bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemical identification and indexing in PubMed full-text articles using deep learning and heuristics
Authors: Almeida Tiago , Antunes Rui , F. Silva João , Almeida João R , Matos Sérgio
Published: July 2022

The identification of chemicals in articles has attracted a large interest in the biomedical scientific community, given its importance in drug development research. Most of previous research have focused on PubMed abstracts, and further investigation using full-text documents is required because these contain additional valuable information that must be explored. The manual expert task of indexing Medical Subject Headings (MeSH) terms to these articles later helps researchers find the most relevant publications for their ongoing work. The BioCreative VII NLM-Chem track fostered the development of systems for chemical identification and indexing in PubMed full-text articles. Chemical identification consisted in identifying the chemical mentions and linking these to unique MeSH identifiers. This manuscript describes our participation system and the post-challenge improvements we made. We propose a three-stage pipeline that individually performs chemical mention detection, entity normalization and indexing. Regarding chemical identification, we adopted a deep-learning solution that utilizes the PubMedBERT contextualized embeddings followed by a multilayer perceptron and a conditional random field tagging layer. For the normalization approach, we use a sieve-based dictionary filtering followed by a deep-learning similarity search strategy. Finally, for the indexing we developed rules for identifying the more relevant MeSH codes for each article. During the challenge, our system obtained the best official results in the normalization and indexing tasks despite the lower performance in the chemical mention recognition task. In a post-contest phase we boosted our results by improving our named entity recognition model with additional techniques. The final system achieved 0.8731, 0.8275 and 0.4849 in the chemical identification, normalization and indexing tasks, respectively. The code to reproduce our experiments and run the pipeline is publicly available.

Database URL

https://github.com/bioinformatics-ua/biocreativeVII_track2
Continuous development of the semantic search engine preVIEW: from COVID-19 to long COVID
Authors: Langnickel Lisa , Darms Johannes , Heldt Katharina , Ducks Denise , Fluck Juliane
Published: July 2022

preVIEW is a freely available semantic search engine for Coronavirus disease (COVID-19)-related preprint publications. Currently, it contains >43 800 documents indexed with >4000 semantic concepts, annotated automatically. During the last 2 years, the dynamic situation of the corona crisis has demanded dynamic development. Whereas new semantic concepts have been added over time—such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of interest—the service has been also extended with several features improving the usability and user friendliness. Most importantly, the user is now able to give feedback on detected semantic concepts, i.e. a user can mark annotations as true positives or false positives. In addition, we expanded our methods to construct search queries. The presented version of preVIEW also includes links to the peer-reviewed journal articles, if available. With the described system, we participated in the BioCreative VII interactive text-mining track and retrieved promising user-in-the-loop feedback. Additionally, as the occurrence of long-term symptoms after an infection with the virus SARS-CoV-2—called long COVID—is getting more and more attention, we have recently developed and incorporated a long COVID classifier based on state-of-the-art methods and manually curated data by experts. The service is freely accessible under https://preview.zbmed.de
Distinct cardiovascular phenotypes are associated with prognosis in systemic sclerosis: a cardiovascular magnetic resonance study
Authors: Knight Daniel S , Karia Nina , Cole Alice R , Maclean Rory H , Brown James T , Masi Ambra , Patel Rishi K , Razvi Yousuf , Chacko Liza , Venneri Lucia , Kotecha Tushar , Martinez-Naharro Ana , Kellman Peter , Scott-Russell Ann M , Schreiber Benjamin E , Ong Voon H , Denton Christopher P , Fontana Marianna , Coghlan J Gerry , Muthurangu Vivek
Published: July 2022

Aims

Cardiovascular involvement in systemic sclerosis (SSc) is heterogeneous and ill-defined. This study aimed to: (i) discover cardiac phenotypes in SSc by cardiovascular magnetic resonance (CMR); (ii) provide a CMR-based algorithm for phenotypic classification; and (iii) examine for associations between phenotypes and mortality.

Methods and results

A retrospective, single-centre, observational study of 260 SSc patients who underwent clinically indicated CMR including native myocardial T1 and T2 mapping from 2016 to 2019 was performed. Agglomerative hierarchical clustering using only CMR variables revealed five clusters of SSc patients with shared CMR characteristics: dilated right hearts with right ventricular failure (RVF); biventricular failure dilatation and dysfunction (BVF); and normal function with average cavity (NF-AC), normal function with small cavity (NF-SC), and normal function with large cavity (NF-LC) sizes. Phenotypes did not co-segregate with clinical or antibody classifications. A CMR-based decision tree for phenotype classification was created. Sixty-three (24%) patients died during a median follow-up period of 3.4 years. After adjustment for age and presence of pulmonary hypertension (PH), independent CMR predictors of all-cause mortality were native T1 (P < 0.001) and right ventricular ejection fraction (RVEF) (P = 0.0032). NF-SC and NF-AC groups had more favourable prognoses (P≤0.036) than the other three groups which had no differences in prognoses between them (P > 0.14). Hazard ratios (HR) were statistically significant for RVF (HR = 8.9, P < 0.001), BVF (HR = 5.2, P = 0.006), and NF-LC (HR = 4.9, P = 0.002) groups. The NF-LC group remained significantly predictive of mortality after adjusting for RVEF, native T1, and PH diagnosis (P = 0.0046).

Conclusion

We identified five CMR-defined cardiac SSc phenotypes that did not co-segregate with clinical data and had distinct outcomes, offering opportunities for a more precision-medicine based management approach.
Tumor necrosis factor-α-inducing protein of Helicobacter pylori promotes epithelial-mesenchymal transition and cancer stem-like cells properties via activation of Wnt/β-catenin signaling pathway in gastric cancer cells
Authors: Guo Kaiyun , Duan Jie , Lu Jingwen , Xiao Lingqiao , Han Liang , Zeng Shasha , Tang Xin , Li Wenjing , Huang Lijun , Zhang Yan
Published: July 2022

Tumor necrosis factor-α-inducing protein (Tipα) is a newly identified toxin that promotes the inflammation and carcinogenesis caused by Helicobacter pylori. However, its mechanism of pathogenesis is still unclear. To investigate the carcinogenic mechanisms of Tipα, SGC7901 cells and SGC7901-derived cancer stem-like cells (CSCs) were stimulated by recombinant Tipα with or without Wnt/β-catenin signaling inhibitor XAV939. qRT-PCR and Western blotting were employed to detect expression of epithelial-mesenchymal transition (EMT), CSCs markers and downstream target genes of this signaling pathway. The cell migration ability was measured by wound healing assay and transwell assay. Our results indicated that Tipα promoted CSC properties of SGC7901 spheroids, including increased expression of CSC specific surface markers CD44, Oct4 and Nanog and an increased capacity for self-renewal. Tipα activated Wnt/β-catenin signaling in both SGC7901 cells or CSCs. Furthermore, Tipα induced the EMT and increased the expressions of downstream target genes of this signaling, including c-myc, cyclin D1 and CD44. However, XAV939 pretreatment inhibited Tipα-induced EMT and CSC properties in SGC7901 cells or CSCs. These results suggest that Tipα promotes EMT and CSC-like properties in gastric cancer cells through activation of Wnt/β-catenin signaling pathway, thereby accelerating the progression of gastric cancer.
Replication-Dependent Organization Constrains Positioning of Long DNA Repeats in Bacterial Genomes
Authors: Malhotra Nitish , Seshasayee Aswin Sai Narain
Published: July 2022

Bacterial genome organization is primarily driven by chromosomal replication from a single origin of replication. However, chromosomal rearrangements, which can disrupt such organization, are inevitable in nature. Long DNA repeats are major players mediating rearrangements, large and small, via homologous recombination. Since changes to genome organization affect bacterial fitness—and more so in fast-growing than slow-growing bacteria—and are under selection, it is reasonable to expect that genomic positioning of long DNA repeats is also under selection. To test this, we identified identical DNA repeats of at least 100 base pairs across ∼6,000 bacterial genomes and compared their distribution in fast- and slow-growing bacteria. We found that long identical DNA repeats are distributed in a non-random manner across bacterial genomes. Their distribution differs in the overall number, orientation, and proximity to the origin of replication, between fast- and slow-growing bacteria. We show that their positioning—which might arise from a combination of the processes that produce repeats and selection on rearrangements that recombination between repeat elements might cause—permits less disruption to the replication-dependent genome organization of bacteria compared with random suggesting it as a major constraint to positioning of long DNA repeats.
Assessing patterns of change in lifestyle behaviours by parity: a longitudinal cohort study
Authors: Makama Maureen , Earnest Arul , Lim Siew , Skouteris Helen , Hill Briony , Teede Helena , Boyle Jacqueline A , Brown Wendy J , Hodge Allison M , Moran Lisa J
Published: July 2022

Background

The time constraints and reprioritization of personal health associated with having children may lead women to adopt less healthy lifestyles. We assessed the patterns of change in weight and lifestyle behaviours associated with having children and whether these differ between primiparous and multiparous women.

Methods

Data were from Surveys 3 and 5 of the 1973–1978 birth cohort of the Australian Longitudinal Study on Women’s Health. In women who were nulliparous at Survey 3, we assessed changes in weight, energy intake, diet (diet quality, macronutrients and micronutrients), physical activity and sitting time by parity status at Survey 5 using one-way analysis of covariance.

Results

Of 4927 eligible women, 2503 gave birth (1090 primiparous and 1413 multiparous) by Survey 5. Women who had given birth 6 years later increased weight (1.0 kg; 95% CI 0.5, 1.5), energy intake (833.9 kJ/day; 95% CI 706.7, 961.1) and diet quality (1.5 units; 95% CI 0.8, 2.1), but decreased physical activity [–405.0 Metabolic Equivalent of Task.min/week; 95% CI –464.2, –345.8] and sitting time (–1.8 h/day; 95% CI –1.9, –1.6) (adjusted mean differences) relative to those who remained nulliparous. In subgroup analysis involving further stratification by parity, the increase in diet quality was only seen in women who became primiparous and the decrease in sitting time was more marked in multiparous women.

Conclusion

Childbearing is associated with increased weight and energy intake, decreased physical activity, increased diet quality and decreased sitting time. More research targeting weight, energy intake and physical activity for improvement in women during the childbearing years is warranted.
Monitoring of Adverse Events in Recipients of the 2-Dose Ebola Vaccine Regimen of Ad26.ZEBOV Followed by MVA-BN-Filo in the UMURINZI Ebola Vaccination Campaign
Authors: Nyombayire Julien , Ingabire Rosine , Magod Ben , Mazzei Amelia , Mazarati Jean-Baptiste , Noben Jozef , Katwere Michael , Parker Rachel , Nsanzimana Sabin , Wall Kristin M , Sayinzoga Felix , Tichacek Amanda , Robinson Cynthia , Hammoud Niina , Priddy Frances , Allen Susan , Karita Etienne
Published: July 2022

Background

From 2019 to 2021, Rwandan residents of the border with the Democratic Republic of the Congo were offered the Ad26.ZEBOV (adenovirus type 26 vector vaccine encoding Ebola virus glycoprotein) and MVA-BN-Filo (modified vaccinia virus Ankara vector vaccine, encoding glycoproteins from Ebola, Sudan, Marburg, and nucleoprotein from Tai Forest viruses) Ebola vaccine regimen.

Methods

Nonpregnant persons aged ≥2 years were eligible. Unsolicited adverse events (UAEs) were reported through phone calls or visits, and serious adverse events (SAEs) were recorded per International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines.

Results

Following Ad26.ZEBOV, UAEs were reported by 0.68% of 216 113 vaccinees and were more common in younger children (aged 2–8 years, 1.2%) compared with older children (aged 9–17 years, 0.4%) and adults (aged ≥18 years, 0.7%). Fever and headache were the most reported symptoms. All 17 SAEs related to vaccine were in children aged 2–8 years (10 postvaccination febrile convulsions ± gastroenteritis and 7 fever and/or gastroenteritis). The incidence of febrile seizures was 8 of 26 062 (0.031%) prior to initiation of routine acetaminophen in December 2020 and 2 of 15 897 (0.013%) thereafter. Nonobstetric SAEs were similar in males and females. All 20 deaths were unrelated to vaccination. Young girls and adult women with UAEs were less likely to receive the second dose than those without UAEs. Seven unrelated SAEs occurred in 203 267 MVA-BN-Filo recipients.

Conclusions

Postvaccination febrile convulsions in young children were rare but not previously described after Ad26.ZEBOV and were reduced with routine acetaminophen. The regimen was otherwise safe and well-tolerated.
Long-Axis Rotation of Jaws of Bamboo Sharks (Chiloscyllium plagiosum) During Suction Feeding
Authors: Scott Bradley R , Brainerd Elizabeth L , Wilga Cheryl A D
Published: July 2022

Synopsis

Long-axis rotation (LAR) of the jaws may be an important component of vertebrate feeding mechanisms, as it has been hypothesized to occur during prey capture or food processing across diverse vertebrate groups including mammals, ray-finned fishes, and sharks and rays. LAR can affect tooth orientation as well as muscle fiber direction and therefore muscle power during feeding. However, to date only a handful of studies have demonstrated this LAR in vivo. Here, we use XROMM to document LAR of the upper and lower jaws in white-spotted bamboo sharks, Chiloscyllium plagiosum, during suction feeding. As the lower jaw begins to depress for suction expansion, both the upper jaw (palatoquadrate) and lower jaw (Meckel's cartilage) evert, such that their toothed surfaces move laterally, and then they invert with jaw closing. Eversion has been shown to tense the dental ligament and erect the teeth in some sharks, but it is not clear how this tooth erection would contribute to suction feeding in bamboo sharks. Two recent XROMM studies have shown LAR of the lower jaws during mastication in mammals and stingrays and our study extends LAR to suction feeding and confirms its presence in shark species. Examples of LAR of the jaws are becoming increasingly widespread across vertebrates with unfused mandibular symphyses. Unfused lower jaws are the plesiomorphic condition for most vertebrate lineages and therefore LAR may be a common component of jaw mechanics unless the mandibular symphysis is fused.
Stimulatory effects of TGFα in granulosa cells of bovine small antral follicles
Authors: Lundberg Allie L , Jaskiewicz Nicole M , Maucieri Abigail M , Townson David H
Published: July 2022

Intraovarian growth factors play a vital role in influencing the fate of ovarian follicles. They affect proliferation and apoptosis of granulosa cells (GC) and can influence whether small antral follicles continue their growth or undergo atresia. Transforming growth factor-alpha (TGFα), an oocyte-derived growth factor, is thought to regulate granulosa cell function; yet its investigation has been largely overshadowed by emerging interest in TGF-beta superfamily members, such as bone morphogenetic proteins (BMP) and anti-Mullerian hormone (AMH). Here, effects of TGFα on bovine GC proliferation, intracellular signaling, and cytokine-induced apoptosis were evaluated. Briefly, all small antral follicles (3–5 mm) from slaughterhouse specimens of bovine ovary pairs were aspirated and the cells were plated in T25 flasks containing DMEM/F12 medium, 10% FBS, and antibiotic-antimycotic, and incubated at 37 °C in 5% CO2 for 3 to 4 d. Once confluent, the cells were sub-cultured for experiments (in 96-, 12-, or 6-well plates) in serum-free conditions (DMEM/F12 medium with ITS). Exposure of the bGC to TGFα (10 or 100 ng/mL) for 24 h stimulated cell proliferation compared to control (P < 0.05; n = 7 ovary pairs). Proliferation was accompanied by a concomitant increase in mitogen-activated protein kinase (MAPK) signaling within 2 h of treatment, as evidenced by phosphorylated ERK1/2 expression (P < 0.05, n = 3 ovary pairs). These effects were entirely negated, however, by the MAPK inhibitor, U0126 (10uM, P < 0.05). Additionally, prior exposure of the bGC to TGFα (100 ng/mL) failed to prevent Fas Ligand (100 ng/mL)-induced apoptosis, as measured by caspase 3/7 activity (P < 0.05, n = 7 ovary pairs). Collectively, the results indicate TGFα stimulates proliferation of bGC from small antral follicles via a MAPK/ERK-mediated mechanism, but this action alone fails to prevent apoptosis, suggesting that TGFα may be incapable of promoting their persistence in follicles during the process of follicular selection/dominance.
Insights from two independent transcriptomic studies of the bovine corpus luteum during pregnancy
Authors: Hughes Camilla H K , Mezera Megan A , Wiltbank Milo C , Pate Joy L
Published: July 2022

Several recent studies have used transcriptomics to investigate luteal changes during the maternal recognition of the pregnancy period in ruminants. Although these studies have contributed to our understanding of luteal function during early pregnancy, few attempts have been made to integrate information across these studies and distinguish key luteal transcripts or functions that are repeatably identified across multiple studies. Therefore, in this study, two independent studies of the luteal transcriptome during early pregnancy were combined and compared. In the first study, corpora lutea (CL) from day 20 of pregnancy were compared with CL collected on day 14 of pregnancy, prior to embryonic signaling. The cattle were nonlactating. In the second study, CL from day 20 of pregnancy were compared with CL collected from day 20 cyclic cattle that had been confirmed as not yet undergoing luteal regression. These were lactating cattle. Three methods were used to compare these two datasets, to identify key luteal regulators. In the first method, all transcripts with Benjamini–Hochberg-adjusted P-value (Q value) < 0.05 in both datasets were considered. This yielded 22 transcripts, including several classical interferon-stimulated genes, as well as regulators of transforming growth factor-beta (TGFB) and latent TGFB-binding proteins (LTBP)1 and 2. In the second, less conservative method, all transcripts with P < 0.01 and changed in the same direction in both datasets were considered. This yielded an additional 20 transcripts that were not identified in the first analysis, for a total of 42 common transcripts. These transcripts were regulators of functions such as inflammatory balance and matrix remodeling. In the third method, transcripts with Q < 0.10 were subject to pathway analysis, and common pathways were identified. Retinoic acid signaling and classical interferon signaling pathways were identified with this method. Finally, regulation by interferon tau (IFNT) was investigated. Among the 42 transcripts identified, 32 were regulated by IFNT in cultured luteal cells (Q < 0.05). Among those not regulated by IFNT were LTBP1 and 2, which are TGFB-binding proteins. In summary, common transcripts from two studies of the luteal transcriptome during early pregnancy were combined and shared changes were identified. This not only generated a list of potential key luteal regulators, which were mostly IFNT regulated, but also included transcripts not regulated by IFNT, including LTBP1 and 2.
Ruminant conceptus-maternal interactions: interferon-tau and beyond
Authors: Mathew Daniel J , Peterson Katie D , Senn L Kirsten , Oliver Mary A , Ealy Alan D
Published: July 2022

Embryonic or fetal loss in cattle is associated with problems that occur during oocyte maturation, early embryonic development, conceptus elongation, maternal recognition of pregnancy (MRP), and/or placental attachment and implantation. Many of these problems manifest as inadequate or asynchronous communication between the developing conceptus and endometrium, resulting in pregnancy failure. This review will provide an overview of how various conceptus-endometrial paracrine signaling systems control the fate of early pregnancy in cattle and other ruminants. We begin by summarizing the actions of interferon-tau, the classic MRP signal in ruminates, and then explore how other secretory factors derived from either the conceptus or endometrium influence establishment and maintenance of pregnancy. Insight into how the endometrium responds to male vs. female conceptuses or conceptuses produced by in vitro methods will also be described. Specific focus will be placed on describing how “omic” technologies and other cutting-edge techniques have assisted with identifying novel conceptus and/or endometrial factors and their functions. Recent findings indicate that the endometrial transcriptome and histotroph are altered by conceptus sex, quality, and origin, suggesting that the endometrium is a sensor of conceptus biochemistry. Although the endometrium has a certain level of flexibility in terms of conceptus-maternal interactions, this interplay is not sufficient to retain some pregnancies. However, new information inspires us to learn more and will help develop technologies that mitigate early embryonic loss and reproductive failure in ruminants and other animals.
Regulation of cellular communication network factor 1 by Ras homolog family member A in bovine steroidogenic luteal cells
Authors: Goulet Michael R , Hutchings Donnelly , Donahue Jacob , Elder Dean , Tsang Paul C W
Published: July 2022

Development of the corpus luteum (CL) requires the growth of a new capillary network from preexisting vasculature, a process known as angiogenesis. Successful building of this capillary network occurs through a sequence of cellular events—differentiation, proliferation, migration, and adhesion—which are regulated by a suite of angiogenic proteins that includes cellular communication network factor 1 (CCN1). We previously reported that the expression of CCN1 was highest in luteal tissue obtained from the early-cycle, 4-d-old bovine CL (i.e., corpus hemorrhagicum) compared to the mid- and late-cycle CL. In the present study, we treated steroidogenic bovine luteal cells from early-cycle CL with luteinizing hormone (LH), but it had no effect on CCN1 expression. Direct stimulation of the canonical LH pathway with forskolin and dibutyryl-cyclic adenosine monophosphate (cAMP), however, inhibited CCN1 mRNA expression. In endothelial cells, stimulation of Ras homolog family member A (RhoA) induces CCN1 expression, whereas RhoA inactivation inhibits it. Yet, it is unknown if regulation of CCN1 in steroidogenic luteal cells works likewise. We hypothesized that a similar mechanism of CCN1 regulation exists in bovine luteal cells and that thrombin, a known RhoA activator, may be a physiologic trigger for this mechanism in the early-cycle CL. To test this hypothesis, ovaries were collected from lactating dairy cows on days 3 or 4 of the estrous cycle, and corpora lutea were dissected and dissociated. Steroidogenic luteal cells were suspended in defined Ham’s F12 medium, supplemented with insulin/transferrin/selenium and gentamicin, and seeded into 6-well plates. After 24 h, spent medium was replaced with fresh Ham’s F12, and the cells were cultured for 24 to 48 h. Cells were treated for 2 h with defined medium, 10% fetal bovine serum (FBS), thrombin (1, 5, 10 U/mL), or Rho Activator II (0.25, 1, 2 μg/mL). Cells were then lysed for RNA extraction, followed by cDNA generation, and quantitative polymerase chain reaction (qPCR). Thrombin (1, 5, 10 U/mL; n = 3) and Rho Activator II (0.25, 1, 2 μg/mL; n = 6) increased (P < 0.05) CCN1 mRNA expression. In summary, CCN1 in bovine steroidogenic luteal cells was induced by thrombin and appeared to be regulated in a Rho-dependent manner. Future work will elucidate the signaling partners downstream of Rho which leads to CCN1 gene expression.
History, insights, and future perspectives on studies into luteal function in cattle
Authors: Bishop Cecily V , Selvaraj Vimal , Townson David H , Pate Joy L , Wiltbank Milo C
Published: July 2022

The corpus luteum (CL) forms following ovulation from the remnant of the Graafian follicle. This transient tissue produces critical hormones to maintain pregnancy, including the steroid progesterone. In cattle and other ruminants, the presence of an embryo determines if the lifespan of the CL will be prolonged to ensure successful implantation and gestation, or if the tissue will undergo destruction in the process known as luteolysis. Infertility and subfertility in dairy and beef cattle results in substantial economic loss to producers each year. In addition, this has the potential to exacerbate climate change because more animals are needed to produce high-quality protein to feed the growing world population. Successful pregnancies require coordinated regulation of uterine and ovarian function by the developing embryo. These processes are often collectively termed “maternal recognition of pregnancy.” Research into the formation, function, and destruction of the bovine CL by the Northeast Multistate Project, one of the oldest continuously funded Hatch projects by the USDA, has produced a large body of evidence increasing our knowledge of the contribution of ovarian processes to fertility in ruminants. This review presents some of the seminal research into the regulation of the ruminant CL, as well as identifying mechanisms that remain to be completely validated in the bovine CL. This review also contains a broad discussion of the roles of prostaglandins, immune cells, as well as mechanisms contributing to steroidogenesis in the ruminant CL. A triadic model of luteolysis is discussed wherein the interactions among immune cells, endothelial cells, and luteal cells dictate the ability of the ruminant CL to respond to a luteolytic stimulus, along with other novel hypotheses for future research.
Preovulatory follicle contributions to oocyte competence in cattle: importance of the ever-evolving intrafollicular environment leading up to the luteinizing hormone surge
Authors: Moorey Sarah E , Hessock Emma A , Edwards J Lannett
Published: July 2022

The preovulatory intrafollicular environment plays a major role in determining oocyte competence. The basis of this review is to highlight the importance of the preovulatory follicle’s physiological status prior to the preovulatory luteinizing hormone (LH) surge and onset of oocyte maturation to promote an optimal follicular microenvironment and optimal oocyte developmental competence in cattle. While the underlying mechanisms remain unclear, and are likely multifactorial, the preovulatory follicle’s physiological status prior to the preovulatory LH surge is highly influential on the oocyte’s capacity to undergo postfertilization embryo development. Changes in the intrafollicular environment of the preovulatory follicle including steroid hormone production, metabolome profiles, and proteome profiles likely support the oocyte’s developmental and metabolic competency. This review focuses on the relationship between bovine oocyte developmental competency and antral follicle progression to the preovulatory phase, the role of the preovulatory follicle in improving oocyte developmental competence in cattle, and the importance of the ever-evolving preovulatory intrafollicular environment for optimal fertility.
Sustained vascular contractile response induced by an R- and S-epimer of the ergot alkaloid ergocristine and attenuation by a noncompetitive antagonist
Authors: Cherewyk Jensen E , Parker Sarah E , Blakley Barry R , Al-Dissi Ahmad N
Published: July 2022

Vasoconstriction is a known effect associated with ergot alkaloid consumption. The vascular contractile responses are often sustained for an extended period after exposure. Ergot alkaloids exist in two molecular configurations, the C-8-(R)-isomer (R-epimer) and the C-8-(S)-isomer (S-epimer). The sustained vascular contractile response to the R-epimers has been studied previously, unlike the S-epimers which are thought to be biologically inactive. Additionally, antagonists have been utilized to attenuate the vascular contraction associated with the R-epimers of ergot alkaloids utilizing ex vivo techniques. This study utilized an arterial tissue bath to examine and compare the sustained vascular contractile response attributed to ergocristine (R) and ergocristinine (S) using dissected bovine metatarsal arteries. The contractile blocking effect of a noncompetitive alpha-adrenergic antagonist, phenoxybenzamine (POB), was also investigated in precontracted arteries. Arteries (n = 6/epimer) were exposed to a single dose of ergocristine or ergocristinine (1 × 10−6 M in buffer). Each of the epimer doses was followed by a POB (1 × 10−3 M) or methanol (control) treatment at 90 min and the response was observed for another 90 min. Both epimers produced a sustained contractile response over the 180-min incubation period in the control groups. The R-epimer caused a greater sustained contractile response from 60 to 180 min post epimer exposure, compared to the S-epimer (P < 0.05, generalized estimating equations, independent t-test). Phenoxybenzamine caused a decrease in the contractile response induced by ergocristine and ergocristinine from 105 to 180 min, compared to the control (P < 0.05, generalized estimating equations, paired t-test). Overall, these results demonstrate the presence of a sustained vascular contractile response attributed to the R- and S-epimer of an ergot alkaloid with differences in contractile response between the epimers, suggesting differences in receptor binding mechanisms. Furthermore, this study demonstrated that a noncompetitive antagonist could attenuate the sustained arterial contractile effects of both ergot configurations ex vivo. Additional investigation into S-epimers of ergot alkaloids is needed. This research contributes to the understanding of the ergot epimer-vascular receptor binding mechanisms, which may support the investigation of different approaches of minimizing ergot toxicity in livestock.
Genetic Evidence for Multiple Invasions of Coptotermes formosanus (Blattodea: Rhinotermitidae) in California
Authors: Tseng Shu-Ping , Taravati Siavash , Choe Dong-Hwan , Rust Michael K , Lee Chow-Yang
Published: July 2022

New infestations of the Formosan subterranean termite, Coptotermes formosanus Shiraki (Blattodea: Rhinotermitidae), were discovered in southern California, namely in Rancho Santa Fe and La Mesa (San Diego County) and Highland Park (Los Angeles County) in 2021. We investigated whether these new infestations were related to the previous infestations in La Mesa (2018) and Canyon Lake, Riverside County (2020). We used two mitochondrial genes (COI and COII) and seven polymorphic microsatellite markers to infer the genetic relationship between southern California colonies and their breeding systems. The samples collected from seven localities belonged to five colonies (inter-colony distances ranged from ~160 m to 185 km, with an average of 97 km). Of these five colonies, two were simple families, and three were extended families. Structure analyses of microsatellite genotypes grouped the termite samples into three distinct genetic clusters, suggesting at least three independent introduction events in southern California.
Habit Formation and the Misallocation of Labor: Evidence from Forced Migrations
Authors: Sarvimäki Matti , Uusitalo Roope , Jäntti Markus
Published: July 2022

We use a research design created by forced migrations to examine the costs and benefits of leaving agriculture in mid-20th century Finland. After World War II, 11% of the Finnish population was resettled from areas ceded to the Soviet Union. Entire rural communities were moved to locations that resembled the origin areas, and displaced farmers were given land and assistance to establish new farms. Despite this policy of reconstructing the pre-war situation, forced migration increased the likelihood of switching to non-agricultural jobs and moving to urban areas. Consequently, forced migration also increased the long-term income of the displaced rural population. By contrast, forced migration decreased the income of the resettled urban population. We examine the extent to which these effects can be explained by the quality of the new farms, human capital investments, networks, and discrimination, but do not find evidence supporting these mechanisms. Instead, we argue that habit formation toward residential locations provides the most compelling rationalization for our results.
Cruelty and Corpo-reality: Connecting Technologies and Practices Integral to the Infliction and Investigation of Torture
Authors: Cakal Ergün
Published: July 2022

Torture has a complex relationship with technology. Technology variably facilitates or hinders modes of inflicting and investigating torture. Torture itself remains a technology for producing proof, simultaneously primitive and sophisticated. Torture techniques and practices evolve and travel, are prevalent in both democratic and autocratic states, and are often accompanied by a pseudo-scientific rhetoric of ‘controlled’ pain. Conversely, juridical processes pursuing accountability for torture also focus their evaluative gaze on the tortured body and to scientific expertise. To this end, sustained transnational efforts have culminated in the crafting of evidentiary technologies to document torture as grounded in state-of-the-art medical and psychological knowledge. What is more, despite this demand and supply, the utility of this ‘technology of knowledge’ remains unfulfilled in practice for different reasons. I start with the dialectic interplay between infliction and investigation produced by these practices—with prevalent methods informing documentation practices, and with those responsible for infliction adjusting their practices accordingly to evade accountability. With the long-anticipated revised version of the UN Istanbul Protocol now at hand, I revisit the origins and promises undergirding these efforts and their implications for anti-torture practice. I conclude with a critical reflection on the contested dynamics of knowledge imbued in these practices—asking how we (and the law) can ever adequately know about the tortured body.
Cost-effectiveness analysis of trastuzumab monotherapy versus adjuvant chemotherapy plus trastuzumab in elderly patients with HER2-positive early breast cancer
Authors: Konishi Takaaki , Fujiogi Michimasa , Michihata Nobuaki , Ohbe Hiroyuki , Matsui Hiroki , Fushimi Kiyohide , Tanabe Masahiko , Seto Yasuyuki , Yasunaga Hideo
Published: July 2022

Background

In elderly patients with human epidermal growth factor 2-positive breast cancer, adjuvant chemotherapy was associated with decreased quality of life, with relatively small benefits for prognosis. We examined the cost-effectiveness of trastuzumab monotherapy versus adjuvant chemotherapy plus trastuzumab in elderly patients with human epidermal growth factor 2-positive breast cancer.

Methods

A Markov model was developed to evaluate the costs and benefits of trastuzumab monotherapy over adjuvant chemotherapy plus trastuzumab for elderly patients with human epidermal growth factor 2-positive breast cancer. We built the model with a yearly cycle over a 20-year time horizon and five health states: disease-free, relapse, post-relapse, metastasis and death. The parameters in the model were based on a previous randomized controlled trial and a nationwide administrative database in Japan. The incremental cost-effectiveness ratio, expressed as Japanese yen per the quality-adjusted life-years, was estimated from the perspective of health care payers. One-way deterministic sensitivity analysis and probabilistic sensitivity analysis with Monte-Carlo simulations of 10 000 samples were conducted.

Results

The incremental cost-effectiveness ratio of trastuzumab monotherapy over adjuvant chemotherapy plus trastuzumab was $\sim$1.8 million Japanese yen /quality-adjusted life-year. The one-way deterministic sensitivity analysis showed that transition probability from disease-free to metastasis status and cost of metastasis status had the greatest influence on the incremental cost-effectiveness ratio. More than half the estimates in the probabilistic sensitivity analysis were located below a threshold of willingness-to-pay of 5 million Japanese yen /quality-adjusted life-year.

Conclusion

In this first comparative cost-effectiveness analysis of adjuvant chemotherapy plus trastuzumab versus trastuzumab monotherapy in the elderly, the latter was found favorable for elderly patients with human epidermal growth factor 2-positive breast cancer.
Panicle Ratio Network: streamlining rice panicle measurement by deep learning with ultra-high-definition aerial images in the field
Authors: Guo Ziyue , Yang Chenghai , Yang Wangnen , Chen Guoxing , Jiang Zhao , Wang Botao , Zhang Jian
Published: July 2022

The heading date and effective tiller percentage are important traits in rice, and they directly affect plant architecture and yield. Both traits are related to the ratio of the panicle number to the maximum tiller number, referred to as the panicle ratio (PR). In this study, an automatic PR estimation model (PRNet) based on a deep convolutional neural network was developed. Ultra-high-definition unmanned aerial vehicle (UAV) images were collected from cultivated rice varieties planted in 2384 experimental plots in 2019 and 2020 and in a large field in 2021. The determination coefficient between estimated PR and ground-measured PR reached 0.935, and the root mean square error values for the estimations of the heading date and effective tiller percentage were 0.687 d and 4.84%, respectively. Based on the analysis of the results, various factors affecting PR estimation and strategies for improving PR estimation accuracy were investigated. The satisfactory results obtained in this study demonstrate the feasibility of using UAVs and deep learning techniques to replace ground-based manual methods to accurately extract phenotypic information of crop micro targets (such as grains per panicle, panicle flowering, etc.) for rice and potentially for other cereal crops in future research.
Death, Introduced
Authors: Cordova Justin C
Published: July 2022

An anesthesiology intern at Walter Reed National Military Medical Center uses poetry to describe the nuances related to an end-of-life discussion with a terminally ill patient. She was a new admission to the oncology service who had already come to grips with her impending death, but had not yet discovered its identity.
SETDB1 acts as a topological accessory to Cohesin via an H3K9me3-independent, genomic shunt for regulating cell fates
Authors: Warrier Tushar , El Farran Chadi , Zeng Yingying , Ho Benedict Shao Quan , Bao Qiuye , Zheng Zi Hao , Bi Xuezhi , Ng Huck Hui , Ong Derrick Sek Tong , Chu Justin Jang Hann , Sanyal Amartya , Fullwood Melissa Jane , Collins James J , Li Hu , Xu Jian , Loh Yuin-Han
Published: July 2022

SETDB1 is a key regulator of lineage-specific genes and endogenous retroviral elements (ERVs) through its deposition of repressive H3K9me3 mark. Apart from its H3K9me3 regulatory role, SETDB1 has seldom been studied in terms of its other potential regulatory roles. To investigate this, a genomic survey of SETDB1 binding in mouse embryonic stem cells across multiple libraries was conducted, leading to the unexpected discovery of regions bereft of common repressive histone marks (H3K9me3, H3K27me3). These regions were enriched with the CTCF motif that is often associated with the topological regulator Cohesin. Further profiling of these non-H3K9me3 regions led to the discovery of a cluster of non-repeat loci that were co-bound by SETDB1 and Cohesin. These regions, which we named DiSCs (domains involving SETDB1 and Cohesin) were seen to be proximal to the gene promoters involved in embryonic stem cell pluripotency and lineage development. Importantly, it was found that SETDB1-Cohesin co-regulate target gene expression and genome topology at these DiSCs. Depletion of SETDB1 led to localized dysregulation of Cohesin binding thereby locally disrupting topological structures. Dysregulated gene expression trends revealed the importance of this cluster in ES cell maintenance as well as at gene ‘islands’ that drive differentiation to other lineages. The ‘unearthing’ of the DiSCs thus unravels a unique topological and transcriptional axis of control regulated chiefly by SETDB1.
Repurposing CRISPR RNA-guided integrases system for one-step, efficient genomic integration of ultra-long DNA sequences
Authors: Cheng Zhou-Hua , Wu Jie , Liu Jia-Qi , Min Di , Liu Dong-Feng , Li Wen-Wei , Yu Han-Qing
Published: July 2022

Genomic integration techniques offer opportunities for generation of engineered microorganisms with improved or even entirely new functions but are currently limited by inability for efficient insertion of long genetic payloads due to multiplexing. Herein, using Shewanella oneidensis MR-1 as a model, we developed an optimized CRISPR-associated transposase from cyanobacteria Scytonema hofmanni (ShCAST system), which enables programmable, RNA-guided transposition of ultra-long DNA sequences (30 kb) onto bacterial chromosomes at ∼100% efficiency in a single orientation. In this system, a crRNA (CRISPR RNA) was used to target multicopy loci like insertion-sequence elements or combining I-SceI endonuclease, thereby allowing efficient single-step multiplexed or iterative DNA insertions. The engineered strain exhibited drastically improved substrate diversity and extracellular electron transfer ability, verifying the success of this system. Our work greatly expands the application range and flexibility of genetic engineering techniques and may be readily extended to other bacteria for better controlling various microbial processes.
Quantitative contribution of the spacer length in the supercoiling-sensitivity of bacterial promoters
Authors: Forquet Raphaël , Nasser William , Reverchon Sylvie , Meyer Sam
Published: July 2022

DNA supercoiling acts as a global transcriptional regulator in bacteria, but the promoter sequence or structural determinants controlling its effect remain unclear. It was previously proposed to modulate the torsional angle between the −10 and −35 hexamers, and thereby regulate the formation of the closed-complex depending on the length of the ‘spacer’ between them. Here, we develop a thermodynamic model of this notion based on DNA elasticity, providing quantitative and parameter-free predictions of the relative activation of promoters containing a short versus long spacer when the DNA supercoiling level is varied. The model is tested through an analysis of in vitro and in vivo expression assays of mutant promoters with variable spacer lengths, confirming its accuracy for spacers ranging from 15 to 19 nucleotides, except those of 16 nucleotides where other regulatory mechanisms likely overcome the effect of this specific step. An analysis at the whole-genome scale in Escherichia coli then demonstrates a significant effect of the spacer length on the genomic expression after transient or inheritable superhelical variations, validating the model’s predictions. Altogether, this study shows an example of mechanical constraints associated to promoter binding by RNA Polymerase underpinning a basal and global regulatory mechanism.
A Cross-sectional Analysis of Linezolid in Combination with Methadone or Buprenorphine as a Cause of Serotonin Toxicity
Authors: Traver Edward C , Heil Emily L , Schmalzle Sarah A
Published: July 2022

Background

Serotonin toxicity (also referred to as serotonin syndrome) results from medications that affect the neurotransmitter serotonin. The antibiotic linezolid and the opioids methadone and buprenorphine are all reported to cause serotonin toxicity, but the degree of risk with use of linezolid in combination with methadone or buprenorphine is unknown.

Methods

We conducted a retrospective cross-sectional analysis of adult patients hospitalized from November 2015 to October 2019 who were administered linezolid in combination with methadone and/or buprenorphine within 24 hours and a subgroup that received the combination for ≥3 days. Cases of serotonin toxicity were identified from the clinical notes in the electronic medical record and were classified as possible or definite based on the clinical record. The Hunter diagnostic criteria were retrospectively applied.

Results

There were 494 encounters in which linezolid was administered concurrently with methadone and buprenorphine. The mean patient age was 42.5 years, and 52.4% of encounters were of female patients. The mean duration of concurrent administration was 1.9 days. There were 106 encounters with a duration of concurrent administration ≥3 days (mean, 5.4 days). Two cases of possible serotonin toxicity and 0 cases of definite serotonin toxicity occurred; neither possible case met the Hunter criteria from the available information. Possible cases occurred in 0.40% of all encounters and 1.89% of encounters with ≥3 days of overlap (upper 1-sided 95% CI, 0.87% and 4.06%).

Conclusions

Serotonin toxicity occurring during the administration of linezolid in combination with methadone and/or buprenorphine occurred rarely among 494 hospital encounters, including 106 encounters with ≥3 days of overlap. Limitations include potential missed diagnoses of serotonin toxicity and short durations of overlap. Further study evaluating the short-term risk of this combination is needed.