bluuebunny/crossref_metadata_2025_split huggingface dataset:
ANRIL promotes the regulation of colorectal cancer on lymphatic endothelial cells via VEGF-C and is the key target for Pien Tze Huang to inhibit cancer metastasis
Authors: Huang Bin , Lu Yao , Ni Zhuona , Liu Jinhong , He Yanbin , An Honglin , Ye Feimin , Shen Jiayu , Lin Minghe , Chen Yong , Lin Jiumao 
Published: June 2023

AbstractlncRNA ANRIL is an oncogene, however the role of ANRIL in the regulation of colorectal cancer on human lymphatic endothelial cells (HLECs) is remain elusive. Pien Tze Huang (PZH, PTH) a Tradition Chinese Medicine (TCM) as an adjunctive medication could inhibit the cancer metastasis, however the mechanism still uncovering. We used network pharmacology, subcutaneous and orthotopic transplanted colorectal tumors models to determine the effect of PZH on tumor metastasis. Differential expressions of ANRIL in colorectal cancer cells, and stimulating the regulation of cancer cells on HLECs by culturing HLECs with cancer cells’ supernatants. Network pharmacology, transcriptomics, and rescue experiments were carried out to verify key targets of PZH. We found PZH interfered with 32.2% of disease genes and 76.7% of pathways, and inhibited the growth of colorectal tumors, liver metastasis, and the expression of ANRIL. The overexpression of ANRIL promoted the regulation of cancer cells on HLECs, leading to lymphangiogenesis, via upregulated VEGF-C secretion, and alleviated the effect of PZH on inhibiting the regulation of cancer cells on HLECs. Transcriptomic, network pharmacology and rescue experiments show that PI3K/AKT pathway is the most important pathway for PZH to affect tumor metastasis via ANRIL. In conclusion, PZH inhibits the regulation of colorectal cancer on HLECs to alleviate tumor lymphangiogenesis and metastasis by downregulating ANRIL dependent PI3K/AKT/VEGF-C pathway.
TMEM11 regulates cardiomyocyte proliferation and cardiac repair via METTL1-mediated m7G methylation of ATF5 mRNA
Authors: Chen Xin-Zhe , Li Xin-Min , Xu Shi-Jun , Hu Shen , Wang Tao , Li Rui-Feng , Liu Cui-Yun , Xue Jun-Qiang , Zhou Lu-Yu , Wang Yun-Hong , Li Pei-Feng , Wang Kun 
Published: June 2023

AbstractThe mitochondrial transmembrane (TMEM) protein family has several essential physiological functions. However, its roles in cardiomyocyte proliferation and cardiac regeneration remain unclear. Here, we detected that TMEM11 inhibits cardiomyocyte proliferation and cardiac regeneration in vitro. TMEM11 deletion enhanced cardiomyocyte proliferation and restored heart function after myocardial injury. In contrast, TMEM11-overexpression inhibited neonatal cardiomyocyte proliferation and regeneration in mouse hearts. TMEM11 directly interacted with METTL1 and enhanced m7G methylation of Atf5 mRNA, thereby increasing ATF5 expression. A TMEM11-dependent increase in ATF5 promoted the transcription of Inca1, an inhibitor of cyclin-dependent kinase interacting with cyclin A1, which suppressed cardiomyocyte proliferation. Hence, our findings revealed that TMEM11-mediated m7G methylation is involved in the regulation of cardiomyocyte proliferation, and targeting the TMEM11-METTL1-ATF5-INCA1 axis may serve as a novel therapeutic strategy for promoting cardiac repair and regeneration.
Faster sorting algorithms discovered using deep reinforcement learning
Authors: Mankowitz Daniel J. , Michi Andrea , Zhernov Anton , Gelmi Marco , Selvi Marco , Paduraru Cosmin , Leurent Edouard , Iqbal Shariq , Lespiau Jean-Baptiste , Ahern Alex , Köppe Thomas , Millikin Kevin , Gaffney Stephen , Elster Sophie , Broshear Jackson , Gamble Chris , Milan Kieran , Tung Robert , Hwang Minjae , Cemgil Taylan , Barekatain Mohammadamin , Li Yujia , Mandhane Amol , Hubert Thomas , Schrittwieser Julian , Hassabis Demis , Kohli Pushmeet , Riedmiller Martin , Vinyals Oriol , Silver David 
Published: June 2023

AbstractFundamental algorithms such as sorting or hashing are used trillions of times on any given day1. As demand for computation grows, it has become critical for these algorithms to be as performant as possible. Whereas remarkable progress has been achieved in the past2, making further improvements on the efficiency of these routines has proved challenging for both human scientists and computational approaches. Here we show how artificial intelligence can go beyond the current state of the art by discovering hitherto unknown routines. To realize this, we formulated the task of finding a better sorting routine as a single-player game. We then trained a new deep reinforcement learning agent, AlphaDev, to play this game. AlphaDev discovered small sorting algorithms from scratch that outperformed previously known human benchmarks. These algorithms have been integrated into the LLVM standard C++ sort library3. This change to this part of the sort library represents the replacement of a component with an algorithm that has been automatically discovered using reinforcement learning. We also present results in extra domains, showcasing the generality of the approach.
Chiral phonons in quartz probed by X-rays
Authors: Ueda Hiroki , García-Fernández Mirian , Agrestini Stefano , Romao Carl P. , van den Brink Jeroen , Spaldin Nicola A. , Zhou Ke-Jin , Staub Urs 
Published: June 2023

AbstractThe concept of chirality is of great relevance in nature, from chiral molecules such as sugar to parity transformations in particle physics. In condensed matter physics, recent studies have demonstrated chiral fermions and their relevance in emergent phenomena closely related to topology1–3. The experimental verification of chiral phonons (bosons) remains challenging, however, despite their expected strong impact on fundamental physical properties4–6. Here we show experimental proof of chiral phonons using resonant inelastic X-ray scattering with circularly polarized X-rays. Using the prototypical chiral material quartz, we demonstrate that circularly polarized X-rays, which are intrinsically chiral, couple to chiral phonons at specific positions in reciprocal space, allowing us to determine the chiral dispersion of the lattice modes. Our experimental proof of chiral phonons demonstrates a new degree of freedom in condensed matter that is both of fundamental importance and opens the door to exploration of new emergent phenomena based on chiral bosons.
A cytosolic surveillance mechanism activates the mitochondrial UPR
Authors: Sutandy F. X. Reymond , Gößner Ines , Tascher Georg , Münch Christian 
Published: June 2023

AbstractThe mitochondrial unfolded protein response (UPRmt) is essential to safeguard mitochondria from proteotoxic damage by activating a dedicated transcriptional response in the nucleus to restore proteostasis1,2. Yet, it remains unclear how the information on mitochondria misfolding stress (MMS) is signalled to the nucleus as part of the human UPRmt (refs. 3,4). Here, we show that UPRmt signalling is driven by the release of two individual signals in the cytosol—mitochondrial reactive oxygen species (mtROS) and accumulation of mitochondrial protein precursors in the cytosol (c-mtProt). Combining proteomics and genetic approaches, we identified that MMS causes the release of mtROS into the cytosol. In parallel, MMS leads to mitochondrial protein import defects causing c-mtProt accumulation. Both signals integrate to activate the UPRmt; released mtROS oxidize the cytosolic HSP40 protein DNAJA1, which leads to enhanced recruitment of cytosolic HSP70 to c-mtProt. Consequently, HSP70 releases HSF1, which translocates to the nucleus and activates transcription of UPRmt genes. Together, we identify a highly controlled cytosolic surveillance mechanism that integrates independent mitochondrial stress signals to initiate the UPRmt. These observations reveal a link between mitochondrial and cytosolic proteostasis and provide molecular insight into UPRmt signalling in human cells.
Ultraviolet radiation shapes dendritic cell leukaemia transformation in the skin
Authors: Griffin Gabriel K. , Booth Christopher A. G. , Togami Katsuhiro , Chung Sun Sook , Ssozi Daniel , Verga Julia A. , Bouyssou Juliette M. , Lee Yoke Seng , Shanmugam Vignesh , Hornick Jason L. , LeBoeuf Nicole R. , Morgan Elizabeth A. , Bernstein Bradley E. , Hovestadt Volker , van Galen Peter , Lane Andrew A. 
Published: June 2023

AbstractTumours most often arise from progression of precursor clones within a single anatomical niche. In the bone marrow, clonal progenitors can undergo malignant transformation to acute leukaemia, or differentiate into immune cells that contribute to disease pathology in peripheral tissues1–4. Outside the marrow, these clones are potentially exposed to a variety of tissue-specific mutational processes, although the consequences of this are unclear. Here we investigate the development of blastic plasmacytoid dendritic cell neoplasm (BPDCN)—an unusual form of acute leukaemia that often presents with malignant cells isolated to the skin5. Using tumour phylogenomics and single-cell transcriptomics with genotyping, we find that BPDCN arises from clonal (premalignant) haematopoietic precursors in the bone marrow. We observe that BPDCN skin tumours first develop at sun-exposed anatomical sites and are distinguished by clonally expanded mutations induced by ultraviolet (UV) radiation. A reconstruction of tumour phylogenies reveals that UV damage can precede the acquisition of alterations associated with malignant transformation, implicating sun exposure of plasmacytoid dendritic cells or committed precursors during BPDCN pathogenesis. Functionally, we find that loss-of-function mutations in Tet2, the most common premalignant alteration in BPDCN, confer resistance to UV-induced cell death in plasmacytoid, but not conventional, dendritic cells, suggesting a context-dependent tumour-suppressive role for TET2. These findings demonstrate how tissue-specific environmental exposures at distant anatomical sites can shape the evolution of premalignant clones to disseminated cancer.
Heritable transcriptional defects from aberrations of nuclear architecture
Authors: Papathanasiou Stamatis , Mynhier Nikos A. , Liu Shiwei , Brunette Gregory , Stokasimov Ema , Jacob Etai , Li Lanting , Comenho Caroline , van Steensel Bas , Buenrostro Jason D. , Zhang Cheng-Zhong , Pellman David 
Published: June 2023

AbstractTranscriptional heterogeneity due to plasticity of the epigenetic state of chromatin contributes to tumour evolution, metastasis and drug resistance1–3. However, the mechanisms that cause this epigenetic variation are incompletely understood. Here we identify micronuclei and chromosome bridges, aberrations in the nucleus common in cancer4,5, as sources of heritable transcriptional suppression. Using a combination of approaches, including long-term live-cell imaging and same-cell single-cell RNA sequencing (Look-Seq2), we identified reductions in gene expression in chromosomes from micronuclei. With heterogeneous penetrance, these changes in gene expression can be heritable even after the chromosome from the micronucleus has been re-incorporated into a normal daughter cell nucleus. Concomitantly, micronuclear chromosomes acquire aberrant epigenetic chromatin marks. These defects may persist as variably reduced chromatin accessibility and reduced gene expression after clonal expansion from single cells. Persistent transcriptional repression is strongly associated with, and may be explained by, markedly long-lived DNA damage. Epigenetic alterations in transcription may therefore be inherently coupled to chromosomal instability and aberrations in nuclear architecture.
Health system-scale language models are all-purpose prediction engines
Authors: Jiang Lavender Yao , Liu Xujin Chris , Nejatian Nima Pour , Nasir-Moin Mustafa , Wang Duo , Abidin Anas , Eaton Kevin , Riina Howard Antony , Laufer Ilya , Punjabi Paawan , Miceli Madeline , Kim Nora C. , Orillac Cordelia , Schnurman Zane , Livia Christopher , Weiss Hannah , Kurland David , Neifert Sean , Dastagirzada Yosef , Kondziolka Douglas , Cheung Alexander T. M. , Yang Grace , Cao Ming , Flores Mona , Costa Anthony B. , Aphinyanaphongs Yindalon , Cho Kyunghyun , Oermann Eric Karl 
Published: June 2023

AbstractPhysicians make critical time-constrained decisions every day. Clinical predictive models can help physicians and administrators make decisions by forecasting clinical and operational events. Existing structured data-based clinical predictive models have limited use in everyday practice owing to complexity in data processing, as well as model development and deployment1–3. Here we show that unstructured clinical notes from the electronic health record can enable the training of clinical language models, which can be used as all-purpose clinical predictive engines with low-resistance development and deployment. Our approach leverages recent advances in natural language processing4,5to train a large language model for medical language (NYUTron) and subsequently fine-tune it across a wide range of clinical and operational predictive tasks. We evaluated our approach within our health system for five such tasks: 30-day all-cause readmission prediction, in-hospital mortality prediction, comorbidity index prediction, length of stay prediction, and insurance denial prediction. We show that NYUTron has an area under the curve (AUC) of 78.7–94.9%, with an improvement of 5.36–14.7% in the AUC compared with traditional models. We additionally demonstrate the benefits of pretraining with clinical text, the potential for increasing generalizability to different sites through fine-tuning and the full deployment of our system in a prospective, single-arm trial. These results show the potential for using clinical language models in medicine to read alongside physicians and provide guidance at the point of care.
Northwest African Neolithic initiated by migrants from Iberia and Levant
Authors: Simões Luciana G. , Günther Torsten , Martínez-Sánchez Rafael M. , Vera-Rodríguez Juan Carlos , Iriarte Eneko , Rodríguez-Varela Ricardo , Bokbot Youssef , Valdiosera Cristina , Jakobsson Mattias 
Published: June 2023

AbstractIn northwestern Africa, lifestyle transitioned from foraging to food production around 7,400 years ago but what sparked that change remains unclear. Archaeological data support conflicting views: (1) that migrant European Neolithic farmers brought the new way of life to North Africa1–3 or (2) that local hunter-gatherers adopted technological innovations4,5. The latter view is also supported by archaeogenetic data6. Here we fill key chronological and archaeogenetic gaps for the Maghreb, from Epipalaeolithic to Middle Neolithic, by sequencing the genomes of nine individuals (to between 45.8- and 0.2-fold genome coverage). Notably, we trace 8,000 years of population continuity and isolation from the Upper Palaeolithic, via the Epipaleolithic, to some Maghrebi Neolithic farming groups. However, remains from the earliest Neolithic contexts showed mostly European Neolithic ancestry. We suggest that farming was introduced by European migrants and was then rapidly adopted by local groups. During the Middle Neolithic a new ancestry from the Levant appears in the Maghreb, coinciding with the arrival of pastoralism in the region, and all three ancestries blend together during the Late Neolithic. Our results show ancestry shifts in the Neolithization of northwestern Africa that probably mirrored a heterogeneous economic and cultural landscape, in a more multifaceted process than observed in other regions.
Class B1 GPCR activation by an intracellular agonist
Authors: Kobayashi Kazuhiro , Kawakami Kouki , Kusakizako Tsukasa , Tomita Atsuhiro , Nishimura Michihiro , Sawada Kazuhiro , Okamoto Hiroyuki H. , Hiratsuka Suzune , Nakamura Gaku , Kuwabara Riku , Noda Hiroshi , Muramatsu Hiroyasu , Shimizu Masaru , Taguchi Tomohiko , Inoue Asuka , Murata Takeshi , Nureki Osamu 
Published: June 2023

AbstractG protein-coupled receptors (GPCRs) generally accommodate specific ligands in the orthosteric-binding pockets. Ligand binding triggers a receptor allosteric conformational change that leads to the activation of intracellular transducers, G proteins and β-arrestins. Because these signals often induce adverse effects, the selective activation mechanism for each transducer must be elucidated. Thus, many orthosteric-biased agonists have been developed, and intracellular-biased agonists have recently attracted broad interest. These agonists bind within the receptor intracellular cavity and preferentially tune the specific signalling pathway over other signalling pathways, without allosteric rearrangement of the receptor from the extracellular side1–3. However, only antagonist-bound structures are currently available1,4–6, and there is no evidence to support that biased agonist binding occurs within the intracellular cavity. This limits the comprehension of intracellular-biased agonism and potential drug development. Here we report the cryogenic electron microscopy structure of a complex of Gs and the human parathyroid hormone type 1 receptor (PTH1R) bound to a PTH1R agonist, PCO371. PCO371 binds within an intracellular pocket of PTH1R and directly interacts with Gs. The PCO371-binding mode rearranges the intracellular region towards the active conformation without extracellularly induced allosteric signal propagation. PCO371 stabilizes the significantly outward-bent conformation of transmembrane helix 6, which facilitates binding to G proteins rather than β-arrestins. Furthermore, PCO371 binds within the highly conserved intracellular pocket, activating 7 out of the 15 class B1 GPCRs. Our study identifies a new and conserved intracellular agonist-binding pocket and provides evidence of a biased signalling mechanism that targets the receptor–transducer interface.
Combined association of physical activity and sitting time with cardiometabolic risk factors in Chilean adults
Authors: Estrada-Saldaña Esteban , Marques Adilson , Silva Danilo R. , Farías‑Valenzuela Claudio , Ferrero‑Hernández Paloma , Guzman-Habinger Juan , Rezende Leandro F. M. , Ferrari Gerson 
Published: June 2023

AbstractIn this study we examined the combined association of physical activity and sitting time with cardiometabolic risk factors in adults in Chile. This is a cross-sectional study based on 3201 adults aged from 18 to 98 years from the Chilean National Health Survey (2016–2017) who responded to the GPAQ questionnaire. Participants were considered inactive if spent < 600 METs-min/wk−1 in physical activity. High sitting time was defined as ≥ 8 h/day. We classified participants into the following 4 groups: active and low sitting time; active and high sitting time; inactive and low sitting time; inactive and high sitting time. The cardiometabolic risk factors considered were metabolic syndrome, body mass index, waist circumference, total cholesterol, and triglycerides. Multivariable logistic regression models were performed. Overall, 16.1% were classified as inactive and high sitting time. Compared to active participants with low sitting time, both inactive participants with low (OR: 1.51; 95% CI 1.10, 1.92) and high sitting time (1.66; 1.10, 2.22) had higher body mass index. Similar results were found for high waist circumference: inactive participants with low (1.57; 1.14, 2.00) and high sitting time (1.84; 1.25, 2.43). We found no combined association of physical activity and sitting time with metabolic syndrome, total cholesterol, and triglycerides. These findings may be useful to inform programs focused on obesity prevention in Chile.
Effect of high-speed steel screw drill geometry on cutting performance when machining austenitic stainless steel
Authors: Sedlak Josef , Zouhar Jan , Kolomy Stepan , Slany Martin , Necesanek Emil 
Published: June 2023

AbstractDrilling into the solid material is one of the basic technological operations, which creates a cylindrical hole in an appropriate time with required quality. Drilling operation demands a favourable removal of chips from the cutting area because a creation of an undesirable shape of chips can impart a lower quality of the drilled hole corresponding with the generation of excess heat due to the intense contact of the chip with drill. The solution for a proper machining is a suitable modification of the drill geometry i.e., point and clearance angles as presented in current study. The tested drills are made of M35 high-speed steel characterized by a very thin core at the point of the drill. An interesting feature of the drills is the use of cutting speed higher than 30 m min−1, with the feed of 0.2 mm per revolution. The surface roughness (Ra and Rz lower than 1 µm and 6 µm respectively), cylindricity (0.045 mm), roundness (0.025 mm), perpendicularity of the hole axis (0.025 mm), diameters and position of the individual holes were achieved for a drill with point angle 138.32°and clearance angle 6.92 respectively. The increase of the drill point angle by 6° resulted in the decrease in the feed force of more than 150 N. In addition, an increase of the clearance angle by 1° resulted with a decrease in the feed force of 70 N. The results of the experiment showed that with the correct geometry of the tool the effective machining without using internal cooling can be realised.
Isolation and characterization of bacteriophages from soil against food spoilage and foodborne pathogenic bacteria
Authors: Artawinata Putri Christy , Lorraine Sesilia , Waturangi Diana Elizabeth 
Published: June 2023

AbstractMicrobial food spoilage and foodborne disease are the main challenges in the food industry regarding food shelf life. Current preservation methods are frequently associated with changes in organoleptic characteristics and loss of nutrients. For this reason, bacteriophage offers an alternative natural method as a biocontrol agent that can reduce bacterial contamination in food without altering the organoleptic properties. This study was conducted to isolate and characterize bacteriophage from soil to control food spoilage bacteria, such as Bacillus cereus and Bacillus subtilis, and foodborne pathogenic bacteria, such as enterotoxigenic Escherichia coli (ETEC) and enterohemorrhagic E. coli (EHEC). Isolation was done by agar overlay assay method, and phages BC-S1, BS-S2, ETEC-S3, and EHEC-S4 were recovered. The host range of all isolated phages tended to be narrow and had high specificity towards the specific bacteria. The phage efficiency were measured where ETEC-S3 showed no effectivity against B. cereus and EHEC-S4 showed low efficiency against Enteropathogenic E. coli (EPEC). Morphology analysis was conducted for phage BC-S1 and ETEC-S3 with Transmission Electron Microscopy (TEM), and it is shown to belong to the Caudovirales order. Phages BC-S1 and BS-S2 significantly reduced the host bacteria when applied to the cooked rice and pasteurized milk samples with miMOI of 0.1. While phage ETEC-S3 at miMOI of 0.001 and phage EHEC-S4 at miMOI of 1 also showed a significant reduction when applied to chicken meat and lettuce samples at storage temperatures of 4 °C and 28 °C. The highest bacterial reduction of 100% was shown by phage BC-S1 on pasteurized milk samples and reduction up to 96.06% by phage ETEC-S3 on chicken meat samples at 28 °C incubation.