bluuebunny/crossref_metadata_2025 huggingface dataset:
Gewalterfahrungen während stationärer kinder- und jugendpsychiatrischer Behandlung – explorative Studie und Implikationen für den Kinderschutz
Authors: Posch Ines , Romanos Marcel , Warnke Andreas , Jans Thomas
Published: November 2022

Zusammenfassung. Fragestellung: Pädagogische und medizinische Institutionen betreuen Kinder und Jugendliche, um Aufsicht, Beschulung, Erziehung, Therapie und Schutz sicherzustellen. Gleichwohl sind Kinder in institutioneller Betreuung potenziellen Gefährdungsmomenten bezüglich Misshandlung und Missbrauch ausgesetzt. Methodik: Im Rahmen der Etablierung des Schutzkonzeptes der Klinik für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie am Universitätsklinikum Würzburg wurde eine retrospektive Patientenbefragung durchgeführt. Das Untersuchungskollektiv bildeten alle ehemaligen stationären Patientinnen und Patienten der Jahre 2006 und 2007, die zum Katamnesezeitpunkt volljährig waren. Die Befragung erfolgte postalisch. Der Fragebogen umfasste neben Items zum Kontext von Gewalterfahrungen etablierte Skalen zur Erfassung von Behandlungszufriedenheit und Lebensqualität (FBB-K, WHO-BREF). Ergebnisse: Von 568 ehemaligen Patientinnen und Patienten gaben 87 (15.3 %) eine gültige Rückantwort (59 weiblich, durchschnittliches Alter zum Befragungszeitpunkt: 24.5 Jahre). 35 ehemalige Patientinnen und Patienten (40.2 % der Teilnehmenden) gaben an, Gewalt während der stationären Behandlung erlebt ( n = 26) oder erlebt und ausgeübt ( n = 7) oder ausschließlich ausgeübt ( n = 2) zu haben. Gewalterfahrungen beinhalteten in den meisten Fällen emotionale Gewalt (34.5 %), aber auch körperliche (5.7 %) und sexuelle Gewalt (10.3 %). Schlussfolgerung: Es zeigte sich ein signifikanter Zusammenhang zwischen Gewalterfahrungen einerseits sowie retrospektiver Behandlungszufriedenheit und aktueller Lebensqualität andererseits. Die Ergebnisse der Befragung unterstreichen die Bedeutung der Etablierung von Schutzkonzepten in Kliniken und anderen Institutionen.
Breaking Up for Good
Authors: Krakowiak K. Maja
Published: November 2022

Abstract: In recent years, entertainment scholars have investigated the extent to which negative emotions such as grief, distress, and loneliness are experienced by viewers following the departure of a favorite character or the cancellation or completion of a television series – also referred to as parasocial breakup (PSB). An online questionnaire ( N = 814) was administered to understand predictors of PSB following the end of a series as they relate to character involvement and holistic enjoyment and appreciation experiences. Findings revealed that a parasocial relationship (PSR) with a favorite character and liking of and identification with the character positively enhanced enjoyment of the series. PSR and identification also facilitated appreciation of the series. Moreover, while PSR and appreciation increased PSB, character liking and enjoyment of the series decreased it. Theoretical implications for the contrasting roles of hedonic and eudaimonic media experiences in predicting PSB are discussed.
Haline Сontrol of Unusually Deep Winter Mixing in the Gulf of Maine Investigated Using a Regional Data‐Assimilative Model
Authors: Levin J. C. , Grodsky S. A. , Vandemark D. , Wilkin J. L.
Published: November 2022

An unusually large positive salinity anomaly was observed across the eastern Gulf of Maine in winter 2017–2018. Buoy measurements in Jordan Basin found this anomaly extended down to at least 100 m, the deepest mixing observed in the past 19 years. Similarly, this is the strongest positive regional salt anomaly ever observed in sea surface salinity (SSS) satellite observations. To determine the source waters driving this event and to diagnose the relative importance of forcing processes, passive tracer adjoint sensitivity experiments are performed using a data assimilating version of the Regional Ocean Modeling System. The model suggests that northeastward Scotian Shelf wind anomalies is one factor in the dramatic decrease in freshwater transport to Jordan Basin, which leads to an early winter upper water column salinity surplus. This salinity change weakens the normally haline‐controlled vertical stratification across the eastern Gulf. Modeled upper ocean density and vertical diffusivity from 2007 to 2021 both show a maximum in January 2018. Winter 2017–2018 is the only period where the enhanced winter mixing extends below 100 m. Thus, anomalous vertical entrainment of saltier subsurface Gulf water is the major factor driving the extreme positive satellite‐observed SSS anomaly across the eastern Gulf including Jordan Basin. Other factors, including a modest increase in wind‐forced slope water transport, and positive fall 2017 salinity anomalies on the Scotian Shelf and Slope Sea, appear to play lesser roles in the observed salinification. The adjoint sensitivity analysis demonstrates its utility for back tracing transport pathways for periods of several months.
Non‐Stationary Probabilistic Tsunami Hazard Assessments Compounding Tides and Sea Level Rise
Authors: Sepúlveda Ignacio , Liu Philip L.‐F. , Grigoriu Mircea , Haase Jennifer S. , Winckler Patricio
Published: November 2022

Tides are often the largest source of sea levels fluctuations. Two new probabilistic tsunami hazard assessments (PTHA) methods are proposed to combine the tidal phase uncertainty at the moment of tsunami occurrence with other sources of uncertainty. The first method adopts a Stochastic Reduced Order Model (SROM) producing sets of tidal phase samples to be used in tsunami simulations. The second method uses tsunami simulations with prescribed collocation tidal phases and tide probability distributions to model the uncertainty. The methods are extended to non‐stationary probabilistic tsunami hazard assessment, compounding tsunamis, tides and sea level rise (SLR). As an illustration, these methods are applied for assessing tsunamis generated in the Manila Subduction Zone, on the coasts of Kao Hsiung and Hong Kong. While the SROM‐based method is faster solving for the PTHA if only tides are considered, the collocation‐based method is faster when both SLR and tides are considered. For the illustration case, tides have a relevant impact on PTHA results, however, the SLR within an exposure time of 100 years has stronger impact. PTHA curves of the maximum tsunami elevation are affected by tides and SLR differently. While tides and SLR increase the dispersion of PTHA hazard curve distributions, the latter also produces a translation toward higher elevations. The development of formulations based on SROM or collocation tides is the key to establishing a method which feasibly can be applied to other regions for comprehensive analysis at a global scale.
Impingement of Subsurface Anticyclonic Eddies on the Kuroshio Mainstream East of Taiwan
Authors: Wang Ran , Nan Feng , Yu Fei , Wang Bin
Published: November 2022

This study shows that North Pacific subtropical mode water (STMW) characterized by low potential vorticity can approach and impinge on the Kuroshio mainstream east of Taiwan. The results of the analyses of observations and output from eddy‐resolving models show that the STMW appears with the frequency of 32.1% and 19.9% in the Kuroshio east of Taiwan. A case study with the output of the ocean general circulation model for the earth simulator during October 2015–March 2016 indicates that mode water moves southwestward toward the Kuroshio in accordance with a vertically lens‐shaped subsurface anticyclonic eddy (SAE). After the shoreward edge of the SAE impinges on the offshore edge of the Kuroshio, the northward velocity, especially subsurface velocity, of the Kuroshio increases significantly in the subsurface layer and the Kuroshio central position (KCP) extends eastward. While the SAE moves and dissipates, the offshore edge of the Kuroshio moves inshore, and then transport decreases. Both the northward velocity and the KCP changes result in the Kuroshio transport change during the impingement of SAE in the case. Statistic analysis further demonstrate that eddies those can trap moving STMW are dominated by SAEs. When SAEs encounter the Kuroshio, their subsurface northward velocity increases by 67.8% and the KCP moves eastward, and thus the northward transport of the Kuroshio increases by 43.4%.
The Effects of Ocean Surface Waves on Tropical Cyclone Intensity: Numerical Simulations Using a Regional Atmosphere‐Ocean‐Wave Coupled Model
Authors: Zhao Biao , Wang Guansuo , Zhang Jun A. , Liu Li , Liu Jiping , Xu Jing , Yu Hao , Zhao Chang , Yu Xinzhu , Sun Chao , Qiao Fangli
Published: November 2022

Tropical cyclones (TCs), especially landfalling intense storms often pose serious threats to life and property in coastal areas. Although TC track forecast skill has been improved in the past decades, the progress of advancing the intensity forecast lags that of the track forecast. One possible limiting factor is the absence of ocean surface waves in forecast systems. To better represent the interaction of TC and underlying ocean, a regional atmosphere‐ocean‐wave coupled model is employed in this study. Twenty‐one TCs of a whole year in 2013 are retrospectively simulated through twin simulations, a Control and a Fully coupled run. Results show that TC intensity bias has been significantly reduced in the fully coupled simulation, in which five ocean surface wave related physical processes are considered, including wave modulation of momentum flux, sea spray effect on enthalpy flux, surface current and Stokes drift on air sea flux, non‐breaking wave induced mixing in the upper ocean as well as rain induced ocean surface cooling. A case study approach is used to diagnose the effect of individual surface wave related physical process on TC simulations. Similar to the effect of sea spray, surface waves also act as positive feedback on TC intensification by modulating air‐sea momentum flux. Absolute angular momentum budget analysis suggests that larger radial inflows and stronger updrafts near the eyewall promote the radial and vertical advections of absolute angular momentum and in turn lead to a stronger TC in Fully coupled simulation. The TC structure and size agree better with observations in Fully coupled simulation.
Assessing Drivers of Coastal Tundra Retreat at Point Hope, Alaska
Authors: Cohn Nicholas , Bosche Lauren V. , Midgley Taber , Small Christopher , Douglas Thomas A. , King Jeffrey
Published: November 2022

Shoreline erosion over the last few decades along the Point Hope, Alaska, USA coastline has led to considerable loss of tundra behind the beach. Analysis of available remote sensing, morphology, and hydrodynamic datasets are used to inform the time scales and mechanisms of coastal land loss at Point Hope, in part through integration of these data into an analytical retreat model originally developed for coastal foredunes. At shorter time scales, these analyses indicate that steeper local beach slopes influence higher wave runup that can enhance the scale of tundra retreat at a particular section of coast. Coastal stretches that are most vulnerable to wave attack of the tundra scarp appear to shift with time related to complex spatio‐temporal variability in shoreline change rates. These local beach erosion rates primarily control the retreat of the tundra at decadal scales. However, independent of the fronting beach morphology, the largest erosion events throughout the region generally occur when there is the coincidence of both high wave energy and elevated still water levels. Additional exploratory modeling results indicate that future changes to sea level and changes in wave energy will further enhance the magnitude of tundra erosion.
NRBF2-mediated autophagy contributes to metabolite replenishment and radioresistance in glioblastoma
Authors: Kim Jeongha , Kang Hyunkoo , Son Beomseok , Kim Min-Jung , Kang JiHoon , Park Kang Hyun , Jeon Jaewan , Jo Sunmi , Kim Hae Yu , Youn HyeSook , Youn BuHyun
Published: November 2022

Overcoming therapeutic resistance in glioblastoma (GBM) is an essential strategy for improving cancer therapy. However, cancer cells possess various evasion mechanisms, such as metabolic reprogramming, which promote cell survival and limit therapy. The diverse metabolic fuel sources that are produced by autophagy provide tumors with metabolic plasticity and are known to induce drug or radioresistance in GBM. This study determined that autophagy, a common representative cell homeostasis mechanism, was upregulated upon treatment of GBM cells with ionizing radiation (IR). Nuclear receptor binding factor 2 (NRBF2)—a positive regulator of the autophagy initiation step—was found to be upregulated in a GBM orthotopic xenograft mouse model. Furthermore, ATP production and the oxygen consumption rate (OCR) increased upon activation of NRBF2-mediated autophagy. It was also discovered that changes in metabolic state were induced by alterations in metabolite levels caused by autophagy, thereby causing radioresistance. In addition, we found that lidoflazine—a vasodilator agent discovered through drug repositioning—significantly suppressed IR-induced migration, invasion, and proliferation by inhibiting NRBF2, resulting in a reduction in autophagic flux in both in vitro models and in vivo orthotopic xenograft mouse models. In summary, we propose that the upregulation of NRBF2 levels reprograms the metabolic state of GBM cells by activating autophagy, thus establishing NRBF2 as a potential therapeutic target for regulating radioresistance of GBM during radiotherapy.
The role of dendritic cells in the immunomodulation to implanted biomaterials
Authors: Wang Siyuan , Chen Yanqi , Ling Zhaoting , Li Jia , Hu Jun , He Fuming , Chen Qianming
Published: November 2022

Considering the substantial role played by dendritic cells (DCs) in the immune system to bridge innate and adaptive immunity, studies on DC-mediated immunity toward biomaterials principally center on their adjuvant effects in facilitating the adaptive immunity of codelivered antigens. However, the effect of the intrinsic properties of biomaterials on dendritic cells has not been clarified. Recently, researchers have begun to investigate and found that biomaterials that are nonadjuvant could also regulate the immune function of DCs and thus affect subsequent tissue regeneration. In the case of proteins adsorbed onto biomaterial surfaces, their intrinsic properties can direct their orientation and conformation, forming “biomaterial-associated molecular patterns (BAMPs)”. Thus, in this review, we focused on the intrinsic physiochemical properties of biomaterials in the absence of antigens that affect DC immune function and summarized the underlying signaling pathways. Moreover, we preliminarily clarified the specific composition of BAMPs and the interplay between some key molecules and DCs, such as heat shock proteins (HSPs) and high mobility group box 1 (HMGB1). This review provides a new direction for future biomaterial design, through which modulation of host immune responses is applicable to tissue engineering and immunotherapy.
In vivo PDX CRISPR/Cas9 screens reveal mutual therapeutic targets to overcome heterogeneous acquired chemo-resistance
Authors: Wirth Anna-Katharina , Wange Lucas , Vosberg Sebastian , Henrich Kai-Oliver , Rausch Christian , Özdemir Erbey , Zeller Christina M. , Richter Daniel , Feuchtinger Tobias , Kaller Markus , Hermeking Heiko , Greif Philipp A. , Senft Daniela , Jurinovic Vindi , Bahrami Ehsan , Jayavelu Ashok Kumar , Westermann Frank , Mann Matthias , Enard Wolfgang , Herold Tobias , Jeremias Irmela
Published: November 2022

Resistance towards cancer treatment represents a major clinical obstacle, preventing cure of cancer patients. To gain mechanistic insights, we developed a model for acquired resistance to chemotherapy by treating mice carrying patient derived xenografts (PDX) of acute lymphoblastic leukemia with widely-used cytotoxic drugs for 18 consecutive weeks. In two distinct PDX samples, tumors initially responded to treatment, until stable disease and eventually tumor re-growth evolved under therapy, at highly similar kinetics between replicate mice. Notably, replicate tumors developed different mutations in TP53 and individual sets of chromosomal alterations, suggesting independent parallel clonal evolution rather than selection, driven by a combination of stochastic and deterministic processes. Transcriptome and proteome showed shared dysregulations between replicate tumors providing putative targets to overcome resistance. In vivo CRISPR/Cas9 dropout screens in PDX revealed broad dependency on BCL2, BRIP1 and COPS2. Accordingly, venetoclax re-sensitized derivative tumors towards chemotherapy, despite genomic heterogeneity, demonstrating direct translatability of the approach. Hence, despite the presence of multiple resistance-associated genomic alterations, effective rescue treatment for polychemotherapy-resistant tumors can be identified using functional testing in preclinical models.
EGFR-induced suppression of HPV E6/E7 is mediated by microRNA-9-5p silencing of BRD4 protein in HPV-positive head and neck squamous cell carcinoma
Authors: Nantajit Danupon , Presta Luana , Sauter Thomas , Tavassoli Mahvash
Published: November 2022

EGFR upregulation is an established biomarker of treatment resistance and aggressiveness in head and neck cancers (HNSCC). EGFR-targeted therapies have shown benefits for HPV-negative HNSCC; surprisingly, inhibiting EGFR in HPV-associated HNSCC led to inferior therapeutic outcomes suggesting opposing roles for EGFR in the two HNSCC subtypes. The current study aimed to understand the link between EGFR and HPV-infected HNSCC particularly the regulation of HPV oncoproteins E6 and E7. We demonstrate that EGFR overexpression suppresses cellular proliferation and increases radiosensitivity of HPV-positive HNSCC cell lines. EGFR overexpression inhibited protein expression of BRD4, a known cellular transcriptional regulator of HPV E6/E7 expression and DNA damage repair facilitator. Inhibition of EGFR by cetuximab restored the expression of BRD4 leading to increased HPV E6 and E7 transcription. Concordantly, pharmacological inhibition of BRD4 led to suppression of HPV E6 and E7 transcription, delayed cellular proliferation and sensitised HPV-positive HNSCC cells to ionising radiation. This effect was shown to be mediated through EGFR-induced upregulation of microRNA-9-5p and consequent silencing of its target BRD4 at protein translational level, repressing HPV E6 and E7 transcription and restoring p53 tumour suppressor functions. These results suggest a novel mechanism for EGFR inhibition of HPV E6/E7 oncoprotein expression through an epigenetic pathway, independent of MAPK, but mediated through microRNA-9-5p/BRD4 regulation. Therefore, targeting EGFR may not be the best course of therapy for certain cancer types including HPV-positive HNSCC, while targeting specific signalling pathways such as BRD4 could provide a better and potentially new treatment to improve HNSCC therapeutic outcome.
ERR-activated GPR35 promotes immune infiltration level of macrophages in gastric cancer tissues
Authors: Shu Chuanjun , Wang Can , Chen Saisai , Huang Xuan , Cui Jiahua , Li Wenchao , Xu Bin
Published: November 2022

Enhancer release and retargeting (ERR) events could activate disease-causing gene promoters for increasing the expression level of oncogenes. Meanwhile, class A orphan GPCRs (oGPCRs) are known as potential biomarkers or drug targets for various cancers, such as gastric cancer (GC). Hence, systemic investigation of ERR events for class A oGPCRs in GC could help to explore biomarkers for GC. In this study, ENCODE and GTEx eQTL data were utilized to define ERR events in GC. Only GPR35 was then detected that could be activated by ERR in GC based on these data and ChIP-seq. Then, activated GPR35 functional in GC cells were explored by flow cytometry, cell-based wound healing assay, Transwell migration assay, and M2 polarization of macrophages assay. Meanwhile, according to TCGA and GEO database, overall survival, immune-related gene expression, and immune cell infiltration level in different GPR35 expressions were calculated. Here, we found ERR event activate GPR35 results in GC cells proliferation and migration, and partly immune cells significance exhaustion (CD8 + T-cells and CD4 + memory T-cells) and/or infiltration (T-cells and macrophage). Meanwhile, high GRP35 level leads to a poor prognosis in GC patients, probably partly due to it promoting the immune infiltration level of macrophages and then inducing polarization of M2 macrophages. Notably, GPR35’s high expression in CTSB+ and CD68 + macrophage could be a genetic indicator for early warning of primary GC. Hence, our findings provide a novel activation approach for oGPCRs, and GPR35 could be determined as a new drugable receptor and early genetic indicator for GC.
Mussel-inspired hydrogel with injectable self-healing and antibacterial properties promotes wound healing in burn wound infection
Authors: Sun Ao , Hu Danrong , He Xinye , Ji Xiao , Li Tao , Wei Xiawei , Qian Zhiyong
Published: November 2022

Burn wound infections cause serious problems for public health. More than 180,000 patients die from burns every year worldwide. In addition, the difficulty of healing wounds and wound infections caused by burns affects the mental health of patients. Therefore, it is very important to develop a wound dressing that can promote wound repair and exhibits good antibacterial effects. Here, we used oxidized konjac glucomannan (OKGM), γ-poly(glutamic acid) modified with dopamine and L-cysteine (γ-PGA-DA-Cys) and ε-polylysine (ε-PL) to produce an OKGM/γ-PGA-DA-Cys/ε-PL (OKPP) hydrogel. This hydrogel was produced by thiol-aldehyde addition and Schiff-base reactions and has the ability to be injected and self-heal. The results showed that the hydrogel exhibits good antibacterial effects on Pseudomonas aeruginosa and Staphylococcus aureus and has antioxidant effects in vitro. Moreover, the hydrogel also exhibits good adhesion. In a burn wound infection model, the hydrogel promoted wound healing and reduced the production of inflammation. These results proved that the hydrogel has clinical potential as a wound dressing for burn wound infection.
On-microscope staging of live cells reveals changes in the dynamics of transcriptional bursting during differentiation
Authors: Jeziorska D. M. , Tunnacliffe E. A. J. , Brown J. M. , Ayyub H. , Sloane-Stanley J. , Sharpe J. A. , Lagerholm B. C. , Babbs C. , Smith A. J. H. , Buckle V. J. , Higgs D. R.
Published: November 2022

Determining the mechanisms by which genes are switched on and off during development is a key aim of current biomedical research. Gene transcription has been widely observed to occur in a discontinuous fashion, with short bursts of activity interspersed with periods of inactivity. It is currently not known if or how this dynamic behaviour changes as mammalian cells differentiate. To investigate this, using an on-microscope analysis, we monitored mouse α-globin transcription in live cells throughout erythropoiesis. We find that changes in the overall levels of α-globin transcription are most closely associated with changes in the fraction of time a gene spends in the active transcriptional state. We identify differences in the patterns of transcriptional bursting throughout differentiation, with maximal transcriptional activity occurring in the mid-phase of differentiation. Early in differentiation, we observe increased fluctuation in transcriptional activity whereas at the peak of gene expression, in early erythroblasts, transcription is relatively stable. Later during differentiation as α-globin expression declines, we again observe more variability in transcription within individual cells. We propose that the observed changes in transcriptional behaviour may reflect changes in the stability of active transcriptional compartments as gene expression is regulated during differentiation.
Spatial analysis of the glioblastoma proteome reveals specific molecular signatures and markers of survival
Authors: Duhamel Marie , Drelich Lauranne , Wisztorski Maxence , Aboulouard Soulaimane , Gimeno Jean-Pascal , Ogrinc Nina , Devos Patrick , Cardon Tristan , Weller Michael , Escande Fabienne , Zairi Fahed , Maurage Claude-Alain , Le Rhun Émilie , Fournier Isabelle , Salzet Michel
Published: November 2022

Molecular heterogeneity is a key feature of glioblastoma that impedes patient stratification and leads to large discrepancies in mean patient survival. Here, we analyze a cohort of 96 glioblastoma patients with survival ranging from a few months to over 4 years. 46 tumors are analyzed by mass spectrometry-based spatially-resolved proteomics guided by mass spectrometry imaging. Integration of protein expression and clinical information highlights three molecular groups associated with immune, neurogenesis, and tumorigenesis signatures with high intra-tumoral heterogeneity. Furthermore, a set of proteins originating from reference and alternative ORFs is found to be statistically significant based on patient survival times. Among these proteins, a 5-protein signature is associated with survival. The expression of these 5 proteins is validated by immunofluorescence on an additional cohort of 50 patients. Overall, our work characterizes distinct molecular regions within glioblastoma tissues based on protein expression, which may help guide glioblastoma prognosis and improve current glioblastoma classification.
Cross-platform comparison of arbitrary quantum states
Authors: Zhu D. , Cian Z. P. , Noel C. , Risinger A. , Biswas D. , Egan L. , Zhu Y. , Green A. M. , Alderete C. Huerta , Nguyen N. H. , Wang Q. , Maksymov A. , Nam Y. , Cetina M. , Linke N. M. , Hafezi M. , Monroe C.
Published: November 2022

As we approach the era of quantum advantage, when quantum computers (QCs) can outperform any classical computer on particular tasks, there remains the difficult challenge of how to validate their performance. While algorithmic success can be easily verified in some instances such as number factoring or oracular algorithms, these approaches only provide pass/fail information of executing specific tasks for a single QC. On the other hand, a comparison between different QCs preparing nominally the same arbitrary circuit provides an insight for generic validation: a quantum computation is only as valid as the agreement between the results produced on different QCs. Such an approach is also at the heart of evaluating metrological standards such as disparate atomic clocks. In this paper, we report a cross-platform QC comparison using randomized and correlated measurements that results in a wealth of information on the QC systems. We execute several quantum circuits on widely different physical QC platforms and analyze the cross-platform state fidelities.
Control of perovskite film crystallization and growth direction to target homogeneous monolithic structures
Authors: Zheng Daming , Raffin Florian , Volovitch Polina , Pauporté Thierry
Published: November 2022

Getting performant organo-metal halide perovskite films for various application remains challenging. Here, we show the behavior of solvent and perovskite elements for four different perovskites families and nine different initial precursor solution systems in the case of the most popular preparation process which includes an anti-solvent dripping-assisted spin coating of a precursor solution and a subsequent thermal annealing. We show how the initial solution composition affects, first, the film formed by spin coating and anti-solvent dripping and, second, the processes occurring upon thermal annealing, including crystal domain evolution and the grain growth mechanism. We propose a universal typology which distinguishes three types for the growth direction of perovskite crystals: downward (Type I), upward (Type II) and lateral (Type III). The latter results in large, monolithic grains and we show that this mode must be targeted for the preparation of efficient perovskite light absorber thin films of solar cells.
Data-driven electron-diffraction approach reveals local short-range ordering in CrCoNi with ordering effects
Authors: Hsiao Haw-Wen , Feng Rui , Ni Haoyang , An Ke , Poplawsky Jonathan D. , Liaw Peter K. , Zuo Jian-Min
Published: November 2022

The exceptional mechanical strength of medium/high-entropy alloys has been attributed to hardening in random solid solutions. Here, we evidence non-random chemical mixing in a CrCoNi alloy, resulting from short-range ordering. A data-mining approach of electron nanodiffraction enabled the study, which is assisted by neutron scattering, atom probe tomography, and diffraction simulation using first-principles theory models. Two samples, one homogenized and one heat-treated, are observed. In both samples, results reveal two types of short-range-order inside nanoclusters that minimize the Cr–Cr nearest neighbors (L12) or segregate Cr on alternating close-packed planes (L11). The L11 is predominant in the homogenized sample, while the L12 formation is promoted by heat-treatment, with the latter being accompanied by a dramatic change in dislocation-slip behavior. These findings uncover short-range order and the resulted chemical heterogeneities behind the mechanical strength in CrCoNi, providing general opportunities for atomistic-structure study in concentrated alloys for the design of strong and ductile materials.
Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy
Authors: Grange Laura J. , Reynolds John J. , Ullah Farid , Isidor Bertrand , Shearer Robert F. , Latypova Xenia , Baxley Ryan M. , Oliver Antony W. , Ganesh Anil , Cooke Sophie L. , Jhujh Satpal S. , McNee Gavin S. , Hollingworth Robert , Higgs Martin R. , Natsume Toyoaki , Khan Tahir , Martos-Moreno Gabriel Á. , Chupp Sharon , Mathew Christopher G. , Parry David , Simpson Michael A. , Nahavandi Nahid , Yüksel Zafer , Drasdo Mojgan , Kron Anja , Vogt Petra , Jonasson Annemarie , Seth Saad Ahmed , Gonzaga-Jauregui Claudia , Brigatti Karlla W. , Stegmann Alexander P. A. , Kanemaki Masato , Josifova Dragana , Uchiyama Yuri , Oh Yukiko , Morimoto Akira , Osaka Hitoshi , Ammous Zineb , Argente Jesús , Matsumoto Naomichi , Stumpel Constance T.R.M. , Taylor Alexander M. R. , Jackson Andrew P. , Bielinsky Anja-Katrin , Mailand Niels , Le Caignec Cedric , Davis Erica E. , Stewart Grant S.
Published: November 2022

Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway,SLF2andSMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability.
Ligand-switchable nanoparticles resembling viral surface for sequential drug delivery and improved oral insulin therapy
Authors: Yang Tiantian , Wang Aohua , Nie Di , Fan Weiwei , Jiang Xiaohe , Yu Miaorong , Guo Shiyan , Zhu Chunliu , Wei Gang , Gan Yong
Published: November 2022

Mutual interference between surface ligands on multifunctional nanoparticles remains a significant obstacle to achieving optimal drug-delivery efficacy. Here, we develop ligand-switchable nanoparticles which resemble viral unique surfaces, enabling them to fully display diverse functions. The nanoparticles are modified with a pH-responsive stretchable cell-penetrating peptide (Pep) and a liver-targeting moiety (Gal) (Pep/Gal-PNPs). Once orally administered, the acidic environments trigger the extension of Pep from surface in a virus-like manner, enabling Pep/Gal-PNPs to traverse intestinal barriers efficiently. Subsequently, Gal is exposed by Pep folding at physiological pH, thereby allowing the specific targeting of Pep/Gal-PNPs to the liver. As a proof-of-concept, insulin-loaded Pep/Gal-PNPs are fabricated which exhibit effective intestinal absorption and excellent hepatic deposition of insulin. Crucially, Pep/Gal-PNPs increase hepatic glycogen production by 7.2-fold, contributing to the maintenance of glucose homeostasis for effective diabetes management. Overall, this study provides a promising approach to achieving full potential of diverse ligands on multifunctional nanoparticles.
Identifying the geometric catalytic active sites of crystalline cobalt oxyhydroxides for oxygen evolution reaction
Authors: Wang Sihong , Jiang Qu , Ju Shenghong , Hsu Chia-Shuo , Chen Hao Ming , Zhang Di , Song Fang
Published: November 2022

Unraveling the precise location and nature of active sites is of paramount significance for the understanding of the catalytic mechanism and the rational design of efficient electrocatalysts. Here, we use well-defined crystalline cobalt oxyhydroxides CoOOH nanorods and nanosheets as model catalysts to investigate the geometric catalytic active sites. The morphology-dependent analysis reveals a ~50 times higher specific activity of CoOOH nanorods than that of CoOOH nanosheets. Furthermore, we disclose a linear correlation of catalytic activities with their lateral surface areas, suggesting that the active sites are exclusively located at lateral facets rather than basal facets. Theoretical calculations show that the coordinatively unsaturated cobalt sites of lateral facets upshift the O 2p-band center closer to the Fermi level, thereby enhancing the covalency of Co-O bonds to yield the reactivity. This work elucidates the geometrical catalytic active sites and enlightens the design strategy of surface engineering for efficient OER catalysts.
YiaC and CobB regulate lysine lactylation in Escherichia coli
Authors: Dong Hanyang , Zhang Jianji , Zhang Hui , Han Yue , Lu Congcong , Chen Chen , Tan Xiaoxia , Wang Siyu , Bai Xue , Zhai Guijin , Tian Shanshan , Zhang Tao , Cheng Zhongyi , Li Enmin , Xu Liyan , Zhang Kai
Published: November 2022

Lysine lactylation (Kla) has recently been reported to participate in regulating transcription in human cells. However, the characterization, regulatory mechanism and functional consequence of Kla in prokaryotes remain unclear. Here, we report that YiaC functions as a lysine lactylase and that CobB serves as a lysine delactylase in the regulation of metabolism. We demonstrate that YiaC catalyzes the addition of Kla, while CobB erases this PTM both in vitro and intracellularly. Moreover, we show that YdiF can catalyze the formation of a lactyl-coenzyme A, which donates lactyl group for Kla. Quantitative proteomic analysis further reveals 446 endogenous Kla sites targeted by CobB and 79 candidates targeted by YiaC in Escherichia coli (E. coli). Furthermore, we present that Kla can influence the functions of metabolic enzymes. Interestingly, we demonstrate that CobB can specifically modulate the activity of PykF by regulating K382la, promoting glycolysis and bacterial growth. Our study identifies the regulatory enzymes and functional network of Kla and reveals a Kla-mediated molecular mechanism catalyzed by CobB for glycolysis regulation in E. coli.
Anisotropic charge trapping in phototransistors unlocks ultrasensitive polarimetry for bionic navigation
Authors: Pan Jing , Wu Yiming , Zhang Xiujuan , Chen Jinhui , Wang Jinwen , Cheng Shuiling , Wu Xiaofeng , Zhang Xiaohong , Jie Jiansheng
Published: November 2022

Being able to probe the polarization states of light is crucial for applications from medical diagnostics and intelligent recognition to information encryption and bio-inspired navigation. Current state-of-the-art polarimeters based on anisotropic semiconductors enable direct linear dichroism photodetection without the need for bulky and complex external optics. However, their polarization sensitivity is restricted by the inherent optical anisotropy, leading to low dichroic ratios of typically smaller than ten. Here, we unveil an effective and general strategy to achieve more than 2,000-fold enhanced polarization sensitivity by exploiting an anisotropic charge trapping effect in organic phototransistors. The polarization-dependent trapping of photogenerated charge carriers provides an anisotropic photo-induced gate bias for current amplification, which has resulted in a record-high dichroic ratio of >104, reaching over the extinction ratios of commercial polarizers. These findings further enable the demonstration of an on-chip polarizer-free bionic celestial compass for skylight-based polarization navigation. Our results offer a fundamental design principle and an effective route for the development of next-generation highly polarization-sensitive optoelectronics.
Tumor factors stimulate lysosomal degradation of tumor antigens and undermine their cross-presentation in lung cancer
Authors: Lu Zhen , Chen Jinyun , Yu Pengfei , Atherton Matthew J. , Gui Jun , Tomar Vivek S. , Middleton Justin D. , Sullivan Neil T. , Singhal Sunil , George Subin S. , Woolfork Ashley G. , Weljie Aalim M. , Hai Tsonwin , Eruslanov Evgeniy B. , Fuchs Serge Y.
Published: November 2022

Activities of dendritic cells (DCs) that present tumor antigens are often suppressed in tumors. Here we report that this suppression is induced by tumor microenvironment-derived factors, which activate the activating transcription factor-3 (ATF3) transcription factor and downregulate cholesterol 25-hydroxylase (CH25H). Loss of CH25H in antigen presenting cells isolated from human lung tumors is associated with tumor growth and lung cancer progression. Accordingly, mice lacking CH25H in DCs exhibit an accelerated tumor growth, decreased infiltration and impaired activation of intratumoral CD8+ T cells. These mice do not establish measurable long-term immunity against malignant cells that undergo chemotherapy-induced immunogenic cell death. Mechanistically, downregulation of CH25H stimulates membrane fusion between endo-phagosomes and lysosomes, accelerates lysosomal degradation and restricts cross-presentation of tumor antigens in the intratumoral DCs. Administration of STING agonist MSA-2 reduces the lysosomal activity in DCs, restores antigen cross presentation, and increases therapeutic efficacy of PD-1 blockade against tumour challenge in a CH25H-dependent manner. These studies highlight the importance of downregulation of CH25H in DCs for tumor immune evasion and resistance to therapy.
Reward expectation extinction restructures and degrades CA1 spatial maps through loss of a dopaminergic reward proximity signal
Authors: Krishnan Seetha , Heer Chad , Cherian Chery , Sheffield Mark E. J.
Published: November 2022

Hippocampal place cells support reward-related spatial memories by forming a cognitive map that over-represents reward locations. The strength of these memories is modulated by the extent of reward expectation during encoding. However, the circuit mechanisms underlying this modulation are unclear. Here we find that when reward expectation is extinguished in mice, they remain engaged with their environment, yet place cell over-representation of rewards vanishes, place field remapping throughout the environment increases, and place field trial-to-trial reliability decreases. Interestingly, Ventral Tegmental Area (VTA) dopaminergic axons in CA1 exhibit a ramping reward-proximity signal that depends on reward expectation and inhibiting VTA dopaminergic neurons largely replicates the effects of extinguishing reward expectation. We conclude that changing reward expectation restructures CA1 cognitive maps and determines map reliability by modulating the dopaminergic VTA-CA1 reward-proximity signal. Thus, internal states of high reward expectation enhance encoding of spatial memories by reinforcing hippocampal cognitive maps associated with reward.
Three-dimensional open architecture enabling salt-rejection solar evaporators with boosted water production efficiency
Authors: Yang Kaijie , Pan Tingting , Dang Saichao , Gan Qiaoqiang , Han Yu
Published: November 2022

Direct solar desalination exhibits considerable potential for alleviating the global freshwater crisis. However, the prevention of salt accumulation while maintaining high water production remains an important challenge that limits its practical applications because the methods currently employed for achieving rapid salt backflow usually result in considerable heat loss. Herein, we fabricate a solar evaporator featuring vertically aligned mass transfer bridges for water transport and salt backflow. The 3D open architecture constructed using mass transfer bridges enables the evaporator to efficiently utilize the conductive heat that would otherwise be lost, significantly improving the water evaporation efficiency without compromising on salt rejection. The fabricated evaporator can treat salt water with more than 10% salinity. Moreover, it can continuously and steadily work in a real environment under natural sunlight with a practical solar-to-water collection efficiency of >40%. Using the discharged water from reverse osmosis plants and sea water from the Red Sea, the evaporator demonstrates a daily freshwater generation rate of ~5 L/m2, which is sufficient to satisfy individual drinking water requirements. With strong salt rejection, high energy efficiency, and simple scalability, the 3D evaporator has considerable promise for freshwater supply for water-stressed and off-grid communities.
Alteration of a brain network with stable and strong functional connections in subjects with schizophrenia
Authors: Yuan Liu , Ma Xiaoqian , Li David , Ouyang Lijun , Fan Lejia , Li Chunwang , He Ying , Chen Xiaogang
Published: November 2022

It is widely accepted that there are some common network patterns in the human brain. However, the existence of stable and strong functional connections in the human brain and whether they change in schizophrenia is still a question. By setting 1% connections with the smallest coefficient of variation, we found a widespread brain functional network (frame network) in healthy people(n = 380, two datasets from public databases). We then explored the alterations in a medicated group (60 subjects with schizophrenia vs 71 matched controls) and a drug-naive first-episode group (68 subjects with schizophrenia vs 45 matched controls). A linear support vector classifier (SVC) was constructed to distinguish patients and controls using the medicated patients’ frame network. We found most frame connections of healthy people had high strength, which were symmetrical and connected the left and right hemispheres. Conversely, significant differences in frame connections were observed in both patient groups, which were positively correlated with negative symptoms (mainly language dysfunction). Additionally, patients’ frame network were more left-lateralized, concentrating on the left frontal lobe, and was quite accurate at distinguishing medicated patients from controls (classifier accuracy was 78.63%, sensitivity was 86.67%, specificity was 76.06%, and the area under the curve (AUC) was 0.83). Furthermore, the results were repeated in the drug-naive set (accuracy was 84.96%, sensitivity was 85.29%, specificity was 88.89%, and AUC was 0.93). These findings indicate that the abnormal pattern of frame network in subjects with schizophrenia might provide new insights into the dysconnectivity in schizophrenia.
Creation and preclinical evaluation of genetically attenuated malaria parasites arresting growth late in the liver
Authors: Franke-Fayard Blandine , Marin-Mogollon Catherin , Geurten Fiona J. A. , Chevalley-Maurel Séverine , Ramesar Jai , Kroeze Hans , Baalbergen Els , Wessels Els , Baron Ludivine , Soulard Valérie , Martinson Thomas , Aleshnick Maya , Huijs Antonius T. G. , Subudhi Amit K. , Miyazaki Yukiko , Othman Ahmad Syibli , Kolli Surendra Kumar , Lamers Olivia A. C. , Roques Magali , Stanway Rebecca R. , Murphy Sean C. , Foquet Lander , Moita Diana , Mendes António M. , Prudêncio Miguel , Dechering Koen J. , Heussler Volker T. , Pain Arnab , Wilder Brandon K. , Roestenberg Meta , Janse Chris J.
Published: November 2022

Whole-sporozoite (WSp) malaria vaccines induce protective immune responses in animal malaria models and in humans. A recent clinical trial with a WSp vaccine comprising genetically attenuated parasites (GAP) which arrest growth early in the liver (PfSPZ-GA1), showed that GAPs can be safely administered to humans and immunogenicity is comparable to radiation-attenuated PfSPZ Vaccine. GAPs that arrest late in the liver stage (LA-GAP) have potential for increased potency as shown in rodent malaria models. Here we describe the generation of four putative P. falciparum LA-GAPs, generated by CRISPR/Cas9-mediated gene deletion. One out of four gene-deletion mutants produced sporozoites in sufficient numbers for further preclinical evaluation. This mutant, PfΔmei2, lacking the mei2-like RNA gene, showed late liver growth arrest in human liver-chimeric mice with human erythrocytes, absence of unwanted genetic alterations and sensitivity to antimalarial drugs. These features of PfΔmei2 make it a promising vaccine candidate, supporting further clinical evaluation. PfΔmei2 (GA2) has passed regulatory approval for safety and efficacy testing in humans based on the findings reported in this study.
Metabolomics profiling in acute liver transplant rejection in a pediatric population
Authors: Frediani Jennifer K. , Beyh Yara S. , Gupta Nitika , Westbrook Adrianna L. , Cleeton Rebecca , Cordero Maria , Hernandez Albert , Tran ViLinh , Jones Dean P. , Vos Miriam B.
Published: November 2022

Pediatric liver transplantation rejection affects 20% of children. Currently, liver biopsy, expensive and invasive, is the best method of diagnosis. Discovery and validation of clinical biomarkers from blood or other biospecimens would improve clinical care. For this study, stored plasma samples were utilized from two cross-sectional cohorts of liver transplant patients at Children’s Healthcare of Atlanta. High resolution metabolic profiling was completed using established methods. Children with (n = 18) or without (n = 25) acute cellular rejection were included in the analysis (n = 43 total). The mean age of these racially diverse cohorts ranged from 12.6 years in the rejection group and 13.6 years in the no rejection group. Linear regression provided 510 significantly differentiating metabolites between groups, and OPLS-DA showed 145 metabolites with VIP > 2. A total of 95 overlapping significant metabolites between OPLS-DA and linear regression analyses were detected. Pathway analysis (p < 0.05) showed bile acid biosynthesis and tryptophan metabolism as the top two differentiating pathways. Network analysis also identified tryptophan and clustered with liver enzymes and steroid use. We conclude metabolic profiling of plasma from children with acute liver transplant rejection demonstrates > 500 significant metabolites. This result suggests that development of a non-invasive biomarker-based test is possible for rejection screening.