal functioning of human IL-10 producing regulatory B cells.

Graphical abstract

MKD = Mevalonate kinase deficiency
Cloning and characterization of Osmotin (OsmSt) alleles from potato cultivar ‘Kufri Chipsona 1’
Authors: Kaur Amanpreet , Kumar Anil
Published: January 2020

The present study was focussed to clone and sequence characterise alleles of osmotin from cDNA ofSolanum tuberosumL. cultivar ‘Kufri Chipsona 1’. The genes vary in sizes as well as were found to have eleven point mutations throughout the coding sequence. One deletion of 7 bp was also found in smaller form of the gene having molecular weight of 19.91 KDa. Osmotin gene is known to impart resistance/tolerance to various fungal diseases in addition to its role as an osmoprotectant, thus, cloned osmotin alleles from important processing grade potato cultivar could become potential candidates for molecular breeding of potato.