bluuebunny/crossref_metadata_2025 huggingface dataset:
†Estelestes ensis (Mammalia, Metatheria) from the early Eocene of Baja California (Mexico) as a generalized polydolopimorphian
Authors: Goin Francisco J. , Vieytes Emma Carolina , Crespo Vicente D. , Oliveira Édison V.
Published: January 2023

Estelestes ensis Novaceck et al., 1991 is a curious Paleogene metatherian mammal recognized on the basis of a single specimen from Baja California (Mexico) in southern North America. It comes from early Eocene (Wasatchian age) levels of the Las Tetas de Cabra Formation at “Marsupial Hill” in the Lomas Las Tetas de Cabra site (also known as Punta Prieta; see Novaceck et al., 1991). The specimen consists of a fragmentary left mandible with the last premolar, the roots of the first two molars, and almost complete last two molars (Fig. 1). It was referred to the Didelphini (Marsupialia, Didelphimorphia, Didelphidae, Didelphinae) even though Novaceck et al. (1991) stated that the overall morphology of the type specimen poses intriguing problems regarding its relationships. For example, the very deep, robust jaw of Estelestes distinguishes it from any other Holarctic “didelphine” (at the time Novaceck et al., 1991 published their work, both the concept and extent of Didelphidae and Didelphinae were much broader than today). Interestingly, they concluded that Estelestes had close affinities with “Mirandotherium” (lapsus calami for Mirandatherium), from the early Eocene of Itaboraí, in southeastern Brazil. “Resemblance between the two taxa is nevertheless striking, once again raising the possibility of close relationships among certain early members of the Northern Hemisphere and South American Didelphinae” (Novaceck et al., 1991, p. 16). The affinities of Mirandatherium are contested, having been regarded as part of the Didelphimorphia (e.g., de Paula Couto, 1952a) or Microbiotheria (e.g., Marshall, 1987; McKenna and Bell, 1997; Oliveira and Goin, 2011), or even as an alphadontian (Carneiro, 2019).
Miocene instead of Jurassic: the importance of sound fieldwork for paleontological data analysis
Authors: Fürsich Franz T. , Bhosale Suraj , Alberti Matthias , Pandey Dhirendra K.
Published: January 2023

A diverse molluscan assemblage dominated by turritellid gastropods found in Kachchh, western India, has been interpreted in the past as Late Jurassic (Oxfordian) in age, based on associated undoubtedly Oxfordian ammonites. Recently, several investigations focused on the assemblage dealing with taxonomic, paleoecological, and evolutionary aspects. An analysis of the associated bivalve fauna, foraminiferal assemblage, and the geological context strongly suggests a Miocene rather than a Jurassic age and invalidates several conclusions drawn from the alleged Jurassic age of the fossils.
“They Have No Property to Lose”: The Impasse of Free Labour in Lombard Silk Manufactures (1760–1810)
Authors: Avellino Lorenzo
Published: January 2023

With the abolition of the guild system and the rise of a new legal regime based on free contract, a central dilemma emerged in Europe: how to enforce labour control in this new era of individual economic freedom. This article examines how this issue was addressed in the State of Milan, where ideas about freedom of contract championed by state reformers such as Pietro Verri and Cesare Beccaria were met with continued requests from merchant-manufacturers to apply corporal punishment and threat of imprisonment to ensure workers’ attendance. Analysing the new regulations, the ideological credos of the new regime, and the effectiveness of the reforms as they played out on the ground in the silk industry, this article shows that the chance that labour relations could be managed within a civil law regime appeared to be in direct contrast with the dominant conception of workers’ conditions, in particular their lack of propriety and good faith. As credit-debt bonds and limitations to weavers’ mobility stood as the most effective means to ensure labour coercion, a closer look at the daily interactions in the workshop allows us to shed new light on the rationality of workers’ practices like Saint Monday, cast by contemporary commentators in merely moralistic terms.
Director Job Security and Corporate Innovation
Authors: Hsu Po-Hsuan , Lü Yiqing , Wu Hong , Xuan Yuhai
Published: January 2023

In this article, we show that firms can become conservative in innovation when their directors face job insecurity. We find that after the staggered enactment of majority voting legislation that strengthens shareholders’ power in director elections, firms produce fewer patents, particularly exploratory patents, and fewer forward citations. This effect is stronger for directors facing higher dismissal costs or threats and for firms with greater needs for board expertise and is mitigated by institutional investors’ expertise in innovation. Overall, our results suggest that heightened job insecurity induces director myopia, which leads to a reduction in investment in risky, long-term innovation projects.
Planarians to schistosomes: an overview of flatworm cell-types and regulators
Authors: Lee J.
Published: January 2023

Schistosomiasis remains a major neglected tropical disease that afflicts over 200 million people globally. Schistosomes, the aetiological agent of schistosomiasis, are parasitic flatworms that propagate between molluscan and mammalian hosts. Inside the mammalian host, schistosomes rapidly grow over 100-fold in size and develop into a sexually mature male or female that thrives in the bloodstream for several decades. Recent work has identified schistosome stem cells as the source that drives parasite transmission, reproduction and longevity. Moreover, studies have begun to uncover molecular programmes deployed by stem cells that are essential for tissue development and maintenance, parasite survival and immune evasion. Such programmes are reminiscent of neoblast-driven development and regeneration of planarians, the free-living flatworm relative of schistosomes. Over the last few decades, research in planarians has employed modern functional genomic tools that significantly enhanced our understanding of stem cell-driven animal development and regeneration. In this review, we take a broad stroke overview of major flatworm organ systems at the cellular and molecular levels. We summarize recent advances on genetic regulators that play critical roles in differentiation and maintenance of flatworm cell types. Finally, we provide perspectives on how investigation of basic parasite biology is critical to discovering new approaches to battle schistosomiasis.
Urbanicity and rates of untreated psychotic disorders in three diverse settings in the Global South
Authors: Roberts Tessa , Susser Ezra , Lee Pow Joni , Donald Casswina , John Sujit , Raghavan Vijaya , Ayinde Olatunde , Olley Bola , Miguel Esponda Georgina , Lam Joseph , Murray Robin M. , Cohen Alex , Weiss Helen A. , Hutchinson Gerard , Thara Rangaswamy , Gureje Oye , Burns Jonathan ,   INTREPID Group, Morgan Craig
Published: January 2023

Background

Extensive evidence indicates that rates of psychotic disorder are elevated in more urban compared with less urban areas, but this evidence largely originates from Northern Europe. It is unclear whether the same association holds globally. This study examined the association between urban residence and rates of psychotic disorder in catchment areas in India (Kancheepuram, Tamil Nadu), Nigeria (Ibadan, Oyo), and Northern Trinidad.

Methods

Comprehensive case detection systems were developed based on extensive pilot work to identify individuals aged 18–64 with previously untreated psychotic disorders residing in each catchment area (May 2018–April/May/July 2020). Area of residence and basic demographic details were collected for eligible cases. We compared rates of psychotic disorder in the more v. less urban administrative areas within each catchment area, based on all cases detected, and repeated these analyses while restricting to recent onset cases (<2 years/<5 years).

Results

We found evidence of higher overall rates of psychosis in more urban areas within the Trinidadian catchment area (IRR: 3.24, 95% CI 2.68–3.91), an inverse association in the Nigerian catchment area (IRR: 0.68, 95% CI 0.51–0.91) and no association in the Indian catchment area (IRR: 1.18, 95% CI 0.93–1.52). When restricting to recent onset cases, we found a modest positive association in the Indian catchment area.

Conclusions

This study suggests that urbanicity is associated with higher rates of psychotic disorder in some but not all contexts outside of Northern Europe. Future studies should test candidate mechanisms that may underlie the associations observed, such as exposure to violence.
Conceivability and perfect being theology
Authors: Leftow Brian
Published: January 2023

According to Jeff Speaks, one sort of perfect being theology takes its rise from a description of God as the greatest conceivable being. Speaks offers two problems for this project. One is finding a suitable sense of ‘conceivable’. The other concerns what he calls ‘troublemakers’, attributes that seem to show that God cannot be the greatest conceivable being. Speaks brings these together in a dilemma.
Thoughts on the etymologies ofennandhinnin Nordic
Authors: Lander Eric T.
Published: January 2023

This contribution focuses on Stroh-Wollin’s (2020 inNJL) etymologies of the Nordic definite articlesennandhinnand contrastivehinn/hitt. While I do not contest her central claim that Old Icelandicennand Mainland Scandinavianhinnhave separate historical origins, I do argue that her etymologies should not be accepted over more conventional ones already present in the literature. First, the etymology ofennshould, along traditional lines, be connected to Germanic cognates such as Gothicjain-, Germanjen-, and Englishyon(rather than derived from an ancient PIE *eno-).1Furthermore, contrastivehinn/hittand definitehinn/hitshould be considered a doublet, both ultimately deriving from a distal/contrastive element (rather than the article having separate origins in an innovated Proto-Nordic proximal demonstrative).
Response to COVID-19 in Lebanon: update, challenges and lessons learned
Authors: Abou Hassan Farouk F. , Bou Hamdan Mirna , Ali Farah , Melhem Nada M.
Published: January 2023

The COVID-19 pandemic remains a public health problem threatening national and global health security. The socio-economic impact of COVID-19 was more severe on developing countries including Lebanon, especially due to the fragile healthcare system, weak surveillance infrastructure and lack of comprehensive emergency preparedness and response plans. Lebanon has been struggling with plethora of challenges at the social, economic, financial, political and healthcare levels prior to the COVID-19 pandemic. The COVID-19 pandemic in Lebanon revealed gaps and challenges across the spectrum of preparedness and response to emergencies. Despite these challenges, the Lebanese response was successful in delaying the steep surge of COVID-19 cases and hospitalisations through imposing strict public health and social measures. The deployment of the national vaccination plan in Lebanon in February 2021 coincided with the reduction in the number of cases and hospitalisation rates. The aim of this manuscript is to advance the epidemiologic evolution of COVID-19 in Lebanon pre- and post-vaccination, the challenges affecting the response and recovery, and the lessons learned.
Antibiotic resistance genes and taxa analysis from mat and planktonic microbiomes of Antarctic perennial ice-covered Lake Fryxell and Lake Bonney
Authors: Tallada Sheetal , Hall Grant , Barich Daniel , Morgan-Kiss Rachael M. , Slonczewski Joan L.
Published: January 2023

The perennial ice-covered lakes of the Antarctic McMurdo Dry Valleys harbour oligotrophic microbial communities that are separated geographically from other aquatic systems. Their microbiomes include planktonic microbes as well as lift-off mat communities that emerge from the ice. We used the ShortBRED protein family profiler to quantify the antibiotic resistance genes (ARGs) from metagenomes of lift-off mats emerging from ice and from filtered water samples of Lake Fryxell and Lake Bonney. The overall proportion of ARG hits was similar to that found in temperate-zone rural ponds with moderate human inputs. Specific ARGs showed distinct distributions for the two lakes and for mat vs planktonic sources. Metagenomic taxa distributions showed that mat phototrophs consisted mainly of cyanobacteria or Betaproteobacteria, whereas the water column phototrophs were mainly protists. An enrichment culture of the Betaproteobacterium Rhodoferax antarcticus from a Lake Fryxell mat sample showed an unusual mat-forming phenotype not previously reported for this species. Its genome showed no ARGs associated with Betaproteobacteria but had ARGs consistent with a minor Pseudomonas component. The Antarctic lake mats and water showed specific ARGs distinctive to the mat and water sources, but overall ARG levels were similar to those of temperate water bodies with moderate human inputs.
On reduction and normalization in the computational core
Authors: Faggian Claudia , Guerrieri Giulio , de’ Liguoro Ugo , Treglia Riccardo
Published: January 2023

We study the reduction in a
$\lambda$
-calculus derived from Moggi’s computational one, which we call the computational core. The reduction relation consists of rules obtained by orienting three monadic laws. Such laws, in particular associativity and identity, introduce intricacies in the operational analysis. We investigate the central notions of returning a value versus having a normal form and address the question of normalizing strategies. Our analysis relies on factorization results.
A new kind of segmented mill from Africa Proconsularis
Authors: Souissi Skander
Published: January 2023

This paper attempts an overview of new kind of segmented mill, examples of which have been found at Thysdrus (El Jem) and Zama in Africa Proconsularis. These grain mills are quite different morphologically and technically from other mills in the ancient Mediterranean world. These rare archaeological finds are not discussed in the ancient literature or in modern scholarship, leaving them difficult to understand. This article explores the history of segmented mills and the operation and dating of this African mill type.
Weak Interactions, Strong Bonds: Live electronics as a complex system
Authors: Ben-Tal Oded
Published: January 2023

This article examines works for live, interactive electronics from the perspective of complex dynamic systems, placing the human–computer interaction within a wider set of relationships. From this perspective, composing equates to constructing a complex system with the performer(s) and the computer as key players within a wider network of interdependence. Using the author’s own compositions as examples, this article investigates the utility of a system view on interactive, live electronics.
User engagement with a popular food brand before, during and after a multi-day interactive marketing campaign on a popular live streaming platform
Authors: Haushalter Keally , Pritschet Sara J , Long John W , Edwards Caitlyn G , Boyland Emma J , Evans Rebecca K , Masterson Travis D
Published: January 2023

Objective:

To assess viewer engagement of a food advertising campaign on the live streaming platform Twitch.tv, a social media platform that allows creators to live stream content and communicate with their audience in real time.

Design:

Observational analysis of chat comments across the Twitch platform containing the word ‘Wendy’s’ or ‘Wendys’ during a 5-day ad campaign compared with two 5-day non-campaign time periods. Comments were categorised as positive, negative or neutral in how their sentiment pertained to the brand Wendy’s.

Setting:

Twitch chatrooms.

Participants:

None.

Results:

There were significantly more chatroom messages related to the Wendy’s brand during the campaign period. When considering all messages, the proportion of messages was statistically different (x2 = 1417·41, P < 0·001) across time periods, with a higher proportion of neutral and positive messages and a lower proportion of negative messages during the campaign compared with the comparison periods. Additionally, the proportion of negative messages following the campaign was lower than before the campaign. When considering only positive and negative messages, the proportion of messages was statistically different (x2 = 366·38, P < 0·001) across each time period with a higher proportion of positive messages and a lower proportion of negative messages during the campaign when compared with the other time periods. Additionally, there was a higher proportion of positive messages and a lower portion of negative messages following the campaign when compared with before the campaign.

Conclusions:

This study demonstrates the impact and sustained impact of a fast-food brand ad campaign on brand engagement on the live streaming platform Twitch.
Penta-band rectangular slot antenna for multi-function wireless communication with linear and circular polarizations
Authors: Wang Haiyang , Liu Xiaoming , Yang Xiaofan , Fang Zhibin , Zhang Ran , Wang Ye
Published: January 2023

This paper presents a multi-band rectangular slot antenna, which can be used in Beidou navigation system, 4G, WLAN and 5G system. The proposed antenna adopts a single feeding line, generating circular polarization for satellite navigation, and linear polarization for mobile communication systems. The proposed antenna consists of three c-type resonators and three rectangular loop slots. A c-type resonator and a rectangular loop slot work together to produce a usable frequency band. Multiple frequency bands can be generated by increasing the number of c-type resonator and rectangular loop slots. It is found that the c-type resonator changes the current distribution on the antenna surface, making the axial ratio less than 3 dB in the low frequency bands. Eventually, five operation frequency bands are realized. Experimentally, it is verified that the impedance bandwidths of each frequency band are 11.8% (1.12–1.26 GHz), 15.4% (1.5–1.75 GHz), 11.9% (2.36–2.66 GHz), 19.7% (3.15–3.84 GHz) and 2.6% (4.47–4.59 GHz), respectively. The measured 3 dB axial ratio bandwidths are 20 MHz at 1.2 and 1.56 GHz, fully covering BDS B1 and B2 bands. The measured gains are 3, 3.59, 4.07, 4.2 and 4.35 dBi, respectively.
Humanitarianism and affect-based education: Emotional experiences at the Jean-Pictet Competition
Authors: Sutton Rebecca , Buis Emiliano J.
Published: January 2023

For international lawyers seeking to promote compliance with international humanitarian law (IHL), some level of affective awareness is essential – but just where one might cultivate an understanding of emotions, and at which juncture of one's career, remains a mystery. This article proposes that what the IHL lawyers and advocates of the future need is an affect-based education. More than a simple mastery of a technical set of emotional intelligence skills, what we are interested in here is the refinement of a disposition or sensibility – a way of engaging with the world, with IHL, and with humanitarianism. In this article, we consider the potential for the Jean-Pictet Competition to provide this education. Drawing on our observations of the competition and a survey with 231 former participants, the discussion examines the legal and affective dimensions of the competition, identifies the precise moments of the competition in which emotional processes take place, and probes the role of emotions in role-plays and simulations. Presenting the Jean-Pictet Competition as a form of interaction ritual, we propose that high “emotional energy” promotes a humanitarian sensibility; indeed, participant interactions have the potential to re-constitute the very concept of humanitarianism. We ultimately argue that a more conscious engagement with emotions at competitions like Pictet has the potential to strengthen IHL training, to further IHL compliance and the development of IHL rules, and to enhance legal education more generally.
The hidden contestation of norms: Decent work in the International Labour Organization and the United Nations
Authors: Drubel Julia , Mende Janne
Published: January 2023

The question of whether global norms are experiencing a crisis allows for two concurrent answers. From a facticity perspective, certain global norms are in crisis, given their worldwide lack of implementation and effectiveness. From a validity perspective, however, a crisis is not obvious, as these norms are not openly contested discursively and institutionally. In order to explain the double diagnosis (crisis/no crisis), this article draws on international relations research on norm contestation and norm robustness. It proposes the concept ofhidden discursive contestationand distinguishes it from three other key types of norm contestation: open discursive, open non-discursive and hidden non-discursive contestation. We identify four manifestations of hidden discursive contestation in: (1) the deflection of responsibility; (2) forestalling norm strengthening; (3) displaying norms as functional means to an end; and (4) downgrading or upgrading single norm elements. Our empirical focus is on the decent work norm, which demonstrates the double diagnosis. While it lacks facticity, it enjoys far-reaching verbal acceptance and high validity. Our qualitative analysis of discursive hidden contestation draws on two case studies: the International Labour Organization’s compliance procedures, which monitor international labour standards, and the United Nations Treaty Process on a binding instrument for business and human rights. Although both fora have different context and policy cycles, they exhibit similar strategies of hidden discursive contestation.
Phenomenology as a resource for translational research in mental health: methodological trends, challenges and new directions
Authors: Ritunnano R. , Papola D. , Broome M.R. , Nelson B.
Published: January 2023

This editorial reflects on current methodological trends in translational research in mental health. It aims to build a bridge between two fields that are frequently siloed off from each other: interventional research and phenomenologically informed research. Recent years have witnessed a revival of phenomenological approaches in mental health, often – but not only – as a means of connecting the subjective character of experience with neurobiological explanatory accounts of illness. Rich phenomenological knowledge accrued in schizophrenia, and wider psychosis research, has opened up new opportunities for improving prediction, early detection, diagnosis, prognostic stratification, treatment and ethics of care. Novel qualitative studies of delusions and hallucinations have challenged longstanding assumptions about their nature and meaning, uncovering highly complex subjective dimensions that are not adequately captured by quantitative methodologies. Interdisciplinary and participatory research efforts, informed by phenomenological insights, have prompted revisions of pre-established narratives of mental disorder dominated by a dysfunction framework and by researcher-centric outcome measures. Despite these recent advances, there has been relatively little effort to integrate and translate phenomenological insights across applied clinical research, with the goal of producing more meaningful, patient-valued results. It is our contention that phenomenological psychopathology – as the basic science of psychiatry – represents an important methodology for advancing evidence-based practices in mental health, and ultimately improving real-world outcomes. Setting this project into motion requires a greater emphasis on subjectivity and the structures of experience, more attention to the quality and patient-centredness of outcome measures, and the identification of treatment targets that matter most to patients.
Automated Classification of Estuarine Sub‐Depositional Environment Using Sediment Texture
Authors: Houghton J. E. , Nichols T. E. , Griffiths J. , Simon N. , Utley J. E. P. , Duller R. A. , Worden R. H.
Published: January 2023

Interpretation of unconsolidated Quaternary sedimentary core is difficult if key diagnostic features are obscured or not present, therefore traditional facies analysis is challenging. However, sediment texture remains a universal attribute which can be used to interpret sedimentary core. Here we present an automated classification workflow which implements Extreme Gradient Boosting and Bayesian Optimization of hyperparameters to differentiate estuarine sub‐depositional environments. We use 19 textural attributes, measured using laser particle size analysis of surface sediment samples from the Ravenglass Estuary, Cumbria, northwest England, to make unbiased classification of sub‐depositional environment and estuarine zone. Two predictive models created using the automated workflow are presented and evaluated using a suite of evaluation metrics, confusion matrices, and spatial analysis to understand their geological implications. Model 1 keeps all sub‐depositional environments discrete and has an overall accuracy of 68.96%. Model 2 merges related sub‐depositional environments to form inner‐coarse and outer‐estuary zones and has an overall accuracy of 84.14%. Both models have been applied to textural data obtained at 5 cm intervals from a Holocene core drilled through a tidal bar in the Ravenglass estuarine succession, NW England, to classify palaeo sub‐depositional environment. Predictive output of the models suggests that the core consistently experienced inner estuary deposition; all inner estuary environments are represented in the core. The workflow presented here could be applied to datasets from other marginal marine depositional systems to enhance the interpretation of their subsurface deposits. Ultimately, detailed interpretations of ancient, buried deposits could be made using models derived from analogous modern systems.
Simulating Global Dynamic Surface Reflectances for Imaging Spectroscopy Spaceborne Missions: LPJ‐PROSAIL
Authors: Poulter Benjamin , Currey Bryce , Calle Leonardo , Shiklomanov Alexey N. , Amaral Cibele H. , Brookshire E. N. Jack , Campbell Petya , Chlus Adam , Cawse‐Nicholson Kerry , Huemmrich Fred , Miller Charles E. , Miner Kimberley , Pierrat Zoe , Raiho Ann M. , Schimel David , Serbin Shawn , Smith William K. , Stavros Natasha , Stutz Jochen , Townsend Phil , Thompson David R. , Zhang Zhen
Published: January 2023

Spectroscopic reflectance data provide novel information on the properties of the Earth's terrestrial and aquatic surfaces. Until recently, imaging spectroscopy missions were dependent mainly on airborne instruments, such as the Next Generation Airborne Visible InfraRed Imaging Spectrometer (AVIRIS‐NG), providing limited spatial and temporal observations. Currently, there is an emergence of spaceborne imaging spectroscopy missions, which require advances in end‐to‐end model support for traceability studies. To provide this support, the LPJ‐wsl dynamic global vegetation model is coupled with the canopy radiative transfer model, PROSAIL, to generate global, gridded, daily visible to shortwave infrared (VSWIR) spectra (400–2,500 nm). LPJ‐wsl variables are cross‐walked to meet required PROSAIL parameters, which include leaf structure, chlorophyll a + b, brown pigment, equivalent water thickness, and dry matter content. Simulated spectra are compared to a boreal forest site, a temperate forest, managed grassland, a dryland and a tropical forest site using reflectance data from tower‐mounted, aircraft, and spaceborne imagers. We find that canopy nitrogen and leaf‐area index are the most uncertain variables in translating LPJ‐wsl to PROSAIL parameters but at first order, LPJ‐PROSAIL successfully simulates surface reflectance dynamics. Future work will optimize functional relationships required for improving PROSAIL parameters and include the development of the LPJ‐model to represent improvements in leaf water content and canopy nitrogen. The LPJ‐PROSAIL model is intended to support missions such as NASA's Surface Biology and Geology and subsequent modeled products related to the carbon cycle and hydrology.
Targeted therapy for head and neck cancer: signaling pathways and clinical studies
Authors: Li Qingfang , Tie Yan , Alu Aqu , Ma Xuelei , Shi Huashan
Published: January 2023

Head and neck cancer (HNC) is malignant, genetically complex and difficult to treat and is the sixth most frequent cancer, with tobacco, alcohol and human papillomavirus being major risk factors. Based on epigenetic data, HNC is remarkably heterogeneous, and treatment remains challenging. There is a lack of significant improvement in survival and quality of life in patients with HNC. Over half of HNC patients experience locoregional recurrence or distal metastasis despite the current multiple traditional therapeutic strategies and immunotherapy. In addition, resistance to chemotherapy, radiotherapy and some targeted therapies is common. Therefore, it is urgent to explore more effective and tolerable targeted therapies to improve the clinical outcomes of HNC patients. Recent targeted therapy studies have focused on identifying promising biomarkers and developing more effective targeted therapies. A well understanding of the pathogenesis of HNC contributes to learning more about its inner association, which provides novel insight into the development of small molecule inhibitors. In this review, we summarized the vital signaling pathways and discussed the current potential therapeutic targets against critical molecules in HNC, as well as presenting preclinical animal models and ongoing or completed clinical studies about targeted therapy, which may contribute to a more favorable prognosis of HNC. Targeted therapy in combination with other therapies and its limitations were also discussed.
Epigenetic and post-translational modifications in autophagy: biological functions and therapeutic targets
Authors: Shu Feng , Xiao Han , Li Qiu-Nuo , Ren Xiao-Shuai , Liu Zhi-Gang , Hu Bo-Wen , Wang Hong-Sheng , Wang Hao , Jiang Guan-Min
Published: January 2023

Autophagy is a conserved lysosomal degradation pathway where cellular components are dynamically degraded and re-processed to maintain physical homeostasis. However, the physiological effect of autophagy appears to be multifaced. On the one hand, autophagy functions as a cytoprotective mechanism, protecting against multiple diseases, especially tumor, cardiovascular disorders, and neurodegenerative and infectious disease. Conversely, autophagy may also play a detrimental role via pro-survival effects on cancer cells or cell-killing effects on normal body cells. During disorder onset and progression, the expression levels of autophagy-related regulators and proteins encoded by autophagy-related genes (ATGs) are abnormally regulated, giving rise to imbalanced autophagy flux. However, the detailed mechanisms and molecular events of this process are quite complex. Epigenetic, including DNA methylation, histone modifications and miRNAs, and post-translational modifications, including ubiquitination, phosphorylation and acetylation, precisely manipulate gene expression and protein function, and are strongly correlated with the occurrence and development of multiple diseases. There is substantial evidence that autophagy-relevant regulators and machineries are subjected to epigenetic and post-translational modulation, resulting in alterations in autophagy levels, which subsequently induces disease or affects the therapeutic effectiveness to agents. In this review, we focus on the regulatory mechanisms mediated by epigenetic and post-translational modifications in disease-related autophagy to unveil potential therapeutic targets. In addition, the effect of autophagy on the therapeutic effectiveness of epigenetic drugs or drugs targeting post-translational modification have also been discussed, providing insights into the combination with autophagy activators or inhibitors in the treatment of clinical diseases.
Transcriptional and post-transcriptional control of autophagy and adipogenesis by YBX1
Authors: Wu Ruifan , Feng Shengchun , Li Fan , Shu Gang , Wang Lina , Gao Ping , Zhu Xiaotong , Zhu Canjun , Wang Songbo , Jiang Qingyan
Published: January 2023

Obesity is strongly associated with metabolic diseases, which have become a global health problem. Exploring the underlying mechanism of adipogenesis is crucial for the treatment of excess white fat. Oncogene YBX1 is a multifunctional DNA- and RNA-binding protein that regulates brown adipogenesis. However, the role of YBX1 in white adipogenesis and adipose tissue expansion remains unknown. Here, we showed that YBX1 deficiency inhibited murine and porcine adipocyte differentiation. YBX1 positively regulated adipogenesis through promoting ULK1- and ULK2-mediated autophagy. Mechanistically, we identified YBX1 serves as a 5-methylcytosine (m5C)-binding protein directly targeting m5C-containingUlk1mRNA by using RNA immunoprecipitation. RNA decay assay further proved that YBX1 upregulated ULK1 expression though stabilizing its mRNA. Meanwhile, YBX1 promotedUlk2transcription and expression as a transcription factor, thereby enhancing autophagy and adipogenesis. Importantly, YBX1 overexpression in white fat enhanced ULK1/ULK2-mediated autophagy and promoted adipose tissue expansion in mice. Collectively, these findings unveil the post-transcriptional and transcriptional mechanism and functional importance of YBX1 in autophagy and adipogenesis regulation, providing an attractive molecular target for therapies of obesity and metabolic diseases.
Single-cell RNA-seq integrated with multi-omics reveals SERPINE2 as a target for metastasis in advanced renal cell carcinoma
Authors: Chen Wen-jin , Dong Ke-qin , Pan Xiu-wu , Gan Si-shun , Xu Da , Chen Jia-xin , Chen Wei-jie , Li Wen-yan , Wang Yu-qi , Zhou Wang , Rini Brian , Cui Xin-gang
Published: January 2023

Tumor growth, metastasis and therapeutic response are believed to be regulated by the tumor and its microenvironment (TME) in advanced renal cell carcinoma (RCC). However, the mechanisms underlying genomic, transcriptomic and epigenetic alternations in RCC progression have not been completely defined. In this study, single-cell RNA-sequencing (scRNA-seq) data were obtained from eight tissue samples of RCC patients, including two matched pairs of primary and metastatic sites (lymph nodes), along with Hi-C, transposable accessible chromatin by high-throughput (ATAC-seq) and RNA-sequencing (RNA-seq) between RCC (Caki-1) and human renal tubular epithelial cell line (HK-2). The identified target was verified in clinical tissue samples (microarray of 407 RCC patients, TMA-30 and TMA-2020), whose function was further validated by in vitro and in vivo experiments through knockdown or overexpression. We profiled transcriptomes of 30514 malignant cells, and 14762 non-malignant cells. Comprehensive multi-omics analysis revealed that malignant cells and TME played a key role in RCC. The expression programs of stromal cells and immune cells were consistent among the samples, whereas malignant cells expressed distinct programs associated with hypoxia, cell cycle, epithelial differentiation, and two different metastasis patterns. Comparison of the hierarchical structure showed that SERPINE2 was related to these NNMF expression programs, and at the same time targeted the switched compartment. SERPINE2 was highly expressed in RCC tissues and lowly expressed in para-tumor tissues or HK-2 cell line. SERPINE2 knockdown markedly suppressed RCC cell growth and invasion, while SERPINE2 overexpression dramatically promoted RCC cell metastasis both in vitro and in vivo. In addition, SERPINE2 could activate the epithelial-mesenchymal transition pathway. The above findings demonstrated that the role of distinct expression patterns of malignant cells and TME played a distinct role in RCC progression. SERPINE2 was identified as a potential therapeutic target for inhibiting metastasis in advanced RCC.
An artificial synapse based on molecular junctions
Authors: Zhang Yuchun , Liu Lin , Tu Bin , Cui Bin , Guo Jiahui , Zhao Xing , Wang Jingyu , Yan Yong
Published: January 2023

Shrinking the size of the electronic synapse to molecular length-scale, for example, an artificial synapse directly fabricated by using individual or monolayer molecules, is important for maximizing the integration density, reducing the energy consumption, and enabling functionalities not easily achieved by other synaptic materials. Here, we show that the conductance of the self-assembled peptide molecule monolayer could be dynamically modulated by placing electrical biases, enabling us to implement basic synaptic functions. Both short-term plasticity (e.g., paired-pulse facilitation) and long-term plasticity (e.g., spike-timing-dependent plasticity) are demonstrated in a single molecular synapse. The dynamic current response is due to a combination of both chemical gating and coordination effects between Ag+ and hosting groups within peptides which adjusts the electron hopping rate through the molecular junction. In the end, based on the nonlinearity and short-term synaptic characteristics, the molecular synapses are utilized as reservoirs for waveform recognition with 100% accuracy at a small mask length.
Cryo-EM structure of hnRNPDL-2 fibrils, a functional amyloid associated with limb-girdle muscular dystrophy D3
Authors: Garcia-Pardo Javier , Bartolomé-Nafría Andrea , Chaves-Sanjuan Antonio , Gil-Garcia Marcos , Visentin Cristina , Bolognesi Martino , Ricagno Stefano , Ventura Salvador
Published: January 2023

hnRNPDL is a ribonucleoprotein (RNP) involved in transcription and RNA-processing that hosts missense mutations causing limb-girdle muscular dystrophy D3 (LGMD D3). Mammalian-specific alternative splicing (AS) renders three natural isoforms, hnRNPDL-2 being predominant in humans. We present the cryo-electron microscopy structure of full-length hnRNPDL-2 amyloid fibrils, which are stable, non-toxic, and bind nucleic acids. The high-resolution amyloid core consists of a single Gly/Tyr-rich and highly hydrophilic filament containing internal water channels. The RNA binding domains are located as a solenoidal coat around the core. The architecture and activity of hnRNPDL-2 fibrils are reminiscent of functional amyloids, our results suggesting that LGMD D3 might be a loss-of-function disease associated with impaired fibrillation. Strikingly, the fibril core matches exon 6, absent in the soluble hnRNPDL-3 isoform. This provides structural evidence for AS controlling hnRNPDL assembly by precisely including/skipping an amyloid exon, a mechanism that holds the potential to generate functional diversity in RNPs.
Integrative analysis of multiple genomic data from intrahepatic cholangiocarcinoma organoids enables tumor subtyping
Authors: Lee Hee Seung , Han Dai Hoon , Cho Kyungjoo , Park Soo Been , Kim Chanyang , Leem Galam , Jung Dawoon E. , Kwon Soon Sung , Kim Chul Hoon , Jo Jung Hyun , Lee Hye Won , Song Si Young , Park Jun Yong
Published: January 2023

As genomic analysis technology has advanced, it has become possible to sub-classify intrahepatic cholangiocarcinoma (ICC) at the histological or molecular level. Here, we verify the recently suggested two subgroups of ICC in the organoids model, compare the characteristics between types. ICC patients are subclassified into small-duct (SD) and large-duct (LD) subtype according to histological characteristics. ICC organoids are established, and unsupervised principal component analysis clustering separates each type of ICC. Differential gene expression reveals enrichment on KRAS, TGFβ and ERBB2 signaling pathways in LD-type compared with SD-type (P < 0.05). Gene set enrichment analysis demonstrates that the cholangiocarcinoma class 2 signature, defined by Andersen et al., is enriched in the LD-type (enrichment Score = 2.19, P < 0.001). A protein-protein interaction network analysis identifies ZNF217 as a significant hub protein (odds ratio = 4.96, P = 0.0105). We perform prospective modeling of histological subtype using patient-derived organoids. Moreover, gene expression profiling of ICC organoids enables identification of type-specific targetable pathways.
Inhibiting myostatin signaling partially mitigates structural and functional adaptations to hindlimb suspension in mice
Authors: Hanson Andrea M. , Young Mary H. , Harrison Brooke C. , Zhou Xiaolan , Han H. Q. , Stodieck Louis S. , Ferguson Virginia L.
Published: January 2023

Novel treatments for muscle wasting are of significant value to patients with disease states that result in muscle weakness, injury recovery after immobilization and bed rest, and for astronauts participating in long-duration spaceflight. We utilized an anti-myostatin peptibody to evaluate how myostatin signaling contributes to muscle loss in hindlimb suspension. Male C57BL/6 mice were left non-suspended (NS) or were hindlimb suspended (HS) for 14 days and treated with a placebo vehicle (P) or anti-myostatin peptibody (D). Hindlimb suspension (HS-P) resulted in rapid and significantly decreased body mass (−5.6% by day 13) with hindlimb skeletal muscle mass losses between −11.2% and −22.5% and treatment with myostatin inhibitor (HS-D) partially attenuated these losses. Myostatin inhibition increased hindlimb strength with no effect on soleus tetanic strength. Soleus mass and fiber CSA were reduced with suspension and did not increase with myostatin inhibition. In contrast, the gastrocnemius showed histological evidence of wasting with suspension that was partially mitigated with myostatin inhibition. While expression of genes related to protein degradation (Atrogin-1 and Murf-1) in the tibialis anterior increased with suspension, these atrogenes were not significantly reduced by myostatin inhibition despite a modest activation of the Akt/mTOR pathway. Taken together, these findings suggest that myostatin is important in hindlimb suspension but also motivates the study of other factors that contribute to disuse muscle wasting. Myostatin inhibition benefitted skeletal muscle size and function, which suggests therapeutic potential for both spaceflight and terrestrial applications.
Diffusion in liquid mixtures
Authors: Vailati A. , Bataller H. , Bou-Ali M. M. , Carpineti M. , Cerbino R. , Croccolo F. , Egelhaaf S. U. , Giavazzi F. , Giraudet C. , Guevara-Carrion G. , Horváth D. , Köhler W. , Mialdun A. , Porter J. , Schwarzenberger K. , Shevtsova V. , De Wit A.
Published: January 2023

The understanding of transport and mixing in fluids in the presence and in the absence of external fields and reactions represents a challenging topic of strategic relevance for space exploration. Indeed, mixing and transport of components in a fluid are especially important during long-term space missions where fuels, food and other materials, needed for the sustainability of long space travels, must be processed under microgravity conditions. So far, the processes of transport and mixing have been investigated mainly at the macroscopic and microscopic scale. Their investigation at the mesoscopic scale is becoming increasingly important for the understanding of mass transfer in confined systems, such as porous media, biological systems and microfluidic systems. Microgravity conditions will provide the opportunity to analyze the effect of external fields and reactions on optimizing mixing and transport in the absence of the convective flows induced by buoyancy on Earth. This would be of great practical applicative relevance to handle complex fluids under microgravity conditions for the processing of materials in space.
Dynamic physiological α-synuclein S129 phosphorylation is driven by neuronal activity
Authors: Ramalingam Nagendran , Jin Shan-Xue , Moors Tim E. , Fonseca-Ornelas Luis , Shimanaka Kazuma , Lei Shi , Cam Hugh P. , Watson Aurelia Hays , Brontesi Lisa , Ding Lai , Hacibaloglu Dinc Yasat , Jiang Haiyang , Choi Se Joon , Kanter Ellen , Liu Lei , Bartels Tim , Nuber Silke , Sulzer David , Mosharov Eugene V. , Chen Weisheng V. , Li Shaomin , Selkoe Dennis J. , Dettmer Ulf
Published: January 2023

In Parkinson’s disease and other synucleinopathies, the elevation of α-synuclein phosphorylated at Serine129 (pS129) is a widely cited marker of pathology. However, the physiological role for pS129 has remained undefined. Here we use multiple approaches to show for the first time that pS129 functions as a physiological regulator of neuronal activity. Neuronal activity triggers a sustained increase of pS129 in cultured neurons (200% within 4 h). In accord, brain pS129 is elevated in environmentally enriched mice exhibiting enhanced long-term potentiation. Activity-dependent α-synuclein phosphorylation is S129-specific, reversible, confers no cytotoxicity, and accumulates at synapsin-containing presynaptic boutons. Mechanistically, our findings are consistent with a model in which neuronal stimulation enhances Plk2 kinase activity via a calcium/calcineurin pathway to counteract PP2A phosphatase activity for efficient phosphorylation of membrane-bound α-synuclein. Patch clamping of rat SNCA−/− neurons expressing exogenous wild-type or phospho-incompetent (S129A) α-synuclein suggests that pS129 fine-tunes the balance between excitatory and inhibitory neuronal currents. Consistently, our novel S129A knock-in (S129AKI) mice exhibit impaired hippocampal plasticity. The discovery of a key physiological function for pS129 has implications for understanding the role of α-synuclein in neurotransmission and adds nuance to the interpretation of pS129 as a synucleinopathy biomarker.
A topographic atlas defines developmental origins of cell heterogeneity in the human embryonic lung
Authors: Sountoulidis Alexandros , Marco Salas Sergio , Braun Emelie , Avenel Christophe , Bergenstråhle Joseph , Theelke Jonas , Vicari Marco , Czarnewski Paulo , Liontos Andreas , Abalo Xesus , Andrusivová Žaneta , Mirzazadeh Reza , Asp Michaela , Li Xiaofei , Hu Lijuan , Sariyar Sanem , Martinez Casals Anna , Ayoglu Burcu , Firsova Alexandra , Michaëlsson Jakob , Lundberg Emma , Wählby Carolina , Sundström Erik , Linnarsson Sten , Lundeberg Joakim , Nilsson Mats , Samakovlis Christos
Published: January 2023

The lung contains numerous specialized cell types with distinct roles in tissue function and integrity. To clarify the origins and mechanisms generating cell heterogeneity, we created a comprehensive topographic atlas of early human lung development. Here we report 83 cell states and several spatially resolved developmental trajectories and predict cell interactions within defined tissue niches. We integrated single-cell RNA sequencing and spatially resolved transcriptomics into a web-based, open platform for interactive exploration. We show distinct gene expression programmes, accompanying sequential events of cell differentiation and maturation of the secretory and neuroendocrine cell types in proximal epithelium. We define the origin of airway fibroblasts associated with airway smooth muscle in bronchovascular bundles and describe a trajectory of Schwann cell progenitors to intrinsic parasympathetic neurons controlling bronchoconstriction. Our atlas provides a rich resource for further research and a reference for defining deviations from homeostatic and repair mechanisms leading to pulmonary diseases.