bluuebunny/crossref_metadata_2025 huggingface dataset:
The Scottish Independence Referendum in an International Context
Authors: Vidmar Jure
Published: October 2021

There are no universally applicable procedural standards under international law for independence referenda. However, in contemporary comparative practice, a minimum requirement has emerged for clarity of both the winning majority and the referendum question. This article demonstrates that Scotland could become an independent state with the lowest popular support in recent international practice, yet this outcome would not compromise the legitimacy of the vote. Even the referendum question is an exemplar of textual clarity. However, the possibility of a referendum on the United Kingdom’s (UK) exit from the European Union (EU) complicates the matter. The author argues that, with independence, Scotland would, prima facie, also exit the EU, unless negotiated otherwise. However, with a potential referendum on the UK’s EU membership on the horizon, Scots do not know whether a vote to remain within the UK is also a vote to remain within the EU. Given the complexity and significance of the EU legal order, Scots have a right to know whether, at least in the near future, the alternative to independence is the UK within or outside the EU. If the two referenda fall too close to each other, the clarity of the Scottish independence referendum could be unduly compromised.
Collaborative writing in L2 classrooms: A research agenda
Authors: Li Mimi , Zhang Meixiu
Published: October 2021

Research on second language (L2) collaborative writing (CW) has proliferated over the recent decade and will continue to bloom due to the changing landscape of writing and learning in the digital age. This article provides a research agenda on CW in L2 classrooms. We illustrate six research themes for future research inquiry by pointing out the research gap, following a brief review of theoretical frameworks and existing empirical efforts on CW. We then expound on six specific research tasks that we deem to be pressing for this domain to progress, including more attention to multimodal CW, expanded frameworks for analyzing peer interaction and writing products, deployment of underused research techniques and improved research practice, development of CW assessment practice, as well as the inquiry of practitioners’ input on CW. We hope to provide guidance for future research endeavors by identifying avenues of investigations on CW and meanwhile contribute to the trajectory of vibrant research on L2 writing and language learning.
Early development of negative and positive affect: Implications for ADHD symptomatology across three birth cohorts
Authors: Gustafsson Hanna C. , Nolvi Saara , Sullivan Elinor L. , Rasmussen Jerod M. , Gyllenhammer Lauren E. , Entringer Sonja , Wadhwa Pathik D. , O'Connor Thomas G. , Karlsson Linnea , Karlsson Hasse , Korja Riikka , Buss Claudia , Graham Alice M. , Nigg Joel T.
Published: October 2021

High levels of early emotionality (of either negative or positive valence) are hypothesized to be important precursors to early psychopathology, with attention-deficit/hyperactivity disorder (ADHD) a prime early target. The positive and negative affect domains are prime examples of Research Domain Criteria (RDoC) concepts that may enrich a multilevel mechanistic map of psychopathology risk. Utilizing both variable-centered and person-centered approaches, the current study examined whether levels and trajectories of infant negative and positive emotionality, considered either in isolation or together, predicted children's ADHD symptoms at 4 to 8 years of age. In variable-centered analyses, higher levels of infant negative affect (at as early as 3 months of age) were associated with childhood ADHD symptoms. Findings for positive affect failed to reach statistical threshold. Results from person-centered trajectory analyses suggest that additional information is gained by simultaneously considering the trajectories of positive and negative emotionality. Specifically, only when exhibiting moderate, stable or low levels of positive affect did negative affect and its trajectory relate to child ADHD symptoms. These findings add to a growing literature that suggests that infant negative emotionality is a promising early life marker of future ADHD risk and suggest secondarily that moderation by positive affectivity warrants more consideration.
Coherence for bicategorical cartesian closed structure
Authors: Fiore Marcelo , Saville Philip
Published: October 2021

We prove a strictification theorem for cartesian closed bicategories. First, we adapt Power’s proof of coherence for bicategories with finite bilimits to show that every bicategory with bicategorical cartesian closed structure is biequivalent to a 2-category with 2-categorical cartesian closed structure. Then we show how to extend this result to a Mac Lane-style “all pasting diagrams commute” coherence theorem: precisely, we show that in the free cartesian closed bicategory on a graph, there is at most one 2-cell between any parallel pair of 1-cells. The argument we employ is reminiscent of that used by Čubrić, Dybjer, and Scott to show normalisation for the simply-typed lambda calculus (Čubrić et al., 1998). The main results first appeared in a conference paper (Fiore and Saville, 2020) but for reasons of space many details are omitted there; here we provide the full development.
Survey about Intention to Engage in Specific Disaster Activities among Disaster Medical Assistance Team Members
Authors: Iyama Keita , Kakamu Takeyasu , Yamashita Kazunori , Shimada Jiro , Tasaki Osamu , Hasegawa Arifumi
Published: October 2021

Introduction:

Different disaster activities should be performed smoothly. In relation to this, human resources for disaster activities must be secured. To achieve a stable supply of human resources, it is essential to improve the intentions of individuals responding to each type of disaster. However, the current intention of Disaster Medical Assistance Team (DMAT) members has not yet been assessed.

Study Objective:

To facilitate a smooth disaster response, this survey aimed to assess the intention to engage in each type of disaster activity among DMAT members.

Methods:

An anonymous web questionnaire survey was conducted. Japanese DMAT members in the nuclear disaster-affected area (Group A; n = 79) and the non-affected area (Group N; n = 99) were included in the analysis. The outcome was the answer to the following question: “Will you actively engage in activities during natural, human-made, and chemical (C), biological (B), radiological/nuclear (R/N), and explosive (E) (CBRNE) disasters?” Then, questionnaire responses were compared according to disaster type.

Results:

The intention to engage in C (50), B (47), R/N (58), and E (52) disasters was significantly lower than that in natural (82) and human-made (82) disasters (P <.001). The intention to engage in CBRNE disasters among younger participants (age ≤39 years) was significantly higher in Group A than in Group N. By contrast, the intention to engage in R/N disasters alone among older participants (age ≥40 years) was higher in Group A than in Group N. However, there was no difference between the two groups in terms of intention to engage in C, B, and E disasters. Moreover, the intention to engage in all disasters between younger and older participants in Group A did not differ. In Group N, older participants had a significantly higher intention to engage in B and R/N disasters.

Conclusion:

Experience with a specific type of calamity at a young age may improve intention to engage in not only disasters encountered, but also other types. In addition, the intention to engage in CBRNE disasters improved with age in the non-experienced population. To respond smoothly to specific disasters in the future, measures must be taken to improve the intention to engage in CBRNE disasters among DMAT members.
Government investment fiscal multipliers: evidence from Euro-area countries
Authors: Deleidi Matteo , Iafrate Francesca , Levrero Enrico Sergio
Published: October 2021

This paper aims to estimate the government investment fiscal multipliers in select European countries for the period 1970–2016. To do this, we combine Structural Vector Autoregression (SVAR) modeling with the Local Projections (LP) approach. We estimate models by also controlling for fiscal foresight, excluding the postcrisis period and distinguishing between Northern and Southern countries. Our findings suggest that an increase in government investment generates a “Keynesian effect” by engendering positive and permanent effects on the GDP level, even when government expenditure expectations are considered. Fiscal multipliers are close to 1 on impact and increase in the years after the implementation of a discretionary fiscal policy.
Morphological and Ultrastructural Studies of Pecten in the Eurasian Tree Sparrow
Authors: Singh Namram S , Dixit Anand S , Khanikar Debashish
Published: October 2021

We studied the fine histological structures of pecten oculi of the Eurasian tree sparrow using various microscopy techniques. The pecten of the tree sparrow was found to be of a pleated type comprising of pleats, bridges, and base. The light microscopic study revealed further that the pleats consist of capillaries of varying sizes, blood vessels, and numerous pigmented cells that give them a black color. Histochemical studies of pecten showed a large deposition of lipid droplets, which were more abundant in the basal area. The transmission electron microscopy displayed capillaries and blood vessels that remain surrounded by a thick fibrous basal membrane. They are formed of endothelial cells having a large lumen and abluminal area with microfolds. Interstitial spaces were found filled with rounded melanocytes, electron-dense pigment granules, and mitochondria. Observations under the scanning electron microscope revealed the presence of a dense vascular network of capillaries and vessels. In addition, large hyalocytes were also observed on the surface of the pleats. The above observations suggest that the histological structure of the pecten of the tree sparrow resembles those present in the pecten of other diurnal birds. However, further investigation is required to ascertain its functional role in birds.
Counterterrorism and the risk of over-classification of situations of violence
Authors: Gaggioli Gloria , Kilibarda Pavle
Published: October 2021

Richard Baxter famously stated that “the first line of defence against international humanitarian law is to deny that it applies at all”. While “under-classification” remains an issue today, a parallel trend needs to be acknowledged. This is the tendency to over-classify situations of violence, especially in relation to transnational terrorist organizations such as the so-called Islamic State group or Al-Qaeda. This tendency stems from practical difficulties inherent in the changing operational environment. The last few years have witnessed a proliferation of armed non-State actors that are labelled or designated as terrorists (e.g., in Iraq, Syria, Mali, Nigeria and Yemen). Terrorist groups are characterized by opaque, often volatile organizational structures and tend to operate in decentralized networks rather than clear hierarchies. The formation of splinter groups, changing alliances, temporary reunification and even open hostility among former allies are common phenomena. This complex factual situation has led to the proliferation of theories of conflict classification, many of them arguing in favour of more flexible classification via the loosening of existing standards. Because international humanitarian law is in many respects less protective than international human rights law, particularly regarding the rules on the use of force and detention, classifying a situation of violence as an armed conflict when the threshold has not been met is a problem that should not be underestimated. In this article, we revisit the criteria of intensity and organization, as well as the related matter of the role of motives in conflict classification, considering conflicts involving armed groups described as terrorists. Our goal is to identify minimum requirements that could diminish the risk of over-classification by various stakeholders.
Epigenetics and DOHaD: how translation to predictive testing will require a better public understanding
Authors: Lynch Fiona , Lewis Sharon , Macciocca Ivan , Craig Jeffrey M.
Published: October 2021

Epigenetics is likely to play a role in the mediation of the effects of genes and environment in risk for many non-communicable diseases (NCDs). The Developmental Origins of Health and Disease (DOHaD) theory presents unique opportunities regarding the possibility of early life interventions to alter the epigenetic makeup of an individual, thereby modifying their risk for a variety of NCDs. While it is important to determine how we can lower the risk of these NCDs, it is equally important to understand how the public’s knowledge and opinion of DOHaD and epigenetic concepts may influence their willingness to undertake such interventions for themselves and their children. In this review, we provide an overview of epigenetics, DOHaD, NCDs, and the links between them. We explore the issues surrounding using epigenetics to identify those at increased risk of NCDs, including the concept of predictive testing of children. We also outline what is currently understood about the public’s understanding and opinion of epigenetics, DOHaD, and their relation to NCDs. In doing so, we demonstrate that it is essential that future research explores the public’s awareness and understanding of epigenetics and epigenetic concepts. This will provide much-needed information which will prepare health professionals for the introduction of epigenetic testing into future healthcare.
New Contamination Concern for Colorado Streams
Authors: Averett Nancy
Published: October 2021

Abandoned hardrock mines and climate change cause metals and other elements to leach into streams. They also put rare earth elements into the water, a new study finds.
Origin of Three‐Dimensional Crustal Stress Over the Conterminous United States
Authors: Cao Zebin , Liu Lijun
Published: October 2021

The crustal stress field determines continental deformation, including intraplate seismicity and topographic undulations. However, the sources of observed crustal stress patterns remain debated, with proposed mechanisms including lateral variations in gravitational potential energy and mantle flow, the latter of which comprises plate boundary interactions and basal tractions. Here, we present a series of geodynamic models that simultaneously consider lithospheric and mantle dynamics in the same physical framework, based on which we investigate the sources of crustal stress over the conterminous U.S. The data‐oriented nature of these models allows us to systematically explore the relative contributions of different dynamic sources to the three‐dimensional crustal stress field. These models reveal that forces from the plate boundaries play a dominant role in generating the directional pattern of long‐wavelength horizontal crustal stress across the conterminous U.S. In the central U.S., especially regions of high‐topography, lithospheric density heterogeneities locally modify the crustal stress field. Similarly, mantle flow beneath the North American plate modulates crustal stress orientation in the eastern U.S., particularly in regions with thin lithosphere. Furthermore, we find that a denser‐than‐ambient lithospheric mantle beneath the central and eastern U.S. is required to match the observed continental‐scale E‐W topographic contrast.
Modifying the m6A brain methylome by ALKBH5-mediated demethylation: a new contender for synaptic tagging
Authors: Martinez De La Cruz Braulio , Markus Robert , Malla Sunir , Haig Maria Isabel , Gell Chris , Sang Fei , Bellows Eleanor , Sherif Mahmoud Awad , McLean Denise , Lourdusamy Anbarasu , Self Tim , Bodi Zsuzsanna , Smith Stuart , Fay Michael , Macdonald Ian A. , Fray Rupert , Knight Helen Miranda
Published: October 2021

Synaptic plasticity processes, which underlie learning and memory formation, require RNA to be translated local to synapses. The synaptic tagging hypothesis has previously been proposed to explain how mRNAs are available at specific activated synapses. However how RNA is regulated, and which transcripts are silenced or processed as part of the tagging process is still unknown. Modification of RNA by N6-methyladenosine (m6A/m) influences the cellular fate of mRNA. Here, by advanced microscopy, we showed that m6A demethylation by the eraser protein ALKBH5 occurs at active synaptic ribosomes and at synapses during short term plasticity. We demonstrated that at activated glutamatergic post-synaptic sites, both the YTHDF1 and YTHDF3 reader and the ALKBH5 eraser proteins increase in co-localisation to m6A-modified RNAs; but only the readers showed high co-localisation to modified RNAs during late-stage plasticity. The YTHDF1 and YTHFDF3 readers also exhibited differential roles during synaptic maturation suggesting that temporal and subcellular abundance may determine specific function. m6A-sequencing of human parahippocampus brain tissue revealed distinct white and grey matter m6A methylome profiles indicating that cellular context is a fundamental factor dictating regulated pathways. However, in both neuronal and glial cell-rich tissue, m6A effector proteins are themselves modified and m6A epitranscriptional and posttranslational modification processes coregulate protein cascades. We hypothesise that the availability m6A effector protein machinery in conjunction with RNA modification, may be important in the formation of condensed synaptic nanodomain assemblies through liquid-liquid phase separation. Our findings support that m6A demethylation by ALKBH5 is an intrinsic component of the synaptic tagging hypothesis and a molecular switch which leads to alterations in the RNA methylome, synaptic dysfunction and potentially reversible disease states.
Liprins in oncogenic signaling and cancer cell adhesion
Authors: Pehkonen Henna , de Curtis Ivan , Monni Outi
Published: October 2021

Liprins are a multifunctional family of scaffold proteins, identified by their involvement in several important neuronal functions related to signaling and organization of synaptic structures. More recently, the knowledge on the liprin family has expanded from neuronal functions to processes relevant to cancer progression, including cell adhesion, cell motility, cancer cell invasion, and signaling. These proteins consist of regions, which by prediction are intrinsically disordered, and may be involved in the assembly of supramolecular structures relevant for their functions. This review summarizes the current understanding of the functions of liprins in different cellular processes, with special emphasis on liprins in tumor progression. The available data indicate that liprins may be potential biomarkers for cancer progression and may have therapeutic importance.
Reduced hippocampal inhibition and enhanced autism-epilepsy comorbidity in mice lacking neuropilin 2
Authors: Eisenberg Carol , Subramanian Deepak , Afrasiabi Milad , Ziobro Patryk , DeLucia Jack , Hirschberg Pamela R. , Shiflett Michael W. , Santhakumar Vijayalakshmi , Tran Tracy S.
Published: October 2021

The neuropilin receptors and their secreted semaphorin ligands play key roles in brain circuit development by regulating numerous crucial neuronal processes, including the maturation of synapses and migration of GABAergic interneurons. Consistent with its developmental roles, the neuropilin 2 (Nrp2) locus contains polymorphisms in patients with autism spectrum disorder (ASD). Nrp2-deficient mice show autism-like behavioral deficits and propensity to develop seizures. In order to determine the pathophysiology in Nrp2 deficiency, we examined the hippocampal numbers of interneuron subtypes and inhibitory regulation of hippocampal CA1 pyramidal neurons in mice lacking one or both copies of Nrp2. Immunostaining for interneuron subtypes revealed that Nrp2−/− mice have a reduced number of parvalbumin, somatostatin, and neuropeptide Y cells, mainly in CA1. Whole-cell recordings identified reduced firing and hyperpolarized shift in resting membrane potential in CA1 pyramidal neurons from Nrp2+/− and Nrp2−/− mice compared to age-matched wild-type controls indicating decrease in intrinsic excitability. Simultaneously, the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) are reduced in Nrp2-deficient mice. A convulsive dose of kainic acid evoked electrographic and behavioral seizures with significantly shorter latency, longer duration, and higher severity in Nrp2−/− compared to Nrp2+/+ animals. Finally, Nrp2+/− and Nrp2−/− but not Nrp2+/+, mice have impaired cognitive flexibility demonstrated by reward-based reversal learning, a task associated with hippocampal circuit function. Together these data demonstrate a broad reduction in interneuron subtypes and compromised inhibition in CA1 of Nrp2−/− mice, which could contribute to the heightened seizure susceptibility and behavioral deficits consistent with an ASD/epilepsy phenotype.
MiR-193b-3p–ERBB4 axis regulates psoriasis pathogenesis via modulating cellular proliferation and inflammatory-mediator production of keratinocytes
Authors: Huang Cong , Zhong Weilong , Ren Xuanyao , Huang Xia , Li Zizhuo , Chen Chaofeng , Jiang Bin , Chen Zhenzhen , Jian Xingling , Yang Lili , Liu Xiaoming , Huang Haiyan , Shen Changbing , Chen Xiaofan , Dou Xia , Yu Bo
Published: October 2021

Psoriasis is an auto-inflammatory skin disease characterized by abnormal activation of epidermal keratinocytes, aberrant neovascularization, and dysregulation of immune cells. MicroRNAs are small non-coding RNAs that mainly function in the post-transcriptional regulation of gene expression. Recently, accumulating evidence has demonstrated that expression of microRNAs is dysregulated in psoriasis patients and microRNAs play key roles in psoriasis pathogenesis. Downregulation of miR-193b-3p has been identified to be associated with psoriasis development. However, the precise functions and action mechanisms of miR-193b-3p in psoriasis pathogenesis remain unclear. In this study, we confirmed the downregulation of miR-193b-3p in psoriasis patients, psoriasis-like inflammatory cellular models, and an imiquimod (IMQ) -induced mouse model. A negative correlation was found between miR-193b-3p level and patient Psoriasis Area and Severity Index (PASI) score. Furthermore, miR-193b-3p suppressed proliferation, inflammatory-factor secretion, and the STAT3 and NF-κB signaling pathways in keratinocytes. Importantly, intradermal injection of agomiR-193b-3p blocked, whereas antagomiR-193b-3p augmented, the psoriasis-like inflammation in the IMQ-induced mouse model. Bioinformatics analysis and the dual-luciferase reporter assay showed that miR-193b-3p targets ERBB4 3ʹ untranslated region (UTR). In addition, ERBB4 induced proliferation, inflammatory-factor production, and the STAT3 and NF-κB pathways in keratinocytes. Most importantly, forced expression of ERBB4 could attenuate the effects of miR-193b-3p in keratinocytes, indicating that miR-193b-3p inhibits keratinocyte activation by directly targeting ERBB4. In conclusion, our findings demonstrated that the miR-193b-3p–ERBB4 axis underlies the hyperproliferation and aberrant inflammatory-factor secretion of psoriatic keratinocytes, providing a novel, microRNA-related causal mechanism and a potential therapeutic target in psoriasis.
A long way to go: caspase inhibitors in clinical use
Authors: Dhani Shanel , Zhao Yun , Zhivotovsky Boris
Published: October 2021

Caspases are an evolutionary conserved family of cysteine-dependent proteases that are involved in many vital cellular processes including apoptosis, proliferation, differentiation and inflammatory response. Dysregulation of caspase-mediated apoptosis and inflammation has been linked to the pathogenesis of various diseases such as inflammatory diseases, neurological disorders, metabolic diseases, and cancer. Multiple caspase inhibitors have been designed and synthesized as a potential therapeutic tool for the treatment of cell death-related pathologies. However, only a few have progressed to clinical trials because of the consistent challenges faced amongst the different types of caspase inhibitors used for the treatment of the various pathologies, namely an inadequate efficacy, poor target specificity, or adverse side effects. Importantly, a large proportion of this failure lies in the lack of understanding various caspase functions. To overcome the current challenges, further studies on understanding caspase function in a disease model is a fundamental requirement to effectively develop their inhibitors as a treatment for the different pathologies. Therefore, the present review focuses on the descriptive properties and characteristics of caspase inhibitors known to date, and their therapeutic application in animal and clinical studies. In addition, a brief discussion on the achievements, and current challenges faced, are presented in support to providing more perspectives for further development of successful therapeutic caspase inhibitors for various diseases.
Mitochondrial genome and its regulator TFAM modulates head and neck tumourigenesis through intracellular metabolic reprogramming and activation of oncogenic effectors
Authors: Hsieh Yi-Ta , Tu Hsi-Feng , Yang Muh-Hwa , Chen Yi-Fen , Lan Xiang-Yun , Huang Chien-Ling , Chen Hsin-Ming , Li Wan-Chun
Published: October 2021

Mitochondrial transcriptional factor A (TFAM) acts as a key regulatory to control mitochondrial DNA (mtDNA); the impact of TFAM and mtDNA in modulating carcinogenesis is controversial. Current study aims to define TFAM mediated regulations in head and neck cancer (HNC). Multifaceted analyses in HNC cells genetically manipulated for TFAM were performed. Clinical associations of TFAM and mtDNA encoded Electron Transport Chain (ETC) genes in regulating HNC tumourigenesis were also examined in HNC specimens. At cellular level, TFAM silencing led to an enhanced cell growth, motility and chemoresistance whereas enforced TFAM expression significantly reversed these phenotypic changes. These TFAM mediated cellular changes resulted from (1) metabolic reprogramming by directing metabolism towards aerobic glycolysis, based on the detection of less respiratory capacity in accompany with greater lactate production; and/or (2) enhanced ERK1/2-Akt-mTORC-S6 signalling activity in response to TFAM induced mtDNA perturbance. Clinical impacts of TFAM and mtDNA were further defined in carcinogen-induced mouse tongue cancer and clinical human HNC tissues; as the results showed that TFAM and mtDNA expression were significantly dropped in tumour compared with their normal counterparts and negatively correlated with disease progression. Collectively, our data uncovered a tumour-suppressing role of TFAM and mtDNA in determining HNC oncogenicity and potentially paved the way for development of TFAM/mtDNA based scheme for HNC diagnosis.
Blood pressure, frailty status, and all-cause mortality in elderly hypertensives; The Nambu Cohort Study
Authors: Inoue Taku , Matsuoka Mitsuteru , Shinjo Tetsuji , Tamashiro Masahiro , Oba Kageyuki , Kakazu Masanori , Moromizato Takuhiro , Arasaki Osamu , Arima Hisatomi
Published: October 2021

Antihypertensive therapy is pivotal for reducing cardiovascular events. The 2019 Guidelines for the Management of Hypertension set a target blood pressure (BP) of <140/90 mmHg for persons older than 75 years of age. Optimal BP levels for older persons with frailty, however, are controversial because evidence for the relationship between BP level and prognosis by frailty status is limited. Here, we evaluated the relationship between systolic BP and frailty status with all-cause mortality in ambulatory older hypertensive patients using data from the Nambu Cohort study. A total of 535 patients (age 78 [70–84] years, 51% men, 37% with frailty) were prospectively followed for a mean duration of 41 (34–43) months. During the follow-up period, 49 patients died. Mortality rates stratified by systolic BP and frailty status were lowest in patients with systolic BP < 140 mmHg and non-frailty, followed by those with systolic BP ≥ 140 mmHg and non-frailty. Patients with frailty had the highest mortality regardless of the BP level. The adjusted hazard ratios (95% confidence intervals) of each category for all-cause mortality were as follows: ≥140 mmHg/Non-frailty 3.19 (1.12–11.40), <140 mmHg/Frailty 4.72 (1.67–16.90), and ≥140 mmHg/Frailty 3.56 (1.16–13.40) compared with <140 mmHg/Non-frailty as a reference. These results indicated that frail patients have a poor prognosis regardless of their BP levels. Non-frail patients, however, with systolic BP levels <140 mmHg had a better prognosis. Frailty may be a marker to differentiate patients who are likely to gain benefit from antihypertensive medication among older hypertensives.
Highly efficient intercellular spreading of protein misfolding mediated by viral ligand-receptor interactions
Authors: Liu Shu , Hossinger André , Heumüller Stefanie-Elisabeth , Hornberger Annika , Buravlova Oleksandra , Konstantoulea Katerina , Müller Stephan A. , Paulsen Lydia , Rousseau Frederic , Schymkowitz Joost , Lichtenthaler Stefan F. , Neumann Manuela , Denner Philip , Vorberg Ina M.
Published: October 2021

Protein aggregates associated with neurodegenerative diseases have the ability to transmit to unaffected cells, thereby templating their own aberrant conformation onto soluble homotypic proteins. Proteopathic seeds can be released into the extracellular space, secreted in association with extracellular vesicles (EV) or exchanged by direct cell-to-cell contact. The extent to which each of these pathways contribute to the prion-like spreading of protein misfolding is unclear. Exchange of cellular cargo by both direct cell contact or via EV depends on receptor-ligand interactions. We hypothesized that enabling these interactions through viral ligands enhances intercellular proteopathic seed transmission. Using different cellular models propagating prions or pathogenic Tau aggregates, we demonstrate that vesicular stomatitis virus glycoprotein and SARS-CoV-2 spike S increase aggregate induction by cell contact or ligand-decorated EV. Thus, receptor-ligand interactions are important determinants of intercellular aggregate dissemination. Our data raise the possibility that viral infections contribute to proteopathic seed spreading by facilitating intercellular cargo transfer.
Scattering interference signature of a pair density wave state in the cuprate pseudogap phase
Authors: Wang Shuqiu , Choubey Peayush , Chong Yi Xue , Chen Weijiong , Ren Wangping , Eisaki H. , Uchida S. , Hirschfeld Peter J. , Davis J. C. Séamus
Published: October 2021

An unidentified quantum fluid designated the pseudogap (PG) phase is produced by electron-density depletion in the CuO2 antiferromagnetic insulator. Current theories suggest that the PG phase may be a pair density wave (PDW) state characterized by a spatially modulating density of electron pairs. Such a state should exhibit a periodically modulating energy gap $${\Delta }_{{{{{{\rm{P}}}}}}}({{{{{\boldsymbol{r}}}}}})$$

Δ

P

(

r

)

in real-space, and a characteristic quasiparticle scattering interference (QPI) signature $${\Lambda }_{{{{{{\rm{P}}}}}}}({{{{{\boldsymbol{q}}}}}})$$

Λ

P

(

q

)

in wavevector space. By studying strongly underdoped Bi2Sr2CaDyCu2O8 at hole-density ~0.08 in the superconductive phase, we detect the 8a0-periodic $${\Delta }_{{{{{{\rm{P}}}}}}}({{{{{\boldsymbol{r}}}}}})$$

Δ

P

(

r

)

modulations signifying a PDW coexisting with superconductivity. Then, by visualizing the temperature dependence of this electronic structure from the superconducting into the pseudogap phase, we find the evolution of the scattering interference signature $$\Lambda ({{{{{\boldsymbol{q}}}}}})$$
Λ

(

q

)

that is predicted specifically for the temperature dependence of an 8a0-periodic PDW. These observations are consistent with theory for the transition from a PDW state coexisting with d-wave superconductivity to a pure PDW state in the Bi2Sr2CaDyCu2O8 pseudogap phase.
A mutational hotspot that determines highly repeatable evolution can be built and broken by silent genetic changes
Authors: Horton James S. , Flanagan Louise M. , Jackson Robert W. , Priest Nicholas K. , Taylor Tiffany B.
Published: October 2021

Mutational hotspots can determine evolutionary outcomes and make evolution repeatable. Hotspots are products of multiple evolutionary forces including mutation rate heterogeneity, but this variable is often hard to identify. In this work, we reveal that a near-deterministic genetic hotspot can be built and broken by a handful of silent mutations. We observe this when studying homologous immotile variants of the bacteria Pseudomonas fluorescens, AR2 and Pf0-2x. AR2 resurrects motility through highly repeatable de novo mutation of the same nucleotide in >95% lines in minimal media (ntrB A289C). Pf0-2x, however, evolves via a number of mutations meaning the two strains diverge significantly during adaptation. We determine that this evolutionary disparity is owed to just 6 synonymous variations within the ntrB locus, which we demonstrate by swapping the sites and observing that we are able to both break (>95% to 0%) and build (0% to 80%) a deterministic mutational hotspot. Our work reveals a key role for silent genetic variation in determining adaptive outcomes.
A metabolome atlas of the aging mouse brain
Authors: Ding Jun , Ji Jian , Rabow Zachary , Shen Tong , Folz Jacob , Brydges Christopher R. , Fan Sili , Lu Xinchen , Mehta Sajjan , Showalter Megan R. , Zhang Ying , Araiza Renee , Bower Lynette R. , Lloyd K. C. Kent , Fiehn Oliver
Published: October 2021

The mammalian brain relies on neurochemistry to fulfill its functions. Yet, the complexity of the brain metabolome and its changes during diseases or aging remain poorly understood. Here, we generate a metabolome atlas of the aging wildtype mouse brain from 10 anatomical regions spanning from adolescence to old age. We combine data from three assays and structurally annotate 1,547 metabolites. Almost all metabolites significantly differ between brain regions or age groups, but not by sex. A shift in sphingolipid patterns during aging related to myelin remodeling is accompanied by large changes in other metabolic pathways. Functionally related brain regions (brain stem, cerebrum and cerebellum) are also metabolically similar. In cerebrum, metabolic correlations markedly weaken between adolescence and adulthood, whereas at old age, cross-region correlation patterns reflect decreased brain segregation. We show that metabolic changes can be mapped to existing gene and protein brain atlases. The brain metabolome atlas is publicly available (https://mouse.atlas.metabolomics.us/) and serves as a foundation dataset for future metabolomic studies.
Coordination tailoring of Cu single sites on C3N4 realizes selective CO2 hydrogenation at low temperature
Authors: Yang Tang , Mao Xinnan , Zhang Ying , Wu Xiaoping , Wang Lu , Chu Mingyu , Pao Chih-Wen , Yang Shize , Xu Yong , Huang Xiaoqing
Published: October 2021

CO2 hydrogenation has attracted great attention, yet the quest for highly-efficient catalysts is driven by the current disadvantages of poor activity, low selectivity, and ambiguous structure-performance relationship. We demonstrate here that C3N4-supported Cu single atom catalysts with tailored coordination structures, namely, Cu–N4 and Cu–N3, can serve as highly selective and active catalysts for CO2 hydrogenation at low temperature. The modulation of the coordination structure of Cu single atom is readily realized by simply altering the treatment parameters. Further investigations reveal that Cu–N4 favors CO2 hydrogenation to form CH3OH via the formate pathway, while Cu–N3 tends to catalyze CO2 hydrogenation to produce CO via the reverse water-gas-shift (RWGS) pathway. Significantly, the CH3OH productivity and selectivity reach 4.2 mmol g–1 h–1 and 95.5%, respectively, for Cu–N4 single atom catalyst. We anticipate this work will promote the fundamental researches on the structure-performance relationship of catalysts.
Photoactivatable ribonucleosides mark base-specific RNA-binding sites
Authors: Bae Jong Woo , Kim Sangtae , Kim V. Narry , Kim Jong-Seo
Published: October 2021

RNA-protein interaction can be captured by crosslinking and enrichment followed by tandem mass spectrometry, but it remains challenging to pinpoint RNA-binding sites (RBSs) or provide direct evidence for RNA-binding. To overcome these limitations, we here developed pRBS-ID, by incorporating the benefits of UVA-based photoactivatable ribonucleoside (PAR; 4-thiouridine and 6-thioguanosine) crosslinking and chemical RNA cleavage. pRBS-ID robustly detects peptides crosslinked to PAR adducts, offering direct RNA-binding evidence and identifying RBSs at single amino acid-resolution with base-specificity (U or G). Using pRBS-ID, we could profile uridine-contacting RBSs globally and discover guanosine-contacting RBSs, which allowed us to characterize the base-specific interactions. We also applied the search pipeline to analyze the datasets from UVC-based RBS-ID experiments, altogether offering a comprehensive list of human RBSs with high coverage (3,077 RBSs in 532 proteins in total). pRBS-ID is a widely applicable platform to investigate the molecular basis of posttranscriptional regulation.
PHF3 regulates neuronal gene expression through the Pol II CTD reader domain SPOC
Authors: Appel Lisa-Marie , Franke Vedran , Bruno Melania , Grishkovskaya Irina , Kasiliauskaite Aiste , Kaufmann Tanja , Schoeberl Ursula E. , Puchinger Martin G. , Kostrhon Sebastian , Ebenwaldner Carmen , Sebesta Marek , Beltzung Etienne , Mechtler Karl , Lin Gen , Vlasova Anna , Leeb Martin , Pavri Rushad , Stark Alexander , Akalin Altuna , Stefl Richard , Bernecky Carrie , Djinovic-Carugo Kristina , Slade Dea
Published: October 2021

The C-terminal domain (CTD) of the largest subunit of RNA polymerase II (Pol II) is a regulatory hub for transcription and RNA processing. Here, we identify PHD-finger protein 3 (PHF3) as a regulator of transcription and mRNA stability that docks onto Pol II CTD through its SPOC domain. We characterize SPOC as a CTD reader domain that preferentially binds two phosphorylated Serine-2 marks in adjacent CTD repeats. PHF3 drives liquid-liquid phase separation of phosphorylated Pol II, colocalizes with Pol II clusters and tracks with Pol II across the length of genes. PHF3 knock-out or SPOC deletion in human cells results in increased Pol II stalling, reduced elongation rate and an increase in mRNA stability, with marked derepression of neuronal genes. Key neuronal genes are aberrantly expressed in Phf3 knock-out mouse embryonic stem cells, resulting in impaired neuronal differentiation. Our data suggest that PHF3 acts as a prominent effector of neuronal gene regulation by bridging transcription with mRNA decay.
Altered growth conditions more than reforestation counteracted forest biomass carbon emissions 1990–2020
Authors: Le Noë Julia , Erb Karl-Heinz , Matej Sarah , Magerl Andreas , Bhan Manan , Gingrich Simone
Published: October 2021

Understanding the carbon (C) balance in global forest is key for climate-change mitigation. However, land use and environmental drivers affecting global forest C fluxes remain poorly quantified. Here we show, following a counterfactual modelling approach based on global Forest Resource Assessments, that in 1990–2020 deforestation is the main driver of forest C emissions, partly counteracted by increased forest growth rates under altered conditions: In the hypothetical absence of changes in forest (i) area, (ii) harvest or (iii) burnt area, global forest biomass would reverse from an actual cumulative net C source of c. 0.74 GtC to a net C sink of 26.9, 4.9 and 0.63 GtC, respectively. In contrast, (iv) without growth rate changes, cumulative emissions would be 7.4 GtC, i.e., 10 times higher. Because this sink function may be discontinued in the future due to climate-change, ending deforestation and lowering wood harvest emerge here as key climate-change mitigation strategies.
A new opportunity for the emerging tellurium semiconductor: making resistive switching devices
Authors: Yang Yifei , Xu Mingkun , Jia Shujing , Wang Bolun , Xu Lujie , Wang Xinxin , Liu Huan , Liu Yuanshuang , Guo Yuzheng , Wang Lidan , Duan Shukai , Liu Kai , Zhu Min , Pei Jing , Duan Wenrui , Liu Dameng , Li Huanglong
Published: October 2021

The development of the resistive switching cross-point array as the next-generation platform for high-density storage, in-memory computing and neuromorphic computing heavily relies on the improvement of the two component devices, volatile selector and nonvolatile memory, which have distinct operating current requirements. The perennial current-volatility dilemma that has been widely faced in various device implementations remains a major bottleneck. Here, we show that the device based on electrochemically active, low-thermal conductivity and low-melting temperature semiconducting tellurium filament can solve this dilemma, being able to function as either selector or memory in respective desired current ranges. Furthermore, we demonstrate one-selector-one-resistor behavior in a tandem of two identical Te-based devices, indicating the potential of Te-based device as a universal array building block. These nonconventional phenomena can be understood from a combination of unique electrical-thermal properties in Te. Preliminary device optimization efforts also indicate large and unique design space for Te-based resistive switching devices.
Exome sequencing and analysis of 454,787 UK Biobank participants
Authors: Backman Joshua D. , Li Alexander H. , Marcketta Anthony , Sun Dylan , Mbatchou Joelle , Kessler Michael D. , Benner Christian , Liu Daren , Locke Adam E. , Balasubramanian Suganthi , Yadav Ashish , Banerjee Nilanjana , Gillies Christopher E. , Damask Amy , Liu Simon , Bai Xiaodong , Hawes Alicia , Maxwell Evan , Gurski Lauren , Watanabe Kyoko , Kosmicki Jack A. , Rajagopal Veera , Mighty Jason ,   Regeneron Genetics Center,   DiscovEHR, Jones Marcus , Mitnaul Lyndon , Stahl Eli , Coppola Giovanni , Jorgenson Eric , Habegger Lukas , Salerno William J. , Shuldiner Alan R. , Lotta Luca A. , Overton John D. , Cantor Michael N. , Reid Jeffrey G. , Yancopoulos George , Kang Hyun M. , Marchini Jonathan , Baras Aris , Abecasis Gonçalo R. , Ferreira Manuel A. R.
Published: October 2021

A major goal in human genetics is to use natural variation to understand the phenotypic consequences of altering each protein-coding gene in the genome. Here we used exome sequencing1 to explore protein-altering variants and their consequences in 454,787 participants in the UK Biobank study2. We identified 12 million coding variants, including around 1 million loss-of-function and around 1.8 million deleterious missense variants. When these were tested for association with 3,994 health-related traits, we found 564 genes with trait associations at P ≤ 2.18 × 10−11. Rare variant associations were enriched in loci from genome-wide association studies (GWAS), but most (91%) were independent of common variant signals. We discovered several risk-increasing associations with traits related to liver disease, eye disease and cancer, among others, as well as risk-lowering associations for hypertension (SLC9A3R2), diabetes (MAP3K15, FAM234A) and asthma (SLC27A3). Six genes were associated with brain imaging phenotypes, including two involved in neural development (GBE1, PLD1). Of the signals available and powered for replication in an independent cohort, 81% were confirmed; furthermore, association signals were generally consistent across individuals of European, Asian and African ancestry. We illustrate the ability of exome sequencing to identify gene–trait associations, elucidate gene function and pinpoint effector genes that underlie GWAS signals at scale.
Chromosome-scale assembly and high-density genetic map of the yellow drum, Nibea albiflora
Authors: Xu Dongdong , Zhang Wanchang , Chen Ruiyi , Song Hongbin , Tian Lu , Tan Peng , Wang Ligai , Zhu Qihui , Wu Bin , Lou Bao , Min Jiumeng , Zhou Juhong
Published: October 2021

The yellow drum (Nibea albiflora) is an economically important sciaenid fish in East Asian countries. In this study, we sequenced and assembled a near-complete gynogenetic yellow drum genome. We generated 45.63 Gb of Illumina short-reads and 80.27 Gb of PacBio long-reads and assembled them into a 628.01-Mb genome with a contig N50 of 4.42 Mb. Twenty-four chromosomes with a scaffold N50 of 26.73 Mb were obtained using the Hi-C analysis. We predicted a set of 27,069 protein-coding genes, of which 1,581 and 2,583 were expanded and contracted gene families, respectively. The most expanded genes were categorised into the protein binding, zinc-ion binding and ATP binding functional pathways. We built a high-density genetic linkage map that spanned 4,300.2 cM with 24 linkage groups and a resolution of 0.69 cM. The high-quality reference genome and annotated profiles that we produced will not only increase our understanding of the genetic architecture of economic traits in the yellow drum, but also help us explore the evolution and unique biological characteristics of sciaenid fishes.
The changing face of floodplains in the Mississippi River Basin detected by a 60-year land use change dataset
Authors: Rajib Adnan , Zheng Qianjin , Golden Heather E. , Wu Qiusheng , Lane Charles R. , Christensen Jay R. , Morrison Ryan R. , Annis Antonio , Nardi Fernando
Published: October 2021

Floodplains provide essential ecosystem functions, yet >80% of European and North American floodplains are substantially modified. Despite floodplain changes over the past century, comprehensive, long-term land use change data within large river basin floodplains are limited. Long-term land use data can be used to quantify floodplain functions and provide spatially explicit information for management, restoration, and flood-risk mitigation. We present a comprehensive dataset quantifying floodplain land use change along the 3.3 million km2 Mississippi River Basin (MRB) covering 60 years (1941–2000) at 250-m resolution. We developed four unique products as part of this work, a(n): (i) Google Earth Engine interactive map visualization interface, (ii) Python code that runs in any internet browser, (iii) online tutorial with visualizations facilitating classroom code application, and (iv) instructional video demonstrating code application and database reproduction. Our data show that MRB’s natural floodplain ecosystems have been substantially altered to agricultural and developed land uses. These products will support MRB resilience and sustainability goals by advancing data-driven decision making on floodplain restoration, buyout, and conservation scenarios.
A magnetic copper organic framework material as an efficient and recyclable catalyst for the synthesis of 1,2,3-triazole derivatives
Authors: Arefi Elham , Khojastehnezhad Amir , Shiri Ali
Published: October 2021

In this study, a core–shell magnetic metal organic framework (MOF) catalyst was introduced based on Fe3O4 magnetic nanoparticles (MNPs) and copper organic frameworks. In this catalyst, Fe3O4 MNPs have been coated with MOFs in which copper was the inorganic nodes and 1,3,5-benzenetricarboxylic acid was the organic linkers. Then, the core–shell structures and catalytic efficiency have been confirmed properly and completely with various analyses such as FT-IR, TEM, SEM, TEM mapping, SEM mapping, EDX, PXRD, TGA, ICP and VSM. The Cu moieties in MOF and shell structures can catalyze the synthesis of 1,2,3-triazole derivatives with good to excellent yields in the presence of water as a green solvent. Moreover, this catalyst showed the high reusability due to the super paramagnetic properties.