bluuebunny/crossref_metadata_2025 huggingface dataset:
Developing genetic resources and genetic analysis of plant architecture-related traits in teosinte-introgressed maize populations
Authors: Adhikari Sneha , Joshi Anjali , Kumar Amarjeet , Singh Narendra Kumar , Jaiswal Jai Prakash , Jeena Anand Singh , Pant Usha
Published: October 2022

Teosinte, the wild progenitor of maize, has immense potential for providing unique traits and is more divergent compared to inbred lines and landraces. One hundred and sixty-nine teosinte-introgressed maize backcross inbred lines were developed to widen the genetic base of maize with predomestication alleles. The population was evaluated phenotypically and genotypic data of 76 SSR markers were used to map quantitative trait loci (QTLs) governing the targeted traits. Sixty-six QTLs were detected for eight plant architect-related traits that are spread over 10 different chromosomes with phenotypic variation ranging from 2.29 to 13.97%. Maximum three stable QTLs were recorded for days to anthesis (DA) followed by two for days to silking (DS), plant height (PH) and node bearing first ear (NBE). For rest of three traits namely flag leaf length (FLL), flag leaf width (FLW) and ears per plant (E/P) only one stable QTL was detected. Among the 16 common QTLs, the marker phi328178-linked QTL governed four characters (DA, DS, FLL, FLW) simultaneously, followed by umc1622-linked (ASI, FLW, E/P), umc2341-linked (DA, DS, NBE) and phi075-linked QTLs (ASI, PH, NBE) controlling three traits each. Remaining 12 QTLs controlled two characters. Molecular association between co-localized QTLs for different traits was also validated at the phenotypic level by significant correlation estimates. For eight studied traits, 53 superior lines were identified which along with parents (teosinte and maize inbred DI-103) were grouped into 12 clusters. Therefore, lines clustered independently can be combined to accumulate desirable traits for the improvement of maize.
Who is the civilian population? Ensuring IHL is implemented for the protection of the entirety of the civilian population – including persons with disabilities
Authors: Priddy Alice
Published: October 2022

Despite progress in recent years, including UN Security Council Resolution 2475 of 2019, there remains a significant gap in our awareness of the disability dynamics of armed conflict and the barriers that persons with disabilities experience in accessing the protections of international humanitarian law (IHL). This brief article will consider the protective purpose of IHL and the diversity of civilian populations, and, focussing on the principle of proportionality as an example, demonstrate how IHL must be interpreted, implemented and monitored in a manner that is inclusive and reflects the reality that civilian populations are diverse.
Nicht-invasive Therapieansätze bei akuten und chronischen Rückenschmerzen
Authors: Bomberg Hagen , Lorenzana David , Schlickeiser Jannis , Dünki Alexandro , Farshad Mazda , Eichenberger Urs
Published: October 2022

Zusammenfassung. Die Therapie von Rückenschmerzen, speziell die medikamentöse Schmerztherapie mit Opioiden, führt bei der behandelnden Ärztin/beim behandelnden Arzt oft zum Dilemma. Spezifische Rückenschmerzen werden durch gezielte Bildgebung diagnostiziert und operativ oder medikamentös erfolgreich therapiert. Im Gegensatz dazu können bei nicht-spezifischen Rückenschmerzen unbegründete Bildgebung, zweifelhafte Operationsindikationen und unkontrollierte Medikamentengabe die Schmerzen verstärken. Hier ist die Aufrechterhaltung der Aktivität und die Bewegungstherapie zentral für die Therapie. Beim Einsatz von Opioiden verhält es sich ähnlich. Opioide sind potente Medikamente zur kurzfristigen Schmerztherapie. Langzeitanwendung kann die Schmerzen verstärken und Störungen im Hormonhaushalt mit Einschränkungen der Lebensqualität und Libido bewirken. Ausserdem haben Opioide ein Gewöhnungs- und Suchtpotenzial. Eine Opioidtherapie, wenn überhaupt, sollte nur nach frustraner Nicht-Opioid-Therapie, zeitlich begrenzt (möglichst kürzer als vier Wochen) und nach klaren Richtlinien erfolgen.
Manganese Limitation of Phytoplankton Physiology and Productivity in the Southern Ocean
Authors: Hawco Nicholas J. , Tagliabue Alessandro , Twining Benjamin S.
Published: October 2022

Although iron and light are understood to regulate the Southern Ocean biological carbon pump, observations have also indicated a possible role for manganese. Low concentrations in Southern Ocean surface waters suggest manganese limitation is possible, but its spatial extent remains poorly constrained and direct manganese limitation of the marine carbon cycle has been neglected by ocean models. Here, using available observations, we develop a new global biogeochemical model and find that phytoplankton in over half of the Southern Ocean cannot attain maximal growth rates because of manganese deficiency. Manganese limitation is most extensive in austral spring and depends on phytoplankton traits related to the size of photosynthetic antennae and the inhibition of manganese uptake by high zinc concentrations in Antarctic waters. Importantly, manganese limitation expands under the increased iron supply of past glacial periods, reducing the response of the biological carbon pump. Overall, these model experiments describe a mosaic of controls on Southern Ocean productivity that emerge from the interplay of light, iron, manganese and zinc, shaping the evolution of Antarctic phytoplankton since the opening of the Drake Passage.
The Signature of Lithospheric Anisotropy at Post‐Subduction Continental Margins: New Insight From XKS Splitting Analysis in Northern Borneo
Authors: Bacon C. A. , Rawlinson N. , Pilia S. , Gilligan A. , Wehner D. , Cornwell D. G. , Tongkul F.
Published: October 2022

The relative paucity of recent post‐subduction environments globally has meant that, so far, little is known about tectonic processes that occur during and after subduction termination, as previously convergent tectonic plates adjust to the new stress regime. The region of Southeast Asia that now encompasses northern Borneo has been host to two sequential episodes of subduction—both now terminated—since the mid‐Paleogene. It is expected that these processes will have left signatures in the fabric of the upper mantle, which are manifest in the form of seismic anisotropy. We investigate the evidence for, and alignment of, anisotropic fabrics by measuring the splitting of a family of teleseismic shear phases. These observations provide a measure of the orientation of the effective anisotropic elastic tensor, in the form of the orientation of the fast shear‐wave polarization, ϕ, and add constraints on the strength of the anisotropic fabric, in the form of the delay time, δt. We observe two principal trends across northern Borneo that appear to be confined to the lithosphere. These patterns are likely related to tectonic processes associated with subduction, continental collision, and oceanic basin formation, events that can exert primary influence on the formation of post‐subduction settings.
Characteristics and Controlling Factors of Rapid Weakening of Tropical Cyclones After Reaching Their Intensity Peaks Over the Western North Pacific
Authors: Zhou Yanchen , Zhan Ruifen , Wang Yuqing , Wu Zhiwei , Chen Guanghua , Wang Lan
Published: October 2022

The sudden transition to rapid weakening immediately after a tropical cyclone (TC) reaches its intensity peak (hereafter TP‐RW) is a challenge to operational TC intensity forecasts, but the characteristics and the controlling factors of the TP‐RW have not been investigated so far. In this study, the main characteristics of the TP‐RW events over the western North Pacific (WNP) and the corresponding key controlling factors and their relative importance are analyzed and quantified. Results show that about 2.5 TP‐RW events occurred each year, which corresponds to about 10% of total TCs over the WNP during 1982–2018. The TP‐RW events occurred in all months but peaked in fall and were the most likely to occur for TCs with intensities between 90 and 145 kt. The sea surface temperature, the TC maximum potential intensity and translational speed, the environmental vertical wind shear and relative humidity are key to the TP‐RW. Four distinct clusters of the TP‐RW events are identified based on their tracks using the K‐means clustering algorithm. The relative contribution of each of the identified key factors to each cluster is quantified using the growth rate from the simplified dynamical system for TC intensity prediction developed by DeMaria. The reversal of the growth rate from positive to negative values is shown to be a good indicator of the TP‐RW processes. Different clusters are predominantly controlled by different key factors. The findings from this study can help better understand TC intensity changes and improve TC intensity forecasts for such kind of RW.
Climatological Significance of δD‐δ18O Line Slopes From Precipitation, Snow Pits, and Ice Cores at Summit, Greenland
Authors: Kopec Ben G. , Feng Xiahong , Osterberg Erich C. , Posmentier Eric S.
Published: October 2022

Hydrogen (δD) and oxygen (δ18O) isotopic ratios are strongly correlated in precipitation over time and space, defining the meteoric water line, and the slope of this δD‐δ18O relationship reflects covariations of deuterium excess (d‐excess) with δD or δ18O. This δD‐δ18O line provides a tool for inferring hydrologic processes from the evaporation source to condensation site. Here, we present δD‐δ18O relationships on seasonal and annual timescales for daily precipitation, snow pits, and a 15‐m ice core (Owen) at Summit, Greenland. Seasonally, precipitation δD‐δ18O slopes are less than 8 (summer = 7.70; winter = 7.77), while the annual slope is greater than 8 (8.27). We suggest that intra‐season slopes result primarily from Rayleigh distillation, which, under prevailing conditions, produces slopes less than 8. The summer line has a greater intercept (higher d‐excess) than the winter line. This separation causes annual slopes to be greater than seasonal ones. We attribute high summer d‐excess primarily to contributions of vapor sublimated from the Greenland Ice Sheet and other terrestrial sources. High sublimated moisture proportions result in a large separation between seasonal δD‐δ18O lines, and thus high annual slopes. Inter‐seasonal weighting of precipitation amount also influences annual slopes because slopes are weighed by the number of storms each season. Using snow pit measurements, we demonstrate that precipitation isotopic signals translate to the snowpack. We generate indices to determine Sublimation Proportion Index and Precipitation Weighting Index, and find that annual Owen core δD‐δ18O line slopes are significantly related to these indices, demonstrating that these factors are recorded in ice cores.
Structural Architecture and Deformation History of Tempe Terra, Mars
Authors: Orlov C. J. , Bramham E. K. , Thomas M. , Byrne P. K. , Piazolo S. , Mortimer E.
Published: October 2022

The structurally complex region of Tempe Terra, located in the northeast of the Tharsis Rise on Mars, preserves deformation related to the growth of Tharsis and lies along the trendline formed by the Tharsis Montes volcanoes. We characterize the spatiotemporal tectonic evolution of Tempe Terra based on comprehensive structural mapping. From this mapping, we identified 16 cross‐cutting fault sets and placed these in relative time order, based on a hybrid approach using cross‐cutting relationships and buffered crater counting. We are thus able to provide a broad framework for understanding the timing of development for the Tharsis Rise and Tharsis Montes axial trend (TMAT). Our work shows that Tempe Terra has experienced three distinct stages of tectonic activity from the Middle Noachian to the Late Hesperian. Stage 1 involved E–W extension followed by localized NE–SW extension, which produced local zones of N and NW faulting through the center and west of Tempe Terra in the Noachian. Stage 2 produced intense NE‐oriented faulting concentrated along the TMAT in the Early Hesperian as a result of a discrete period of NW–SE extension and local volcanism. Stage 3 involved NW–SE extension coinciding with Tharsis volcanic activity, which generated a regional fabric of ENE‐trending graben distributed across Tempe Terra from the Early to Late Hesperian. We observe an overall peak in tectonic activity in the Early Hesperian and find that Tharsis‐related extensional deformation in the form of NE‐oriented radial faulting did not start in Tempe Terra until this time.
Enlighten the non-illuminated region by phase segregation of mixed halide perovskites
Authors: Lv Yan , Zhang Junran , Chen Xiaolong , Wang Lin
Published: October 2022

The well-known ion migration in mixed halide perovskites has been intensely investigated within the area under uniform light illumination. Here, the authors demonstrate that the anion segregation in these materials is a nonlocal effect of which the ion redistribution may occur at a macroscopic or mesoscopic scale beyond.
Dynamic regulation of KIF15 phosphorylation and acetylation promotes focal adhesions disassembly in pancreatic cancer
Authors: He Zhiwei , Wang Jie , Xu Jian , Jiang Xueyi , Liu Xinyuan , Jiang Jianxin
Published: October 2022

Pancreatic cancer (PC) is prone to distant metastasis in the early stage, which is attributed to the strong migration ability of tumor cells. Focal adhesion turnover is essential for cancer cell metastasis, and the integrin recycling process is a key activation pathway for focal adhesion depolymerization. To identify the key motor protein involving in the integrin β1 recycling, we screened kinesin proteins involved in integrin β1 recycling using a kinesin family siRNA library and identified kinesin family 15 (KIF15) as a key regulator. KIF15 was upregulated in metastasis PC tissues and promoted PC cell migration and invasion. We identified KIF15 as a key component mediating integrin β1/FAK signaling that accelerated FA disassembly in a FAK-Y397-dependent manner. KIF15 recruited PI3K-C2α to promote integrin β1/FAK signaling and FA disassembly in a RAB11A-dependent manner. The C-terminal tail of KIF15 is required for the PI3K-C2α interaction and RAB11A activation. In addition, we also found that SIRT1-mediated acetylation of KIF15 is essential for KIF15 phosphorylation, which is the key activation event in motor protein function. Together, these findings indicate that KIF15 interacts with PI3K-C2α to promote FA turnover in PC cells by controlling the endosome recycling of integrin β1 in a SIRT1 acetylation modification-dependent manner, eventually promoting focal adhesions turnover and distant metastasis in PC.
Role of ferroptosis on tumor progression and immunotherapy
Authors: Gong Deting , Chen Mingjun , Wang Yuhan , Shi Juanjuan , Hou Yongzhong
Published: October 2022

Ferroptosis is triggered by intracellular iron leading to accumulation of lipid peroxidation consequent promotion of cell death. Cancer cell exhibits ability to evade ferroptosis by activation of antioxidant signaling pathways such as SLC7A11/GPX4 axis. In addition to transcriptional regulation on ferroptosis by NRF2, SREBP1, YAP, and p53, ferroptosis is modulated by ubiquitination or autophagic degradation. Moreover, zinc or Ca2+ could modulate ferroptosis by inducing lipid peroxidation and ferroptosis. Induction of ferroptosis enhances immune cell activity such as T cells or macrophages, which is associated with the release of DAMPs (damage-associated molecular patterns) and IFNγ. Therefore, combined immune checkpoint inhibitors with ferroptosis inducers effectively enhance antitumor immunotherapy, whereas induction of ferroptosis could impair T cell activity or survival, suggesting that rational combined therapy for cancer is essential. In this review, we discussed the regulatory role of ferroptosis on tumor progression and immunotherapy.
An MSH6 germline pathogenic variant p.Gly162Ter associated with Lynch syndrome
Authors: Vostrukhina Olga A. , Mirlina Elena D. , Khmelkova Darya N. , Butrovich Galina M. , Shakhmatova Alexandra D. , Kil Yury V. , Polyatskin Yliya L. , Artemyeva Anna S. , Gulyaev Alexey V. , Verbenko Valery N.
Published: October 2022

We identified a three-generation Russian family with Lynch syndrome with a novel germline variant of the MSH6 gene. An 84-year-old female was diagnosed with endometrial adenocarcinoma at the age of 49 years. Her son was diagnosed with colorectal tubular adenoma at the age of 32 years. A germline nonsense variant (c.484 G > T:p.Gly162Ter) in exon 3 of the MSH6 gene was revealed by whole-exome sequencing. Sanger sequencing confirmed the cosegregation of the MSH6 nonsense variant in family members.
Salience memories formed by value, novelty and aversiveness jointly shape object responses in the prefrontal cortex and basal ganglia
Authors: Ghazizadeh Ali , Hikosaka Okihide
Published: October 2022

Ecological fitness depends on maintaining object histories to guide future interactions. Recent evidence shows that value memory changes passive visual responses to objects in ventrolateral prefrontal cortex (vlPFC) and substantia nigra reticulata (SNr). However, it is not known whether this effect is limited to reward history and if not how cross-domain representations are organized within the same or different neural populations in this corticobasal circuitry. To address this issue, visual responses of the same neurons across appetitive, aversive and novelty domains were recorded in vlPFC and SNr. Results showed that changes in visual responses across domains happened in the same rather than separate populations and were related to salience rather than valence of objects. Furthermore, while SNr preferentially encoded outcome related salience memory, vlPFC encoded salience memory across all domains in a correlated fashion, consistent with its role as an information hub to guide behavior.
Subcellular localization of type IV pili regulates bacterial multicellular development
Authors: Ellison Courtney K. , Fei Chenyi , Dalia Triana N. , Wingreen Ned S. , Dalia Ankur B. , Shaevitz Joshua W. , Gitai Zemer
Published: October 2022

In mammals, subcellular protein localization of factors like planar cell polarity proteins is a key driver of the multicellular organization of tissues. Bacteria also form organized multicellular communities, but these patterns are largely thought to emerge from regulation of whole-cell processes like growth, motility, cell shape, and differentiation. Here we show that a unique intracellular patterning of appendages known as type IV pili (T4P) can drive multicellular development of complex bacterial communities. Specifically, dynamic T4P appendages localize in a line along the long axis of the cell in the bacterium Acinetobacter baylyi. This long-axis localization is regulated by a functionally divergent chemosensory Pil-Chp system, and an atypical T4P protein homologue (FimV) bridges Pil-Chp signaling and T4P positioning. We further demonstrate through modeling and empirical approaches that subcellular T4P localization controls how individual cells interact with one another, independently of T4P dynamics, with different patterns of localization giving rise to distinct multicellular architectures. Our results reveal how subcellular patterning of single cells regulates the development of multicellular bacterial communities.
Functional and metabolic alterations of gut microbiota in children with new-onset type 1 diabetes
Authors: Yuan Xiaoxiao , Wang Ruirui , Han Bing , Sun ChengJun , Chen Ruimin , Wei Haiyan , Chen Linqi , Du Hongwei , Li Guimei , Yang Yu , Chen Xiaojuan , Cui Lanwei , Xu Zhenran , Fu Junfen , Wu Jin , Gu Wei , Chen Zhihong , Fang Xin , Yang Hongxiu , Su Zhe , Wu Jing , Li Qiuyue , Zhang Miaoying , Zhou Yufeng , Zhang Lei , Ji Guang , Luo Feihong
Published: October 2022

Gut dysbiosis has been linked to type 1 diabetes (T1D); however, microbial capacity in T1D remains unclear. Here, we integratively profiled gut microbial functional and metabolic alterations in children with new-onset T1D in independent cohorts and investigated the underlying mechanisms. In T1D, the microbiota was characterized by decreased butyrate production and bile acid metabolism and increased lipopolysaccharide biosynthesis at the species, gene, and metabolite levels. The combination of 18 bacterial species and fecal metabolites provided excellently discriminatory power for T1D. Gut microbiota from children with T1D induced elevated fasting glucose levels and declined insulin sensitivity in antibiotic-treated mice. In streptozotocin-induced T1D mice, butyrate and lipopolysaccharide exerted protective and destructive effects on islet structure and function, respectively. Lipopolysaccharide aggravated the pancreatic inflammatory response, while butyrate activated Insulin1 and Insulin2 gene expression. Our study revealed perturbed microbial functional and metabolic traits in T1D, providing potential avenues for microbiome-based prevention and intervention for T1D.
Common evolutionary origin of acoustic communication in choanate vertebrates
Authors: Jorgewich-Cohen Gabriel , Townsend Simon William , Padovese Linilson Rodrigues , Klein Nicole , Praschag Peter , Ferrara Camila R. , Ettmar Stephan , Menezes Sabrina , Varani Arthur Pinatti , Serano Jaren , Sánchez-Villagra Marcelo R.
Published: October 2022

Acoustic communication, broadly distributed along the vertebrate phylogeny, plays a fundamental role in parental care, mate attraction and various other behaviours. Despite its importance, comparatively less is known about the evolutionary roots of acoustic communication. Phylogenetic comparative analyses can provide insights into the deep time evolutionary origin of acoustic communication, but they are often plagued by missing data from key species. Here we present evidence for 53 species of four major clades (turtles, tuatara, caecilian and lungfish) in the form of vocal recordings and contextual behavioural information accompanying sound production. This and a broad literature-based dataset evidence acoustic abilities in several groups previously considered non-vocal. Critically, phylogenetic analyses encompassing 1800 species of choanate vertebrates reconstructs acoustic communication as a homologous trait, and suggests that it is at least as old as the last common ancestor of all choanate vertebrates, that lived approx. 407 million years before present.
Revealing β-TrCP activity dynamics in live cells with a genetically encoded biosensor
Authors: Paul Debasish , Kales Stephen C. , Cornwell James A. , Afifi Marwa M. , Rai Ganesha , Zakharov Alexey , Simeonov Anton , Cappell Steven D.
Published: October 2022

The F-box protein beta-transducin repeat containing protein (β-TrCP) acts as a substrate adapter for the SCF E3 ubiquitin ligase complex, plays a crucial role in cell physiology, and is often deregulated in many types of cancers. Here, we develop a fluorescent biosensor to quantitatively measure β-TrCP activity in live, single cells in real-time. We find β-TrCP remains constitutively active throughout the cell cycle and functions to maintain discreet steady-state levels of its substrates. We find no correlation between expression levels of β-TrCP and β-TrCP activity, indicating post-transcriptional regulation. A high throughput screen of small-molecules using our reporter identifies receptor-tyrosine kinase signaling as a key axis for regulating β-TrCP activity by inhibiting binding between β-TrCP and the core SCF complex. Our study introduces a method to monitor β-TrCP activity in live cells and identifies a key signaling network that regulates β-TrCP activity throughout the cell cycle.
Eya-controlled affinity between cell lineages drives tissue self-organization during Drosophila oogenesis
Authors: Weichselberger Vanessa , Dondl Patrick , Classen Anne-Kathrin
Published: October 2022

Cooperative morphogenesis of cell lineages underlies the development of functional units and organs. To study mechanisms driving the coordination of lineages, we investigated soma-germline interactions during oogenesis. From invertebrates to vertebrates, oocytes develop as part of a germline cyst that consists of the oocyte itself and so-called nurse cells, which feed the oocyte and are eventually removed. The enveloping somatic cells specialize to facilitate either oocyte maturation or nurse cell removal, which makes it essential to establish the right match between germline and somatic cells. We uncover that the transcriptional regulator Eya, expressed in the somatic lineage, controls bilateral cell–cell affinity between germline and somatic cells in Drosophila oogenesis. Employing functional studies and mathematical modelling, we show that differential affinity and the resulting forces drive somatic cell redistribution over the germline surface and control oocyte growth to match oocyte and nurse cells with their respective somatic cells. Thus, our data demonstrate that differential affinity between cell lineages is sufficient to drive the complex assembly of inter-lineage functional units and underlies tissue self-organization during Drosophila oogenesis.
Clonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer
Authors: Martins Filipe Correia , Couturier Dominique-Laurent , de Santiago Ines , Sauer Carolin Margarethe , Vias Maria , Angelova Mihaela , Sanders Deborah , Piskorz Anna , Hall James , Hosking Karen , Amirthanayagam Anumithra , Cosulich Sabina , Carnevalli Larissa , Davies Barry , Watkins Thomas B. K. , Funingana Ionut G. , Bolton Helen , Haldar Krishnayan , Latimer John , Baldwin Peter , Crawford Robin , Eldridge Matthew , Basu Bristi , Jimenez-Linan Mercedes , Mcpherson Andrew W. , McGranahan Nicholas , Litchfield Kevin , Shah Sohrab P. , McNeish Iain , Caldas Carlos , Evan Gerard , Swanton Charles , Brenton James D.
Published: October 2022

Chromosomal instability is a major challenge to patient stratification and targeted drug development for high-grade serous ovarian carcinoma (HGSOC). Here we show that somatic copy number alterations (SCNAs) in frequently amplified HGSOC cancer genes significantly correlate with gene expression and methylation status. We identify five prevalent clonal driver SCNAs (chromosomal amplifications encompassing MYC, PIK3CA, CCNE1, KRAS and TERT) from multi-regional HGSOC data and reason that their strong selection should prioritise them as key biomarkers for targeted therapies. We use primary HGSOC spheroid models to test interactions between in vitro targeted therapy and SCNAs. MYC chromosomal copy number is associated with in-vitro and clinical response to paclitaxel and in-vitro response to mTORC1/2 inhibition. Activation of the mTOR survival pathway in the context of MYC-amplified HGSOC is statistically associated with increased prevalence of SCNAs in genes from the PI3K pathway. Co-occurrence of amplifications in MYC and genes from the PI3K pathway is independently observed in squamous lung cancer and triple negative breast cancer. In this work, we show that identifying co-occurrence of clonal driver SCNA genes could be used to tailor therapeutics for precision medicine.
Optogenetic-controlled immunotherapeutic designer cells for post-surgical cancer immunotherapy
Authors: Yu Yuanhuan , Wu Xin , Wang Meiyan , Liu Wenjing , Zhang Li , Zhang Ying , Hu Zhilin , Zhou Xuantong , Jiang Wenzheng , Zou Qiang , Cai Fengfeng , Ye Haifeng
Published: October 2022

Surgical resection is the main treatment option for most solid tumors, yet cancer recurrence after surgical resection remains a significant challenge in cancer therapy. Recent advances in cancer immunotherapy are enabling radical cures for many tumor patients, but these technologies remain challenging to apply because of side effects related to uncontrollable immune system activation. Here, we develop far-red light-controlled immunomodulatory engineered cells (FLICs) that we load into a hydrogel scaffold, enabling the precise optogenetic control of cytokines release (IFN-β, TNF-α, and IL-12) upon illumination. Experiments with a B16F10 melanoma resection mouse model show that FLICs-loaded hydrogel implants placed at the surgical wound site achieve sustainable release of immunomodulatory cytokines, leading to prevention of tumor recurrence and increased animal survival. Moreover, the FLICs-loaded hydrogel implants elicit long-term immunological memory that prevents against tumor recurrence. Our findings illustrate that this optogenetic perioperative immunotherapy with FLICs-loaded hydrogel implants offers a safe treatment option for solid tumors based on activating host innate and adaptive immune systems to inhibit tumor recurrence after surgery. Beyond extending the optogenetics toolbox for immunotherapy, we envision that our optogenetic-controlled living cell factory platform could be deployed for other biomedical contexts requiring precision induction of bio-therapeutic dosage.
Revealing the role of ionic liquids in promoting fuel cell catalysts reactivity and durability
Authors: Avid Arezoo , Ochoa Jesus López , Huang Ying , Liu Yuanchao , Atanassov Plamen , Zenyuk Iryna V.
Published: October 2022

Ionic liquids (ILs) have shown to be promising additives to the catalyst layer to enhance oxygen reduction reaction in polymer electrolyte fuel cells. However, fundamental understanding of their role in complex catalyst layers in practically relevant membrane electrode assembly environment is needed for rational design of highly durable and active platinum-based catalysts. Here we explore three imidazolium-derived ionic liquids, selected for their high proton conductivity and oxygen solubility, and incorporate them into high surface area carbon black support. Further, we establish a correlation between the physical properties and electrochemical performance of the ionic liquid-modified catalysts by providing direct evidence of ionic liquids role in altering hydrophilic/hydrophobic interactions within the catalyst layer interface. The resulting catalyst with optimized interface design achieved a high mass activity of 347 A g−1Pt at 0.9 V under H2/O2, power density of 0.909 W cm−2 under H2/air and 1.5 bar, and had only 0.11 V potential decrease at 0.8 A cm−2 after 30 k accelerated stress test cycles. This performance stems from substantial enhancement in Pt utilization, which is buried inside the mesopores and is now accessible due to ILs addition.
Polerovirus N-terminal readthrough domain structures reveal molecular strategies for mitigating virus transmission by aphids
Authors: Schiltz Carl J. , Wilson Jennifer R. , Hosford Christopher J. , Adams Myfanwy C. , Preising Stephanie E. , DeBlasio Stacy L. , MacLeod Hannah J. , Van Eck Joyce , Heck Michelle L. , Chappie Joshua S.
Published: October 2022

Poleroviruses, enamoviruses, and luteoviruses are icosahedral, positive sense RNA viruses that cause economically important diseases in food and fiber crops. They are transmitted by phloem-feeding aphids in a circulative manner that involves the movement across and within insect tissues. The N-terminal portion of the viral readthrough domain (NRTD) has been implicated as a key determinant of aphid transmission in each of these genera. Here, we report crystal structures of the NRTDs from the poleroviruses turnip yellow virus (TuYV) and potato leafroll virus (PLRV) at 1.53-Å and 2.22-Å resolution, respectively. These adopt a two-domain arrangement with a unique interdigitated topology and form highly conserved dimers that are stabilized by a C-terminal peptide that is critical for proper folding. We demonstrate that the PLRV NRTD can act as an inhibitor of virus transmission and identify NRTD mutant variants that are lethal to aphids. Sequence conservation argues that enamovirus and luteovirus NRTDs will follow the same structural blueprint, which affords a biological approach to block the spread of these agricultural pathogens in a generalizable manner.
Subcellular spatial transcriptomics identifies three mechanistically different classes of localizing RNAs
Authors: Cassella Lucia , Ephrussi Anne
Published: October 2022

Intracellular RNA localization is a widespread and dynamic phenomenon that compartmentalizes gene expression and contributes to the functional polarization of cells. Thus far, mechanisms of RNA localization identified in Drosophila have been based on a few RNAs in different tissues, and a comprehensive mechanistic analysis of RNA localization in a single tissue is lacking. Here, by subcellular spatial transcriptomics we identify RNAs localized in the apical and basal domains of the columnar follicular epithelium (FE) and we analyze the mechanisms mediating their localization. Whereas the dynein/BicD/Egl machinery controls apical RNA localization, basally-targeted RNAs require kinesin-1 to overcome a default dynein-mediated transport. Moreover, a non-canonical, translation- and dynein-dependent mechanism mediates apical localization of a subgroup of dynein-activating adaptor-encoding RNAs (BicD, Bsg25D, hook). Altogether, our study identifies at least three mechanisms underlying RNA localization in the FE, and suggests a possible link between RNA localization and dynein/dynactin/adaptor complex formation in vivo.
Cone opponent functional domains in primary visual cortex combine signals for color appearance mechanisms
Authors: Li Peichao , Garg Anupam K. , Zhang Li A. , Rashid Mohammad S. , Callaway Edward M.
Published: October 2022

Studies of color perception have led to mechanistic models of how cone-opponent signals from retinal ganglion cells are integrated to generate color appearance. But it is unknown how this hypothesized integration occurs in the brain. Here we show that cone-opponent signals transmitted from retina to primary visual cortex (V1) are integrated through highly organized circuits within V1 to implement the color opponent interactions required for color appearance. Combining intrinsic signal optical imaging (ISI) and 2-photon calcium imaging (2PCI) at single cell resolution, we demonstrate cone-opponent functional domains (COFDs) that combine L/M cone-opponent and S/L + M cone-opponent signals following the rules predicted from psychophysical studies of color perception. These give rise to an orderly organization of hue preferences of the neurons within the COFDs and the generation of hue “pinwheels”. Thus, spatially organized neural circuits mediate an orderly transition from cone-opponency to color appearance that begins in V1.
Deciphering the atomic-scale structural origin for large dynamic electromechanical response in lead-free Bi0.5Na0.5TiO3-based relaxor ferroelectrics
Authors: Yin Jie , Shi Xiaoming , Tao Hong , Tan Zhi , Lv Xiang , Ding Xiangdong , Sun Jun , Zhang Yang , Zhang Xingmin , Yao Kui , Zhu Jianguo , Huang Houbing , Wu Haijun , Zhang Shujun , Wu Jiagang
Published: October 2022

Despite the extraordinary electromechanical properties of relaxor ferroelectrics, correlating their properties to underlying atomic-scale structures remains a decisive challenge for these “mess” systems. Here, taking the lead-free relaxor ferroelectric Bi0.5Na0.5TiO3-based system as an example, we decipher the atomic-scale structure and its relationship to the polar structure evolution and large dynamic electromechanical response, using the direct atomic-scale point-by-point correlation analysis. With judicious chemical modification, we demonstrate the increased defect concentration is the main driving force for deviating polarizations with high-angle walls, leading to the increased random field. Meanwhile, the main driving force for deviating polarizations with low-angle walls changes from the anti-phase oxygen octahedral tilting to the multidirectional A-O displacement, leading to the decreased anisotropy field. Benefiting from the competitive and synergetic equilibrium of anisotropic field versus random field, the facilitated polarization rotation and extension versus facilitated domain switching are identified to be responsible for the giant electromechanical response. These observations lay a foundation for understanding the “composition-structure-property” relationships in relaxor ferroelectric systems, guiding the design of functional materials for electromechanical applications.
Global thermal spring distribution and relationship to endogenous and exogenous factors
Authors: Tamburello G. , Chiodini G. , Ciotoli G. , Procesi M. , Rouwet D. , Sandri L. , Carbonara N. , Masciantonio C.
Published: October 2022

Here we present digitization and analysis of the thermal springs of the world dataset compiled by Gerald Ashley Waring in 1965 into a collection of analog maps. We obtain the geographic coordinates of ~6,000 geothermal spring areas, including complementary data (e.g., temperature, total dissolved solids, flow rate), making them available in electronic format. Using temperature and flow rate, we derive the heat discharged from 1483 thermal spring areas (between ~10−5 and ~103 MW, with a median value of ~0.5 MW and ~8300 MW in total). We integrate this data set with other global data sets to study the relationship between thermalism and endogenous and exogenous factors with a supervised machine learning algorithm. This analysis confirms a dominant role of the terrestrial heat flow, topography, volcanism and extensional tectonics. This data set offers new insights and will boost future studies in geothermal energy exploration.
Crystal structure of the Na+/H+ antiporter NhaA at active pH reveals the mechanistic basis for pH sensing
Authors: Winkelmann Iven , Uzdavinys Povilas , Kenney Ian M. , Brock Joseph , Meier Pascal F. , Wagner Lina-Marie , Gabriel Florian , Jung Sukkyeong , Matsuoka Rei , von Ballmoos Christoph , Beckstein Oliver , Drew David
Published: October 2022

The strict exchange of protons for sodium ions across cell membranes by Na+/H+exchangers is a fundamental mechanism for cell homeostasis. At active pH, Na+/H+exchange can be modelled as competition between H+and Na+to an ion-binding site, harbouring either one or two aspartic-acid residues. Nevertheless, extensive analysis on the model Na+/H+antiporter NhaA fromEscherichia coli, has shown that residues on the cytoplasmic surface, termed the pH sensor, shifts the pH at which NhaA becomes active. It was unclear how to incorporate the pH senor model into an alternating-access mechanism based on the NhaA structure at inactive pH 4. Here, we report the crystal structure of NhaA at active pH 6.5, and to an improved resolution of 2.2 Å. We show that at pH 6.5, residues in the pH sensor rearrange to form new salt-bridge interactions involving key histidine residues that widen the inward-facing cavity. What we now refer to as a pH gate, triggers a conformational change that enables water and Na+to access the ion-binding site, as supported by molecular dynamics (MD) simulations. Our work highlights a unique, channel-like switch prior to substrate translocation in a secondary-active transporter.
Dual interfacial engineering of a Chevrel phase electrode material for stable hydrogen evolution at 2500 mA cm−2
Authors: Liu Heming , Xie Ruikuan , Luo Yuting , Cui Zhicheng , Yu Qiangmin , Gao Zhiqiang , Zhang Zhiyuan , Yang Fengning , Kang Xin , Ge Shiyu , Li Shaohai , Gao Xuefeng , Chai Guoliang , Liu Le , Liu Bilu
Published: October 2022

Constructing stable electrodes which function over long timescales at large current density is essential for the industrial realization and implementation of water electrolysis. However, rapid gas bubble detachment at large current density usually results in peeling-off of electrocatalysts and performance degradation, especially for long term operations. Here we construct a mechanically-stable, all-metal, and highly active CuMo6S8/Cu electrode by in-situ reaction between MoS2 and Cu. The Chevrel phase electrode exhibits strong binding at the electrocatalyst-support interface with weak adhesion at electrocatalyst-bubble interface, in addition to fast hydrogen evolution and charge transfer kinetics. These features facilitate the achievement of large current density of 2500 mA cm−2 at a small overpotential of 334 mV which operate stably at 2500 mA cm−2 for over 100 h. In-situ total internal reflection imaging at micrometer level and mechanical tests disclose the relationships of two interfacial forces and performance of electrocatalysts. This dual interfacial engineering strategy can be extended to construct stable and high-performance electrodes for other gas-involving reactions.
Electrically regulating nonlinear optical limiting of metal-organic framework film
Authors: Ma Zhi-Zhou , Li Qiao-Hong , Wang Zirui , Gu Zhi-Gang , Zhang Jian
Published: October 2022

Regulating nonlinear optical (NLO) property of metal−organic frameworks (MOFs) is of pronounced significance for their scientific research and practical application, but the regulation through external stimuli is still a challenging task. Here we prepare and electrically control the nonlinear optical regulation of conductive MOFs Cu-HHTP films with [001]- (Cu-HHTP[001]) and [100]-orientations (Cu-HHTP[100]). Z-scan results show that the nonlinear absorption coefficient (β) of Cu-HHTP[001] film (7.60 × 10−6 m/W) is much higher than that of Cu-HHTP[100] film (0.84 × 10−6 m/W) at 0 V and the β of Cu-HHTP[001] and Cu-HHTP[100] films gradually increase to 3.84 × 10−5 and 1.71 × 10−6 m/W at 10 V by increasing the applied voltage, respectively. Due to 2D Cu-HHTP having anisotropy of charge transfer in different orientations, the NLO of MOFs film can be dependent on their growth orientations and improved by tuning the electrical field. This study provides more avenues for the regulation and NLO applications of MOFs.
HiFi metagenomic sequencing enables assembly of accurate and complete genomes from human gut microbiota
Authors: Kim Chan Yeong , Ma Junyeong , Lee Insuk
Published: October 2022

Advances in metagenomic assembly have led to the discovery of genomes belonging to uncultured microorganisms. Metagenome-assembled genomes (MAGs) often suffer from fragmentation and chimerism. Recently, 20 complete MAGs (cMAGs) have been assembled from Oxford Nanopore long-read sequencing of 13 human fecal samples, but with low nucleotide accuracy. Here, we report 102 cMAGs obtained by Pacific Biosciences (PacBio) high-accuracy long-read (HiFi) metagenomic sequencing of five human fecal samples, whose initial circular contigs were selected for complete prokaryotic genomes using our bioinformatics workflow. Nucleotide accuracy of the final cMAGs was as high as that of Illumina sequencing. The cMAGs could exceed 6 Mbp and included complete genomes of diverse taxa, including entirely uncultured RF39 and TANB77 orders. Moreover, cMAGs revealed that regions hard to assemble by short-read sequencing comprised mostly genomic islands and rRNAs. HiFi metagenomic sequencing will facilitate cataloging accurate and complete genomes from complex microbial communities, including uncultured species.
Rescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome
Authors: Fulton Sasha L. , Wenderski Wendy , Lepack Ashley E. , Eagle Andrew L. , Fanutza Tomas , Bastle Ryan M. , Ramakrishnan Aarthi , Hays Emma C. , Neal Arianna , Bendl Jaroslav , Farrelly Lorna A. , Al-Kachak Amni , Lyu Yang , Cetin Bulent , Chan Jennifer C. , Tran Tina N. , Neve Rachael L. , Roper Randall J. , Brennand Kristen J. , Roussos Panos , Schimenti John C. , Friedman Allyson K. , Shen Li , Blitzer Robert D. , Robison Alfred J. , Crabtree Gerald R. , Maze Ian
Published: October 2022

With an incidence of ~1 in 800 births, Down syndrome (DS) is the most common chromosomal condition linked to intellectual disability worldwide. While the genetic basis of DS has been identified as a triplication of chromosome 21 (HSA21), the genes encoded from HSA21 that directly contribute to cognitive deficits remain incompletely understood. Here, we found that the HSA21-encoded chromatin effector, BRWD1, was upregulated in neurons derived from iPS cells from an individual with Down syndrome and brain of trisomic mice. We showed that selective copy number restoration of Brwd1 in trisomic animals rescued deficits in hippocampal LTP, cognition and gene expression. We demonstrated that Brwd1 tightly binds the BAF chromatin remodeling complex, and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescued aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings establish BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes.
METTL3 acetylation impedes cancer metastasis via fine-tuning its nuclear and cytosolic functions
Authors: Li Yuanpei , He Xiaoniu , Lu Xiao , Gong Zhicheng , Li Qing , Zhang Lei , Yang Ronghui , Wu Chengyi , Huang Jialiang , Ding Jiancheng , He Yaohui , Liu Wen , Chen Ceshi , Cao Bin , Zhou Dawang , Shi Yufeng , Chen Juxiang , Wang Chuangui , Zhang Shengping , Zhang Jian , Ye Jing , You Han
Published: October 2022

The methyltransferase like 3 (METTL3) has been generally recognized as a nuclear protein bearing oncogenic properties. We find predominantly cytoplasmic METTL3 expression inversely correlates with node metastasis in human cancers. It remains unclear if nuclear METTL3 is functionally distinct from cytosolic METTL3 in driving tumorigenesis and, if any, how tumor cells sense oncogenic insults to coordinate METTL3 functions within these intracellular compartments. Here, we report an acetylation-dependent regulation of METTL3 localization that impacts on metastatic dissemination. We identify an IL-6-dependent positive feedback axis to facilitate nuclear METTL3 functions, eliciting breast cancer metastasis. IL-6, whose mRNA transcript is subjected to METTL3-mediated m6A modification, promotes METTL3 deacetylation and nuclear translocation, thereby inducing global m6A abundance. This deacetylation-mediated nuclear shift of METTL3 can be counterbalanced by SIRT1 inhibition, a process that is further enforced by aspirin treatment, leading to ablated lung metastasis via impaired m6A methylation. Intriguingly, acetylation-mimetic METTL3 mutant reconstitution results in enhanced translation and compromised metastatic potential. Our study identifies an acetylation-dependent regulatory mechanism determining the subcellular localization of METTL3, which may provide mechanistic clues for developing therapeutic strategies to combat breast cancer metastasis.
Comparison of COPD primary care in England, Scotland, Wales, and Northern Ireland
Authors: Stone Philip W. , Hickman Katherine , Holmes Steve , Feary Johanna R. , Quint Jennifer K.
Published: October 2022

Currently the National Asthma and COPD audit programme (NACAP) only undertakes audit of COPD primary care in Wales due to its near complete data coverage. We aimed to determine if the quality of COPD primary care in the other UK nations is comparable with Wales. We found that English, Scottish, and Northern Irish practices were significantly worse than Welsh practices at recording coded lung function parameters used in COPD diagnosis (ORs: 0.51 [0.43–0.59], 0.29 [0.23–0.36], 0.42 [0.31–0.58], respectively) and referring appropriate patients for pulmonary rehabilitation (ORs: 0.10 [0.09–0.11], 0.12 [0.11–0.14], 0.22 [0.19–0.25], respectively). Completing national audits of primary care in Wales only may have led to improvements in care, or at least improvements in the recording of care in Wales that are not occurring elsewhere in the UK. This highlights the potential importance of audit in improving care quality and accurate recording of that care.