bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of Forester Traits and Advising Approaches on Landowners’ Intention to Follow Recommendations About Maple Sugarbush Management among Sap Producers in Wisconsin
Authors: Chang Chen-Ting , Shaw Bret R , Solin Jeremy , Gorby Tricia A , Robinson Patrick
Published: June 2023

The maple syrup industry has growth potential in the United States. Foresters can help expand the maple syrup industry by supporting private forest management decisions to improve maple tree health and sap production. This study examined the influence of advice solicitation, active listening, and forester traits (i.e., expertise, confidence, trustworthiness, shared forestland values) on outcomes of professional advice about maple syrup production and sugarbush management. Regression models were used to analyze data from a survey targeted at Wisconsin maple syrup producers (n = 149). Compared with unsolicited advice, advice outcomes were more positive when landowners actively sought it, although advice solicitation had a stronger influence on perceived quality of advice than advice utilization. Landowners evaluated advice more positively and had greater intention to use the advice when the forester actively listened to them. Perceiving positive traits in the forester has the strongest impact on landowners’ evaluations and adoption of advice.

Study Implications: By examining the role of forester traits, giving (un)solicited advice, and active listening in affecting private forest landowners’ perceptions and use of advice about maple syrup production and sugarbush management, this study informs the design of training programs aimed at equipping foresters with effective communication skills. To achieve optimal communication outcomes, foresters should tactfully create the perception that the landowner requested their advice, such as by eliciting questions and encouraging landowners to explain their management motivations. Further, foresters should demonstrate expertise, show confidence, build trust, and create compatible management philosophies with the landowner by acknowledging the landowner’s perspectives.
Trajectories of Traumatic Stress Symptoms Among Siblings of Children With Cancer: The First Two Years Post-Diagnosis
Authors: Alderfer Melissa A , Amaro Christina M , Kripalani Simran , Taggi Pinto Alison , Lewis Amanda M , Arasteh Kamyar , Hildenbrand Aimee K , Lown E Anne , Long Kristin A
Published: June 2023

Objective

Identify and describe trajectories of cancer-related posttraumatic stress symptoms (PTSS) among siblings of children with cancer within two years of diagnosis.

Method

Siblings (aged 8–18; M = 11.2 years) across the United States, and for each, one caregiver, were recruited for a cohort sequential longitudinal study with three data collection points six months apart beginning at 6- or 12-months after cancer diagnosis. Siblings (N = 229; 42% of eligible/approached; 53% identifying as female; 68% identifying as non-Hispanic White) completed the Child Posttraumatic Stress Disorder Symptom Scale. Caregivers completed the Strengths and Difficulties Questionnaire (SDQ). Latent class growth analysis (LCGA) and growth mixture modeling (GMM) identified PTSS patterns across time.

Results

Fit statistics supported models with three to five PTSS trajectories. The three-class LCGA model included a large mild PTSS group (61%), a moderate PTSS group (35%), and a small (4%) stable severe PTSS group. The four-class LCGA and three- and four-class GMM included groups improving from moderate to mild PTSS (7–21%) and worsening to moderate PTSS across time (12–17%). Across models, siblings with mild PTSS had fewer caregiver-reported emotional and behavioral difficulties on the SDQ.

Conclusions

A large group of siblings of children with cancer demonstrate resiliency, however, substantial subsets experience patterns of PTSS that include levels in the moderate-to-severe range during the first two years post-diagnosis. Future research should examine these patterns in more diverse/representative samples and identify factors associated with increasing and sustained severe PTSS to inform intervention targets and reduce cancer-related burden on families.
Personality recognition in Digital Humanities: A review of computational approaches in the humanities
Authors: Picca Davide , Pitteloud Jocelin
Published: June 2023

One of the most fascinating aspects of human beings is their personality. Two models that are currently being researched and widely used in computational approaches are the Myers–Briggs Type Indicator and the Big Five (or OCEAN). In this study, we will briefly examine the history of these two models and the current state of their applications in the Digital Humanities field. Although categorizing research in Digital Humanities is a challenging task, we have chosen to include works that, while primarily psychological in nature, use methodologies and methods from Digital Humanities, specifically in literary texts. Consequently, we can divide this research into two categories. On the one hand, there are works that aim to study and identify the personalities of fictional characters in literature or movies. On the other hand, there are works that aim to recreate personalities in virtual characters based on a predetermined model. We will therefore examine the works proposed by the scientific community for both approaches.
StarUnLink: identifying and mitigating signals from communication satellites in stellar spectral surveys
Authors: Bialek Spencer , Lucatello Sara , Fabbro Sebastien , Yi Kwang Moo , Venn Kim A
Published: June 2023

A relatively new concern for the forthcoming massive spectroscopic sky surveys is the impact of contamination from low earth orbit satellites. Several hundred thousand of these satellites are licensed for launch in the next few years and it has been estimated that, in some cases, up to a few per cent of spectra could be contaminated when using wide field, multifibre spectrographs. In this paper, a multistaged approach is used to assess the practicality and limitations of identifying and minimizing the impact of satellite contamination in a WEAVE-like stellar spectral survey. We develop a series of convolutional-network-based architectures to attempt identification, stellar parameter and chemical abundances recovery, and source separation of stellar spectra that we artificially contaminate with satellite (i.e. solar-like) spectra. Our results show that we are able to flag 67 per cent of all contaminated sources at a precision level of 80 per cent for low-resolution spectra and 96 per cent for high-resolution spectra. Additionally, we are able to remove the contamination from the spectra and recover the clean spectra with a <1 per cent reconstruction error. The errors in stellar parameter predictions reduce by up to a factor of 2–3 when either including contamination as an augmentation to a training set or by removing the contamination from the spectra, with overall better performance in the former case. The presented methods illustrate several machine learning mitigation strategies that can be implemented to improve stellar parameters for contaminated spectra in the WEAVE stellar spectroscopic survey and others like it.
A Novel HRD Signature Is Predictive of FOLFIRINOX Benefit in Metastatic Pancreatic Cancer
Authors: Chen Kuei-Ting , Madison Russell , Moore Jay , Jin Dexter , Fleischmann Zoe , Newberg Justin , Schrock Alexa , Bhardwaj Neeru , Lofgren Katherine T , He Jie , Frampton Garrett , Hegde Priti , Fabrizio David , Pishvaian Michael J , Ebot Ericka , Singhi Aatur , Sokol Ethan
Published: June 2023

Background

Pancreatic cancer (PC) represents an aggressive disease with median overall survival (OS) of less than 1 year in the front-line setting. FOLFIRINOX and gemcitabine and paclitaxel (GP) are standard of care options for these patients; however, optimal selection of therapy is challenging.

Methods

Comprehensive genomic profiling was performed on 8358 PC patients. Outcomes were available for 1149 metastatic PC patients treated with 1L FOLFIRINOX or GP. A scar-based measure of HRD was called using a machine learning-based algorithm incorporating copy number and indel features.

Results

A scar-based HRD signature (HRDsig) was identified in 9% of patients. HRDsig significantly co-occurred with biallelic alterations in BRCA1/2, PALB2, BARD1, and RAD51C/D, but encompassed a larger population than that defined by BRCA1/BRCA2/PALB2 (9% vs. 6%). HRDsig was predictive of 1L FOLFIRNOX chemotherapy benefit with doubled OS relative to gemcitabine and paclitaxel (GP) (rwOS aHR 0.37 [0.22-0.62]), including 25% of the population with long-term (2 year+) survival in a real-world cohort of patients. Less benefit from FOLFIRINOX was observed in the HRDsig(−) population. Predictive value was seen in both the BRCA1/2/PALB2 mutant and wildtype populations, suggesting additional value to mutational profiling.

Conclusion

A scar-based HRD biomarker was identified in a significant fraction of PC patients and is predictive of FOLFIRINOX benefit. Incorporating a biomarker like HRDsig could identify the right patients for platinum chemotherapy and potentially reduce FOLFIRINOX use by over 40%, minimizing toxicities with similar survival outcomes. Confirmatory studies should be performed.
Altered Sex Differences in Hippocampal Subfield Volumes in Schizophrenia
Authors: Barth Claudia , Nerland Stener , Jørgensen Kjetil N , Haatveit Beathe , Wortinger Laura A , Melle Ingrid , Haukvik Unn K , Ueland Torill , Andreassen Ole A , Agartz Ingrid
Published: June 2023

Background and Hypothesis

The hippocampus is a heterogenous brain structure that differs between the sexes and has been implicated in the pathophysiology of psychiatric illnesses. Here, we explored sex and diagnostic group differences in hippocampal subfield volumes, in individuals with schizophrenia spectrum disorder (SZ), bipolar disorders (BD), and healthy controls (CTL).

Study Design

One thousand and five hundred and twenty-one participants underwent T1-weighted magnetic resonance imaging (SZ, n = 452, mean age 30.7 ± 9.2 [SD] years, males 59.1%; BD, n = 316, 33.7 ± 11.4, 41.5%; CTL, n = 753, 34.1 ± 9.1, 55.6%). Total hippocampal, subfield, and intracranial volumes were estimated with Freesurfer (v6.0.0). Analysis of covariance and multiple regression models were fitted to examine sex-by-diagnostic (sub)group interactions in volume. In SZ and BD, separately, associations between volumes and clinical as well as cognitive measures were examined between the sexes using regression models.

Study Results

Significant sex-by-group interactions were found for the total hippocampus, dentate gyrus, molecular layer, presubiculum, fimbria, hippocampal-amygdaloid transition area, and CA4, indicating a larger volumetric deficit in male patients relative to female patients when compared with same-sex CTL. Subgroup analyses revealed that this interaction was driven by males with schizophrenia. Effect sizes were overall small (partial η < 0.02). We found no significant sex differences in the associations between hippocampal volumes and clinical or cognitive measures in SZ and BD.

Conclusions

Using a well-powered sample, our findings indicate that the pattern of morphological sex differences in hippocampal subfields is altered in individuals with schizophrenia relative to CTL, due to higher volumetric deficits in males.
Physicians’ perspectives on different therapeutic approaches for aluminum phosphide poisoning and their relevant outcomes
Authors: Sobh Zahraa K , Ghanem Maha , Kholief Marwa
Published: June 2023

Background

Aluminum phosphide is a highly toxic pesticide that results in high mortality. To date, there is neither a definitive antidote nor a unified protocol for managing acute aluminum phosphide poisoning.

Objectives

This cross-sectional questionnaire-based study aims to explore different management approaches and rely on the expertise of Egyptian medical professionals to enhance the prognosis for acute aluminum phosphide poisoning.

Subjects and methods

A self-administered questionnaire was formulated and electronically distributed according to published literature and experience of senior physicians.

Results and conclusions

Responses were received from 151 physicians from 10 governorates. Management modalities were variable among respondents. Noradrenaline was used by 90.7% of respondents with no fixed-dose regimen. In all, 84.1% of participants utilized oil in gastrointestinal decontamination; paraffin oil was the most used solution. Overall, 92.1, 61.6, 46.4, and 34.4% of participants used sodium bicarbonate, proton pump inhibitors, IV magnesium sulfate, and antioxidants, respectively. Regarding the frequency of acute aluminum phosphide poisoning, 47% of participants managed these cases daily or a few times a week. Participants' responses denoted a poor prognosis of acute aluminum phosphide poisoning, and high percentages attributed the prognosis to exposure factors rather than treatment modalities. Statistical analysis revealed that using oil in gastrointestinal decontamination improved the outcome by 4.62-fold. Clinical toxicologists were more likely to rescue ≥ 30% of the cases about 3-fold (2.97) than other specialties. Clinical toxicologists used oil in gastrointestinal decontamination, magnesium sulfate, and antioxidant therapy and calculated base deficit before administration of sodium bicarbonate by 7.70-, 5.30-, 3.26-, and 2.08-fold than other specialties.
Cranial variation between coastal and offshore bottlenose dolphins, Tursiops truncatus (Cetacea: Delphinidae) in Ecuador and the Mediterranean: a three-dimensional geometric morphometric study
Authors: Dromby Morgane , Félix Fernando , Haase Ben , Simões-Lopes Paulo C , Costa Ana P B , Lalis Aude , Bens Celine , Podestà Michela , Doria Giuliano , Moura Andre E
Published: June 2023

Skull shape analysis provides useful information on wildlife ecology and potential local adaptations. Common bottlenose dolphins (Tursiops truncatus) often differentiate between coastal and offshore populations worldwide, and skull shape analyses can be particularly useful in this context. Here we quantify skull shape variation between coastal populations from the Gulf of Guayaquil (Ecuador) and the Mediterranean Sea, compared to offshore specimens from multiple oceans. We analysed skull shape differences using 3D models from museum specimens through geometric morphometrics (3DGM). Two complementary landmark approaches included single-point semi-landmarks in homologous features, as well as pseudo-landmarks placed automatically. Results show skull shape distinction between both coastal populations and offshore specimens. Offshore specimens showed little differentiation between distinct locations. Skull shape patterns mostly diverged in the shape and length of rostrum, as well as the shape of the ascending processes of the maxilla, pterygoids, and occipital bones. However, both coastal populations differed in the patterns and direction of change of those features and were also morphologically distinct. Our results are consistent with local data on site fidelity and social structure in the coastal populations. Skull shape changes suggest divergent feeding and sound production patterns are potential drivers, probably specific to the local environment of each community.
Drugs of Abuse and Sexual Function: What Is New?
Authors: Marques-Pinto André , Machado Ana Sofia , Dias-Amaral Ana
Published: June 2023

The association between drugs of abuse and sexual function is thought to be prehistoric. In our era, science has shed some light on the roles of different neurotransmitters on sexual function.

Objective:

This systematic review aims to summarize the role of drugs of abuse on human sexuality.

Methods:

A systematic review was undertaken, according to PRISMA guidelines, for PubMed indexed English articles between 2008 and 2020.

Results:

The use of addictive substances is associated with poorer relationship functioning. Additionally, they can be both a trigger and a maintaining factor for sexual dysfunction by affecting any or all phases of sexual response models. These substances include alcohol, tobacco, cannabis, opioids, cocaine, amphetamines, and party drugs. Failure to address drug-induced sexual problems and dysfunctions or their treatment may induce relapses or represent the loss of a precious therapeutic opportunity.

Conclusion:

Health care providers should be aware of the relationship between drugs of abuse and sexual function, and use the permission, limited information, specific suggestions, intensive therapy model. We believe addiction professionals should have skills on clinical sexology, and conversely, clinical sexologists should have training in addictions.

L’association faite entre les drogues illicites et le fonctionnement sexuel est perçu comme étant archaïque. De nos jours, la science a apportée une certaine lumière sur les rôles des différents neurotransmetteurs dans le fonctionnement sexuel.

Objectifs:

Cette revue systématique vise à résumer le rôle des drogues illicites sur la sexualité humaine.

Méthodes:

Une revue systématique a été entreprise, conformément aux directives PRISMA, pour les articles en anglais indexés PubMed entre 2008 et 2020.

Résultats:

La consommation de substances addictives est associée à un fonctionnement relationnel inférieur. De plus, ils peuvent être à la fois un déclencheur et un facteur de maintien de la dysfonction sexuelle en affectant une ou toutes les phases des modèles de réponse sexuelle. Ces substances comprennent l’alcool, le tabac, le cannabis, les opioïdes, la cocaïne, les amphétamines et les drogues festives (party drugs). Ne pas s’attaquer aux problèmes et dysfonctionnements sexuels induits par ces drogues ou à leur traitement peut provoquer des rechutes ou représenter la perte d’une précieuse opportunité thérapeutique.

Conclusions:

Les pourvoyeurs de soins de santé devraient être conscients de la relation entre les drogues et le fonctionnement sexuel, et utiliser le modèle PLISSIT. Nous pensons que les professionnels de l’addiction devraient avoir des compétences en sexologie clinique et, à l’inverse, les sexologues cliniciens devraient avoir une formation en addiction.
Risks of Recidivism in Criminally Involved Persons With Addiction at Risk of Deportation: A Case Commentary and Review
Authors: Jadir Deeshpaul Singh , Gill Harbir Singh
Published: June 2023

A clinical case is presented for a patient in sustained remission from opioid use disorder following 12 months of evidence-based treatment who faces deportation due to criminal behavior conducted whilst in active and untreated addiction. A review of the criminal justice and addiction literature suggests that the chance of relapse and recidivism to criminal behavior is low when engaged in evidence-based addiction treatment for over 12 months. Deportation has been shown to disrupt recovery activity and increase recidivism and relapse risk. As addiction is widely now understood to be a disease based in neurobiology, and treatable, we believe that the evidence supports our assertion of deportation as a cruel and unjust treatment of a chronic disease.

La présentation du cas clinique d’un patient en rémission prolongée causé par un trouble lié à l’usage d’opioïdes. Après 12 mois de traitement fondé sur des données probantes, le patient risque l’expulsion en raison d’un comportement criminel mené alors qu’il était dans une dépendance active et non traitée. Une revue de la justice pénale et de la littérature sur l’addiction suggère que le risque de rechute et de récidive au comportement criminel est faible lorsque le patient est engagé dans un traitement de l’addiction fondé sur des données probantes pendant plus de 12 mois. Il a été démontré que l’expulsion perturbe les activités de rétablissement et augmente les risques de récidive et de rechute. Comme l’addiction est désormais largement comprise comme une maladie basée sur la neurobiologie et traitable, nous pensons que la preuve étaye notre affirmation selon laquelle l’expulsion est un traitement cruel et injuste d’une maladie chronique.
Phase-locking of hippocampal CA3 neurons to distal CA1 theta oscillations selectively predicts memory performance
Authors: Ku Shih-Pi , Atucha Erika , Alavi Nico , Yoshida Motoharu , Csicsvari Joszef , Sauvage Magdalena M.
Published: June 2023

How the coordination of neuronal spiking activity and brain rhythms between hippocampal subregions supports memory function remains elusive. We studied interregional coordination of CA3 neuronal spiking activity with CA1 theta oscillations by recording electrophysiological signals along the proximodistal axis of the hippocampus in rats performing a high memory demand recognition memory task adapted from humans. We found that CA3 population spiking activity occurs preferentially at the peak of distal CA1 theta oscillations only when animals recalled previously encountered stimuli. In addition, decoding analyses revealed that only population cell firing of proximal CA3 together with that of distal CA1 can predict memory performance in the present non-spatial task. Overall, our work demonstrates an important role of the synchronization of CA3 neuronal activity with CA1 theta oscillations for successful recognition memory.
Wildlife vaccination strategies for eliminating bovine tuberculosis at the wildlife-livestock interface
Authors: Pandey Aakash , Feuka Abigail B , Cosgrove Melinda , Moriarty Megan , Duffiney Anthony , VerCauteren Kurt C , Campa Henry , Pepin Kim M
Published: June 2023

Many pathogens of humans and livestock also infect wildlife that can act as a reservoir and challenge disease control or elimination. Efficient and effective prioritization of research and management actions requires an understanding of the potential for new tools to improve elimination probability with feasible deployment strategies that can be implemented at scale. Wildlife vaccination is gaining interest as a tool for managing several wildlife diseases. To evaluate the effect of vaccinating white-tailed deer (Odocoileus virginianus), in combination with harvest, in reducing and eliminating bovine tuberculosis from deer populations in Michigan, we developed a mechanistic age-structured disease transmission model for bovine tuberculosis with integrated disease management. We evaluated the impact of pulse vaccination across a range of vaccine properties. Pulse vaccination was effective for reducing disease prevalence rapidly with even low (30%) to moderate (60%) vaccine coverage of the susceptible and exposed deer population and was further improved when combined with increased harvest. The impact of increased harvest depended on the relative strength of transmission modes, i.e., direct vs indirect transmission. Vaccine coverage and efficacy were the most important vaccine properties for reducing and eliminating disease from the local population. By fitting the model to the core endemic area of bovine tuberculosis in Michigan, USA, we identified feasible integrated management strategies involving vaccination and increased harvest that reduced disease prevalence in free-ranging deer. Few scenarios led to disease elimination due to the chronic nature of bovine tuberculosis. A long-term commitment to regular vaccination campaigns, and further research on increasing vaccines efficacy and uptake rate in free-ranging deer are important for disease management.
Proteolytic Remodeling of 3D Bioprinted Tumor Microenvironments
Authors: Boroojeni Fatemeh Rasti , Naeimipour Sajjad , Lifwergren Philip , Abrahamsson Annelie , Dabrosin Charlotta , Selegård Robert , Aili Daniel
Published: June 2023

In native tissue, remodeling of the pericellular space is essential for cellular activities and is mediated by tightly regulated proteases. Protease activity is dysregulated in many diseases, including many forms of cancer. Increased proteolytic activity is directly linked to tumor invasion into stroma, metastasis, and angiogenesis as well as all other hallmarks of cancer. Here we show how integrated 3D bioprinted structures with distinctly different responses to proteolytic activity can be utilized for systematic investigation of proteolytic remodeling of the extra cellular matrix and the impact of stromal cells on protease driven processes. Bioprinted structures combining non-degradable and degradable hydrogels were designed and demonstrated to be selectively degraded by proteases allowing for protease-mediated material reorganization with high spatial resolution. Bioprinting of tumor microenvironments combining bioinks with different susceptibilities to proteolytic degradation shows that breast cancer cell proliferation, migration into stromal compartments, and spheroid size are significantly increased in protease degradable hydrogels, but only in the presence of fibroblasts. Proteolytic remodeling of the tumor microenvironment has a significant effect on tumor progression and is drastically influenced by the intimate crosstalk between fibroblast and breast cancer cells.
Monitoring norepinephrine releasein vivousing next-generation GRABNEsensors
Authors: Feng Jiesi , Dong Hui , Lischinsky Julieta , Zhou Jingheng , Deng Fei , Zhuang Chaowei , Miao Xiaolei , Wang Huan , Xie Hao , Cui Guohong , Lin Dayu , Li Yulong
Published: June 2023

Norepinephrine (NE) is an essential biogenic monoamine neurotransmitter, yet researches using prototype NE sensors were limited by their low sensitivities. Here, we developed next-generation versions of GPCR activation-based NE sensors (GRABNE2mand GRABNE2h) with a superior response, high sensitivity and selectivity to NE bothin vitroandin vivo. Notably, these sensors can detect NE release triggered by either optogenetic or behavioral stimuli in freely moving mice, producing robust signals in the locus coeruleus and hypothalamus. With the development of a novel transgenic mouse line, we recorded both NE release and calcium dynamics with dual-color fiber photometry throughout the sleep-wake cycle; moreover, dual-color mesoscopic imaging revealed cell type‒specific spatiotemporal dynamics of NE and calcium during sensory processing and locomotion. Thus, these new GRABNEsensors are valuable tools for monitoring the precise spatiotemporal release of NEin vivo, providing new insights into the physiological and pathophysiological roles of NE.
Technique for rapidly forming networks of microvessel-like structures
Authors: Hewes Sarah A. , Ahmad Fariha N. , Connell Jennifer P. , Grande-Allen K. Jane
Published: June 2023

Modelling organ-blood barriers through the inclusion of microvessel networks withinin vitrotissue models could lead to more physiologically accurate results, especially since organ-blood barriers are crucial to the normal function, drug transport, and disease states of vascularized organs. Microvessel networks are difficult to form, since they push the practical limit of most fabrication methods, and it is difficult to coax vascular cells to self-assemble into structures larger than capillaries. Here we present a method for rapidly forming networks of microvessel-like structures using sacrificial, alginate structures. Specifically, we encapsulated endothelial cells within short alginate threads, then embedded them in collagen gel. Following enzymatic degradation of the alginate, the collagen gel contained a network of hollow channels seeded with cells, all surrounding a perfusable central channel. This method uses a 3D printed coaxial extruder and syringe pumps to generate short threads in a way that is repeatable and easily transferrable to other labs. The cell-laden, sacrificial alginate threads can be frozen after fabrication and thawed before embedding without significant loss of cell viability. The ability to freeze the threads enables future scale up and ease of use. Within millifluidic devices that restrict access to media, the threads enhance cell survival under static conditions. These results indicate the potential for use of this method in a range of tissue engineering applications.

Impact Statement

Generating microvascular networks is a challenge in tissue engineering. Popular 3D bioprinting techniques use sacrificial structures to generate vascular networks, but those approaches can require expensive equipment and extensive troubleshooting. In this article, a method is presented for easy and rapid generation of centimeter-scale microvascular networks using endothelial cells frozen within sacrificial structures. The method for fabricating and freezing the sacrificial threads of alginate containing cells using a 3D printed coaxial extruder is also described. Experimental results indicate that these microstructures have the potential to enhance cell survival in environments with restricted access to media.
Cell swelling enhances canonical β-adrenergic signaling
Authors: Sirbu Alexei , Bathe-Peters Marc , Kumar Jothi L.M. , Inoue Asuka , Lohse Martin J. , Annibale Paolo
Published: June 2023

G protein-coupled receptors’ conformational landscape can be affected by their local, microscopic interactions within the cell plasma membrane. We employ here a pleiotropic stimulus, namely osmotic swelling, to alter the cortical environment within intact cells and monitor the response in terms of receptor function and downstream signaling. We observe that in osmotically swollen cells the β2-adrenergic receptor, a prototypical GPCR, favors an active conformation, resulting in cAMP transient responses to adrenergic stimulation that have increased amplitude. The results are validated in primary cell types such as adult cardiomyocytes, a model system where swelling occurs upon ischemia-reperfusion injury. Our results suggest that receptors’ function is finely modulated by their biophysical context, and specifically that osmotic swelling acts as a potentiator of downstream signaling, not only for the β2-adrenergic receptor, but also for other receptors, hinting at a more general regulatory mechanism.
Repression of Aurora kinase B prevents growth and tissue invasion in medulloblastoma
Authors: Gries Alexandre , Kumar Karthiga Santhana , Kuttler Fabien , Grotzer Michael A. , Baumgartner Martin
Published: June 2023

Novel treatment strategies are required to overcome therapy-associated sequelae in survivors of pediatric medulloblastoma (MB) while maintaining therapeutic efficacy. The tissue impact on drug response in MB is not well understood and drug profiling in the physiological context of the tissue may reveal novel therapy targets.

To gain insights into the growth and dissemination behavior of the MB tumor cells under treatment, we combined three-dimensional cell culture screening withex vivoorganotypic cerebellum slice co-culture (OCSC), which allowed assessing tumor cell behavior in the tissue context.

We screened a panel of 274 kinase inhibitors and identified aurora kinase B (AURKB) as a potential anti-invasion drug target in MB. We validated tumor suppressive activities of the AURKB inhibitor (AURKBi) barasertib and the structurally unrelated compound GSK-1070916 in cerebellum slice culture models for SHH, Grp3 and Grp4 MB at nanomolar concentrations. We confirmed the necessity of AURKB for tumor growth through genetic suppression of AURKB by siRNA in the tissue context. We revealed that the combination of AURKBi with the SRC/BCR-ABL inhibitor dasatinib acts synergistically to repress tumor growth and invasiveness in the SHH MB cell model ONS76, but not in Grp3 MB cells. Finally, we demonstrate that pharmacological repression of AURKB in the tissue context is as effective as X-ray irradiation to repress tumor growth.

Our data highlight that AURKBi is equally efficient as irradiation, suggesting that pharmacological targeting of AURKB may constitute a novel means to overcome radiotherapy limitations in patients younger than three years.

Importance of the study

Our data demonstrate anti-tumor activity of AURKB inhibitors in the tissue context for MB tumor cells that arein vitroresistant to the treatment. This indication of a tissue component to drug response contributes critical insights for drug response profiling for brain tumors. AURKB inhibitors barasertib and GSK-1070916 block growth and invasiveness of SHH, Grp3 and Grp4 MB tumor cells as well as primary ATRT. Importantly, AURKBi is equally efficient as irradiation. In conclusion, a tissue component contributes to sensitivity to AURKB inhibition and pharmacological targeting of AURKB may constitute a novel means to overcome radiotherapy limitations in patients younger than three years.

Key points

AURKB is essential for in tissue growth of MB.

Inactivation of AURKB causes p53 upregulation and decreased in tissue growth and dissemination.

AURKB inhibition in the tissue context is as effective as irradiation to restrict tumor cell growth.
Vocabulary Matters: An Annotation Pipeline and Two Deep Learning Algorithms for Enzyme Named Entity Recognition
Authors: Wang Meiqi , Vijayaraghavan Avish , Beck Tim , Posma Joram M.
Published: June 2023

Enzymes are indispensable substances in many biological processes. With biomedical literature growing exponentially, it becomes more difficult to review the literature effectively. Hence, text-mining techniques are needed to facilitate and speed up literature review. The aims of this study are to create a corpus with annotated enzymes to train and evaluate enzyme named-entity recognition (NER) models. A novel pipeline was built using a combination of dictionary matching and rulebased keyword searching to automatically annotate enzyme entities in over 4,800 biomedical full texts. Two Bidirectional Long Short-Term Memory (BiLSTM) networks using BioBERT and SciBERT as tokeniser and word embedding layers were trained on this corpus and evaluated on a manually annotated test set of 526 full-text publications. The dictionary- and rule-based annotation pipeline achieved an F1-score of 0.863 (precision 0.996, recall 0.762). The SciBERT-BiLSTM model (F1-score 0.965, precision 0.981, recall 0.954) largely out-performed the BioBERT-BiLSTM model (F1-score 0.955, precision 0.981, recall 0.937). This study contributed a novel dictionary- and rule-based automatic pipeline with almost perfect precision which runs in a matter of seconds on a standard laptop. Both deep learning (DL) models achieved state-of-the-art performance (F1>0.95) for enzyme NER, with the SciBERT-based model outperforming the BioBERT-based model in terms of recall, demonstrating the vocabulary used by models matters. The proposed pipeline with the DL models can facilitate more effective enzyme text-mining and information extraction research for literature review and are the first algorithms specifically for enzyme NER.

Availability

All codes are available for automatic annotation and model training (including data), with instructions on how to deploy the model on new text, fromhttps://github.com/omicsNLP/enzymeNER.
Alternative splicing and environmental adaptation in house mice
Authors: Manahan David N. , Nachman Michael W.
Published: June 2023

A major goal of evolutionary genetics is to understand the genetic and molecular mechanisms underlying adaptation. Previous work has established that changes in gene regulation may contribute to adaptive evolution, but most studies have focused on mRNA abundance and only a few studies have investigated the role of post-transcriptional processing. Here, we use a combination of exome sequences and short-read RNA-Seq data from wild house mice (Mus musculus domesticus) collected along a latitudinal transect in eastern North America to identify candidate genes for local adaptation through alternative splicing. First, we identified alternatively spliced transcripts that differ in frequency between mice from the northern-most and southern-most populations in this transect. We then identified the subset of these transcripts that exhibit clinal patterns of variation among all populations in the transect. Finally, we conducted association studies to identifycis-acting splicing quantitative trait loci (cis-sQTL), and we identifiedcis-sQTL that overlapped with previously ascertained targets of selection from genome scans. Together, these analyses identified a small set of alternatively spliced transcripts that may underlie environmental adaptation in house mice. Many of these genes have known phenotypes associated with body size, a trait that varies clinally in these populations. We observed no overlap between these genes and genes previously identified by changes in transcript level, indicating that alternative splicing and changes in mRNA abundance may provide separate molecular mechanisms of adaptation.
Single neuron analysis of aging associated changes in learning reveals progressive impairments in transcriptional plasticity
Authors: Badal Kerriann K , Sadhu Abhishek , McCracken Carrie , Raveendra Bindu L , Lozano-Villada Sebastian , Shetty Amol C , Gillette Phillip , Zhao Yibo , Stommes Dustin , Fieber Lynne A , Schmale Michael C , Mahurkar Anup , Hawkins Robert D , Puthanveettil Sathyanarayanan V
Published: June 2023

Molecular mechanisms underlying aging associated impairments in learning and long-term memory storage are poorly understood. Here we leveraged the single identified motor neuron L7 inAplysia,which mediates a form of non-associative learning, sensitization of the siphon-withdraw reflex, to assess the transcriptomic correlates of aging associated changes in learning. RNAseq analysis of the single L7 motor neuron isolated following short-term or long-term sensitization training of 8,10 and 12 months oldAplysia,corresponding to mature, late mature and senescent stages, has revealed progressive impairments in transcriptional plasticity during aging. Specifically, we observed modulation of the expression of multiple lncRNAs and mRNAs encoding transcription factors, regulators of translation, RNA methylation, and cytoskeletal rearrangements during learning and their deficits during aging. Our comparative gene expression analysis also revealed the recruitment of specific transcriptional changes in two other neurons, the motor neuron L11 and the giant cholinergic neuron R2 whose roles in long-term sensitization were previously not known. Taken together, our analyses establish cell type specific progressive impairments in the expression of learning- and memory-related components of the transcriptome during aging.
Hyperosmolarity-induced suppression of group B1 Raf-like protein kinases modulates drought-growth trade-off inArabidopsis
Authors: Kamiyama Yoshiaki , Katagiri Sotaro , Yamashita Kota , Li Yangdan , Takase Hinano , Umezawa Taishi
Published: June 2023

When plants are exposed to drought stress, there is a trade-off between plant growth and stress responses. Here, we identified a signaling mechanism for the initial steps of the drought-growth trade-off. Phosphoproteomic profiling revealed that Raf13, a B1 subgroup Raf-like kinase, is dephosphorylated under drought conditions. Raf13 and the related B1-Raf Raf15 are required for growth rather than the acquisition of osmotolerance. We also found that Raf13 interacts with B55-family regulatory subunits of protein phosphatase 2A (PP2A), which mediates hyperosmolarity-induced dephosphorylation of Raf13. In addition, Raf13 interacts with an AGC kinase INCOMPLETE ROOT HAIR ELONGATION HOMOLOG 1 (IREH1), and Raf13 and IREH1 have similar functions in regulating cellular responses that promote plant growth. Overall, our results support a model in which Raf13-IREH1 activity promotes growth under nonstressed conditions, whereas PP2A activity suppresses Raf13-IREH1 during osmotic stress to modulate the physiological “trade-off” between plant growth and stress responses.
Diverse viralcasgenes antagonize CRISPR immunity
Authors: Katz Mark A , Sawyer Edith M , Kozlova Albina , Williams Madison C , Margolis Shally R , Oriolt Luke , Johnson Matthew , Bondy-Denomy Joseph , Meeske Alexander J
Published: June 2023

Prokaryotic CRISPR-Cas immunity is subverted via anti-CRISPRs (Acrs), small proteins that inhibit Cas protein activities when expressed during the phage lytic cycle or from resident prophages or plasmids. CRISPR-Cas defenses are classified into 6 types and 33 subtypes, which employ a diverse suite of Cas effectors and differ in their mechanisms of interference. As Acrs often work via binding to a cognate Cas protein, inhibition is almost always limited to a single CRISPR type. Furthermore, whileacrgenes are frequently organized together in phage-associated gene clusters, how such inhibitors initially evolve has remained unclear. Here we have investigated the Acr content and inhibition specificity of a collection ofListeriaisolates, which naturally harbor four diverse CRISPR-Cas systems (types I-B, II-A, II-C, and VI-A). We observed widespread antagonism of CRISPR, which we traced to 12 novel and 4 known Acr gene families encoded on endogenous mobile genetic elements. Among these were two Acrs that possess sequence homology to type I-B Cas proteins and assemble into a defective interference complex. Surprisingly, an additional type I-B Cas homolog did not affect type I immunity, but instead inhibited the RNA-targeting type VI CRISPR system through sequestration of crRNA. By probing the IMGVR database of viral genomes, we detected abundant orphancasgenes located within putative anti-defense gene clusters. We experimentally verified the Acr activity of one viralcasgene, a particularly broad-spectrumcas3homolog that inhibits type I-B, II-A, and VI-A CRISPR immunity. Our observations provide direct evidence of Acr evolution viacasgene co-option, and new genes with potential for broad-spectrum control of genome editing technologies.
Robust Homeostasis of Cellular Cholesterol via Antithetic Integral Control
Authors: Scheepers Ronél , Araujo Robyn P.
Published: June 2023

Although cholesterol is essential for cellular viability and proliferation, it is highly toxic in excess. The concentration of cellular cholesterol must therefore be maintained within tight tolerances, and is thought to be subject to a stringent form of homeostasis known as Robust Perfect Adaptation (RPA). While much is known about the cellular signalling interactions involved in cholesterol regulation, the specific chemical reaction network structures that might be responsible for the robust homeostatic regulation of cellular cholesterol have been entirely unclear until now. In particular, the molecular mechanisms responsible for sensing excess whole-cell cholesterol levels have not been identified previously, and no mathematical models to date have been able to capture an integral control implementation that could impose RPA on cellular cholesterol. Here we provide a detailed mathematical description of cholesterol regulation pathways in terms of biochemical reactions, based on an extensive review of experimental and clinical literature. We are able to decompose the associated chemical reaction network structures into several independent subnetworks, one of which is responsible for conferring RPA on several intracellular forms of cholesterol. Remarkably, our analysis reveals that RPA in the cholesterol concentration in the endoplasmic reticulum (ER) is almost certainly due to a well-characterised control strategy known as antithetic integral control which, in this case, involves the high-affinity binding of a multi-molecular transcription factor complex with cholesterol molecules that are excluded from the ER membrane. Our model provides a detailed framework for exploring the necessary biochemical conditions for robust homeostatic control of essential and tightly regulated cellular molecules such as cholesterol.
PARP14 is a writer, reader and eraser of mono-ADP-ribosylation
Authors: Torretta Archimede , Chatzicharalampous Constantinos , Ebenwaldner Carmen , Schüler Herwig
Published: June 2023

PARP14/BAL2 is a large multidomain enzyme involved in signaling pathways with relevance to cancer, inflammation, and infection. Inhibition of its mono-ADP-ribosylating PARP homology domain and its three ADP-ribosyl binding macro domains has been regarded as a potential means of therapeutic intervention. Macrodomains-2 and -3 are known to stably bind to ADP-ribosylated target proteins; but the function of macrodomain-1 has remained some-what elusive. Here, we used biochemical assays of ADP-ribosylation levels to characterize PARP14 macrodomain-1 and the homologous macrodomain-1 of PARP9. Our results show that both macrodomains display an ADP-ribosyl glycohydrolase activity that is not directed toward specific protein side chains. PARP14 macrodomain-1 is unable to degrade poly(ADP-ribose), the enzymatic product of PARP1. The F926A mutation of PARP14 and the F244A mutation of PARP9 strongly reduced ADP-ribosyl glycohydrolase activity of the respective macrodomains, suggesting mech-anistic homology to the Mac1 domain of the SARS-CoV-2 Nsp3 protein. This study adds two new enzymes to the previously known six human ADP-ribosyl glycohydrolases. Our results have key implications for how PARP14 and PARP9 will be studied and how their functions will be understood.
Does the OFDI promotion effect of the Belt and Road “crowd in” or “crowd out” domestic investment?
Authors: Ge Pengfei , Wu Xiaoxu , Zhou Bole , Han Xianfeng
Published: June 2023

Purpose

This study aims to determine how and through what mechanisms the outward foreign direct investment (OFDI) promotion effect of the Belt and Road initiative (BRI-OFDI) affects domestic investment. It is motivated by the context that China is fostering a new development pattern, as well as by the impetus from the Belt and Road initiative for the new pattern.

Design/methodology/approach

Drawing on data of Chinese-listed companies, this study uses a difference-in-difference method to explore the effect of the BRI-OFDI on domestic investment and a mediation model to illustrate the mechanisms.

Findings

The BRI-OFDI has a significantly positive effect on domestic investment, meaning that the Belt and Road initiative's OFDI promotion effect crowds in domestic investment. The results are heterogeneous: the crowding-in effect mainly exists in non-state-owned and technology-intensive enterprises, while a crowding-out effect is seen in state-owned and labor-intensive enterprises. The easing of corporate financing constraints and the expansion of market demand are two important mechanisms.

Originality/value

This study uses the Belt and Road initiative as an exogenous shock to investigate the impact of the initiative-induced OFDI promotion effect on domestic investment. It addresses the potential endogeneity issue confronting the studies on the relationship between OFDI and domestic investment in the literature. The authors focus on the possible spillover effects of the Belt and Road initiative discussing the impact of the BRI-OFDI on domestic investment from the micro-firm perspective. It offers a new perspective to objectively assess the initiative's policy effect.