bluuebunny/crossref_metadata_2025 huggingface dataset:
Deadenylation kinetics of mixed poly(A) tails at single-nucleotide resolution
Authors: Lee Young-suk , Levdansky Yevgen , Jung Yoonseok , Kim V. Narry , Valkov Eugene
Published: February 2024

Shortening of messenger RNA poly(A) tails, or deadenylation, is a rate-limiting step in mRNA decay and is highly regulated during gene expression. The incorporation of non-adenosines in poly(A) tails, or ‘mixed tailing’, has been observed in vertebrates and viruses. Here, to quantitate the effect of mixed tails, we mathematically modeled deadenylation reactions at single-nucleotide resolution using an in vitro deadenylation system reconstituted with the complete human CCR4–NOT complex. Applying this model, we assessed the disrupting impact of single guanosine, uridine or cytosine to be equivalent to approximately 6, 8 or 11 adenosines, respectively. CCR4–NOT stalls at the 0, −1 and −2 positions relative to the non-adenosine residue. CAF1 and CCR4 enzyme subunits commonly prefer adenosine but exhibit distinct sequence selectivities and stalling positions. Our study provides an analytical framework to monitor deadenylation and reveals the molecular basis of tail sequence-dependent regulation of mRNA stability.
Whole Genome Sequence Dataset of Mycobacterium tuberculosis Strains from Patients of Campania Region
Authors: Folliero Veronica , Ferravante Carlo , Iovane Valentina , Salvati Annamaria , Crescenzo Laura , Perna Rossella , Corvino Giusy , Della Rocca Maria T. , Panetta Vittorio , Tranfa Alessandro , Greco Giuseppe , Baldoni Teresa , Pagnini Ugo , Finamore Emiliana , Giurato Giorgio , Nassa Giovanni , Coppola Mariagrazia , Atripaldi Luigi , Greco Rita , D’Argenio Annamaria , Foti Maria Grazia , Abate Rosamaria , Del Giudice Annalisa , Sarnelli Bruno , Weisz Alessandro , Iovane Giuseppe , Pinto Renato , Franci Gianluigi , Galdiero Massimiliano
Published: February 2024

Tuberculosis (TB) is one of the deadliest infectious disorders in the world. To effectively TB manage, an essential step is to gain insight into the lineage of Mycobacterium tuberculosis (MTB) and the distribution of drug resistance. Although the Campania region is declared a cluster area for the infection, to contribute to the effort to understand TB evolution and transmission, still poorly known, we have generated a dataset of 159 genomes of MTB strains, from Campania region collected during 2018–2021, obtained from the analysis of whole genome sequence. The results show that the most frequent MTB lineage is the 4 according for 129 strains (81.11%). Regarding drug resistance, 139 strains (87.4%) were classified as multi susceptible, while the remaining 20 (12.58%) showed drug resistance. Among the drug-resistance strains, 8 were isoniazid-resistant MTB, 4 multidrug-resistant MTB, while only one was classified as pre-extensively drug-resistant MTB. This dataset expands the existing available knowledge on drug resistance and evolution of MTB, contributing to further TB-related genomics studies to improve the management of this disease.
A raster-based spatial clustering method with robustness to spatial outliers
Authors: Wang Haoyu , Song Changqing , Wang Jinfeng , Gao Peichao
Published: February 2024

Spatial clustering is an essential method for the comprehensive understanding of a region. Spatial clustering divides all spatial units into different clusters. The attributes of each cluster of the spatial units are similar, and simultaneously, they are as continuous as spatially possible. In spatial clustering, the handling of spatial outliers is important. It is necessary to improve spatial integration so that each cluster is connected as much as possible, while protecting spatial outliers can help avoid the excessive masking of attribute differences This paper proposes a new spatial clustering method for raster data robust to spatial outliers. The method employs a sliding window to scan the entire region to determine spatial outliers. Additionally, a mechanism based on the range and standard deviation of the spatial units in each window is designed to judge whether the spatial integration should be further improved or the spatial outliers should be protected. To demonstrate the usefulness of the proposed method, we applied it in two case study areas, namely, Changping District and Pinggu District in Beijing. The results show that the proposed method can retain the spatial outliers while ensuring that the clusters are roughly contiguous. This method can be used as a simple but powerful and easy-to-interpret alternative to existing geographical spatial clustering methods.
Examining the gray cube effect on naïve viewers’ appreciation of street-based art in Hong Kong and Poland
Authors: Szubielska Magdalena , Ho Robbie , Witeska-Młynarczyk Anna , Kopiś-Posiej Natalia
Published: February 2024

The present research investigates the appreciation of sanctioned street-based art among naïve viewers. It examines the role of viewing context in art appreciation, by experimentally testing agray cube effect, which posits that street-based artworks are more likely to be identified as art (H1), liked more (H2), and understood more (H3) when viewed on the street. Identical procedures were carried out in Hong Kong (Experiment 1) and Lublin, Poland (Experiment 2), separately, sampling local artworks and local viewers. Experiment 1 tested 14 murals with 100 Hong Kongers; Experiment 2 tested 7 sculptures and 7 murals with 88 Poles. Participants were randomly assigned to either viewing street-based artworks on the street (gray cube) or viewing digital images of street-based artworks in a laboratory. The participants assessed each artwork in terms of art identification, liking, and understanding. These “twin” experiments yielded identical results, i.e., street-based artworks were liked more (H2) and understood more (H3) but not more likely to be identified as art (H1) on the street than in the laboratory. Overall, the present findings support the gray cube effect with ecologically valid data, and the effect seems robust across Western and Eastern cultural contexts and across genres of sculpture and mural.
Different responses of foliar nutrient resorption efficiency in two dominant species to grazing in the desert steppe
Authors: Zhao Qingge , Zhang Yuhan , Wang Yunbo , Han Guodong
Published: February 2024

Nitrogen and phosphorus resorption (NRE and PRE) is a critical nutrient conservation mechanism maintaining plant growth in already disturbed barren ecosystems. The complexity of plant nutrient resorption variations in long-term grazing regions is regulated by plant traits, nutritional utilization strategies, and soil conditions following changes in grazing patterns. Therefore, a detailed investigation into their underlying mechanism is still required. Here we investigated leaf nutrient concentration and resorption in dominant species Cleistogenes songorica (C. squarrosa) and Stipa breviflora (S. breviflora) response to 15-years continuous grazing (moderate and heavy grazing) in desert steppe. Moderate grazing enhanced green leaf N and P content in C. songorica and partially increased N content in S. breviflora. Heavy grazing consistently increased N content in C. songorica, but its P content as well as N and P content in S. breviflora were largely stable. Moderate grazing enhanced NRE but unaffected PRE in both S. breviflora and C. songorica. Heavy grazing reduced NRE and PRE in C. songorica. Although soil variables (nutrients and moisture) did not affect foliar nutrients, it’s a key driver of nutrient resorption efficiency. Of all measured influence factors, soil moisture is the one most important and negatively correlated with NRE and PRE in S. breviflora. While it was not observed in C. songorica. In S. breviflora, its NRE was adversely linked with soil N, in addition, both NRE and PRE were positively associated with green leaf nutrients. Senesced leaf nutrients are the predominant factor influencing nutrient resorption efficiency in C. songorica, which were adversely associated. Overall, our results indicate significant variations in nutrient resorption efficiency patterns between the two dominant species due to divergent plant adaptation strategies to grazing and the local environment. The foliar nutritional status and soil conditions may play significant roles in regulating nutrient resorption in arid long-term grazing desert steppe.
Modeling the impact of future rainfall changes on the effectiveness of urban stormwater control measures
Authors: Nodine Tyler G. , Conley Gary , Riihimaki Catherine A. , Holland Craig , Beck Nicole G.
Published: February 2024

The convergence of urban expansion, deteriorating infrastructure, and a changing climate will escalate the risks of stormwater pollution and urban flooding in the coming decades. Using outputs from an ensemble of global climate models to drive a high spatial resolution stormwater model, we analyzed climate change impacts on urban stormwater runoff and control measures for 23 cities across the United States. Runoff model outputs for two future emissions scenarios ending in 2055 were compared against a historical scenario to assess changes. All cities showed increases in average annual stormwater runoff, with changes up to 30% over the next 30 years due to a greater frequency of high intensity storm events. Runoff model outputs showed substantial variation across cities with untreated stormwater runoff increasing by as much as 48%. Patterns of future runoff impacts within cities will affect the performance of distributed treatment strategies such as Green Stormwater Infrastructure (GSI) to meet municipal water quality improvement and runoff reduction goals. Results indicate that adoption of adaptable design standards and decision support tools that readily accommodate projected precipitation changes are critical for supporting more resilient designs of stormwater control measures.
A comparative study of the bacterial diversity and composition of nursery piglets’ oral fluid, feces, and housing environment
Authors: Buiatte Vinicius , Fonseca Ana , Alonso Madureira Paloma , Nakashima Vaz Andréia Cristina , Tizioto Polyana Cristine , Centola Vidal Ana Maria , Ganda Erika , de Azevedo Ruiz Vera Letticie
Published: February 2024

The oral cavity is the portal of entry for many microorganisms that affect swine, and the swine oral fluid has been used as a specimen for the diagnosis of several infectious diseases. The oral microbiota has been shown to play important roles in humans, such as protection against non-indigenous bacteria. In swine, studies that have investigated the microbial composition of the oral cavity of pigs are scarce. This study aimed to characterize the oral fluid microbiota of weaned pigs from five commercial farms in Brazil and compare it to their respective fecal and environmental microbiotas. Bacterial compositions were determined by 16S rRNA gene sequencing and analyzed in R Studio. Oral fluid samples were significantly less diverse (alpha diversity) than pen floor and fecal samples (P < 0.01). Alpha diversity changed among farms in oral fluid and pen floor samples, but no differences were observed in fecal samples. Permutational ANOVA revealed that beta diversity was significantly different among sample types (P = 0.001) and farms (P = 0.001), with separation of sample types (feces, pen floor, and oral fluid) on the principal coordinates analysis. Most counts obtained from oral fluid samples were classified as Firmicutes (80.4%) and Proteobacteria (7.7%). The genera Streptococcus, members of the Pasteurellaceae family, and Veillonella were differentially abundant in oral fluid samples when compared to fecal samples, in which Streptococcus was identified as a core genus that was strongly correlated (SparCC) with other taxa. Firmicutes and Bacteroidota were the most relatively abundant phyla identified in fecal and pen floor samples, and Prevotella_9 was the most classified genus. No differentially abundant taxa were identified when comparing fecal samples and pen floor samples. We concluded that under the conditions of our study, the oral fluid microbiota of weaned piglets is different (beta diversity) and less diverse (alpha diversity) than the fecal and environmental microbiotas. Several differentially abundant taxa were identified in the oral fluid samples, and some have been described as important colonizers of the oral cavity in human microbiome studies. Further understanding of the relationship between the oral fluid microbiota and swine is necessary and would create opportunities for the development of innovative solutions that target the microbiota to improve swine health and production.
Somatostatin receptor 2 (SSTR2) expression is associated with better clinical outcome and prognosis in rectal neuroendocrine tumors
Authors: Kim Joo Young , Kim Jisup , Kim Yong-il , Yang Dong-Hoon , Yoo Changhoon , Park In Ja , Ryoo Baek-Yeol , Ryu Jin-Sook , Hong Seung-Mo
Published: February 2024

Somatostatin analogues have recently been used as therapeutic targets for metastatic or surgically unresectable gastroenteropancreatic (GEP) neuroendocrine tumors (NETs), and associated somatostatin receptor (SSTR) expression has been well demonstrated in most GEP NETs, with the exception of rectal NETs. SSTR2 immunohistochemical expressions were evaluated in 350 surgically or endoscopically resected rectal NETs and compared to clinicopathologic factors. SSTR2 expression was observed in 234 (66.9%) rectal NET cases and associated tumors with smaller size (p = 0.001), low pT classification (p = 0.030), low AJCC tumor stage (p = 0.012), and absence of chromogranin expression (p = 0.009). Patients with rectal NET and SSTR2 expression had significantly better overall survival than those without SSTR2 expression both by univariable (p = 0.006) and multivariable (p = 0.014) analyses. In summary, approximately two-thirds of rectal NETs expressed SSTR2. SSTR2 expression was significantly associated with favorable behavior and good overall survival in patients with rectal NETs. Furthermore, SSTR2 expression can be used as prognostic factors. When metastatic disease occurs, SSTR2 expression can be used a possible target for somatostatin analogues.
Development of a digital intervention for psychedelic preparation (DIPP)
Authors: McAlpine Rosalind G. , Sacchet Matthew D. , Simonsson Otto , Khan Maisha , Krajnovic Katarina , Morometescu Larisa , Kamboj Sunjeev K.
Published: February 2024

Psychedelic substances induce profound alterations in consciousness. Careful preparation is therefore essential to limit adverse reactions, enhance therapeutic benefits, and maintain user safety. This paper describes the development of a self-directed, digital intervention for psychedelic preparation. Drawing on elements from the UK Medical Research Council (MRC) framework for developing complex interventions, the design was informed by a four-factor model of psychedelic preparedness, using a person-centred approach. Our mixed-methods investigation consisted of two studies. The first involved interviews with 19 participants who had previously attended a ‘high-dose’ psilocybin retreat, systematically exploring their preparation behaviours and perspectives on the proposed intervention. The second study engaged 28 attendees of an ongoing psilocybin retreat in co-design workshops, refining the intervention protocol using insights from the initial interviews. The outcome is a co-produced 21-day digital course (Digital Intervention for Psychedelic Preparation (DIPP)), that is organised into four modules: Knowledge–Expectation, Psychophysical–Readiness, Safety–Planning, and Intention–Preparation. Fundamental components of the course include daily meditation practice, supplementary exercises tied to the weekly modules, and mood tracking. DIPP provides a comprehensive and scalable solution to enhance psychedelic preparedness, aligning with the broader shift towards digital mental health interventions.
Process optimization for green synthesis of silver nanoparticles using Rubus discolor leaves extract and its biological activities against multi-drug resistant bacteria and cancer cells
Authors: Ghasemi Saeed , Dabirian Sara , Kariminejad Faezeh , Koohi Diba Eghbali , Nemattalab Mehran , Majidimoghadam Sina , Zamani Ehsan , Yousefbeyk Fatemeh
Published: February 2024

Multi-drug resistant (MDR) bacteria are considered a serious public health threat. Also, increasing rate of resistance to anticancer drugs, as well as their toxicity, is another point of concern. Therefore, the new antibacterial and anticancer agents are always needed. The synthesizing silver nanoparticles (AgNPs) using medicinal plants, is an effective approach for developing novel antibacterial and anticancer agents. Rubus discolor, a native species of the Caucasus region, produces leaves that are typically discarded as a by-product of raspberry production. The present study has focused on optimizing the green synthesis of AgNPs using R. discolor leaves extract through response surface methodology. The optimal values for AgNPs synthesis were an AgNO3 concentration of 7.11 mM, a time of 17.83 h, a temperature of 56.51 °C, and an extract percentage of 29.22. The production of AgNPs was confirmed using UV–visible spectroscopy (λmax at 456.01 nm). TEM analysis revealed well-dispersed AgNPs (an average size of 37 nm). The XRD analysis confirmed the crystalline structure. The EDX detected a strong peak at 3 keV corresponded to Ag. The zeta potential value (− 44.2 mV) indicated the stability of nanoparticles. FT-IR spectra showed the presence of various functional groups from plant compounds, which play an important role in the capping and bio-reduction processes. The AgNPs revealed impressive antibacterial activities against MDR Escherichia coli and Pseudomonas aeruginosa (MIC ranging from 0.93 to 3.75 mg ml−1). The phytochemical analysis indicated the presence of phenolics, tannins, and flavonoids on the surface of AgNPs. They also showed significant cytotoxic effects on A431, MCF-7, and HepG2 cells (IC50 values ranging from 11 to 49.1 µg ml−l).
Serum α-Klotho and fibroblast growth factor 23 levels are not associated with non-proliferative diabetic retinopathy in type 1 diabetes mellitus
Authors: Oner Can , Dogan Burcu , Tuzun Sabah , Ekinci Asiye , Feyizoglu Gunes , Basok Banu Isbilen
Published: February 2024

Diabetic retinopathy is a commonly observed cause of blindness and is a common problem in individuals with diabetes. Recent investigations have showed the capability of serum α-Klotho and FGF 23 in mitigating the effects of diabetic retinopathy. This study aimed to discover the correlation between FGF 23, α-Klotho, and diabetic retinopathy in type 1 diabetics. This case–control study included 63 diabetic patients and 66 healthy controls. Following an overnight duration of fasting, morning blood samples were taken from both the patient and the control groups. The serum concentrations of α-Klotho and FGF 23 were quantified. An experienced ophthalmologist inspected the retinopathy. All participants in this study have moderate non-proliferative retinopathy. A p value under 0.05 was considered statistically significant. The mean α-Klotho level for retinopathic diabetic patients was 501.7 ± 172.2 pg/mL and 579.6 ± 312.1 pg/mL for non-retinopathic diabetic patients. In comparison, α-Klotho level of the control group was 523.2 ± 265.4 pg/mL (p = 0.531). The mean of FGF 23 level did not demonstrate a significant difference (p = 0.259). The mean FGF 23 level were 75.7 ± 14.0 pg/mL, 74.0 ± 14.8 pg/mL and 79.3 ± 14.4 pg/mL in groups, respectively. In conclusion, there was no significant difference in FGF 23 and α-Klotho levels between type 1 diabetics with and without retinopathy when compared to the control group.
War drives forest fire risks and highlights the need for more ecologically-sound forest management in post-war Ukraine
Authors: Matsala Maksym , Odruzhenko Andrii , Hinchuk Taras , Myroniuk Viktor , Drobyshev Igor , Sydorenko Serhii , Zibtsev Sergiy , Milakovsky Brian , Schepaschenko Dmitry , Kraxner Florian , Bilous Andrii
Published: February 2024

Since 24 February 2022, Ukraine has experienced full-scale military aggression initiated by the Russian Federation. The war has had a major negative impact on vegetation cover of war-affected regions. We explored interactions between pre-war forest management and the impacts of military activities in three of the most forested Ukrainian areas of interest (AOI), affected by the war. These were forests lying between Kharkiv and Luhansk cities (AOI ‘East’), forests along the Dnipro River delta (AOI ‘Kherson’), and those of the Chornobyl Exclusion Zone (AOI CEZ). We used Sentinel satellite imagery to create damaged forest cover masks for the year 2022. We mapped forests with elevated fire hazard, which was defined as a degree of exposure to the fire-supporting land use (mostly an agricultural land, a common source of ignitions in Ukraine). We evaluated the forest disturbance rate in 2022, as compared to pre-war rates. We documented significant increases in non-stand replacing disturbances (low severity fires and non-fire disturbances) for all three of the AOIs. Damaged forest cover varied among the AOIs (24,180 ± 4,715 ha, or 9.3% ± 1.8% in the ‘East’ AOI; 7,293 ± 1,925 ha, or 15.7% ± 4.1% in the ‘Kherson’ AOI; 7,116 ± 1,274 ha, or 5.0% ± 0.9% in the CEZ AOI). Among the forests damaged in 2022, the ‘Kherson’ AOI will likely have the highest proportion of an area with elevated fire hazard in the coming decades, as compared to other regions (89% vs. 70% in the ‘East’ and CEZ AOIs respectively). Future fire risks and extensive war-related disturbance of forest cover call for forest management to develop strategies explicitly addressing these factors.
Prediction of steel plate-based damper for improving the behavior of concentrically braced frames based on RSM and ML approaches for sustainable structures
Authors: Onyelowe Kennedy C. , Yaulema Castañeda Jorge Luis , Adam Ali F. Hussain , Ñacato Estrella Diego Ramiro , Ganasen Nakkeeran
Published: February 2024

The stiffness (K) and slenderness factor (λ) of a steel plate-based damper has been studied on the basis of elastic-inelastic-plastic buckling (EIP) modes and flexural/shear/flexural-shear failure mechanisms (FSF-S), which has been designed for the improvement of the behavior of concentrically braced frames. Steel plate-based dampers offer significant benefits in terms of mode shapes and failure mechanisms, contributing to improved dynamic performance, enhanced structural resilience, and increased safety of civil engineering structures. Their effectiveness in mitigating dynamic loads makes them a valuable tool for engineers designing structures to withstand extreme environmental conditions and seismic events. This study was undertaken by using the learning abilities of the response surface methodology (RSM), artificial neural network (ANN) and the evolutionary polynomial regression (EPR). Steel plate dampers are special structural designs used to withstand the effect of special loading conditions especially seismic effects. Its design based on the prediction of its stiffness (K) and slenderness factor (λ) cannot be overlooked in the present-day artificial intelligence technology. In this research work, thirty-three entries based on the steel plate damper geometrical properties were recorded and deployed for the intelligent forecast of the fundamental properties (λ and K). Design ratios of the steel plate damper properties were considered and models behavior was recorded. From the outcome of the model, it can be observed that even though the EPR and ANN in that order outclassed the other techniques, the RSM produced model minimization and maximization features of the desirability levels, color factor scales and 3D surface observation, which shows the real model behaviors. Overall, the EPR with R2 of 0.999 and 1.000 for the λ and K, respectively showed to be the decisive model but the RSM has features that can be beneficial to the structural design of the studied steel plate damper for a more robust and sustainable construction. With these performances recorded in this exercise, the techniques have shown their potential to be applied in the prediction of steel damper stiffness with optimized characteristic features to withstand structural stresses.
The impact of using reinforcement learning to personalize communication on medication adherence: findings from the REINFORCE trial
Authors: Lauffenburger Julie C. , Yom-Tov Elad , Keller Punam A. , McDonnell Marie E. , Crum Katherine L. , Bhatkhande Gauri , Sears Ellen S. , Hanken Kaitlin , Bessette Lily G. , Fontanet Constance P. , Haff Nancy , Vine Seanna , Choudhry Niteesh K.
Published: February 2024

Text messaging can promote healthy behaviors, like adherence to medication, yet its effectiveness remains modest, in part because message content is rarely personalized. Reinforcement learning has been used in consumer technology to personalize content but with limited application in healthcare. We tested a reinforcement learning program that identifies individual responsiveness (“adherence”) to text message content and personalizes messaging accordingly. We randomized 60 individuals with diabetes and glycated hemoglobin A1c [HbA1c] ≥ 7.5% to reinforcement learning intervention or control (no messages). Both arms received electronic pill bottles to measure adherence. The intervention improved absolute adjusted adherence by 13.6% (95%CI: 1.7%–27.1%) versus control and was more effective in patients with HbA1c 7.5- < 9.0% (36.6%, 95%CI: 25.1%–48.2%, interaction p < 0.001). We also explored whether individual patient characteristics were associated with differential response to tested behavioral factors and unique clusters of responsiveness. Reinforcement learning may be a promising approach to improve adherence and personalize communication at scale.
The cultural evolution of collective property rights for sustainable resource governance
Authors: Andrews Jeffrey , Clark Matthew , Hillis Vicken , Borgerhoff Mulder Monique
Published: February 2024

With commons encompassing approximately 65% of Earth’s surface and vast tracts of the ocean, a critical challenge for sustainability involves establishing effective institutions for governing these common-pool resources (CPR). While examples of successful governance exist, the circumstances and mechanisms behind their development have often faded from historical records and memories. Drawing on ethnographic work, we introduce a generic evolutionary multigroup modelling framework that examines the emergence, stability and temporal dynamics of collective property rights. Our research reveals a fundamental insight: when intergroup conflicts over resources exist, establishing and enforcing ‘access rights’ becomes an essential prerequisite for evolving sustainable ‘use rights’. These access rights, in turn, enable cultural group selection and facilitate the evolution of sustainable use rights through the imitation of successful groups. Moreover, we identify four crucial aspects within these systems: (1) seizures in CPR systems create individual-level incentives to enforce use and access rights; (2) support for collective property rights is frequency dependent and prone to oscillations; (3) the maximum sustainable yield (MSY) is a tipping point that alters the interplay between individual and group-level selection pressures; (4) success-biased social learning (imitation) of out-group members plays a vital role in spreading sustainable institutions and preventing the tragedy of the commons.
High-performance, power-efficient three-dimensional system-in-package designs with universal chiplet interconnect express
Authors: Das Sharma Debendra , Pasdast Gerald , Tiagaraj Sathya , Aygün Kemal
Published: February 2024

Universal chiplet interconnect express (UCIe) is an open industry standard interconnect for a chiplet ecosystem in which chiplets from multiple suppliers can be packaged together. The UCIe 1.0 specification defines interoperability using standard and advanced packaging technologies with planar interconnects. Here we examine the development of UCIe as the bump interconnect pitches reduce with advances in packaging technologies for three-dimensional integration of chiplets. We report a die-to-die solution for the continuum of package bump pitches down to 1 µm, providing circuit architecture details and performance results. Our analysis suggests that—contrary to trends seen in traditional signalling interfaces—the most power-efficient performance for these architectures can be achieved by reducing the frequency as the bump pitch goes down. Our architectural approach provides power, performance and reliability characteristics approaching or exceeding that of a monolithic system-on-chip design as the bump pitch approaches 1 µm.
A lower crust shear zone facilitates delamination and continental subduction under the Apennines
Authors: Menichelli Irene , Bianchi Irene , Chiarabba Claudio
Published: February 2024

Physical properties and structure of the lithosphere are the first step to constrain the evolution of mountain belts. Here we show detailed shear wave velocity profiles of the lithosphere in the Apennines that clarify a controversial aspect of continental subduction: the intricate mechanism of crust delamination from the downgoing plate. From the analysis of complete and dense teleseismic Receiver Function data set, we find that the delamination of the continental lithosphere is favored by the development of a low seismic shear wave velocity zone in the middle-lower crust. We observe a double Moho below the external portions of the present mountain range, suggesting the progressive formation of the shallow interface. The delamination edge is located in the forearc, far eastward than expected, implying that the re-equilibration of the thermal unbalance, generated by the mantle substitution, may last 10-7 Myr.
Rapid sea level rise causes loss of seagrass meadows
Authors: Capistrant-Fossa Kyle A. , Dunton Kenneth H.
Published: February 2024

As global declines in seagrass populations continue to cause great concern, long-term assessment of seagrass meadows show promise in furnishing valuable clues into fundamental causes of seagrass loss and drivers of environmental change. Here we report two long-term records of seagrass presence in western Gulf of Mexico coastal waters (Laguna Madre) that provided insight into their rapid decline in a relatively pristine ecosystem. Coincident with unprecedented increases in water depth starting in 2014 (14–25 mm y−1), monthly measurements at a deep edge fixed station revealed that two ubiquitous seagrass species (Halodule wrightii and Syringodium filiforme) vanished altogether in just five years; a subsequent basin-wide assessment revealed that seagrasses disappeared at 23% of 144 sentinel stations. Models that incorporate differing sea level rise scenarios and water depth thresholds reveal potential global losses of seagrass habitat (14,000 km2), with expansion into newly created shallow habitats constrained by altered natural shorelines.
Global ecosystem responses to flash droughts are modulated by background climate and vegetation conditions
Authors: O Sungmin , Park Seon Ki
Published: February 2024

Flash droughts and their physical processes have received increasing attention in recent years due to concerns about the potential of flash droughts to affect water resources and ecosystems. Yet to date, the response of ecosystems during flash drought events, particularly on a large scale, and the determinants of the ecosystem responses to flash droughts have been underexplored. Here we analyse temporal variations in vegetation anomalies during flash drought events at a global scale between 2001 and 2020 using observation-based leaf area index, gross primary productivity, and solar-induced chlorophyll fluorescence data. We identify divergent ecosystem responses in terms of the timing and intensification of drought-induced vegetation stress across different regions around the world. Furthermore, we find that these regional differences are largely modulated by background climate and vegetation conditions, rather than meteorological conditions, with ecosystems being subjected to more rapidly developing and greater degrees of vegetation stress in arid and short vegetation-dominated regions as compared to humid forests. Our results highlight the spatially heterogeneous ecological impacts of flash droughts, implying the need to comprehensively integrate aspects of both atmospheric and bioclimatic properties in flash drought monitoring and forecasting systems to improve our ability to track their evolution and impacts.
Generalisable deep learning method for mammographic density prediction across imaging techniques and self-reported race
Authors: Khara Galvin , Trivedi Hari , Newell Mary S. , Patel Ravi , Rijken Tobias , Kecskemethy Peter , Glocker Ben
Published: February 2024

Background

Breast density is an important risk factor for breast cancer complemented by a higher risk of cancers being missed during screening of dense breasts due to reduced sensitivity of mammography. Automated, deep learning-based prediction of breast density could provide subject-specific risk assessment and flag difficult cases during screening. However, there is a lack of evidence for generalisability across imaging techniques and, importantly, across race.

Methods

This study used a large, racially diverse dataset with 69,697 mammographic studies comprising 451,642 individual images from 23,057 female participants. A deep learning model was developed for four-class BI-RADS density prediction. A comprehensive performance evaluation assessed the generalisability across two imaging techniques, full-field digital mammography (FFDM) and two-dimensional synthetic (2DS) mammography. A detailed subgroup performance and bias analysis assessed the generalisability across participants’ race.

Results

Here we show that a model trained on FFDM-only achieves a 4-class BI-RADS classification accuracy of 80.5% (79.7–81.4) on FFDM and 79.4% (78.5–80.2) on unseen 2DS data. When trained on both FFDM and 2DS images, the performance increases to 82.3% (81.4–83.0) and 82.3% (81.3–83.1). Racial subgroup analysis shows unbiased performance across Black, White, and Asian participants, despite a separate analysis confirming that race can be predicted from the images with a high accuracy of 86.7% (86.0–87.4).

Conclusions

Deep learning-based breast density prediction generalises across imaging techniques and race. No substantial disparities are found for any subgroup, including races that were never seen during model development, suggesting that density predictions are unbiased.
Carotid body dysregulation contributes to Long COVID symptoms
Authors: El-Medany Ahmed , Adams Zoe H. , Blythe Hazel C. , Hope Katrina A. , Kendrick Adrian H. , Abdala Sheikh Ana Paula , Paton Julian F. R. , Nightingale Angus K. , Hart Emma C.
Published: February 2024

Background

The symptoms of long COVID, which include fatigue, breathlessness, dysregulated breathing, and exercise intolerance, have unknown mechanisms. These symptoms are also observed in heart failure and are partially driven by increased sensitivity of the carotid chemoreflex. As the carotid body has an abundance of ACE2 (the cell entry mechanism for SARS-CoV-2), we investigated whether carotid chemoreflex sensitivity was elevated in participants with long COVID.

Methods

Non-hositalised participants with long-COVID (n = 14) and controls (n = 14) completed hypoxic ventilatory response (HVR; the measure of carotid chemoreflex sensitivity) and cardiopulmonary exercise tests. Parametric and normally distributed data were compared using Student’s unpaired t-tests or ANOVA. Nonparametric equivalents were used where relevant. Peason’s correlation coefficient was used to examine relationships between variables.

Results

During cardiopulmonary exercise testing the VE/VCO2 slope (a measure of breathing efficiency) was higher in the long COVID group (37.8 ± 4.4) compared to controls (27.7 ± 4.8, P = 0.0003), indicating excessive hyperventilation. The HVR was increased in long COVID participants (−0.44 ± 0.23 l/min/ SpO2%, R2 = 0.77 ± 0.20) compared to controls (−0.17 ± 0.13 l/min/SpO2%, R2 = 0.54 ± 0.38, P = 0.0007). The HVR correlated with the VE/VCO2 slope (r = −0.53, P = 0.0036), suggesting that excessive hyperventilation may be related to carotid body hypersensitivity.

Conclusions

The carotid chemoreflex is sensitised in long COVID and may explain dysregulated breathing and exercise intolerance in these participants. Tempering carotid body excitability may be a viable treatment option for long COVID patients.
Bone morphogenic protein-4 availability in the cardiac microenvironment controls inflammation and fibrosis in autoimmune myocarditis
Authors: Perez-Shibayama Christian , Gil-Cruz Cristina , Cadosch Nadine , Lütge Mechthild , Cheng Hung-Wei , De Martin Angelina , Frischmann Kira , Joachimbauer Anna , Onder Lucas , Papadopoulou Iliana , Papadopoulou Chrysa , Ring Sandra , Krebs Philippe , Vu Vivian P. , Nägele Matthias P. , Rossi Valentina A. , Parianos Danaë , Zsilavecz Valentin W. , Cooper Leslie T. , Flammer Andreas , Ruschitzka Frank , Rainer Peter P. , Schmidt Dörthe , Ludewig Burkhard
Published: February 2024

Myocarditis is an inflammatory heart disease that leads to loss of cardiomyocytes and frequently precipitates fibrotic remodeling of the myocardium, culminating in heart failure. However, the molecular mechanisms underlying immune cell control and maintenance of tissue integrity in the inflamed cardiac microenvironment remain elusive. In this study, we found that bone morphogenic protein-4 (BMP4) gradients maintain cardiac tissue homeostasis by single-cell transcriptomics analyses of inflamed murine and human myocardial tissues. Cardiac BMP pathway dysregulation was reflected by reduced BMP4 serum concentration in patients with myocarditis. Restoration of BMP signaling by antibody-mediated neutralization of the BMP inhibitors gremlin-1 and gremlin-2 ameliorated T cell-induced myocardial inflammation in mice. Moreover, progression to inflammatory cardiomyopathy was blocked through the reduction of fibrotic remodeling and preservation of cardiomyocyte integrity. These results unveil the BMP4–gremlin axis as a druggable pathway for the treatment of myocardial inflammation, limiting the severe sequelae of cardiac fibrosis and heart failure.
Real-life behavioral and neural circuit markers of physical activity as a compensatory mechanism for social isolation
Authors: Benedyk Anastasia , Reichert Markus , Giurgiu Marco , Timm Irina , Reinhard Iris , Nigg Carina , Berhe Oksana , Moldavski Alexander , von der Goltz Christoph , Braun Urs , Ebner-Priemer Ulrich , Meyer-Lindenberg Andreas , Tost Heike
Published: February 2024

Social isolation and loneliness pose major societal challenges accelerated by the coronavirus disease 2019 pandemic, especially for mental health. In this cohort study using accelerometry, electronic diaries and neuroimaging in a community-based sample of 317 young adults, we show that people felt affectively worse when lacking social contact, but less so when engaging in physical activity. This putative compensatory mechanism was present even at small physical activity doses and was pronounced in individuals with higher brain functional connectivity within the default mode network signaling risk for depression. Social-affective benefits of movement were higher in people showing exacerbated loneliness and were replicated throughout the pandemic. These findings extend the state of knowledge on the dynamic interplay of social contact and physical activity in daily life identifying an accessible protective strategy to mitigate the negative effects of social isolation, particularly among at-risk individuals, which comes with the potential to improve public health in the post-pandemic world.
A Raman topography imaging method toward assisting surgical tumor resection
Authors: Czaja Alexander , Jiang Alice J. , Blanco Matt Zacchary , Eremina Olga E. , Zavaleta Cristina
Published: February 2024

Achieving complete tumor resection upon initial surgical intervention can lead to better patient outcomes by making adjuvant treatments more efficacious and reducing the strain of repeat surgeries. Complete tumor resection can be difficult to confirm intraoperatively. Methods like touch preparation (TP) have been inconsistent for detecting residual malignant cell populations, and fatty specimens like breast cancer lumpectomies are too fatty to process for rapid histology. We propose a novel workflow of immunostaining and topographic surface imaging of freshly excised tissue to ensure complete resection using highly sensitive and spectrally separable surface-enhanced Raman scattering nanoparticles (SERS NPs) as the targeted contrast agent. Biomarker-targeting SERS NPs are ideal contrast agents for this application because their sensitivity enables rapid detection, and their narrow bands enable extensive intra-pixel multiplexing. The adaptive focus capabilities of an advanced Raman instrument, combined with our rotational accessory device for exposing each surface of the stained specimen to the objective lens, enable topographic mapping of complete excised specimen surfaces. A USB-controlled accessory for a Raman microscope was designed and fabricated to enable programmatic and precise angular manipulation of specimens in concert with instrument stage motions during whole-surface imaging. Specimens are affixed to the accessory on an anti-slip, sterilizable rod, and the tissue surface exposed to the instrument is adjusted on demand using a programmed rotating stepper motor. We demonstrate this topographic imaging strategy on a variety of phantoms and preclinical tissue specimens. The results show detail and texture in specimen surface topography, orientation of findings and navigability across surfaces, and extensive SERS NP multiplexing and linear quantitation capabilities under this new Raman topography imaging method. We demonstrate successful surface mapping and recognition of all 26 of our distinct SERS NP types along with effective deconvolution and localization of randomly assigned NP mixtures. Increasing NP concentrations were also quantitatively assessed and showed a linear correlation with Raman signal with an R2coefficient of determination of 0.97. Detailed surface renderings color-encoded by unmixed SERS NP abundances show a path forward for content-rich, interactive surgical margin assessment.
Tantalum oxide nanoparticles as versatile and high-resolution X-ray contrast agent for intraductal image-guided ablative procedure in rodent models of breast cancer
Authors: Zaluzec Erin K. , Kenyon Elizabeth , Volk Maximilian , Hayat Hasaan , Powell Katherine , Loomis Alexander , Chakravarty Shatadru , Hix Jeremy M. L. , Schipper Josh , Chang Chi , Kiupel Matti , Wang Ping , Shapiro Erik M. , Sempere Lorenzo F.
Published: February 2024

There are limited options for primary prevention of breast cancer (BC). Experimental procedures to locally prevent BC have shown therapeutic efficacy in animal models. To determine the suitability of FDA-approved iodine-containing and various metal-containing (bismuth, gold, iodine, or tantalum) preclinical nanoparticle-based contrast agents for image-guided intraductal (ID) ablative treatment of BC in rodent models, we performed a prospective longitudinal study to determine the imaging performance, local retention and systemic clearance, safety profile, and compatibility with ablative solution of each contrast agent. At least six abdominal mammary glands (>3 female FVB/JN mice and/or Sprague-Dawley rats, 10–11 weeks of age) were intraductally injected with commercially available contrast agents (Omnipaque® 300, Fenestra® VC, MVivoTM Au, MVivoTM BIS) or in-house synthesized tantalum oxide (TaOx) nanoparticles. Contrast agents were administered at stock concentration or diluted in 70% ethanol (EtOH) and up to 1% ethyl cellulose (EC) as gelling agent to assess their compatibility with our image-guided ablative procedure. Mammary glands were serially imaged by microCT for up to 60 days after ID delivery. Imaging data were analyzed by radiologists and deep learning to measure in vivo signal disappearance of contrast agents. Mammary glands and major organs were ultimately collected for histopathological examination. TaOx-containing solutions provided best imaging performance for nitid visualization of ductal tree immediately after infusion, low outward diffusion (<1 day) and high homogeneity. Of all nanoparticles, TaOx had the highest local clearance rate (46% signal decay as stock and 36% as ablative solution 3 days after ID injection) and exhibited low toxicity. TaOx-containing ablative solution with 1% EC caused same percentage of epithelial cell death (88.62% ± 7.70% vs. 76.38% ± 9.99%, p value = 0.089) with similar minimal collateral damage (21.56 ± 5.28% vs. 21.50% ± 7.14%, p value = 0.98) in mouse and rat mammary glands, respectively. In conclusion, TaOx-nanoparticles are a suitable and versatile contrast agent for intraductal imaging and image-guided ablative procedures in rodent models of BC with translational potential to humans.
Lowering mutant huntingtin by small molecules relieves Huntington’s disease symptoms and progression
Authors: Bahat Anat , Itzhaki Elad , Weiss Benjamin , Tolmasov Michael , Tsoory Michael , Kuperman Yael , Brandis Alexander , Shurrush Khriesto A , Dikstein Rivka
Published: February 2024

Huntington’s disease (HD) is an incurable inherited disorder caused by a repeated expansion of glutamines in the huntingtin gene (Htt). The mutant protein causes neuronal degeneration leading to severe motor and psychological symptoms. Selective downregulation of the mutant Htt gene expression is considered the most promising therapeutic approach for HD. We report the identification of small molecule inhibitors of Spt5-Pol II, SPI-24 and SPI-77, which selectively lower mutant Htt mRNA and protein levels in HD cells. In the BACHD mouse model, their direct delivery to the striatum diminished mutant Htt levels, ameliorated mitochondrial dysfunction, restored BDNF expression, and improved motor and anxiety-like phenotypes. Pharmacokinetic studies revealed that these SPIs pass the blood-brain-barrier. Prolonged subcutaneous injection or oral administration to early-stage mice significantly delayed disease deterioration. SPI-24 long-term treatment had no side effects or global changes in gene expression. Thus, lowering mutant Htt levels by small molecules can be an effective therapeutic strategy for HD.
mGluR7 allosteric modulator AMN082 corrects protein synthesis and pathological phenotypes in FXS
Authors: Kumar Vipendra , Lee Kwan Young , Acharya Anirudh , Babik Matthew S , Christian-Hinman Catherine A , Rhodes Justin S , Tsai Nien-Pei
Published: February 2024

Fragile X syndrome (FXS) is the leading cause of inherited autism and intellectual disabilities. Aberrant protein synthesis due to the loss of fragile X messenger ribonucleoprotein (FMRP) is the major defect in FXS, leading to a plethora of cellular and behavioral abnormalities. However, no treatments are available to date. In this study, we found that activation of metabotropic glutamate receptor 7 (mGluR7) using a positive allosteric modulator named AMN082 represses protein synthesis through ERK1/2 and eIF4E signaling in an FMRP-independent manner. We further demonstrated that treatment of AMN082 leads to a reduction in neuronal excitability, which in turn ameliorates audiogenic seizure susceptibility in Fmr1 KO mice, the FXS mouse model. When evaluating the animals’ behavior, we showed that treatment of AMN082 reduces repetitive behavior and improves learning and memory in Fmr1 KO mice. This study uncovers novel functions of mGluR7 and AMN082 and suggests the activation of mGluR7 as a potential therapeutic approach for treating FXS.
A novel fluorescence–electrochemiluminescence dual-mode sensing platform for high-precision BRAF gene detection
Authors: Yu Fengyao , Qin Longyue , Zhang Hua , Qin Longshua , Fan Hao
Published: February 2024

In this study, we innovatively synthesized bipyridine ruthenium cluster nanosheets (RuMOFNCs), a novel metal–organic framework material that exhibits both fluorescence and electrochemiluminescence.