bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of pharmacogenomics in precision mental health care
Authors: Hamilton Joshua M.
Published: March 2024

Pharmacogenomics is the study of how genes affect a person's response to medications. This science has given rise to the practice of “precision health care,” which combines pharmacology (the study of medication) and genomics (the study of genes and their functions) to inform a more personalized approach. Related considerations include which medications to prescribe to different individuals and what doses will have the most therapeutic effects (with the fewest side effects). A case of recalcitrant depression and anxiety (in the context of chronic inflammatory and autoimmune disease) serves as the basis for discussion of psychopharmacogenomics to inform a more effective treatment approach for psychiatric symptoms. A contemporary understanding of neurobiology and neuropathology, enhanced by genetic and genomic information, supports new models for diagnosis and precision treatment of commonly recurring mental health problems.
Impact of sex differences on the feasibility and safety of distal radial access for coronary procedures: a multicenter prospective observational study
Authors: Rivera Kristian , Fernández-Rodríguez Diego , Bullones Juan , Gorriño Susana , Sánchez Espino Alejandro , Garcia-Guimarães Marcos , Casanova-Sandoval Juan , Irigaray Patricia , Costa-Mateu Joan , Arroyo-Calpe David , Roig-Boira Oriol , Tornel-Cerezo María , Baiget-Pons Anna , Worner Fernando , Ferreiro José Luis
Published: March 2024

Background

Conventional transradial access in women is associated with a lower success rate and a higher incidence of spasm compared to men. To date, the effect of sex on the performance of distal radial access (DRA) has not been fully elucidated. The aim of this study was to assess the impact of sex on catheterization success and other performance parameters of DRA procedures.

Methods

This is a prospective three-center observational study. From August 2020 to September 2022, data from all consecutive patients who underwent DRA for coronary procedures were collected.

Results

A total of 868 procedures were registered and stratified into two groups according to sex: women (n = 258) and men (n = 610). Female patients had less favorable baseline characteristics than male patients in terms of absent or weak pulse (29% vs. 17%;P < 0.001), distal radial diameter (2.2 ± 0.3 vs. 2.4 ± 0.4 mm;P < 0.001) and proximal radial diameter (2.5 ± 0.7 vs. 2.7 ± 0.7 mm;P = 0.001). No differences in success rates were found in women compared to men (94.2% vs. 96.6%;P = 0.135), with a higher presence of arterial spasm in women (5.8% vs. 3.0%;P = 0.044). The preprocedural ultrasound evaluation was the only predictor of DRA success [odds ratio = 20.0 (4.739–83.333);P < 0.001].

Conclusion

In patients undergoing coronary procedures, the success rate of DRA was high regardless of sex, with a higher incidence of arterial spasm in women.
New Graduate Nurse Transition into Rural Home
Authors: Generous Laurie
Published: March 2024

The global shortage of nurses and high attrition rates for newly graduated nurses along with the shifting demand for home care has created a critical need for retention strategies that address the specific challenges of rural settings. The effectiveness of structured transition or mentoring programs are primarily studied in acute care settings, making it difficult to translate to the unique context of rural home care nursing. The complexities of the independent nature of home care nursing practice and limited resources to address transition shock make it difficult to successfully transition newly graduated nurses to rural home care. A case study supports mentorship facilitation as a readily available, effective strategy that can overcome the challenges of rural home care settings. A comparative analysis will link Duchscher's (2008) transition shock theory to mentorship as an effective strategy for supporting NGNs' transition in home care nursing. Recommendations offer rural care leaders practical strategies bundled with mentorship to optimize the successful transition and retention of newly graduated nurses in their workplaces.
Supporting the Health and Well-Being of Caregivers of Persons with Pain Strategies to address stress and improve self-care
Authors: Tonkikh Orly , Chi Nai-Ching , Herr Keela A. , Fishman Scott M. , Young Heather M.
Published: March 2024

This article is part of a series, Supporting Family Caregivers: No Longer Home Alone, published in collaboration with the AARP Public Policy Institute. Results of focus groups, conducted as part of the AARP Public Policy Institute's No Longer Home Alone video project, supported evidence that family caregivers aren't given the information they need to manage the complex care regimens of family members. This series of articles and accompanying videos aims to help nurses provide caregivers with the tools they need to manage their family member's health care at home.

This new group of articles provides practical information nurses can share with family caregivers of persons living with pain. To use this series, nurses should read the articles first, so they understand how best to help family caregivers. Then they can refer caregivers to the informational tear sheet—Information for Family Caregivers—and instructional videos, encouraging them to ask questions. For additional information, see Resources for Nurses. Cite this article as: Tonkikh, O., et al. Supporting the Health and Well-Being of Caregivers of Persons with Pain. Am J Nurs 2023; 123 (6): 55-61.
Discrimination and Cardiovascular Health in Black Americans: Exploring Inflammation as a Mechanism and Perceived Control as a Protective Factor
Authors: Merritt Carrington C. , Muscatell Keely A.
Published: March 2024

Objective

Inflammation may be an integral physiological mechanism through which discrimination impacts cardiovascular health and contributes to racial health disparities. Limited research has examined psychosocial factors that protect against the negative effects of discrimination on inflammation. Perceived control is a promising possible protective factor, given that it has been shown to moderate the relationship between other psychosocial stressors and physiological outcomes. This study thus tested whether systemic inflammation mediated the link between discrimination and cardiovascular health and whether perceived control moderated this relationship.

Methods

Data for this project included 347 non-Hispanic/Latinx Black adults (mean [standard deviation] age = 51.64 [11.24] years; 33% female) taken from the Midlife in the United States study. Perceived control and daily discrimination were assessed via self-report, and inflammation was measured via circulating levels of C-reactive protein (CRP), interleukin-6 (IL-6), fibrinogen, and tumor necrosis factor α. Cardiovascular health was measured by morbidity of cardiovascular conditions: heart disease, hypertension, and/or stroke.

Results

CRP (indirect effect: b = 0.004, 95% confidence interval [CI] = 0.001–0.007) and fibrinogen (indirect effect: b = 0.002, 95% CI = 0.0003–0.005) mediated the link between discrimination and cardiovascular conditions. Perceived control moderated the relationship between discrimination and CRP (F(1, 293) = 4.58, ΔR
2 = 0.013, b = −0.02, SE = 0.01, p = .033). CRP mediated the link between discrimination and cardiovascular conditions only for those who reported low levels of perceived control (Index = −0.003, 95% CI = −0.007 to −0.0001).

Conclusion

Findings provide empirical evidence of inflammation as a mechanism linking discrimination to cardiovascular conditions among Black Americans. Additionally, perceived control may be protective. Findings could suggest beliefs about control as a potential intervention target to help reduce the negative effects of discrimination on cardiovascular health among Black Americans.
Automated Breast Volume Scanner Is More Valuable Than Hand-Held Ultrasound in Diagnosis of Small Breast cancer
Authors: Yan Lixia , Jing Luxia , Lu Qing , Wang Xi , Mao Wujian , Wang Peilei , Zhan Mengna , Huang Beijian
Published: March 2024

This study aimed to evaluate the clinical value of automated breast volume scanner (ABVS) compared with hand-held ultrasound (HHUS). From January 2015 to May 2019, a total of 912 breast lesions in 725 consecutive patients were included in this study. κ statistics were calculated to identify interobserver agreement of ABVS and HHUS. The diagnostic performance for ABVS and HHUS was expressed as the area under the receiver operating characteristic curve, as well as the corresponding 95% confidence interval, sensitivity, and specificity. The sensitivities of ABVS and HHUS were 95.95% and 93.69%, and the specificities were 85.47% and 81.20%, respectively. A difference that nearly reached statistical significance was observed in sensitivities between ABVS and HHUS (P = 0.0525). The specificity of ABVS was significantly higher than that of HHUS (P = 0.006). When lesions were classified according to their maximum diameter, the sensitivity and specificity of ABVS were significantly higher than HHUS for lesions ≤20 mm, while they made no statistical significance between ABVS and HHUS for lesions >20 mm. The interobserver agreement for ABVS was better than that of HHUS. Automated breast volume scanner was more valuable than HHUS in diagnosing breast cancer, especially for lesions ≤20 mm, and it could be a valuable diagnostic tool for breast cancer.
Serial Nerve Conduction Studies in Guillain–Barré Syndrome: Its Usefulness and Precise Timing
Authors: Lee Hyung-Soo , Suh Bum Chun , Kim Jong Kuk , Kim Byung-Jo , Nam Tai-Seung , Oh Jeeyoung , Bae Jong Seok , Shin Kyong Jin , Kim Seung Woo , Kim Seung Min , Shin Ha Young
Published: March 2024

Purpose:

Nerve conduction study (NCS) is essential for subclassifying Guillain–Barré syndrome (GBS). It is well known that the GBS subclassification can change through serial NCSs. However, the usefulness of serial NCSs is debatable, especially in patients with early stage GBS.

Methods:

Follow-up NCS data within 3 weeks (early followed NCS, EFN) and within 3 to 10 weeks (late-followed NCS, LFN) were collected from 60 patients with GBS who underwent their first NCS (FN) within 10 days after symptom onset. Each NCS was classified into five subtypes (normal, demyelinating, axonal, inexcitable, and equivocal), according to Hadden's and Rajabally's criteria. We analyzed the frequency of significant changes in classification (SCCs) comprising electrodiagnostic aggravation and subtype shifts between demyelinating and axonal types according to follow-up timing.

Results:

Between FN and EFN, 33.3% of patients with Hadden's criteria and 18.3% with Rajabally's criteria showed SCCs. Between FN and LFN, 23.3% of patients with Hadden's criteria and 21.7% with Rajabally's criteria showed SCCs, of which 71.4% (Hadden's criteria) and 46.2% (Rajabally's criteria) already showed SCCs from the EFN. The conditions of delayed SCCs between EFN and LFN were very early FN, mild symptoms at the FN, or persistent electrophysiological deterioration 3 weeks after symptom onset.

Conclusions:

A substantial proportion of patients with GBS showed significant changes in neurophysiological classification at the early stage. Serial NCS may be helpful for precise neurophysiological classification. This study suggests that follow-up NCSs should be performed within 3 weeks of symptom onset in patients with GBS in whom FN was performed within 10 days of symptom onset.
A dynamical perspective: moving towards mechanism in single-cell transcriptomics
Authors: Maizels Rory J.
Published: March 2024

As the field of single-cell transcriptomics matures, research is shifting focus from phenomenological descriptions of cellular phenotypes to a mechanistic understanding of the gene regulation underneath. This perspective considers the value of capturing dynamical information at single-cell resolution for gaining mechanistic insight; reviews the available technologies for recording and inferring temporal information in single cells; and explores whether better dynamical resolution is sufficient to adequately capture the causal relationships driving complex biological systems.

This article is part of a discussion meeting issue ‘Causes and consequences of stochastic processes in development and disease’.
On epigenetic stochasticity, entropy and cancer risk
Authors: Teschendorff Andrew E.
Published: March 2024

Epigenetic changes are known to accrue in normal cells as a result of ageing and cumulative exposure to cancer risk factors. Increasing evidence points towards age-related epigenetic changes being acquired in a quasi-stochastic manner, and that they may play a causal role in cancer development. Here, I describe the quasi-stochastic nature of DNA methylation (DNAm) changes in ageing cells as well as in normal cells at risk of neoplastic transformation, discussing the implications of this stochasticity for developing cancer risk prediction strategies, and in particular, how it may require a conceptual paradigm shift in how we select cancer risk markers. I also describe the mounting evidence that a significant proportion of DNAm changes in ageing and cancer development are related to cell proliferation, reflecting tissue-turnover and the opportunity this offers for predicting cancer risk via the development of epigenetic mitotic-like clocks. Finally, I describe how age-associated DNAm changes may be causally implicated in cancer development via an irreversible suppression of tissue-specific transcription factors that increases epigenetic and transcriptomic entropy, promoting a more plastic yet aberrant cancer stem-cell state.

This article is part of a discussion meeting issue ‘Causes and consequences of stochastic processes in development and disease’.
Cardiorespiratory demands of firearms training instruction and 15m shuttle tests in British law enforcement
Authors: Warwick Joseph , Cooper Sophie , Ronca Flaminia
Published: March 2024

Objectives

Law enforcement agencies require minimum fitness standards to safeguard their officers and training staff. Firearms instructors (FI) are expected to maintain the same standards as their operational counterparts. This study aimed to quantify the daily physiological demands placed on FI.

Methods

19 FI (45 ± 5 years) completed occupational tasks whilst wearing heart rate (HR) monitors for a minimum 10 days. Maximal oxygen consumption (VO2max) testing was conducted on FI during a treadmill test (TT) and a multistage shuttle test (ST). Linear regression models were used to model the relationship between VO2and HR throughout the TT. This model was applied to HR data from occupational tasks to infer oxygen consumption. Repeated Measures ANOVAs were used to compare time spent in VO2max equivalent zones throughout.

Results

The VO2max achieved during ST (45.1 ± 5.6 ml/kg/min) was significantly higher than TT (39 ± 3 ml/kg/min) (p = 0.014). Time to exhaustion (TTE) was sooner on ST (06:26 min) compared to TT (13:16 min) (p < .001). FI spent ∼85% of occupational time with an oxygen demand ≤20 ml/kg/min (p < .005). The most intense occupational tasks saw FI achieve VO2max ≥30 ml/kg/min, but <40 ml/kg/min.

Conclusion

Using ST to assess cardiorespiratory fitness resulted in a quicker TTE and a higher VO2max. Predominantly, FI occupational tasks are low intensity with sporadic exposures requiring a VO2max of >40 ml/kg/min. To safeguard FI from occupational-related cardiorespiratory or long-term health issues, it is intuitive to suggest fitness standards should exceed a VO2max of 40 ml/kg/min.
SEGUID v2: Extending SEGUID checksums for circular, linear, single- and double-stranded biological sequences
Authors: Pereira Humberto , Silva Paulo César , Davis M. Wayne , Abraham Louis , Babnigg György , Bengtsson Henrik , Johansson Björn
Published: March 2024

Background

Synthetic biology involves combining different DNA fragments, each containing functional biological parts, to address specific problems. Fundamental gene-function research often requires cloning and propagating DNA fragments, such as those from the iGEM Parts Registry or Addgene, typically distributed as circular plasmids.

Addgene’s repository alone offers around 150,000 plasmids. To ensure data integrity, cryptographic checksums can be calculated for the sequences. Each sequence has a unique checksum, making checksums useful for validation and quick lookups of associated annotations. For example, the SEGUID checksum, uniquely identifies protein sequences with a 27-character string.

Objectives

The original SEGUID, while effective for protein sequences and single-stranded DNA (ssDNA), is not suitable for circular and double-stranded DNA (dsDNA) due to topological differences. Challenges include how to uniquely represent linear dsDNA, circular ssDNA, and circular dsDNA. To meet these needs, we propose SEGUID v2, which extends the original SEGUID to handle additional types of sequences.

Conclusions

SEGUID v2 produces orientation and rotation invariant checksums for single-stranded, double-stranded, possibly staggered, linear, and circular DNA and RNA sequences. Customizable alphabets allow for other types of sequences. In contrast to the original SEGUID, which uses Base64, SEGUID v2 uses Base64url to encode the SHA-1 hash. This ensures SEGUID v2 checksums can be used as-is in filenames, regardless of platform, and in URLs, with minimal friction.

Availability

SEGUID v2 is readily available for major programming languages, distributed under the MIT license. JavaScript packageseguidis available on npm, Python packageseguidon PyPi, R packageseguidon CRAN, and a Tcl script on GitHub. These tools, along with documentation, examples, and an onlineSEGUID Calculator, can be found athttps://www.seguid.org.
Choices to landscapes: Mechanisms of animal movement scale to landscape patterns
Authors: Rogers Will , Yanco Scott , Jetz Walter
Published: March 2024

Understanding the geographic distributions of animals is central to ecological inquiry and conservation planning. Movement-based habitat selection models, like discrete-time step-selection functions, are useful for identifying key environmental attributes which animals select upon and can nearly perfectly capture preference patterns between environmental conditions. However, predictions based only on selection can often fail to accurately describe true geographic distributions. We show that by integrating local selection patterns, movement models, and explicit landscape constraints within the same framework, we can better predict simulated distributions than occurrence-based frameworks of selection alone. Using three case studies, we show that this framework can better predict distributions of organisms across increasing scales of out-of-sample prediction: within individuals, between individuals, and even between regional contexts. Movement modeling is a powerful tool to describe both the selection paradigm that organisms apply to the environment and the movement patterns that enable them to apply those selection paradigms. By understanding movement and selection at the same time, habitats that species “prefer” may not be ultimately occupied, as many “preferred” patches may be unreachable given movement strategies and landscape context, often leading to smaller geographic distributions than estimated by selection or occurrence alone.
Loss of factor VIII in zebrafish rebalances antithrombin deficiency but has a limited bleeding diathesis
Authors: Richter Catherine E , Raghunath Azhwar , Griffin Megan S , Yaman Murat , Arruda Valder R , Samelson-Jones Benjamin J , Shavit Jordan
Published: March 2024

Deficiencies in coagulation factor VIII (FVIII, F8) result in the bleeding disorder hemophilia A. An emerging novel therapeutic strategy for bleeding disorders is to enhance hemostasis by limiting natural anticoagulants, such as antithrombin (AT3). To study pro/anticoagulant hemostatic balance in an in vivo model, we used genome editing to create null alleles for f8 and von Willebrand factor (vwf) in zebrafish, a model organism with a high degree of homology to the mammalian hemostatic system and unique attributes, including external development and optical transparency. f8 homozygous mutant larvae surprisingly formed normal thrombi when subjected to laser-mediated endothelial injury, had no overt signs of hemorrhage, but had a modest increase in mortality. We have previously shown that at3-/- larvae develop disseminated intravascular coagulation (DIC), with spontaneous thrombosis and fibrinogen consumption, resulting in bleeding phenotype marked by secondary lack of induced thrombus formation upon endothelial injury. We found that with loss of FVIII (f8-/-;at3-/-), larvae no longer developed spontaneous fibrin thrombi and did produce clots in response to endothelial injury. However, homozygous loss of zebrafish Vwf failed to rescue the at3 DIC phenotype. These studies demonstrate an altered balance of natural anticoagulants that mitigates FVIII deficiency in zebrafish, similar to human clinical pipeline products. The data also suggest that zebrafish FVIII might circulate independently of Vwf. Further study of this unique balance could provide new insights for management of hemophilia A and von Willebrand disease.
Chlomito: a novel tool for precise elimination of organelle genome contamination in nuclear genome assemblies
Authors: Song Wei , Li Chong , Lu Yanming , Shen Dawei , Jia Yunxiao , Huo Yixin , Piao Weilan , Jin Hua
Published: March 2024

Accurate genome assemblies are crucial for understanding biological evolution, mechanisms of disease, and biodiversity. However, contamination from organelle genomes in nuclear genome analyses often leads to inaccuracies and unreliability in results. To address this issue, we developed a tool named Chlomito, which employs innovative algorithms to precisely identify and eliminate organelle genome contamination sequences from nuclear genome assemblies. Compared to conventional approaches, Chlomito can not only detect and eliminate organelle sequences but also effectively distinguish true organelle sequences from those transferred into the nucleus via horizontal gene transfer. To evaluate the accuracy of Chlomito, we conducted tests using sequencing data from Plum and Mango. The results confirmed that Chlomito can accurately detect contigs originating from the organelle genome, and the identified contigs covered most regions of the organelle reference genomes, demonstrating its efficiency and precision in comprehensively recognizing organelle genome sequences. Additionally, for user convenience, we packaged this method into a Docker image, simplifying the data processing workflow. Overall, Chlomito provides a highly efficient and accurate method for identifying and removing contigs derived from organelle genomes in genomic assembly data, thereby contributing to the improvement of genome assembly quality and advancing research in genomics and evolutionary biology.
Effects of noncanonical genomic imprinting in monoaminergic pathways on the regulation of social behaviors
Authors: O’Leary Erin M. , Rahman Samuel J. , Tamas Andrei L. , Huang Tony , Dweydari Moudar , Eggleston Rachel L. , Meling Daryl D. , Bonthuis Paul J.
Published: March 2024

Genomic imprinting in the brain is theorized to provide parental control over offspring social behaviors. Noncanonical genomic imprinting is a form of epigenetic regulation in which one of a gene’s alleles, either that of maternal or paternal inheritance, exhibits a bias towards higher expression of one parental allele compared to the other. This bias can differ depending on tissue type, and the degree of the parental allele expression bias can even vary across anatomical domains within the same tissue. Dopa decarboxylase (Ddc) and tyrosine hydroxylase (Th) are both noncanonically imprinted genes that preferentially express their maternal alleles in the brain andDdcalso has a paternal allele expression bias in the periphery. These two genes encode catecholamine synthesis enzymes for the production of dopamine (DA), norepinephrine (NE), and epinephrine (E), andDdcis also in the serotonin (5-HT) synthesis pathway. These four neurotransmitters are critical regulators of social behavior and disruptions to them are implicated in human mental illnesses. Here we investigated the functional effects of noncanonical imprinting ofDdcandThon social behavior in mice. By using reciprocal heterozygous mutant mice, we tested the impacts ofDdcand/orThmaternally and paternally inherited alleles on aggression, social recognition, dominance, and social preference behaviors. We found thatDdcpaternal-null alleles affect aggression and social recognition behavior,Thmaternal-null alleles affect sociability preferences, and compound inheritance ofThandDdcmaternal-null alleles influence preferences for social novelty. These results are consistent withThandDdcmaternal allele biased expression in central monoaminergic systems regulating sociability, andDdcpaternal allele biased expression in peripheral monoaminergic systems regulating aggression and social recognition.
Two-photon imaging of excitatory and inhibitory neural response to infrared neural stimulation
Authors: Fu Peng , Liu Yin , Zhu Liang , Wang Mengqi , Yu Yuan , Yang Fen , Zhang Weijie , Zhang Hequn , Shoham Shy , Roe Anna Wang , Xi Wang
Published: March 2024

Significance

Pulsed infrared neural stimulation (INS, 1875 nm) is an emerging neurostimulation technology that delivers focal pulsed heat to activate functionally specific mesoscale networks and holds promise for clinical application. However, little is known about its effect on excitatory and inhibitory cell types in cerebral cortex.

Aim

Estimates of summed population neuronal response timecourses provide a potential basis for neural and hemodynamic signals described in other studies.

Approach

Using two-photon calcium imaging in mouse somatosensory cortex, we have examined the effect of INS pulse train application on hSyn neurons and mDlx neurons tagged with GCaMP6s.

Results

We find that, in anesthetized mice, each INS pulse train reliably induces robust response in hSyn neurons exhibiting positive going responses. Surprisingly, mDlx neurons exhibit negative going responses. Quantification using the index of correlation illustrates responses are reproducible, intensity-dependent, and distance-dependent. Also, a contralateral activation is observed when INS application.

Conclusions

In sum, the population of neurons stimulated by INS includes both hSyn and mDlx neurons; within a range of stimulation intensities, this leads to overall excitation in the stimulated population, leading to the previously observed activations at distant post-synaptic sites.
Enhanced intracranial aneurysm development in a rat model of polycystic kidney disease
Authors: Cayron Anne F. , Morel Sandrine , Azam Maral , Haemmerli Julien , Aoki Tomohiro , Bijlenga Philippe , Allémann Eric , Kwak Brenda R.
Published: March 2024

Background

Polycystic kidney disease (PKD) patients have a high intracranial aneurysms (IAs) incidence and risk of rupture. The mechanisms that make PKD patients more vulnerable to IA disease are still not completely understood. The PCK rat is a well-known PKD model and has been extensively used to study cyst development and kidney damage. Here, we used this rat model to study IA induction and vulnerability.

Methods

IAs were induced in wild-type (WT) and PCK rats and their incidence was followed. Variation in the anatomy of the circle of Willis was studied in PCK rats and PKD patients. The expression of tight junction proteins was examined by immunohistochemistry in rats and in human ruptured and unruptured IAs from patients enrolled in the @neurIST study.

Results

An increased frequency of fatal aortic dissection was unexpectedly observed in PCK rats after IA induction, which was due to modifications in the elastic architecture of the aorta in combination with the induced hypertension. Interestingly, IAs developed faster in PCK rats compared to WT rats. Variations in the anatomy of the circle of Willis were identified in PCK rats and PKD patients, a risk factor that may (in part) explain the higher IA incidence found in these groups. At 2-weeks after induction, the endothelium of IAs from PCK rats showed a decrease in the tight junction proteins zonula occludens-1 and claudin-5. This decrease in tight junction proteins was also observed in the endothelium of human ruptured IAs compared to unruptured IAs, making it a potential marker of IA wall vulnerability.

Conclusions

Our study showed that PCK rats are more sensitive to IA induction. Variations in the anatomy of the circle of Willis and impaired regulation of tight junction proteins might put PCK rats and PKD patients more at risk of developing vulnerable IAs.
Fetal Growth Associated with Maternal Rheumatoid Arthritis and Juvenile Idiopathic Arthritis
Authors: Chock Eugenia Y. , Liew Zeyan , Pedersen Lars Henning , Thunbo Mette Østergaard
Published: March 2024

Structured Abstract

Background

Prior studies indicated that women with rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) are at twice higher risk of developing adverse pregnancy outcomes, this include preterm births and infants with low birth weight. A wide knowledge gap exists in our current understanding of how RA and JIA affect fetal growth during pregnancy.

Objective

We aimed to evaluate fetal growth among patients with RA/JIA by comparing fetal growth indicators of offspring born to this population, compared to individuals without RA/JIA. We hypothesized that fetal growth among patients with RA/JIA is reduced, compared to individuals without RA/JIA.

Study Design

We conducted a population-based cohort study in Denmark from 2008-2018 which included 503,491 individuals with singleton pregnancies. Among them, 2,206 were patients with RA and JIA. We linked several nationwide databases and clinical registries in Denmark to achieve our aim. Through the Danish Fetal Medicine Database (DFMD), we obtained fetal biometric measurements gathered from second trimester fetal ultrasound scans. We used International Classification of Diseases (ICD)-10 codes to identify pregnant patients with RA/JIA from the Danish National Patient Registry and linked them to the DFMD, other variables of interest were obtained from different Danish clinical registries. Next, we computed fetal growth gradient between second trimester and birth, using the mean difference in Z-score distances for each fetal growth indicator. We also estimated the risk of small for gestational age (SGA), all outcomes were compared between pregnant individuals with and without RA/JIA and adjusted for confounders.

Results

Maternal RA and JIA was not associated with a reduction of estimated fetal weight (EFW) at mid-pregnancy [adjusted mean EFW Z-score difference of 0.05 (95% CI 0.01, 0.10;p=0.022)], but lower birth weights were observed among offspring [adjusted mean Z-score difference of -0.08 (95% CI -0.13, -0.04;p<0.001)]. We observed reduced mean Z-score differences in weight gradient from second trimester to birth among offspring of patients with RA/JIA who used corticosteroids [-0.26 (95% CI -0.11, -0.41;p<0.001)], and sulfasalazine [-0.61 (95% CI -0.45, -0.77;p<0.001)] during pregnancy. Maternal RA/JIA was also associated with SGA [aOR of 1.47 (95% CI 1.16, 1.83;p<0.001)]. Similarly, the risk estimates were higher among corticosteroid [aOR 3.44 (95% CI 2.14, 5.25;p<0.001)] and sulfasalazine [(aOR 2.28 (95% CI 1.22, 3.88;p=0.005)) users.

Conclusion

Among pregnant patients with RA/JIA, fetal growth restriction may be most apparent after 18 to 22 weeks of gestational age. Closer antenatal monitoring around this period should be considered for this population.
Influence of environmental variables, small-scale fisheries and vessel traffic on the distribution and behavior of bottlenose dolphins in a tropical lagoon
Authors: Brevet M. , Jaquemet S. , Wagner J. , Kiszka JJ.
Published: March 2024

The distribution of marine predators is influenced by a variety of natural and, in some cases, anthropogenic environmental factors. In particular, the optimal foraging theory predicts that micro-habitat selection should be the result of a trade-off between prey availability, energy expenditure, and predation risk. In addition, the risk-disturbance hypothesis suggests that anthropogenic disturbance may be perceived by animals in the same way as predation risk. Habitat selection may also be locally influenced by individual behavior and physiological state (defining functional habitats): variation in their needs should affect their optimal trade-off. We tested these hypotheses in a population of bottlenose dolphins living in a tropical lagoon using a habitat modeling approach. Bottlenose dolphins were predominantly distributed within the lagoon, with a preference for the vicinity of fringing and inner reefs (with lower predation risk than the outer reef), and were located in areas of high fish productivity, consistent with optimal habitat selection. We also observed an interaction between habitat and dolphin behavior, suggesting the existence of functional habitats: foraging was more common in nearshore habitats with probable higher prey density while resting and socializing were more common further from shore. Similarly, females with calves were preferentially found in shallower waters compared to other social groups. We did not observe any effects of anthro-pogenic disturbance variables and therefore cannot conclude on the risk-disturbance hypothesis for this population.
CYB561 supports the neuroendocrine phenotype in castration-resistant prostate cancer
Authors: Azur Romie Angelo G. , Olarte Kevin Christian V. , Ybañez Weand S. , Ocampo Alessandria Maeve M. , Bagamasbad Pia D.
Published: March 2024

Castration-resistant prostate cancer (CRPC) is associated with resistance to androgen deprivation therapy, and an increase in the population of neuroendocrine (NE) differentiated cells. It is hypothesized that NE differentiated cells secrete neuropeptides that support androgen-independent tumor growth and induce aggressiveness of adjacent proliferating tumor cells through a paracrine mechanism. The cytochrome b561 (CYB561) gene, which codes for a secretory vesicle transmembrane protein, is constitutively expressed in NE cells and highly expressed in CRPC. CYB561 is involved in the α-amidation-dependent activation of neuropeptides, and contributes to regulating iron metabolism which is often dysregulated in cancer. These findings led us to hypothesize that CYB561 may be a key player in the NE differentiation process that drives the progression and maintenance of the highly aggressive NE phenotype in CRPC. In our study, we found thatCYB561expression is upregulated in metastatic and NE prostate cancer (NEPC) tumors and cell lines compared to normal prostate epithelia, and that its expression is independent of androgen regulation. Knockdown ofCYB561in androgen-deprived LNCaP cells dampened NE differentiation potential and transdifferentiation-induced increase in iron levels. In NEPC PC-3 cells, depletion of CYB561 reduced the secretion of growth-promoting factors, lowered intracellular ferrous iron concentration, and mitigated the highly aggressive nature of these cells in complementary assays for cancer hallmarks. These findings demonstrate the role of CYB561 in facilitating transdifferentiation and maintenance of NE phenotype in CRPC through its involvement in neuropeptide biosynthesis and iron metabolism pathways.
Cold stress induces a rapid redistribution of the antagonistic marks H3K4me3 and H3K27me3 inArabidopsis thaliana
Authors: Faivre Léa , Kinscher Nathalie-Francesca , Kuhlmann Ana Belén , Xu Xiaocai , Kaufmann Kerstin , Schubert Daniel
Published: March 2024

When exposed to low temperatures, plants undergo a drastic reprogramming of their transcriptome in order to adapt to their new environmental conditions, which primes them for potential freezing temperatures. While the involvement of transcription factors in this process, termed cold acclimation, has been deeply investigated, the potential contribution of chromatin regulation remains largely unclear. A large proportion of cold-inducible genes carries the repressive mark histone 3 lysine 27 trimethylation (H3K27me3), which has been hypothesized as maintaining them in a silenced state in the absence of stress, but which would need to be removed or counteracted upon stress perception. However, the fate of H3K27me3 during cold exposure has not been studied genome-wide. In this study, we offer an epigenome profiling of H3K27me3 and its antagonistic active mark H3K4me3 during short-term cold exposure. Both chromatin marks undergo rapid redistribution upon cold exposure, however, the gene sets undergoing H3K4me3 or H3K27me3 differential methylation are distinct, refuting the simplistic idea that gene activation relies on a switch from an H3K27me3 repressed chromatin to an active form enriched in H3K4me3. Coupling the ChIP-seq experiments with transcriptome profiling reveals that differential histone methylation correlates with changes in expression. Interestingly, only a subset of cold-regulated genes lose H3K27me3 during their induction, indicating that H3K27me3 is not an obstacle to transcriptional activation. In the H3K27me3 methyltransferasecurly leaf (clf)mutant, many cold regulated genes display reduced H3K27me3 levels but their transcriptional activity is not altered prior or during a cold exposure, suggesting that H3K27me3 may serve a more intricate role in the cold response than simply repressing the cold-inducible genes in naïve conditions.
Towards Targeted Protein Degradation in Escherichia coli - depletion of the essential GroEL protein using CLIPPERs.
Authors: Izert-Nowakowska Matylda Anna , Klimecka Maria Magdalena , Antosiewicz Anna , Wróblewski Karol , Bandyra Katarzyna Justyna , Góral Tomasz K , Kmiecik Sebastian , Serwa Remigiusz A , Górna Maria Wiktoria
Published: March 2024

New, universal tools for targeted protein degradation in bacteria can help to accelerate protein function studies and antimicrobial research. We have created a new method for degrading bacterial proteins using plasmid-encoded degrader peptides which deliver target proteins for degradation by a highly conserved ClpXP protease. We demonstrated the mode-of-action of the degraders on a challenging essential target GroEL. The studies in bacteria were complemented by in vitro binding and structural studies. Expression of degrader peptides resulted in a temperature-dependent growth inhibition and depletion of GroEL levels over time. The reduction of GroEL levels was accompanied by dramatic proteome alterations. The presented method offers a new alternative approach for regulating protein levels in bacteria without genomic modifications or tag fusions. Our studies demonstrate that ClpXP is an attractive protease for the future use in bacterial targeted protein degradation.
A generalised protein identification method for novel and diverse sequencing technologies
Authors: Bhandari Bikash Kumar , Goldman Nick
Published: March 2024

Protein sequencing is a rapidly evolving field with much progress towards the realisation of a new generation of protein sequencers. The early devices, however, may not be able to reliably discriminate all 20 amino acids, resulting in a partial, noisy and possibly error-prone signature of a protein. Rather than achievingde novosequencing, these devices may aim to identify target proteins by comparing such signatures to databases of known proteins. However, there are no broadly applicable methods for this identification problem. Here, we devise a hidden Markov model method to study the generalized problem of protein identification from noisy signature data. Using a hypothetical sequencing device that can simulate several novel devices, we show that on the human protein database (N=20,181) our method has a good performance under many different operating conditions such as various levels of signal resolvability, different numbers of discriminated amino acids, sequence fragments and insertion and deletion error rates. Our results demonstrate the possibility of protein identification with high accuracy on many early experimental devices. We anticipate our method to be applicable for a wide range of protein sequencing devices in the future.
Prostaglandin D2 synthase controls Schwann cells metabolism
Authors: Trimarco Amelia , Audano Matteo , Marca Rosa La , Cariello Mariaconcetta , Falco Marta , Pedretti Silvia , Imperato Gabriele , Cestaro Alessandro , Podini Paola , Dina Giorgia , Quattrini Angelo , Massimino Luca , Caruso Donatella , Mitro Nico , Taveggia Carla
Published: March 2024

We previously reported that in the absence of Prostaglandin D2 synthase (L–PGDS) peripheral nerves are hypomyelinated in development and that with aging they present aberrant myelin sheaths. We now demonstrate that L–PGDS expressed in Schwann cells is part of a coordinated program aiming at preserving myelin integrity.In vivoandin vitrolipidomic, metabolomic and transcriptomic analyses confirmed that myelin lipids composition, Schwann cells energetic metabolism and key enzymes controlling these processes are altered in the absence of L–PGDS. Moreover, Schwann cells undergo a metabolic rewiring and turn to acetate as the main energetic source. Further, they produce ketone bodies to ensure glial cell and neuronal survival. Importantly, we demonstrate that all these changes correlate with morphological myelin alterations and describe the first physiological pathway implicated in preserving PNS myelin.

Collectively, we posit that myelin lipids serve as a reservoir to provide ketone bodies, which together with acetate represent the adaptive substrates Schwann cells can rely on to sustain the axo-glial unit and preserve the integrity of the PNS.
Variable efficiency of nonsense-mediated mRNA decay across human tissues, tumors and individuals
Authors: Palou-Márquez Guillermo , Supek Fran
Published: March 2024

Nonsense-mediated mRNA decay (NMD) is a quality-control pathway that degrades mRNA bearing premature termination codons (PTCs) resulting from mutation or mis-splicing, and that additionally participates in gene regulation of unmutated transcripts. We analyzed ∼10,000 exomes and ∼27,000 transcriptomes from human tumors and healthy tissues to quantify individual-level NMD efficiency, and assess its variability between tissues and between individuals. This was done by monitoring allele-specific expression of germline PTCs, and independently supported by mRNA levels of endogenous NMD target transcripts. Nervous system and reproductive system tissues have lower NMD efficiency than other tissues such as the digestive tract. Next, there is considerable systematic inter-individual variability in NMD efficiency, and we identify two underlying mechanisms. First, in cancers there are somatic copy number alterations that robustly associate with NMD efficiency, prominently the commonly-occurring gain at chromosome 1q that encompasses two core NMD genes:SMG5andSMG7and additional functionally interacting genes such asPMF1andGON4L. Second, loss-of-function germline variants in various genes such as theKDM6Bchromatin modifier can associate with higher or lower NMD efficiency in individuals, affecting different tissues thereof. Variable NMD efficiency should have clinical implications as it modulates positive selection upon somatic nonsense mutations in tumor suppressor genes, and is associated with survival of cancer patients, with relevance to predicting immunotherapy responses across cancer types.
Systematic computer-aided disulfide design as a general strategy to stabilize prefusion class I fusion proteins
Authors: Gonzalez Karen J , Yim Kevin , Blanco Jorge Carlos , Boukhvalova Marina S , Strauch Eva-Maria
Published: March 2024

Numerous enveloped viruses, such as coronaviruses, influenza, and respiratory syncytial virus (RSV), utilize class I fusion proteins for cell entry. During this process, the proteins transition from a prefusion to a postfusion state, undergoing substantial and irreversible conformational changes. The prefusion conformation has repeatedly shown significant potential in vaccine development. However, the instability of this state poses challenges for its practical application in vaccines. While non-native disulfides have been effective in maintaining the prefusion structure, identifying stabilizing disulfide bonds remains an intricated task. Here, we present a general computational approach to systematically identify prefusion-stabilizing disulfides. Our method assesses the geometric constraints of disulfide bonds and introduces a ranking system to estimate their potential in stabilizing the prefusion conformation. We found, for the RSV F protein, that disulfides restricting the initial stages of the conformational switch can offer higher stability to the prefusion state than those preventing unfolding at a later stage. The implementation of our algorithm on the RSV F protein led to the discovery of prefusion-stabilizing disulfides, providing evidence that supports our hypothesis. Furthermore, the evaluation of our top design as a vaccine candidate in a cotton rat model demonstrated robust protection against RSV infection, highlighting the potential of our approach for vaccine development.
PKHD1L1 is required for stereocilia bundle maintenance, durable hearing function and resilience to noise exposure
Authors: Strelkova Olga S. , Osgood Richard T. , Tian Chunjie J. , Zhang Xinyuan , Hale Evan , De-la-Torre Pedro , Hathaway Daniel M. , Indzhykulian Artur A.
Published: March 2024

Sensory hair cells of the cochlea are essential for hearing, relying on the mechanosensitive stereocilia bundle at their apical pole for their function. Polycystic Kidney and Hepatic Disease 1-Like 1 (PKHD1L1) is a stereocilia protein required for normal hearing in mice, and for the formation of the transient stereocilia surface coat, expressed during early postnatal development. While the function of the stereocilia coat remains unclear, growing evidence supports PKHD1L1 as a human deafness gene. In this study we carry out in depth characterization of PKHD1L1 expression in mice during development and adulthood, analyze hair-cell bundle morphology and hearing function in aging PKHD1L1-defficient mouse lines, and assess their susceptibility to noise damage. Our findings reveal that PKHD1L1-deficient mice display no disruption to bundle cohesion or tectorial membrane attachment-crown formation during development. However, starting from 6 weeks of age, PKHD1L1-defficient mice display missing stereocilia and disruptions to bundle coherence. Both conditional and constitutive PKHD1L1 knock-out mice develop high-frequency hearing loss progressing to lower frequencies with age. Furthermore, PKHD1L1-deficient mice are susceptible to permanent hearing loss following moderate acoustic overexposure, which induces only temporary hearing threshold shifts in wild-type mice. These results suggest a role for PKHD1L1 in establishing robust sensory hair bundles during development, necessary for maintaining bundle cohesion and function in response to acoustic trauma and aging.