bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating the ChatGPT family of models for biomedical reasoning and classification
Authors: Chen Shan , Li Yingya , Lu Sheng , Van Hoang , Aerts Hugo J W L , Savova Guergana K , Bitterman Danielle S
Published: January 2024

Objective

Large language models (LLMs) have shown impressive ability in biomedical question-answering, but have not been adequately investigated for more specific biomedical applications. This study investigates ChatGPT family of models (GPT-3.5, GPT-4) in biomedical tasks beyond question-answering.

Materials and Methods

We evaluated model performance with 11 122 samples for two fundamental tasks in the biomedical domain—classification (n = 8676) and reasoning (n = 2446). The first task involves classifying health advice in scientific literature, while the second task is detecting causal relations in biomedical literature. We used 20% of the dataset for prompt development, including zero- and few-shot settings with and without chain-of-thought (CoT). We then evaluated the best prompts from each setting on the remaining dataset, comparing them to models using simple features (BoW with logistic regression) and fine-tuned BioBERT models.

Results

Fine-tuning BioBERT produced the best classification (F1: 0.800-0.902) and reasoning (F1: 0.851) results. Among LLM approaches, few-shot CoT achieved the best classification (F1: 0.671-0.770) and reasoning (F1: 0.682) results, comparable to the BoW model (F1: 0.602-0.753 and 0.675 for classification and reasoning, respectively). It took 78 h to obtain the best LLM results, compared to 0.078 and 0.008 h for the top-performing BioBERT and BoW models, respectively.

Discussion

The simple BoW model performed similarly to the most complex LLM prompting. Prompt engineering required significant investment.

Conclusion

Despite the excitement around viral ChatGPT, fine-tuning for two fundamental biomedical natural language processing tasks remained the best strategy.
Prevalence of white spot syndrome virus (WSSV) in wild-caught and commodity decapod crustaceans in coastal South Carolina, USA
Authors: Sasson Daniel A , Allen Jacqueline M , Walker Matt J , Huber Jeanette H , Rothman Gregory K , Kingsley-Smith Peter R , Darden Tanya L , Kendrick Michael R
Published: January 2024

White spot syndrome virus (WSSV) is a highly contagious and economically costly virus that affects many crustacean species. Since its introduction into the United States in the 1990s, it has spread from aquaculture shrimp and crayfish to wild crustaceans throughout the southeastern United States. Transmission to natural systems may occur through contact between commodity (i.e., store-bought) and wild crustaceans or the use of infected frozen shrimp as bait, which has been proven capable of transmitting the virus. In this study, we surveyed both live (Penaeus setiferus (Linnaeus, 1767) and P. aztecusIves, 1891) and frozen commodity shrimp (Penaeus vannameiBoone, 1931) and crayfish (Procambarus troglodytes (Le Conte, 1856) and P. clarkii (Girard, 1852)) as well as wild populations of some of these species of shrimp, crayfish, and blue crabs (Callinectes sapidusRathbun, 1896) in South Carolina for WSSV. We found extremely low levels of the virus in wild-caught decapods but high levels of WSSV in commodity crayfish (50%) and imported frozen shrimp (43.3%). While additional work is needed to understand the environmental conditions that affect the transmission potential of WSSV, these results suggest that care must be taken with commodity crustaceans to prevent introductions of WSSV and subsequent harm to natural ecosystems.
Hessian fly (Diptera: Cecidomyiidae) virulence in Louisiana: assessment of field populations from 2023 to efficacy of 27 Hessian fly resistance genes in wheat
Authors: Schemerhorn Brandon J , Cambron Sue E , Subramanyam Subhashree
Published: January 2024

The Hessian fly, Mayetiola destructor (Say), is one of the most important insect pest plaguing wheat (Triticum aestivum, L) producers across the United States and around the world. Genetic resistance is the stalwart for control of Hessian fly. However, new genotypes (biotypes) arise in deployment of wheat containing resistance genes, so field populations must be evaluated periodically to provide information on the efficacy of those deployed genes. Louisiana (LA), with its diverse agricultural landscape, is not exempt from the challenges posed by this destructive pest. We previously documented the resistance response of wheat lines harboring Hessian fly resistance (H) genes against field populations collected in 2008 from across the southeastern United States, including Iberville Parish, LA. In the spring of 2023, we reevaluated the resistance response of 27 H genes from the field populations collected from Iberville Parish, LA, and compared the results with those observed in 2008. Sixteen H genes showed comparable resistance to the field populations from both years. While 3 of the H genes, H11, H23, and H24, showed a significant decrease in resistance, 2 genes, H16 and H31, had marked increase in resistance. Furthermore, 6 additional H genes were evaluated in 2023, with 4 showing >70% resistance. Our results clearly identify a total of 20 H genes that are moderate to highly effective against the 2023 Hessian fly population from Iberville Parish, LA. The resistance response documented in this study offers valuable information to wheat breeders in the region for effective management of this insect pest.
Herbivore-induced plant volatiles emitted by citrus in response to spider mite infestation can attract predatory mites
Authors: Song Cancan , Chen Die , Jiang Chunxian , Li Chengcheng , Chen Lin , Huang Rong , Wang Xian , Qin Jie , Li Qing
Published: January 2024

Understanding the nutritional interplay among plants, pests, and natural enemies is essential for sustainable pest management. Enhancing the efficiency of natural enemies, such as Neoseiulus californicus (McGregor) (Acari: Phytoseiidae) is critical, and exploiting herbivore-induced plant volatiles (HIPVs) offers a promising approach. However, N. californicus has rarely been reported to utilize HIPVs to improve their biological control capabilities. Our research revealed a significant difference in the diversity of volatile compounds detected in clean Citrus reticulata Blanco leaves compared to those in C. reticulata leaves infested with Panonychus citri (McGregor) (Acari: Tetranychidae), regardless of mite presence. This suggests that P. citri infestation induces a wide array of HIPVs in C. reticulata leaves. We conducted olfactory behavioral assays to evaluate the response of N. californicus to synthetic HIPVs. Results revealed that linalool (1.00 mg/mL), 2,2,4-trimethylpentane (10.0 mg/mL), undecylcyclohexane (1.00 mg/mL), and (+)-dibenzoyl-L-tartaric anhydride (10.0 mg/mL) significantly attracted N. californicus while pentadecanal (1.00 mg/mL) significantly deterred it. A 3-component blend of linalool, undecylcyclohexane, and (+)-dibenzoyl-L-tartaric anhydride was better than other combinations in attracting N. californicus. This combination provided the basis for developing an attractant for N. californicus, facilitating the rate of its dispersal to enhance its biological control of pests. Consequently, this research offers vital insights into improving the sustainable pest control potential of predatory mites.
Crustal structure of the southern Lower Yangtze region and its geological implications: a deep reflection seismic profile
Authors: Zhang Penghui , Wang Tong , Li Guangcai , Liu Jianxun , Fang Hui , Li Pei , Li Hongkui
Published: January 2024

The southern part of the Lower Yangtze Region, located in the area bounded by the Jiangnan and Dabie orogenic belts, is characterized by a complex fault structure and unique magmatism, and is one of the key areas in regional tectonic evolution and magmatism. In this study the authors used a 45-km-long deep reflection seismic profile to study the crustal structure of the southern Lower Yangtze Region. The results show that the crust in the study area is ∼31.5–33.6 km thick, with the Huaining Basin as the thinnest part. A detachment surface at a depth of around 12 km divides the crust into the upper and lower crust, act as a key tectonic decoupling layer. Two sets of thrust nappe faults with opposite tendencies have horizontally developed above the detachment surface, with the Huaining Basin as the centre. A typical wedge-shaped structure has developed below the Qianshan Basin, suggesting that two sets of thrust nappe faults may have formed in the same dynamic system. The reflection patterns of the lower crust on both sides of the profile exhibit a monoclinic feature with opposite tendencies, while the lower part of the Huaining Basin exhibits an arcuate upward-arch feature. A prominent ductile shear zone in the lower crust has developed on the west side of the Huaining Basin, which can provide a favourable channel for magma migration. The results of this study deepen our understanding of the deep structure of the Lower Yangtze Region, and provide important constraint data for research on dynamic mechanisms.
Secretory expression of amylosucrase in Bacillus licheniformis through twin-arginine translocation pathway
Authors: Wang Caizhe , Niu Dandan , Mchunu Nokuthula Peace , Zhang Meng , Singh Suren , Wang Zhengxiang
Published: January 2024

Amylosucrase (EC 2.4.1.4) is a versatile enzyme with significant potential in biotechnology and food production. To facilitate its efficient preparation, a novel expression strategy was implemented in Bacillus licheniformis for the secretory expression of Neisseria polysaccharea amylosucrase (NpAS). The host strain B. licheniformis CBBD302 underwent genetic modification through the deletion of sacB, a gene responsible for encoding levansucrase that synthesizes extracellular levan from sucrose, resulting in a levan-deficient strain, B. licheniformis CBBD302B. Neisseria polysaccharea amylosucrase was successfully expressed in B. licheniformis CBBD302B using the highly efficient Sec-type signal peptide SamyL, but its extracellular translocation was unsuccessful. Consequently, the expression of NpAS via the twin-arginine translocation (TAT) pathway was investigated using the signal peptide SglmU. The study revealed that NpAS could be effectively translocated extracellularly through the TAT pathway, with the signal peptide SglmU facilitating the process. Remarkably, 62.81% of the total expressed activity was detected in the medium. This study marks the first successful secretory expression of NpAS in Bacillus species host cells, establishing a foundation for its future efficient production.

One-Sentence Summary

Amylosucrase was secreted in Bacillus licheniformis via the twin-arginine translocation pathway.
Two decades of endemic dengue in Bangladesh (2000–2022): trends, seasonality, and impact of temperature and rainfall patterns on transmission dynamics
Authors: Hasan Mohammad Nayeem , Khalil Ibrahim , Chowdhury Muhammad Abdul Baker , Rahman Mahbubur , Asaduzzaman Md , Billah Masum , Banu Laila Arjuman , Alam Mahbub-Ul , Ahsan Atik , Traore Tieble , Uddin Md Jamal , Galizi Roberto , Russo Ilaria , Zumla Alimuddin , Haider Najmul
Published: January 2024

The objectives of this study were to compare dengue virus (DENV) cases, deaths, case-fatality ratio [CFR], and meteorological parameters between the first and the recent decades of this century (2000–2010 vs. 2011–2022) and to describe the trends, seasonality, and impact of change of temperature and rainfall patterns on transmission dynamics of dengue in Bangladesh. For the period 2000–2022, dengue cases and death data from Bangladesh’s Ministry of Health and Family Welfare’s website, and meteorological data from the Bangladesh Meteorological Department were analyzed. A Poisson regression model was performed to identify the impact of meteorological parameters on the monthly dengue cases. A forecast of dengue cases was performed using an autoregressive integrated moving average model. Over the past 23 yr, a total of 244,246 dengue cases were reported including 849 deaths (CFR = 0.35%). The mean annual number of dengue cases increased 8 times during the second decade, with 2,216 cases during 2000–2010 vs. 18,321 cases during 2011–2022. The mean annual number of deaths doubled (21 vs. 46), but the overall CFR has decreased by one-third (0.69% vs. 0.23%). Concurrently, the annual mean temperature increased by 0.49 °C, and rainfall decreased by 314 mm with altered precipitation seasonality. Monthly mean temperature (Incidence risk ratio [IRR]: 1.26), first-lagged rainfall (IRR: 1.08), and second-lagged rainfall (IRR: 1.17) were significantly associated with monthly dengue cases. The increased local temperature and changes in rainfall seasonality might have contributed to the increased dengue cases in Bangladesh.
Efficient RNAi knockdown at 20 °C in Aedes albopictus (Diptera: Culicidae)
Authors: Heilig Mara , Armbruster Peter A
Published: January 2024

RNA interference (RNAi) is a conserved cellular pathway found in nearly all eukaryotes that leads to the silencing of target mRNAs. Using RNAi as a mechanism to knockdown specific genes has enabled functional and reverse genetics studies in a wide range of eukaryotes. Previous work suggests that RNAi is inhibited at lower temperatures, potentially limiting the possibility to perform knockdown studies on ecologically relevant phenotypes that are only expressed at low temperatures. To determine whether RNAi is inhibited at low temperatures in Aedes albopictus (Skuse), we injected mosquitoes reared at 20 ± 1 °C, with dsRNA targeting yellow-g2 and compared knockdown efficacy to mosquitoes injected at 26.5 ± 1 °C. Our results demonstrate efficient knockdown at both temperatures, thereby establishing the feasibility of RNAi for functional genetic studies in A. albopictus at low temperatures.
The Borders of Migrant and Refugee Activism in South Africa
Authors: Vanyoro Kudakwashe
Published: January 2024

This article examines the relationship between the activities of civil society organizations (CSOs) on migration and refugee issues with state-making processes and discourses in South Africa, based upon key informant interviews, discourse analysis, and ethnographic research. It argues that this relationship brings attention to the defining and reinforcement of national borders set against the backdrop of the ‘corporate pact’ between the South African government and CSOs that has necessitated public participation in social movements and voluntary associations involved in a range of different xenophobic activities that are legitimized by political parties seeking popularity, and the state. Financial resources operate as ‘material disciplines’ by influencing the kind of problems that are visible, and, in turn, categories that non-state actors like philanthropies, charities, and donors consider worthy of protection. Those affected by shifting categories and their influence on NGO support like Zimbabweans have taken matters into their own hands to counter this novel border from below.
Masturbation, sexual function, and genital self-image of undergraduate women: a cross-sectional study
Authors: Soares Renata Fernandes , Leites Gabriela Tomedi , de Araujo Tatiane Gomes , Pedreti Gabriela Paludo , Cerentini Taís Marques , da Rosa Patricia Viana
Published: January 2024

Background

The relationship between factors related to masturbation, sexual function, and genital self-image among women has not been fully explored in the literature.

Aim

The study sought to investigate the association between masturbation frequency, feelings, and behaviors with sexual function and genital self-image in young women.

Methods

A cross-sectional survey among 110 undergraduate female students was conducted. Online self-administered questionnaires to assess sociodemographic characteristics, masturbatory frequency, feelings, and behavior were completed. Participants also answered the Brazilian version of the Female Sexual Function Index (FSFI) and the Female Genital Self-Image Scale (FGSIS).

Outcomes

The outcome includes masturbation frequency and behaviors associated, as well as scores on the FSFI and FGSIS.

Results

Women showed higher scores in FSFI subdomains when masturbation was considered important for them, along with reported feelings of empowerment and satisfaction during this activity. However, those who experienced negative emotions during masturbation, such as shame or guilt, demonstrated a significant association with lower scores in both FSFI and FGSIS. Masturbation frequency was found to correlate with better sexual function specifically in the desire domain among women who engaged in daily masturbation. Additionally, an association was observed between higher scores in the FGSIS and increased scores in the domains of satisfaction, arousal, and orgasm within the FSFI. There was an association in the domain’s satisfaction, arousal, and orgasm of the FSFI with greater scores in FGSIS.

Clinical Implications

The clinical implications encompass the augmentation of understanding pertaining to female sexual function.

Strengths and Limitations

The study provides valuable insights into the sexual behavior of undergraduate female students, and its methodology improves openness in responses, as it provides anonymity given the sensitive nature of the topic studied. Study limitations include the unsuitability of the FSFI questionnaire for sexually inactive women in the past 4 weeks; the participation bias and reporting bias in sexuality searches; and the unknown validity of the investigator-derived questionnaire about masturbation, as it has not been previously validated.

Conclusion

Masturbation frequency has minimal to no impact on female sexual function, whereas harboring positive feelings toward it and maintaining a positive genital self-image may exert a positive influence on sexual function.
Uncommon causes of hemoglobin E flags identified during measurement of hemoglobin A1c by ion-exchange high-performance liquid chromatography
Authors: Herb Thomas , Taylor Alexander S , Li Shih-Hon , Manthei David M , Gherasim Carmen
Published: January 2024

We present 3 cases of discordant results from screening hemoglobin A1c (HbA1c) measured by ion-exchange high-performance liquid chromatography (HPLC) all due to various forms of interference and flagged by the instrument as “suspected hemoglobin E (HbE).” The first case was due to a rare hemoglobin variant, later confirmed to be hemoglobin Hoshida, the second due to “true” heterozygous HbE, and the third a result of analytical artifact causing splitting of the HbA1c peak without an underlying variant hemoglobin. We examine the similarities in these cases along with the laboratory work-up to classify each cause of interference to demonstrate the wide array of potential causes for the suspected HbE flag and why it warrants proper work-up. Because there is no standardized method of reporting out hemoglobin variant interference in HbA1c measurement, we discuss our laboratory’s process of investigating discordant HbA1c measurements and reporting results in cases with variant interference as 1 possible model to follow, along with discussing the associated laboratory, ethical, and clinical considerations. We also examine the structure of hemoglobin Hoshida, HbE, and conduct a brief literature review of previous reports.
Multiple populations and a CH star found in the 300S globular cluster stellar stream
Authors: Usman Sam A , Ji Alexander P , Li Ting S , Pace Andrew B , Cullinane Lara R , Da Costa Gary S , Koposov Sergey E , Lewis Geraint F , Zucker Daniel B , Belokurov Vasily , Bland-Hawthorn Joss , Ferguson Peter S , Hansen Terese T , Limberg Guilherme , Martell Sarah L , McKenzie Madeleine , Simon Joshua D ,   (S5 Collaboration)
Published: January 2024

Milky Way globular clusters (GCs) display chemical enrichment in a phenomenon called multiple stellar populations (MSPs). While the enrichment mechanism is not fully understood, there is a correlation between a cluster’s mass and the fraction of enriched stars found therein. However, present-day GC masses are often smaller than their masses at the time of formation due to dynamical mass-loss. In this work, we explore the relationship between mass and MSPs using the stellar stream 300S. We present the chemical abundances of eight red giant branch member stars in 300S with high-resolution spectroscopy from Magellan/MIKE. We identify one enriched star characteristic of MSPs and no detectable metallicity dispersion, confirming that the progenitor of 300S was a GC. The fraction of enriched stars (12.5 per cent) observed in our 300S stars is less than the 50 per cent of stars found enriched in Milky Way GCs of comparable present-day mass (∼104.5 $\mathrm{\, {\rm M}_{\odot }}$). We calculate the mass of 300S’s progenitor and compare it to the initial masses of intact GCs, finding that 300S aligns well with the trend between the system mass at formation and enrichment. 300S’s progenitor may straddle the critical mass threshold for the formation of MSPs and can therefore serve as a benchmark for the stellar enrichment process. Additionally, we identify a CH star, with high abundances of s-process elements, probably accreted from a binary companion. The rarity of such binaries in intact GCs may imply stellar streams permit the survival of binaries that would otherwise be disrupted.
Analytical solutions for the evolution of MHD wind-driven accretion discs
Authors: Shadmehri Mohsen , Khajenabi Fazeleh
Published: January 2024

We present new analytical solutions for the evolution of protoplanetary discs (PPDs) where magnetohydrodynamic (MHD) wind-driven processes dominate. Our study uses a 1D model which incorporates equations detailing angular momentum extraction by MHD winds and mass-loss rates. Our solutions demonstrate that the disc retains its initial state during the early phases; however, it rapidly evolves towards a self-similar state in the later stages of disc evolution. The total disc mass undergoes a continuous decline over time, with a particularly rapid reduction occurring beyond a certain critical time threshold. This gradual decrease in mass is influenced by the wind parameters and the initial surface density of the disc. In the MHD wind-dominated regime, we show that the disc’s lifespan correlates positively with the magnetic lever arm up to a certain threshold, irrespective of the initial disc size. PPDs with a larger magnetic lever arm are found to maintain significantly higher total disc mass over extended periods compared to their counterparts. The mass ejection-to-accretion ratio increases in efficient wind scenarios and is further amplified by a steeper initial surface density profile. Our analysis also reveals varied evolutionary trajectories in the plane of accretion rate and total disc mass, influenced by magnetic parameters and initial disc size. In scenarios with efficient MHD winds, discs with bigger sizes have extended operation time for mechanisms governing planet formation.
Sub-kpc scale gas density histogram of the galactic molecular gas: a new statistical method to characterize galactic-scale gas structures
Authors: Matsusaka Ren , Handa Toshihiro , Fujimoto Yusuke , Murase Takeru , Hirata Yushi , Nishi Junya , Ito Takumi , Sasaki Megumi , Mizoguchi Tomoki
Published: January 2024

To understand physical properties of the interstellar medium (ISM) on various scales, we investigate it at parsec resolution on the kiloparsec scale. Here, we report on the sub-kpc scale gas density histogram (GDH) of the Milky Way. The GDH is a density probability distribution function (PDF) of the gas volume density. Using this method, we are free from an identification of individual molecular clouds and their spatial structures. We use survey data of 12CO and 13CO (J = 1–0) emission in the Galactic plane (l = 10○–50○) obtained as a part of the FOREST Unbiased Galactic plane Imaging survey with the Nobeyama 45m telescope (FUGIN). We make a GDH for every channel map of 2○ × 2○ area including the blank sky component, and without setting cloud boundaries. This is a different approach from previous works for molecular clouds. The GDH fits well to a single or double lognormal distribution, which we name the low-density lognormal (L-LN) and high-density lognormal (H-LN) components, respectively. The multi-lognormal components suggest that the L-LN and H-LN components originate from two different stages of structure formation in the ISM. Moreover, we find that both the volume ratios of H-LN components to total (fH) and the width of the L-LN along the gas density axis (σL) show coherent structure in the Galactic-plane longitude-velocity diagram. It is possible that these GDH parameters are related to strong galactic shocks and other weak shocks in the Milky Way.
Long-term monitoring of the Oe star VES 735: Ope! not so quiet after all
Authors: Marshall Brandon , Kerton C R
Published: January 2024

Only 3–4 per cent of Galactic O stars are observed to display the emission features representative of the OBe phenomenon, compared to Galactic B stars, which display these characteristics in 25–35 per cent of B0 and B1 stars. We present new observations of the high-mass O star, VES 735, which confirms its classification as one of these rare emission-line stars. These are its first recorded observations that display strong spectroscopic variations in nearly 30 yr of monitoring, with the H α profile exhibiting a 10-fold increase in emission compared to observations taken between 1996 and 2014 and having variations which show episodes of inflowing and outflowing material. These observations, coupled with photometric variations in the visible and infrared, show behaviour that is consistent with the mass reservoir effect for viscous decretion discs. We propose that in 2015 VES 735 began an approximately 3 yr event in which mass was being injected into the circumstellar environment followed by re-accretion towards the star. We also find evidence that the re-accretion may have been interrupted with another, smaller, mass-injection event based on observations in 2022 and 2023. Observational cadences ranging from hours to months show no evidence that VES 735 is part of a binary system, making it an ideal candidate for future observations to further investigate the evolution of high-mass stars and the OBe phenomenon as it pertains to their circumstellar environment.
Viscous dissipation and dynamics in simulations of rotating, stratified plane-layer convection
Authors: Lance Simon R W , Currie Laura K , Browning Matthew K
Published: January 2024

Convection in stars and planets must be maintained against viscous and Ohmic dissipation. Here, we present the first systematic investigation of viscous dissipation in simulations of rotating, density-stratified plane layers of convection. Our simulations consider an anelastic ideal gas, and employ the open-source code Dedalus. We demonstrate that when the convection is sufficiently vigorous, the integrated dissipative heating tends towards a value that is independent of viscosity or thermal diffusivity, but depends on the imposed luminosity and the stratification. We show that knowledge of the dissipation provides a bound on the magnitude of the kinetic energy flux in the convection zone. In our non-rotating cases with simple flow fields, much of the dissipation occurs near the highest possible temperatures, and the kinetic energy flux approaches this bound. In the rotating cases, although the total integrated dissipation is similar, it is much more uniformly distributed (and locally balanced by work against the stratification), with a consequently smaller kinetic energy flux. The heat transport in our rotating simulations is in good agreement with results previously obtained for 3D Boussinesq convection, and approaches the predictions of diffusion-free theory.
Deleterious variants in X-linked RHOXF1 cause male infertility with oligo- and azoospermia
Authors: Yi Sibing , Wang Weili , Su Lilan , Meng Lanlan , Li Yong , Tan Chen , Liu Qiang , Zhang Huan , Fan Liqing , Lu Guangxiu , Hu Liang , Du Juan , Lin Ge , Tan Yue-Qiu , Tu Chaofeng , Zhang Qianjun
Published: January 2024

Oligozoospermia and azoospermia are two common phenotypes of male infertility characterized by massive sperm defects owing to failure of spermatogenesis. The deleterious impact of candidate variants with male infertility is to be explored. In our study, we identified three hemizygous missense variants (c.388G>A: p.V130M, c.272C>T: p.A91V, and c.467C>T: p.A156V) and one hemizygous nonsense variant (c.478C>T: p.R160X) in the Rhox homeobox family member 1 gene (RHOXF1) in four unrelated cases from a cohort of 1201 infertile Chinese men with oligo- and azoospermia using whole-exome sequencing and Sanger sequencing. RHOXF1 was absent in the testicular biopsy of one patient (c.388G>A: p.V130M) whose histological analysis showed a phenotype of Sertoli cell-only syndrome. In vitro experiments indicated that RHOXF1 mutations significantly reduced the content of RHOXF1 protein in HEK293T cells. Specifically, the p.V130M, p.A156V, and p.R160X mutants of RHOXF1 also led to increased RHOXF1 accumulation in cytoplasmic particles. Luciferase assays revealed that p.V130M and p.R160X mutants may disrupt downstream spermatogenesis by perturbing the regulation of doublesex and mab-3 related transcription factor 1 (DMRT1) promoter activity. Furthermore, ICSI treatment could be beneficial in the context of oligozoospermia caused by RHOXF1 mutations. In conclusion, our findings collectively identified mutated RHOXF1 to be a disease-causing X-linked gene in human oligo- and azoospermia.
Reconstructing DNA methylation maps of ancient populations
Authors: Barouch Arielle , Mathov Yoav , Meshorer Eran , Yakir Benjamin , Carmel Liran
Published: January 2024

Studying premortem DNA methylation from ancient DNA (aDNA) provides a proxy for ancient gene activity patterns, and hence valuable information on evolutionary changes in gene regulation. Due to statistical limitations, current methods to reconstruct aDNA methylation maps are constrained to high-coverage shotgun samples, which comprise a small minority of available ancient samples. Most samples are sequenced using in-situ hybridization capture sequencing which targets a predefined set of genomic positions. Here, we develop methods to reconstruct aDNA methylation maps of samples that were not sequenced using high-coverage shotgun sequencing, by way of pooling together individuals to obtain a DNA methylation map that is characteristic of a population. We show that the resulting DNA methylation maps capture meaningful biological information and allow for the detection of differential methylation across populations. We offer guidelines on how to carry out comparative studies involving ancient populations, and how to control the rate of falsely discovered differentially methylated regions. The ability to reconstruct DNA methylation maps of past populations allows for the development of a whole new frontier in paleoepigenetic research, tracing DNA methylation changes throughout human history, using data from thousands of ancient samples.
Trans-complementation by the RecB nuclease domain of RecBCD enzyme reveals new insight into RecA loading upon χ recognition
Authors: Pavankumar Theetha L , Wong C Jason , Wong Yun Ka , Spies Maria , Kowalczykowski Stephen C
Published: January 2024

The loading of RecA onto ssDNA by RecBCD is an essential step of RecBCD-mediated homologous recombination. RecBCD facilitates RecA-loading onto ssDNA in a χ-dependent manner via its RecB nuclease domain (RecBn). Before recognition of χ, RecBn is sequestered through interactions with RecBCD. It was proposed that upon χ-recognition, RecBn undocks, allowing RecBn to swing out via a contiguous 70 amino acid linker to reveal the RecA-loading surface, and then recruit and load RecA onto ssDNA. We tested this hypothesis by examining the interactions between RecBn (RecB928–1180) and truncated RecBCD (RecB1–927CD) lacking the nuclease domain. The reconstituted complex of RecB1–927CD and RecBn is functional in vitro and in vivo. Our results indicate that despite being covalently severed from RecB1–927CD, RecBn can still load RecA onto ssDNA, establishing that RecBn does not function while only remaining tethered to the RecBCD complex via the linker. Instead, RecBCD undergoes a χ-induced intramolecular rearrangement to reveal the RecA-loading surface.
Checkpoint activation by Spd1: a competition-based system relying on tandem disordered PCNA binding motifs
Authors: Olsen Johan G , Prestel Andreas , Kassem Noah , Broendum Sebastian S , Shamim Hossain Mohammad , Simonsen Signe , Grysbæk Martin , Mortensen Josefine , Rytkjær Louise Lund , Haxholm Gitte W , Marabini Riccardo , Holmberg Christian , Carr Antony M , Crehuet Ramon , Nielsen Olaf , Kragelund Birthe B
Published: January 2024

DNA regulation, replication and repair are processes fundamental to all known organisms and the sliding clamp proliferating cell nuclear antigen (PCNA) is central to all these processes. S-phase delaying protein 1 (Spd1) from S. pombe, an intrinsically disordered protein that causes checkpoint activation by inhibiting the enzyme ribonucleotide reductase, has one of the most divergent PCNA binding motifs known. Using NMR spectroscopy, in vivo assays, X-ray crystallography, calorimetry, and Monte Carlo simulations, an additional PCNA binding motif in Spd1, a PIP-box, is revealed. The two tandemly positioned, low affinity sites exchange rapidly on PCNA exploiting the same binding sites. Increasing or decreasing the binding affinity between Spd1 and PCNA through mutations of either motif compromised the ability of Spd1 to cause checkpoint activation in yeast. These results pinpoint a role for PCNA in Spd1-mediated checkpoint activation and suggest that its tandemly positioned short linear motifs create a neatly balanced competition-based system, involving PCNA, Spd1 and the small ribonucleotide reductase subunit, Suc22R2. Similar mechanisms may be relevant in other PCNA binding ligands where divergent binding motifs so far have gone under the PIP-box radar.
Genomic overview of INA-induced NPR1 targeting and transcriptional cascades in Arabidopsis
Authors: Yun Se-Hun , Khan Irfan Ullah , Noh Bosl , Noh Yoo-Sun
Published: January 2024

The phytohormone salicylic acid (SA) triggers transcriptional reprogramming that leads to SA-induced immunity in plants. NPR1 is an SA receptor and master transcriptional regulator in SA-triggered transcriptional reprogramming. Despite the indispensable role of NPR1, genome-wide direct targets of NPR1 specific to SA signaling have not been identified. Here, we report INA (functional SA analog)-specific genome-wide targets of Arabidopsis NPR1 in plants expressing GFP-fused NPR1 under its native promoter. Analyses of NPR1-dependently expressed direct NPR1 targets revealed that NPR1 primarily activates genes encoding transcription factors upon INA treatment, triggering transcriptional cascades required for INA-induced transcriptional reprogramming and immunity. We identified genome-wide targets of a histone acetyltransferase, HAC1, including hundreds of co-targets shared with NPR1, and showed that NPR1 and HAC1 regulate INA-induced histone acetylation and expression of a subset of the co-targets. Genomic NPR1 targeting was principally mediated by TGACG-motif binding protein (TGA) transcription factors. Furthermore, a group of NPR1 targets mostly encoding transcriptional regulators was already bound to NPR1 in the basal state and showed more rapid and robust induction than other NPR1 targets upon SA signaling. Thus, our study unveils genome-wide NPR1 targeting, its role in transcriptional reprogramming, and the cooperativity between NPR1, HAC1, and TGAs in INA-induced immunity.
Single-molecule characterization of Sen1 translocation properties provides insights into eukaryotic factor-dependent transcription termination
Authors: Wang Shuang , Han Zhong , Strick Terence R
Published: January 2024

Sen1 is an essential helicase for factor-dependent transcription termination in Saccharomyces cerevisiae, whose molecular-motor mechanism has not been well addressed. Here, we use single-molecule experimentation to better understand the molecular-motor determinants of its action on RNA polymerase II (Pol II) complex. We quantify Sen1 translocation activity on single-stranded DNA (ssDNA), finding elevated translocation rates, high levels of processivity and ATP affinities. Upon deleting the N- and C-terminal domains, or further deleting different parts of the prong subdomain, which is an essential element for transcription termination, Sen1 displays changes in its translocation properties, such as slightly reduced translocation processivities, enhanced translocation rates and statistically identical ATP affinities. Although these parameters fulfil the requirements for Sen1 translocating along the RNA transcript to catch up with a stalled Pol II complex, we observe significant reductions in the termination efficiencies as well as the factions of the formation of the previously described topological intermediate prior to termination, suggesting that the prong may preserve an interaction with Pol II complex during factor-dependent termination. Our results underscore a more detailed rho-like mechanism of Sen1 and a critical interaction between Sen1 and Pol II complex for factor-dependent transcription termination in eukaryotes.
Translation variation across genetic backgrounds reveals a post-transcriptional buffering signature in yeast
Authors: Teyssonniere Elie M , Shichino Yuichi , Mito Mari , Friedrich Anne , Iwasaki Shintaro , Schacherer Joseph
Published: January 2024

Gene expression is known to vary among individuals, and this variability can impact the phenotypic diversity observed in natural populations. While the transcriptome and proteome have been extensively studied, little is known about the translation process itself. Here, we therefore performed ribosome and transcriptomic profiling on a genetically and ecologically diverse set of natural isolates of the Saccharomyces cerevisiae yeast. Interestingly, we found that the Euclidean distances between each profile and the expression fold changes in each pairwise isolate comparison were higher at the transcriptomic level. This observation clearly indicates that the transcriptional variation observed in the different isolates is buffered through a phenomenon known as post-transcriptional buffering at the translation level. Furthermore, this phenomenon seemed to have a specific signature by preferentially affecting essential genes as well as genes involved in complex-forming proteins, and low transcribed genes. We also explored the translation of the S. cerevisiae pangenome and found that the accessory genes related to introgression events displayed similar transcription and translation levels as the core genome. By contrast, genes acquired through horizontal gene transfer events tended to be less efficiently translated. Together, our results highlight both the extent and signature of the post-transcriptional buffering.
Leveraging external control data in the design and analysis of neuro-oncology trials: Pearls and perils
Authors: Polley Mei-Yin C , Schwartz Daniel , Karrison Theodore , Dignam James J
Published: January 2024

Background

Randomized controlled trials have been the gold standard for evaluating medical treatments for many decades but they are often criticized for requiring large sample sizes. Given the urgent need for better therapies for glioblastoma, it has been argued that data collected from patients treated with the standard regimen can provide high-quality external control data to supplement or replace concurrent control arm in future glioblastoma trials.

Methods

In this article, we provide an in-depth appraisal of the use of external control data in the context of neuro-oncology trials. We describe several clinical trial designs with particular attention to how external information is utilized and address common fallacies that may lead to inappropriate adoptions of external control data.

Results

Using 2 completed glioblastoma trials, we illustrate the use of an assessment tool that lays out a blueprint for assembling a high-quality external control data set. Using statistical simulations, we draw caution from scenarios where these approaches can fall short on controlling the type I error rate.

Conclusions

While this approach may hold promise in generating informative data in certain settings, this sense of optimism should be tampered with a healthy dose of skepticism due to a myriad of design and analysis challenges articulated in this review. Importantly, careful planning is key to its successful implementation.
Long-Term Survival in Patients With Relapsed/Refractory Advanced Renal Cell Carcinoma Treated With Tivozanib: Analysis of the Phase III TIVO-3 Trial
Authors: Beckermann Kathryn E , Asnis-Alibozek Aviva G , Atkins Michael B , Escudier Bernard , Hutson Thomas E , Kasturi Vijay , McDermott David F , Pal Sumanta K , Porta Camillo , Rini Brian I , Verzoni Elena
Published: January 2024

Background

Tivozanib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) with efficacy in advanced renal cell carcinoma (RCC). Long-term exploratory analyses from the TIVO-3 trial in relapsed/refractory (R/R) RCC including patients (26%) with prior immuno-oncology (IO) therapy are reported.

Methods

Patients with R/R advanced RCC that progressed with 2 or 3 prior systemic therapies (≥1 VEGFR TKI) were randomized to tivozanib 1.5 mg QD or sorafenib 400 mg BID, stratified by IMDC risk and previous therapy. Safety, investigator-assessed long-term progression-free survival (LT-PFS), and serial overall survival (OS) were assessed.

Results

Mean time on treatment was 11.0 months with tivozanib (n = 175) and 6.3 months with sorafenib (n = 175). Fewer grade ≥3 treatment-related adverse events occurred with tivozanib (46%) than sorafenib (55%). Dose modification rates were lower with tivozanib than sorafenib across age/prior IO subgroups; prior IO therapy did not impact dose reductions or discontinuations in either arm. Landmark LT-PFS rates were higher with tivozanib (3 years: 12.3% vs 2.4%; 4 years: 7.6% vs 0%). After 22.8 months mean follow-up, the OS HR was 0.89 (95% CI, 0.70-1.14); when conditioned on 12-month landmark PFS, tivozanib showed significant OS improvement over sorafenib (HR, 0.45; 95% CI, 0.22-0.91; 2-sided P = .0221).

Conclusions

Tivozanib demonstrated a consistent safety profile and long-term survival benefit in patients with R/R advanced RCC who were alive and progression free at 12 months. These post hoc exploratory analyses of LT-PFS and conditional OS support a clinically meaningful improvement with tivozanib versus sorafenib in this advanced RCC population.
Pathogen perception and signaling in plant immunity
Authors: Dodds Peter N , Chen Jian , Outram Megan A
Published: January 2024

Plant diseases are a constant and serious threat to agriculture and ecological biodiversity. Plants possess a sophisticated innate immunity system capable of detecting and responding to pathogen infection to prevent disease. Our understanding of this system has grown enormously over the past century. Early genetic descriptions of plant disease resistance and pathogen virulence were embodied in the gene-for-gene hypothesis, while physiological studies identified pathogen-derived elicitors that could trigger defense responses in plant cells and tissues. Molecular studies of these phenomena have now coalesced into an integrated model of plant immunity involving cell surface and intracellular detection of specific pathogen-derived molecules and proteins culminating in the induction of various cellular responses. Extracellular and intracellular receptors engage distinct signaling processes but converge on many similar outputs with substantial evidence now for integration of these pathways into interdependent networks controlling disease outcomes. Many of the molecular details of pathogen recognition and signaling processes are now known, providing opportunities for bioengineering to enhance plant protection from disease. Here we provide an overview of the current understanding of the main principles of plant immunity, with an emphasis on the key scientific milestones leading to these insights.
Pointing Calibration of GroundBIRD Telescope Using Moon Observation Data
Authors: Sueno Y , Baselmans J J A , Coppens A H M , Génova-Santos R T , Hattori M , Honda S , Karatsu K , Kutsuma H , Lee K , Nagasaki T , Oguri S , Otani C , Peel M , Suzuki J , Tajima O , Tanaka T , Tsujii M , Thoen D J , Won E
Published: January 2024

Understanding telescope pointing (i.e. line of sight) is important for observing the cosmic microwave background (CMB) and astronomical objects. The Moon is a candidate astronomical source for pointing calibration. Although the visible size of the Moon (30′) is larger than that of the planets, we can frequently observe the Moon once a month with a high signal-to-noise ratio. We developed a method for performing pointing calibration using observational data from the Moon. We considered the tilts of the telescope axes as well as the encoder and collimation offsets for pointing calibration. In addition, we evaluated the effects of the nonuniformity of the brightness temperature of the Moon, which is a dominant systematic error. As a result, we successfully achieved a pointing accuracy of 3.3′. This is one order of magnitude smaller than an angular resolution of 36′. This level of accuracy competes with past achievements in other ground-based CMB experiments using observational data from the planets.
Outside Options in the Labour Market
Authors: Caldwell Sydnee , Danieli Oren
Published: January 2024

This paper develops a method to estimate workers’ outside employment opportunities. We outline a matching model with two-sided heterogeneity, from which we derive a sufficient statistic, the “outside options index” (OOI), for the effect of outside options on earnings, holding worker productivity constant. The OOI uses the cross-sectional concentration of similar workers across job types to quantify workers’ outside options as a function of workers’ commuting costs, preferences, and skills. Using German micro-data, we find that differences in options explain 20% of the gender earnings gap, and that gender gaps in options are mostly due to differences in the implicit costs of commuting and moving.