bluuebunny/crossref_metadata_2025 huggingface dataset:
Sequential combination of sonic hedgehog inhibitors followed by consolidation radiotherapy in locally advanced basal cell carcinoma
Authors: Boileau Marie , Dubois Manon , Pruvot Clément , Desmedt Eve , Templier Carole , Meyer Nicolas , Mirabel Xavier , Mortier Laurent
Published: March 2024

Background

Sonic hedgehog inhibitors (SHHis) are an effective treatment in locally advanced basal cell carcinoma (laBCC). However, the use of these drugs is limited by adverse events, and relapse at discontinuation in around one-half of patients. A few cases of patients treated concomitantly by radiotherapy (RT) and SHHis have been reported in the literature, suggesting that the combination results in an improved overall response. Maintaining complete response after stopping treatment is a concern, especially as resuming treatment in the case of relapse does not guarantee a new therapeutic response. The optimal combination and sequence of treatment to improve local control of laBCCs are not yet defined.

Objectives

We hypothesized that consolidation RT after complete response to SHHis could reduce the risk of relapse at discontinuation.

Methods

We present a case series of patients with laBCCs who achieved complete response after SHHi treatment and were treated with consolidation RT. Patients were evaluated by a skin cancer board. The closure RT technique and dosage were refined by a radiotherapist.

Results

Eleven patients were included. SHHis were prescribed for a median 5 months (range 4–11). Consolidation RT was performed after complete response to SHHis and discontinuation. RT was delivered at a median dose of 45 Gy (range 40.5–66) in 10 fractions (range 9–33). With a median follow-up of 23 months, all patients maintained complete clinical response. This strategy was well tolerated with no grade 3 adverse events.

Conclusions

SHHi treatment followed by consolidation RT after drug discontinuation seems effective and safe. Further studies are needed to develop a precise strategy for the management of laBCCs.
Association of cumulative health status with subsequent mortality in patients with acute heart failure
Authors: Peng Yue , He Guangda , Wang Wei , Lei Lubi , Li Jingkuo , Pu Boxuan , Huo Xiqian , Yu Yanwu , Zhang Lihua , Li Jing
Published: March 2024

Aims

We aim to examine the association between long-term cumulative health status and subsequent mortality among patients with acute heart failure (HF).

Methods and results

Based on a national prospective cohort study of patients hospitalized for HF, we measured health status by Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 at four time points, i.e. admission and 1, 6 and 12 months after discharge. Cumulative health status was interpreted by cumulative KCCQ-12 score and cumulative times of good health status. Outcomes included subsequent all-cause and cardiovascular mortality. Multivariable Cox proportional hazard models were performed to examine the association between cumulative health status and subsequent mortality. Totally, 2328 patients {36.7% women with median age 66 [interquartile range (IQR): 56–75] years} were included, and the median follow-up was 4.34 (IQR: 3.93–4.96) years. Compared with quartile 4, the lowest quartile 1 had the highest hazard ratio (HR) for all-cause mortality [2.96; 95% confidence interval (CI): 2.26–3.87], followed by quartile 2 (1.79; 95% CI: 1.37–2.34) and quartile 3 (1.62; 95% CI: 1.23–2.12). Patients with zero times of good health status had the highest risk of all-cause mortality (HR: 2.41, 95% CI: 1.69–3.46) compared with patients with four times of good health status. Similar associations persisted for cardiovascular mortality.

Conclusion

A greater burden of cumulative health status indicated worse survival among patients hospitalized for HF. Repeated KCCQ measurements could be helpful to monitor long-term health status and identify patients vulnerable to death.
Restoring Obrecht’s Missa Scaramella
Authors: Fitch Fabrice
Published: March 2024

This article reports on the restoration of the four-voice Missa Scaramella by Jacob Obrecht. Preserved uniquely in Berlin, Former Preußische Staatsbibliothek, Ms. Mus. 40634 (now in Kraków, Biblioteka Jagiellońska), only two of the original partbooks remain, leaving the discantus and tenor parts to be supplied in their entirety. The work, begun with the late Philip Weller, has been completed with the assistance of Paul Kolb. I consider the specific challenges it has entailed and its implications for the practice of restoring fragmentary polyphonies, with reference to two sections, which pose very different challenges. In particular, the statements of the Italian monophonic tune that serves as the work’s model have had to be identified. Often this has been straightforward, but in a few cases it has been less so. I also attempt to draw a few general conclusions about the process of restoration. The restorer’s principal focus is attentiveness to the implications of the extant material. Obrecht’s compositional practice might be described as a ‘game of consequences’, which means that the clues in the extant voices are perhaps especially plentiful and suggestive.
Digest: Does the insertion preference of a transposable element represent a strategy for the mitigation of genetic conflicts with the host?
Authors: Zattera Michelle Louise , Bruschi Daniel Pacheco
Published: March 2024

Transposable elements can exhibit a predilection for specific insertion regions. In a recent study, Munasinghe et al. (2023) consider how variation in where TE families prefer to insert within the genome influences their copy number evolution. The study emphasizes how a preference for neutral insertion sites is only advantageous in conjunction with host restriction mechanisms, which suggests that insertion preference may be a strategy to mitigate genetic conflicts with the host.
The contribution of an X chromosome QTL to non-Mendelian inheritance and unequal chromosomal segregation in Auanema freiburgense
Authors: Al-Yazeedi Talal , Adams Sally , Tandonnet Sophie , Turner Anisa , Kim Jun , Lee Junho , Pires-daSilva Andre
Published: March 2024

Auanema freiburgense is a nematode with males, females, and selfing hermaphrodites. When XO males mate with XX females, they typically produce a low proportion of XO offspring because they eliminate nullo-X spermatids. This process ensures that most sperm carry an X chromosome, increasing the likelihood of X chromosome transmission compared to random segregation. This occurs because of an unequal distribution of essential cellular organelles during sperm formation, likely dependent on the X chromosome. Some sperm components are selectively segregated into the X chromosome's daughter cell, while others are discarded with the nullo-X daughter cell. Intriguingly, the interbreeding of 2 A. freiburgense strains results in hybrid males capable of producing viable nullo-X sperm. Consequently, when these hybrid males mate with females, they yield a high percentage of male offspring. To uncover the genetic basis of nullo-spermatid elimination and X chromosome drive, we generated a genome assembly for A. freiburgense and genotyped the intercrossed lines. This analysis identified a quantitative trait locus spanning several X chromosome genes linked to the non-Mendelian inheritance patterns observed in A. freiburgense. This finding provides valuable clues to the underlying factors involved in asymmetric organelle partitioning during male meiotic division and thus non-Mendelian transmission of the X chromosome and sex ratios.
Occlusal force orchestrates alveolar bone homeostasis via Piezo1 in female mice
Authors: Yang Yiling , Dai Qinggang , Gao Xin , Zhu Yanfei , Chung Mi Ri , Jin Anting , Liu Yuanqi , Wang Xijun , Huang Xiangru , Sun Siyuan , Xu Hongyuan , Liu Jingyi , Jiang Lingyong
Published: March 2024

Healthy alveolar bone is the cornerstone of oral function and oral treatment. Alveolar bone is highly dynamic during the entire lifespan and is affected by both systemic and local factors. Importantly, alveolar bone is subjected to unique occlusal force in daily life, and mechanical force is a powerful trigger of bone remodeling, but the effect of occlusal force in maintaining alveolar bone mass remains ambiguous. In this study, the Piezo1 channel is identified as an occlusal force sensor. Activation of Piezo1 rescues alveolar bone loss caused by a loss of occlusal force. Moreover, we identify Piezo1 as the mediator of occlusal force in osteoblasts, maintaining alveolar bone homeostasis by directly promoting osteogenesis and by sequentially regulating catabolic metabolism through Fas ligand (FasL)-induced osteoclastic apoptosis. Interestingly, Piezo1 activation also exhibits remarkable efficacy in the treatment of alveolar bone osteoporosis caused by estrogen deficiency, which is highly prevalent among middle-aged and elderly women. Promisingly, Piezo1 may serve not only as a treatment target for occlusal force loss-induced alveolar bone loss but also as a potential target for metabolic bone loss, especially in older patients.
The use of environmental data in descriptive and predictive models of vector-borne disease in North America
Authors: Kiryluk Hanna D , Beard Charles B , Holcomb Karen M
Published: March 2024

Vector-borne disease incidence and burden are on the rise. Weather events and climate patterns are known to influence vector populations and disease distribution and incidence. Changes in weather trends and climatic factors can shift seasonal vector activity and host behavior, thus altering pathogen distribution and introducing diseases to new geographic regions. With the upward trend in global temperature, changes in the incidence and distribution of disease vectors possibly linked to climate change have been documented. Forecasting and modeling efforts are valuable for incorporating climate into predicting changes in vector and vector-borne disease distribution. These predictions serve to optimize disease outbreak preparedness and response. The purpose of this scoping review was to describe the use of climate data in vector-borne disease prediction in North America between 2000 and 2022. The most investigated diseases were West Nile virus infection, Lyme disease, and dengue. The uneven geographical distribution of publications could suggest regional differences in the availability of surveillance data required for vector-borne disease predictions and forecasts across the United States, Canada, and Mexico. Studies incorporated environmental data from ground-based sources, satellite data, previously existing data, and field-collected data. While environmental data such as meteorological and topographic factors were well-represented, further research is warranted to ascertain if relationships with less common variables, such as oceanographic characteristics and drought, hold among various vector populations and throughout wider geographical areas. This review provides a catalogue of recently used climatic data that can inform future assessments of the value of such data in vector-borne disease models.
Medical tourism and medical tourists: providing a sustainable course to integrating health treatments with tourism
Authors: McCartney Glenn , Wang Chu Feng
Published: March 2024

Highlight

Medical tourism (MT) is an expanding multidisciplinary economic activity that combines the healthcare and tourist industries, with patients increasingly travelling worldwide for medical treatments. MT provides economic benefits to destinations while raising ethical, quality, informed and risk concerns for medical tourists. Greater cross-disciplinary studies and collaboration across sectors are advocated.
Attitudes toward research and scholarly activities among medical laboratory science professionals in the United States
Authors: Smith Melissa J , Yuen Hon K , Davenport-Landry Lindsey , O’Donnell Julia , Abdi Ibsa , Josephat Floyd , Gao Jie
Published: March 2024

Background

Medical laboratory science (MLS) professionals play a crucial role in health care teams. However, research culture in the profession has not been well developed or studied. It is necessary to characterize attitudes toward research and scholarly activities among MLS professionals and identify ways to promote research in the profession.

Methods

A cross-sectional survey was administered through American Society for Clinical Laboratory Science channels. Survey responses were summarized using descriptive statistics, and linear regression models were constructed to identify characteristics that predicted 2 research attitudes: “valuing the role of research” and “perceived research environment” in the profession.

Results

Of the 116 MLS professionals in this study, 53% reported currently participating in research activities. Opinions toward research were generally positive, although many respondents were not currently conducting research. Individuals with education and research practice focuses tended to place greater value on research, and education level was a significant predictor of perceived research environment. Dedicated research time and mentorship were cited as effective ways for employers to promote research in MLS.

Conclusion

Overall, respondents had favorable attitudes toward research in MLS, but approximately half of participants noted a lack of incentives to conduct research. This study highlights several initiatives that may be effective for promoting increased research activity among MLS professionals.
How regional attitudes towards immigration shape the chance to obtain asylum: Evidence from Germany
Authors: Gundacker Lidwina , Kosyakova Yuliya , Schneider Gerald
Published: March 2024

Asylum recognition rates in advanced democracies differ not only across states but also vary within them, translating into fluctuating individual chances to obtain protection. Existing studies on the determinants of these regional inequities typically rely on aggregate data. Utilizing a German refugee survey and leveraging a quasi-natural experiment arising from state-based allocation rules tied to national dispersal policies, we test two explanations for the perplexing regional differences. Drawing on principal–agent models of administrative decision-making, we test whether asylum decision-makers consciously or unconsciously comply with regional political preferences between 2015 and 2017 in Germany, one of the major European destination countries for refugee migration. We furthermore explore whether such biased decision-making amplifies in times of organizational stress as suggested by the statistical discrimination theory. Using mixed-effects logistic regressions, our analyses confirm a lower approval probability in regions with more immigration-averse residents or governments. We cannot confirm, however, that this association is mediated by high workloads or large knowledge gaps. Our results thus suggest that regional political biases affect the individual chance of asylum-seekers to obtain protection irrespective of temporal administrative conditions.
Evolution of a Restriction Factor by Domestication of a Yeast Retrotransposon
Authors: Hannon-Hatfield J Adam , Chen Jingxuan , Bergman Casey M , Garfinkel David J
Published: March 2024

Transposable elements drive genome evolution in all branches of life. Transposable element insertions are often deleterious to their hosts and necessitate evolution of control mechanisms to limit their spread. The long terminal repeat retrotransposon Ty1 prime (Ty1′), a subfamily of the Ty1 family, is present in many Saccharomyces cerevisiae strains, but little is known about what controls its copy number. Here, we provide evidence that a novel gene from an exapted Ty1′ sequence, domesticated restriction of Ty1′ relic 2 (DRT2), encodes a restriction factor that inhibits Ty1′ movement. DRT2 arose through domestication of a Ty1′ GAG gene and contains the C-terminal domain of capsid, which in the related Ty1 canonical subfamily functions as a self-encoded restriction factor. Bioinformatic analysis reveals the widespread nature of DRT2, its evolutionary history, and pronounced structural variation at the Ty1′ relic 2 locus. Ty1′ retromobility analyses demonstrate DRT2 restriction factor functionality, and northern blot and RNA-seq analysis indicate that DRT2 is transcribed in multiple strains. Velocity cosedimentation profiles indicate an association between Drt2 and Ty1′ virus-like particles or assembly complexes. Chimeric Ty1′ elements containing DRT2 retain retromobility, suggesting an ancestral role of productive Gag C-terminal domain of capsid functionality is present in the sequence. Unlike Ty1 canonical, Ty1′ retromobility increases with copy number, suggesting that C-terminal domain of capsid–based restriction is not limited to the Ty1 canonical subfamily self-encoded restriction factor and drove the endogenization of DRT2. The discovery of an exapted Ty1′ restriction factor provides insight into the evolution of the Ty1 family, evolutionary hot-spots, and host–transposable element interactions.
Treatment and Prognosis of Male Breast Cancer: A Multicentric, Retrospective Study Over 11 Years in the Czech Republic
Authors: Bielcikova Zuzana , Holanek Milos , Selingerova Iveta , Sorejs Ondrej , Kolarova Iveta , Soumarova Renata , Proks Jan , Reifova Lucie , Cmejlova Vlastimila , Linkova Lenka , Zabojnikova Michaela , Chodacka Martina , Janovska Lucie , Lisnerova Lenka , Kasparova Karolina , Pohankova Denisa , Petruzelka Lubos
Published: March 2024

Purpose

Male breast cancer (MBC) is a rare, but increasingly common disease, and lacks prospective studies. Collaborative efforts are needed to understand and address MBC, including its prognosis, in different countries.

Methods

We retrospectively reviewed the clinical, histopathological, and molecular-genetic characteristics, treatments, and survival outcomes of MBC diagnosed between 2007 and 2017 in the Czech Republic. Prognostic factors of overall survival (OS), recurrence-free interval (RFi), and breast cancer-specific mortality (BCSM) were analyzed and indirectly compared to international data.

Results

We analyzed 256 patients with MBC (median age 66 years), including 12% with de novo metastatic (M1). Of 201 non-metastatic (M0) patients, 6% were <40 years old, 29% had stage I, 55% were cN0, and 54% underwent genetic testing. Overall, 97% of tumors had estrogen receptor expression ≥10%, 61% had high Ki67 index, 40% were high-grade (G3), and 68% were luminal B-like (HER2-negative). Systemic therapies included endocrine therapy (90%) and chemotherapy (53%). Few (5%) patients discontinued adjuvant endocrine therapy for reasons other than disease relapse or death. Patients treated with aromatase inhibitors alone had significantly shorter RFi (P < .001). OS, RFi, and BCSM were associated with disease stage, T stage, N stage, progesterone receptor expression, grade, and Ki67 index. Median OS reached 122 and 42 months in M0 and de novo M1 patients, respectively.

Conclusion

Due to the rarity of MBC, this study highlights important findings from real clinical practice. Although the number of patients with MBC with unfavorable features was higher in this Czech dataset than in international studies, the prognosis remains consistent with real-world evidence.
Impulsive gas fueling to the galactic center in a barred galaxy due to falls of gas clouds
Authors: Matsui Hidenori , Masakawa Toshiyasu , Habe Asao , Saitoh Takayuki R
Published: March 2024

We have studied the evolution of the central hundred parsec region of barred galaxies by performing numerical simulations realizing the multi-phase nature of gas. Our simulations have shown that a stellar bar produces an oval gas ring, namely the x-2 ring, within 1 kpc as the bar grows. The ring is self-gravitationally unstable enough to trigger the formation of gas clouds. Although the gas clouds initially rotate in the x-2 ring, cloud–cloud collisions and$/$or energy injections into the gas ring by Type II supernovae causes some of the clouds to deviate from the ring orbit. After the deviation, the deviated clouds repeat collisions with the other clouds, which rotate in the x-2 ring, during several rotations. These processes effectively reduce the angular momentum of the deviated gas cloud. As a result, the gas cloud finally falls into the galactic center, and episodic gas supply to the galactic center takes place.
The Ginkgo biloba microRNA160–ERF4 module participates in terpene trilactone biosynthesis
Authors: Zheng Jiarui , He Xiao , Zhou Xian , Liu Xiaomeng , Yi Yuwei , Su Dongxue , Zhang Weiwei , Liao Yongling , Ye Jiabao , Xu Feng
Published: March 2024

Terpene trilactones (TTLs) are important secondary metabolites in ginkgo (Ginkgo biloba); however, their biosynthesis gene regulatory network remains unclear. Here, we isolated a G. biloba ethylene response factor 4 (GbERF4) involved in TTL synthesis. Overexpression of GbERF4 in tobacco (Nicotiana tabacum) significantly increased terpenoid content and upregulated the expression of key enzyme genes (3-hydroxy-3-methylglutaryl-CoA reductase [HMGR], 3-hydroxy-3-methylglutaryl-CoA synthase [HMGS], 1-deoxy-D-xylulose-5-phosphate reductoisomerase [DXR], 1-deoxy-D-xylulose-5-phosphate synthase [DXS], acetyl-CoA C-acetyltransferase [AACT], and geranylgeranyl diphosphate synthase [GGPPS]) in the terpenoid pathway in tobacco, suggesting that GbERF4 functions in regulating the synthesis of terpenoids. The expression pattern analysis and previous microRNA (miRNA) sequencing showed that gb-miR160 negatively regulates the biosynthesis of TTLs. Transgenic experiments showed that overexpression of gb-miR160 could significantly inhibit the accumulation of terpenoids in tobacco. Targeted inhibition and dual-luciferase reporter assays confirmed that gb-miR160 targets and negatively regulates GbERF4. Transient overexpression of GbERF4 increased TTL content in G. biloba, and further transcriptome analysis revealed that DXS, HMGS, CYPs, and transcription factor genes were upregulated. In addition, yeast 1-hybrid and dual-luciferase reporter assays showed that GbERF4 could bind to the promoters of the HMGS1, AACT1, DXS1, levopimaradiene synthase (LPS2), and GGPPS2 genes in the TTL biosynthesis pathway and activate their expression. In summary, this study investigated the molecular mechanism of the gb-miR160–GbERF4 regulatory module in regulating the biosynthesis of TTLs. It provides information for enriching the understanding of the regulatory network of TTL biosynthesis and offers important gene resources for the genetic improvement of G. biloba with high contents of TTLs.
Acyl carrier protein OsMTACP2 confers rice cold tolerance at the booting stage
Authors: Hou Xiu-Li , Han Xiangyan , Meng Ying , Wang Lizhi , Zhang Wenqi , Yang Chao , Li Hui , Tang Shanjie , Guo Zhenhua , Liu Chunyan , Qin Yongmei , Zhang Shaohua , Shui Guanghou , Cao Xiaofeng , Song Xianwei
Published: March 2024

Low temperatures occurring at the booting stage in rice (Oryza sativa L.) often result in yield loss by impeding male reproductive development. However, the underlying mechanisms by which rice responds to cold at this stage remain largely unknown. Here, we identified MITOCHONDRIAL ACYL CARRIER PROTEIN 2 (OsMTACP2), the encoded protein of which mediates lipid metabolism involved in the cold response at the booting stage. Loss of OsMTACP2 function compromised cold tolerance, hindering anther cuticle and pollen wall development, resulting in abnormal anther morphology, lower pollen fertility, and seed setting. OsMTACP2 was highly expressed in tapetal cells and microspores during anther development, with the encoded protein localizing to both mitochondria and the cytoplasm. Comparative transcriptomic analysis revealed differential expression of genes related to lipid metabolism between the wild type and the Osmtacp2-1 mutant in response to cold. Through a lipidomic analysis, we demonstrated that wax esters, which are the primary lipid components of the anther cuticle and pollen walls, function as cold-responsive lipids. Their levels increased dramatically in the wild type but not in Osmtacp2-1 when exposed to cold. Additionally, mutants of two cold-induced genes of wax ester biosynthesis, ECERIFERUM1 and WAX CRYSTAL-SPARSE LEAF2, showed decreased cold tolerance. These results suggest that OsMTACP2-mediated wax ester biosynthesis is essential for cold tolerance in rice at the booting stage.
Anthocyanin biosynthesis in goji berry is inactivated by deletion in a bHLH transcription factor LrLAN1b promoter
Authors: Li Tingting , Wang Jingjin , Zhang Zihan , Fan Yunfang , Qin Huan , Yin Yue , Dai Guoli , Cao Youlong , Tang Lin
Published: March 2024

Black goji berry (Lycium ruthenicum Murray) contains a rich source of health-promoting anthocyanins which are used in herbal medicine and nutraceutical foods in China. A natural variant producing white berries allowed us to identify two key genes involved in the regulation of anthocyanin biosynthesis in goji berries: one encoding a MYB transcription factor (LrAN2-like) and one encoding a basic helix-loop-helix (bHLH) transcription factor (LrAN1b). We previously found that LrAN1b expression was lost in the white berry variant, but the molecular basis for this phenotype was unknown. Here, we identified the molecular mechanism for loss of anthocyanins in white goji berries. In white goji, the LrAN1b promoter region has a 229 bp deletion that removes three MYB-binding elements and one bHLH-binding element, which are key to its expression. Complementation of the white goji berry LrAN1b allele with the LrAN1b promoter restored pigmentation. Virus-induced gene silencing of LrAN1b in black goji berry reduced fruit anthocyanin biosynthesis. Molecular analyses showed that LrAN2-like and another bHLH transcription factor LrJAF13 can activate LrAN1b by binding directly to the MYB-recognizing element and bHLH-recognizing element of its promoter-deletion region. LrAN1b expression is enhanced by the interaction of LrAN2-like with LrJAF13 and the WD40 protein LrAN11. LrAN2-like and LrAN11 interact with either LrJAF13 or LrAN1b to form two MYB–bHLH–WD40 complexes, which hierarchically regulate anthocyanin biosynthesis in black goji berry. This study on a natural variant builds a comprehensive anthocyanin regulatory network that may be manipulated to tailor goji berry traits.
Phosphorylation of sugar transporter TST2 by protein kinase CPK27 enhances drought tolerance in tomato
Authors: Zhu Changan , Jing Beiyu , Lin Teng , Li Xinyan , Zhang Min , Zhou Yanhong , Yu Jingquan , Hu Zhangjian
Published: March 2024

Drought is a major environmental stress threatening plant growth and productivity. Calcium-dependent protein kinases (CPKs) are plant-specific Ca2+ sensors with multifaceted roles in signaling drought responses. Nonetheless, the mechanisms underpinning how CPKs transmit downstream drought signaling remain unresolved. Through genetic investigations, our study unveiled that knocking out CPK27 reduced drought tolerance in tomato (Solanum lycopersicum) plants and impaired abscisic acid (ABA)-orchestrated plant response to drought stress. Proteomics and phosphoproteomics revealed that CPK27-dependent drought-induced proteins were highly associated with the sugar metabolism pathway, which was further verified by reduced soluble sugar content in the cpk27 mutant under drought conditions. Using protein–protein interaction assays and phosphorylation assessments, we demonstrated that CPK27 directly interacted with and phosphorylated tonoplast sugar transporter 2 (TST2), promoting intercellular soluble sugar accumulation during drought stress. Furthermore, Ca2+ and ABA enhanced CPK27-mediated interaction and phosphorylation of TST2, thus revealing a role of TST2 in tomato plant drought tolerance. These findings extend the toolbox of potential interventions for enhancing plant drought stress tolerance and provide a target to improve drought tolerance by manipulating CPK27-mediated soluble sugar accumulation for rendering drought tolerance in a changing climate.
The shortest path method (SPM) webserver for computational enzyme design
Authors: Casadevall Guillem , Casadevall Jordi , Duran Cristina , Osuna Sílvia
Published: March 2024

SPMweb is the online webserver of the Shortest Path Map (SPM) tool for identifying the key conformationally-relevant positions of a given enzyme structure and dynamics. The server is built on top of the DynaComm.py code and enables the calculation and visualization of the SPM pathways. SPMweb is easy-to-use as it only requires three input files: the three-dimensional structure of the protein of interest, and the two matrices (distance and correlation) previously computed from a Molecular Dynamics simulation. We provide in this publication information on how to generate the files for SPM construction even for non-expert users and discuss the most relevant parameters that can be modified. The tool is extremely fast (it takes less than one minute per job), thus allowing the rapid identification of distal positions connected to the active site pocket of the enzyme. SPM applications expand from computational enzyme design, especially if combined with other tools to identify the preferred substitution at the identified position, but also to rationalizing allosteric regulation, and even cryptic pocket identification for drug discovery. The simple user interface and setup make the SPM tool accessible to the whole scientific community. SPMweb is freely available for academia at http://spmosuna.com/.
Treatment and Mortality Following Cancer Diagnosis Among People With Non-affective Psychotic Disorders in Ontario, Canada: A Retrospective Cohort Study
Authors: Wootten Jared C , Richard Lucie , Lam Melody , Blanchette Phillip S , Solmi Marco , Anderson Kelly K
Published: March 2024

Background and Hypothesis

People with psychotic disorders have a higher risk of mortality following cancer diagnosis, compared to people without psychosis. The extent to which this disparity is influenced by differences in cancer-related treatment is currently unknown. We hypothesized that, following a cancer diagnosis, people with psychotic disorders were less likely to receive treatment and were at higher risk of death than those without psychosis.

Study Design

We constructed a retrospective cohort of cases of non-affective psychotic disorder (NAPD) and a general population comparison group, using Ontario Health (OH) administrative data. We identified cases of all cancers diagnosed between 1995 and 2019 and obtained information on cancer-related treatment and mortality. Cox proportional hazards models were used to compare the probability of having a consultation with an oncologist and receiving cancer-related treatment, adjusting for tumor site and stage. We also compared the rate of all-cause and cancer-related mortality between the two groups, adjusting for tumor site.

Study Results

Our analytic sample included 24 944 people diagnosed with any cancer. People with NAPD were less likely to receive treatment than people without psychosis (HR = 0.87, 95% CI = 0.82, 0.91). In addition, people with NAPD had a greater risk of death from any cause (HR = 1.68, 95% CI = 1.60, 1.76), compared to people without NAPD.

Conclusions

The lower likelihood of receiving cancer treatment reflects disparities in accessing cancer care for people with psychotic disorders, which may partially explain the higher mortality risk following cancer diagnosis. Future research should explore mediating factors in this relationship to identify targets for reducing health disparities.
A Girl With Adenovirus Type 2 Induced Interstitial Pneumonitis Acutely Exacerbated With Primary Human Herpesvirus 7 Infection
Authors: Kawamura Yoshiki , Kozawa Kei , Koinuma Goro , Onda Tetsuo , Cho Kazutoshi , Higashimoto Yuki , Miura Hiroki , Yoshikawa Tetsushi
Published: March 2024

We encountered a previously healthy 3-year-old girl with interstitial pneumonitis that initially developed due to human adenovirus type 2 infection and exacerbated by primary human herpesvirus 7 infection. A comprehensive serum biomarker analysis showed patterns that differed by viral infection, suggesting that respiratory and lymphotropic viral infections might have different pathophysiology in interstitial pneumonitis.
Respiratory Syncytial Virus Bronchiolitis Before and After COVID-19 Pandemic: Has the Immunity Debt Been Paid Off?
Authors: Nenna Raffaella , Pierangeli Alessandra , Matera Luigi , Petrarca Laura , Conti Maria Giulia , Mancino Enrica , di Mattia Greta , La Regina Domenico Paolo , Virgili Fabrizio , Papoff Paola , Bonci Enea , Midulla Fabio
Published: March 2024

Background:

Our aim was to hypothesize that the COVID-19 pandemic influenced the characteristics of viral bronchiolitis by comparing the last 3 epidemics with 3 pre-COVID-19 epidemics in infants hospitalized with bronchiolitis.

Methods:

We prospectively enrolled 637 consecutive infants (median age 3.0 ± 2.1 months, 58.5% males), hospitalized for bronchiolitis during 6 consecutive annual epidemic seasons from 2017 to 2023. All parents of the children were given a structured anamnestic questionnaire. A nasopharyngeal aspirate was tested for 15 respiratory viruses. As measures of severity, we evaluated the O2 supplementation and the admission at the pediatric intensive care unit.

Results:

A total of 166 were hospitalized with bronchiolitis in 2017–2018, 97 in 2018–2019, 69 in 2019–2020, 0 in 2020–2021, 129 in 2021–2022 and 176 in 2022–2023. Taking together the 332 bronchiolitis cases hospitalized during the 3 prepandemic seasons, they peaked between December and January; after the flat curve in 2020–2021, the cases of bronchiolitis peaked in November 2021 and in December 2022. While the 2021–2022 season registered a less severe clinical presentation, O2 supplementation and pediatric intensive care unit admissions increased in 2022–2023 with respect to the prepandemic seasons (P < 0.001).

Conclusions:

This study represents an important scientific demonstration of the impact of primary prevention measures on the epidemiology of viral infections; their fluctuations were related to the intensity of restrictive measures and to the changing trend of respiratory viruses. It is essential to predict the real temporal trend of bronchiolitis not to leave high-risk children uncovered and to guide hospitals to maintain a high level of readiness.
The association of breast surgery ASPIRE: breast pain pathway rapid evaluation project – study protocol
Authors: Hubbard Thomas J. E. , Isaac Anna T. , Cui Alice , Cutress Ramsey I. , Dave Rajiv , Ellis Katy , Fields Jo , Halliday Suzanne , Hu Jennifer , Potter Shelley , Chagla Leena , Cox Karina , Holcombe Christopher
Published: March 2024

Background:

Breast pain accounts for 20–40% of new referrals to breast units in the UK and these patients have a very low risk of breast cancer. Patients have previously been assessed in resource-intensive, cancer-exclusion, one stop clinics, which are now failing to meet government targets due to excessive demand. UK Breast units are increasingly piloting Breast Pain-only Pathways (BPP) to assess these patients, and there is no consensus for the optimal pathway. The aim of this prospective multicentre study is to assess the safety and patient satisfaction of different BPPs to inform future BPP design and implementation.

Methods:

All UK breast units will be invited to join the ASPIRE study between January 2023 and December 2023. Units with a BPP are invited to submit their pathway for evaluation; and those without a BPP who see patients with breast pain-only in a one stop clinics setting are also invited to join the study to evaluate the traditional pathway model concurrently. Patient satisfaction assessments will be collected after their initial consultation and patient outcomes, including subsequent cancer diagnosis, will be followed up at 12 months to determine if they have cancer diagnosis after discharge to assess pathway safety.
Human spinal cord activation during filling and emptying of the bladder
Authors: Agyeman K. A. , Lee D.J. , Abedi A. , Sakellaridi S. , Kreydin E.I. , Russin J. , Lo Y.T. , Wu K. , Choi W. , Edgerton V.R. , Liu C. , Christopoulos V.N.
Published: March 2024

Recording neural activity from the spinal cord is crucial for gaining insights into how it functions. However, the neural activity of the human spinal cord is notoriously difficult to measure. The bony and fascial enclosures combined with the relatively small anatomic size of the spinal cord make it an unfavorable target for traditional functional neuroimaging techniques. Functional ultrasound imaging (fUSI) is an emerging neuroimaging technology that represents a new platform for studying large-scale neural dynamics with high sensitivity, spatial coverage and spatiotemporal resolution. Although it was originally developed for studying brain function, fUSI was recently extended for imaging the spinal cord in animals and humans. While these studies are significant, their primary focus is on the neuroactivation of the spinal cord in response to external sensory stimulations. Here, we combined fUSI with urodynamically-controlled bladder filling and emptying to characterize the hemodynamic response of the human spinal cord during the micturition cycle. Our findings provide the first practical evidence of the existence of bladder pressure-responsive regions, whose hemodynamic signal is strongly correlated with the bladder pressure.
Nitrogen metabolism in the picoalga Pelagomonas calceolata: disentangling cyanate lyase function under different nutrient conditions.
Authors: Guerin Nina , Seyman Chloe , Orvain Celine , Bertrand Laurie , Gourvil Priscillia , Probert Ian , Vacherie Benoit , Brun Elodie , Magdelenat Ghislaine , Labadie Karine , Wincker Patrick , Thurotte Adrien , Carradec Quentin
Published: March 2024

Cyanate (OCN-) is potentially an important organic nitrogen source in aquatic environments given the prevalence and activity of cyanate lyase genes in microalgae. However, the conditions under which these genes are expressed and the actual capacity of microalgae to assimilate cyanate remain underexplored. Here, we studied the nitrogen metabolism of the cosmopolitan picoalga Pelagomonas calceolata (Pelagophyceae, Stramenopiles) in environmental metatranscriptomes and transcriptomes from culture experiments under different nitrogen sources and concentrations. We observed that cyanate lyase is over-expressed in nitrate-poor oceanic regions, suggesting that cyanate is an important molecule contributing to the persistence of P. calceolata in oligotrophic environments. In the laboratory, we confirmed that this gene is over-expressed in low-nitrate medium together with several genes involved in nitrate recycling from endogenous molecules. Non-axenic cultures of P. calceolata were capable of growing on various nitrogen sources, including nitrate, urea and cyanate, but not ammonium. RNA sequencing of these cultures revealed that cyanate lyase was under-expressed in the presence of cyanate, indicating that this gene in not involved in the catabolism of extracellular cyanate to ammonia. Conversely, axenic P. calceolata cultures were not able to grow on cyanate, suggesting that the bacterial community consumes cyanate and provides an available form of nitrogen for growth of the alga. Based on environmental datasets and laboratory experiments, we propose that cyanate lyase is important in nitrate-poor environments to reduce the toxicity of intracellular cyanate produced by endogenous nitrogenous compound recycling, rather than being used to metabolise imported extracellular cyanate as an alternative nitrogen source.
Monosynaptically-interconnected Network Module (MNM) Approach for High-Resolution Brain Sub-Network Analysis
Authors: Kim Sunwhi , Kim Yong-Eun , Ujihara Yusuke , Kim Il Hwan
Published: March 2024

We introduce the Monosynaptically-interconnected Network Module (MNM) approach, an innovative method designed for efficiently analyzing the anatomical structure and functional dynamics of specific brain network modulesin vivo. Utilizing an Intein-mediated split-Cre system combined with bidirectional adeno-associated viruses, this technique precisely targets and manipulates monosynaptically interconnected modular subnetworks in freely moving animals. We demonstrate its utility through anatomical and functional mapping of a specific MNM encompassing the prefrontal cortex (PFC), basolateral amygdala (BLA), and intermediary hub regions. Specifically, the MNM approach with Cre-reporter mice visualizes detailed network architecture and enables the tracing of axonal connections among the nodes in the network. Furthermore, integration of the MNM approach with Cre-dependent Ca2+indicator and multi-fiber photometry in freely moving mice reveals enhanced correlative network activities in social contexts. This versatile technique offers significant potential for advancing our understanding of network functions that underlie complex behaviors, providing a modular network perspective.
Graspable foods and tools elicit similar responses in visual cortex
Authors: Ritchie J. Brendan , Andrews Spencer , Vaziri-Pashkam Maryam , Baker Christopher I.
Published: March 2024

Extrastriatal visual cortex is known to exhibit distinct response profiles to complex stimuli of varying ecological importance (e.g., faces, scenes, and tools). The dominant interpretation of these effects is that they reflect activation of distinct “category-selective” brain regions specialized to represent these and other stimulus categories. We sought to explore an alternative perspective: that the response to these stimuli is determined less by whether they form distinct categories, and more by their relevance to different forms of natural behavior. In this regard, food is an interesting test case, since it is primarily distinguished from other objects by its edibility, not its appearance, and there is evidence of food-selectivity in human visual cortex. Food is also associated with a common behavior, eating, and food consumption typically also involves the manipulation of food, often with the hands. In this context, food items share many properties in common with tools: they are graspable objects that we manipulate in self-directed and stereotyped forms of action. Thus, food items may be preferentially represented in extrastriatal visual cortex in part because of these shared affordance properties, rather than because they reflect a wholly distinct kind of category. We conducted fMRI and behavioral experiments to test this hypothesis. We found that behaviorally graspable food items and tools were judged to be similar in their action-related properties, and that the location, magnitude, and patterns of neural responses for images of graspable food items were similar in profile to the responses for tool stimuli. Our findings suggest that food-selectivity may reflect the behavioral affordances of food items rather than a distinct form of category-selectivity.
Expansion microscopy reveals unique ultrastructural features of pathogenic budding yeast species
Authors: Reza Md. Hashim , Dutta Srijana , Goyal Rohit , Shah Hiral , Dey Gautam , Sanyal Kaustuv
Published: March 2024

Candida albicansis the most prevalent fungal pathogen isolated from patients with candidemia. As is the case for many other fungi, the complex life cycle ofC. albicanshas been challenging to study with high-resolution microscopy techniques due to its small size. We employed ultrastructure expansion microscopy (U-ExM) to directly visualise sub-cellular structures at high resolution in theC. albicansyeast and during its transition to hyphal growth. NHS-ester pan-labelling in combination with immunofluorescence (IF) provided the first comprehensive map of nucleolar and mitochondrial dynamics through theC. albicanscell cycle. Analysis of microtubules (MTs) and spindle pole bodies (SPBs) stained with marker proteins suggests that contrary to the pole-to-pole arrangement observed inSaccharomyces cerevisiae, C. albicansyeast cells display a unique side-by-side arrangement of SPBs with a short mitotic spindle and longer astral MTs (aMTs) at the pre-anaphase stage. Modifications to the established U-ExM protocol enabled the expansion of several medically relevant human fungal pathogens, revealing that the side-by-side SPB configuration is a plausible conserved feature shared by many fungal species. We highlight the power of U-ExM to investigate sub-cellular organisation and organellar dynamics at high resolution and low cost in poorly studied, medically relevant microbial pathogens.
ACE1 knockout in neurons selectively dysregulates the hippocampal renin angiotensin system and causes vascular loss
Authors: Jeon Sohee , Salvo Miranda A. , Alia Alia O. , Popovic Jelena , Zagardo Mitchell , Chandra Sidhanth , Nassan Malik , Gate David , Vassar Robert , Cuddy Leah K.
Published: March 2024

Angiotensin I converting enzyme (ACE1) maintains blood pressure homeostasis by converting angiotensin I (angI) into angiotensin II (angII) in the renin-angiotensin system (RAS). ACE1 is expressed in the brain, where an intrinsic RAS regulates complex cognitive functions including learning and memory. ACE1 has been implicated in neurodegenerative disorders including Alzheimer’s disease (AD) and Parkinson’s disease (PD), but the mechanisms remain incompletely understood. Here, we performed single-nucleus RNA sequencing to characterize the expression RAS genes in the hippocampus and discovered thatAceis mostly expressed in CA region excitatory neurons. To gain a deeper understanding of the function of neuronal ACE1, we generated ACE1 conditional knockout (cKO) mice lacking ACE1 expression specifically in hippocampal and cortical excitatory neurons. Interestingly, ACE1 cKO mice exhibited hippocampus-dependent memory impairment in the Morris water maze, y-maze, and fear conditioning tests, but exhibited normal motor skills in rotarod. Total ACE1 level was significantly reduced in the cortex and hippocampus of ACE1 cKO mice showing that excitatory neurons are the predominant cell type expressing ACE1 in the forebrain. Despite similar reductions in total ACE1 level in both the hippocampus and cortex, the RAS pathway was dysregulated in the hippocampus only. Importantly, ACE cKO mice exhibited exacerbated age-related capillary loss selectively in the hippocampus. Here, we show selective vulnerability of the hippocampal microvasculature and RAS pathway to neuronal ACE1 knockout. Our results provide important insights into the function of ACE1 in the brain and demonstrate a connection between neuronal ACE and cerebrovascular function in the hippocampus.
Probing Phosphorylation-Induced Vibrational Couplings in CFTR by 2D IR Spectra Simulations
Authors: Zhu Jing , Chen Tunan , Zhao Yu , Ji Guangfu
Published: March 2024

Phosphorylation of the regulator (R) domain underlies the basis for gating in the human cystic fibrosis transmembrane conductance regulator (CFTR), malfunction or down regulation of CFTR leads to defective apical chloride transport. The biophysical mechanism that underlies the regulatory effect of R domain is still unclear. Here, we utilize a combination of molecular dynamics simulations and theoretically calculated two-dimensional infrared (2D IR) spectra to probe both the structure and spectral signature of phosphorylated and unphosphorylated CFTR. We uncover an ATP-independent asymptotic movement of nucleotide binding domains (NBDs) driven by phosphorylated R domain. Utilizing non-rephasing cross ground-state bleach infrared (GB IR) spectra simulation, we overcome the interpretation hurdle caused by overlaps of multiple vibrational modes, and find distinct vibrational couplings induced by phosphorylation. By calculating exciton eigenfrequencies, we pinpoint specific vibrational couplings to individual amide I modes (carbonyl stretches), unveiling a critical role of serine residues in modulating the coupling state of neighboring amino acids. Our findings offer a bond-specific perspective on how intramolecular interactions within the R domain translate into its broader regulatory function.