bluuebunny/crossref_metadata_2025 huggingface dataset:
Roles of alternative splicing in infectious diseases: from hosts, pathogens to their interactions
Authors: Lyu Mengyuan , Lai Hongli , Wang Yili , Zhou Yanbing , Chen Yi , Wu Dongsheng , Chen Jie , Ying Binwu
Published: March 2023

Alternative splicing (AS) is an evolutionarily conserved mechanism that removes introns and ligates exons to generate mature messenger RNAs (mRNAs), extremely improving the richness of transcriptome and proteome. Both mammal hosts and pathogens require AS to maintain their life activities, and inherent physiological heterogeneity between mammals and pathogens makes them adopt different ways to perform AS. Mammals and fungi conduct a two-step transesterification reaction by spliceosomes to splice each individual mRNA (named cis-splicing). Parasites also use spliceosomes to splice, but this splicing can occur among different mRNAs (named trans-splicing). Bacteria and viruses directly hijack the host's splicing machinery to accomplish this process. Infection-related changes are reflected in the spliceosome behaviors and the characteristics of various splicing regulators (abundance, modification, distribution, movement speed, and conformation), which further radiate to alterations in the global splicing profiles. Genes with splicing changes are enriched in immune-, growth-, or metabolism-related pathways, highlighting approaches through which hosts crosstalk with pathogens. Based on these infection-specific regulators or AS events, several targeted agents have been developed to fight against pathogens. Here, we summarized recent findings in the field of infection-related splicing, including splicing mechanisms of pathogens and hosts, splicing regulation and aberrant AS events, as well as emerging targeted drugs. We aimed to systemically decode host–pathogen interactions from a perspective of splicing. We further discussed the current strategies of drug development, detection methods, analysis algorithms, and database construction, facilitating the annotation of infection-related splicing and the integration of AS with disease phenotype.
Global medical mission with surgical education objectives: a quality report regarding sustainability in an affiliated hospital in Quito, Ecuador
Authors: Petersen Christopher , Aronowitz Danielle I. , Andrade Miguel , Cardenas Maria , Rosa Jeffrey , Leon Gustavo , Jarrin Patricia , Maldonado Augusto , Gonzalez Dario , Farina Gino , Sugiyama Gianosuke , Coppa Gene , Barrera Rafael
Published: March 2023

This report seeks to describe the logistics, outcomes, and push toward building a sustainable model for global surgical missions as viewed through the lens of Northwell Health’s 2020 Surgical Mission composed of both operations and international education. The Northwell-Quito 2020 medical mission to Ecuador was envisioned and successfully executed to help achieve Northwell Health’s goal of becoming a globally recognized leader in high-quality, socially conscious health care, and health education. A Northwell-sponsored team of 30 employees and community volunteers partnered with Hospital Padre Carollo, Fundación Tierra Nueva, and the Ecuadorian Ministry of Public Health to provide surgical services to the indigent and underserved of Quito, Ecuador from January 19 to January 24, 2020. During this mission, a total of 127 patients were evaluated, which included preoperative evaluations, operations, as well as postoperative follow-up from prior missions’ surgical interventions. Of the 56 patients scheduled for surgery, 53 operations were performed, including 30 adult and 23 pediatric procedures. No major complications occurred, and all patients were recovering appropriately at the postoperative evaluation on January 24, 2020. Northwell team members provided didactic and practical training for Ecuadorian health care providers, residents, and students to fulfill the educational mission of providing sustainable perioperative care. For the first time, Northwell’s Center for Global Health partnered with Universidad de San Francisco in Quito to organize a Global Health Week focused on the development of research, education, and mental health outreach and partnerships seeking toward building a sustainable model inclusive of logistics alongside international and cross-cultural care.
High prevalence of vitamin D deficiency in Pakistan and its relation to uterine fibroids development and progression
Authors: Arif Aabiya , Lal Priyanka Mohan , Shaikh Omer Ahmed , Mohan Anmol
Published: March 2023

Vitamin D insufficiency is a condition that affects more than a billion individuals globally and is escalating in prevalence. According to Riaz et al., 31.2% of Pakistan’s population had low vitamin D levels, while 53.5% of the country’s population had deficiencies. Recent research suggests that vitamin D insufficiency, a severe health problem with numerous effects, including a higher risk of female reproductive malignancies, may have an impact on the growth and progression of uterine leiomyomas. The most prevalent benign pelvic tumor, uterine fibroids, do not have an effective long-term medical solution. Surgery, such as hysterectomy and myomectomy, is currently the most common type of treatment for symptomatic UFs; however, these procedures increase the risk of an operation’s complications for patients and are exceedingly expensive for healthcare systems.The key is that vitamin D supplements can be utilized to prevent, treat, or reduce the size of UF and that vitamin D insufficiency is a significant risk factor for the onset and progression of UF. As a result, there is an urgent need to promote vitamin D supplementation as a prospective treatment for uterine fibroids and to fill the gap left by the lack of non-invasive options.
ALTERNATIVE INTRAVITREAL ANTIBIOTICS
Authors: Velez-Montoya Raul , Monroy-Esquivel Luz , Ortiz-Guevara Rocío , Quiroz-Mercado Hugo , Fromow-Guerra Jans ,   For the Mexican Endophthalmitis Study Group (Mex-ESG)
Published: March 2023

Purpose:

To organize, categorize, and create a quick reference guide for the use of intravitreal antibiotic alternatives to the standard combination of vancomycin and ceftazidime for the treatment of endophthalmitis.

Methods:

A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. The authors searched for all available information regarding intravitreal antibiotics in the last 21 years. Manuscripts were selected according to relevance, level of information, and the available data regarding intravitreal dose, potential adverse effects, bacterial coverage, and relevant pharmacokinetic information.

Results:

The authors included 164 of 1810 manuscripts. The antibiotics were classified according to their class into fluoroquinolones, cephalosporins, glycopeptide and lipopeptide, penicillins and beta-lactams, tetracyclines, and miscellaneous. The authors also included information regarding intravitreal adjuvants for the treatment of endophthalmitis and one ocular antiseptic.

Conclusion:

The treatment of infectious endophthalmitis is a therapeutic challenge. The current review summarizes the properties of possible intravitreal antibiotic alternatives that should be considered in cases of suboptimal response to initial treatment.
Impact of Season on Incidence of Sinusitis-related Orbital Cellulitis
Authors: Wladis Edward J. , Narravula Raghav , Foyt Alexander K. , Pauze Denis R.
Published: March 2023

Purpose:

To explore the impact of season on the incidence of presentation to emergency departments with sinusitis-related orbital cellulitis in the United States.

Methods:

The National Emergency Department Sample was queried to identify cases of patients with sinusitis-related orbital cellulitis. Patient's age, location, and the month of presentation were recorded. Statistical correlations were analyzed via a dedicated software package.

Results:

A total of 439 patients with sinusitis-related orbital cellulitis were identified. The overall incidence was higher during the winter months (p < 0.05); while children were more likely to develop this disease during the winter (p < 0.05), season was not statistically correlated with its incidence among adults (p = 0.16). The incidence of orbital cellulitis was higher during the winter in the midwest and south regions of the United States (p < 0.05 for each region), although this correlation did not apply in the northeast and west (p = 0.60 and 0.99, respectively).

Conclusions:

While sinusitis incidence increases during the winter, the relationship between season and orbital cellulitis is complex and varies by age and geographic location. These findings may help to facilitate screening protocols for this disease and to define staffing issues for emergent ophthalmic care.
Alemtuzumab-Induced Thyroid Eye Disease: A Comprehensive Case Series and Review of the Literature
Authors: Nirmalan Aravindh , Blecher Nathanael , Hyder Sayyada , Couch Steven M. , Godfrey Kyle J. , Stan Marius N. , Bradley Elizabeth A. , Wagner Lilly H. , Tooley Andrea A.
Published: March 2023

Purpose:

To present 5 cases of alemtuzumab-induced thyroid eye disease (AI-TED) and review the literature to highlight the natural history, severity, and outcomes as compared with conventional thyroid eye disease (TED).

Methods:

A multi-institutional retrospective case series of patients with AI-TED was compiled. Chart review evaluated for clinical characteristics, imaging findings, and treatment for AI-TED. Additionally, a comprehensive review of the literature identified all previously published cases of AI-TED.

Results:

Five new patients with AI-TED were included in this series. The average clinical activity score on presentation was 2.8 (range 1–4) and reached an average peak of 5.0 during the active phase of the disease (4–7). Patients were treated medically with selenium (40%) or monoclonal antibodies including teprotumumab or tocilizumab (40%). Surgical treatment with orbital decompression for compressive optic neuropathy was performed on 2 (40%) patients. Combined with 11 previously reported cases, these 16 patients with AI-TED had an average clinical activity score on presentation of 3.3. The average length of the AI-TED phase was 14.0 months, and all patients were treated with medical and/or surgical interventions for their disease.

Conclusions:

Clinical and imaging findings in AI-TED mirror that of conventional TED, however, AI-TED may present with greater severity. AI-TED may develop many months after Graves’ disease; therefore, providers should be aware of this association and monitor patients for the development of severe TED.
Elevated Intraocular Pressure in Periorbital Sweet’s Syndrome
Authors: Keen Jamie A. , Fisher Mark D. , Yu Caroline Y. , Swick Brian L. , Shriver Erin M.
Published: March 2023

A 66-year-old immunocompromised man presented with cellulitis around the left eye that was initially concerning for necrotizing fasciitis. Exam findings were remarkable for exquisite periocular tenderness with rigid, immobile eyelids resulting from severe erythema, edema, and induration. Given the concern for orbital compartment syndrome and a necrotizing infection, the patient was taken urgently to the operating room for debridement of the eyelid skin as well as an urgent lateral canthotomy and cantholysis. His eye exam revealed 360° of hemorrhagic chemosis, no relative afferent pupillary defect, and an ipsilateral elevated intraocular pressure of 35 mm Hg. No visual acuity measurement could be obtained secondary to the patient’s altered mental status. His intraocular pressure normalized after treatment with antihypertensive drops and further extension of the canthotomy. Histopathological analysis showed extensive neutrophilic infiltrate of the dermis which was compatible with a diagnosis of Sweet’s syndrome.
Daily pain and opioid administration in hospitalized patients with cancer: the importance of psychological factors, recent surgery, and current opioid use
Authors: Azizoddin Desiree R. , Wilson Jenna M. , Flowers Kelsey Mikayla , Beck Meghan , Chai Peter , Enzinger Andrea C. , Edwards Robert , Miaskowski Christine , Tulsky James A. , Schreiber Kristin L.
Published: March 2023

Pain is common and variable in its severity among hospitalized patients with cancer. Although biopsychosocial factors are well established as modulators of chronic pain, less is known about what patient-level factors are associated with worse pain outcomes among hospitalized cancer patients. This prospective cohort study included patients with active cancer presenting to the emergency department (ED) with pain severity of ≥4/10 and followed pain outcomes longitudinally throughout hospital admission. Baseline demographic, clinical, and psychological factors were assessed on ED presentation, and daily average clinical pain ratings and opioid consumption during hospitalization were abstracted. Univariable and multivariable generalized estimating equation analyses examined associations of candidate biopsychosocial, demographic, and clinical predictors with average daily pain and opioid administration. Among 113 hospitalized patients, 73% reported pain as the primary reason for presenting to the ED, 43% took outpatient opioids, and 27% had chronic pain that predated their cancer. Higher pain catastrophizing (B= 0.1,P≤ 0.001), more recent surgery (B= −0.2,P≤ 0.05), outpatient opioid use (B= 1.4,P≤ 0.001), and history of chronic pain before cancer diagnosis (B= 0.8,P≤ 0.05) were independently associated with greater average daily pain while admitted to the hospital. Higher pain catastrophizing (B= 1.6,P≤ 0.05), higher anxiety (B= 3.7,P≤ 0.05), lower depression (B= −4.9,P≤ 0.05), metastatic disease (B= 16.2,P≤ 0.05), and outpatient opioid use (B= 32.8,P≤ 0.001) were independently associated with higher daily opioid administration. Greater psychological distress, especially pain catastrophizing, as well as pain and opioid use history, predicted greater difficulty with pain management among hospitalized cancer patients, suggesting that early assessment of patient-level characteristics may help direct consultation for more intensive pharmacologic and nonpharmacologic interventions.
Metabolomics signatures of plant protein intake: effects of amino acids and compounds associated with plant protein on cardiometabolic health
Authors: Gueugneau Marine , Capel Frederic , Monfoulet Laurent-Emmanuel , Polakof Sergio
Published: March 2023

Purpose of review

An increase in the plant-based characteristics of the diet is now recommended for human and planetary health. There is growing evidence that plant protein (PP) intake has beneficial effects on cardiometabolic risk. However, proteins are not consumed isolated and the protein package (lipid species, fiber, vitamins, phytochemicals, etc) may contribute, besides the protein effects per se, to explain the beneficial effects associated with PP-rich diets.

Recent findings

Recent studies have shown the potential of nutrimetabolomics to apprehend the complexity of both the human metabolism and the dietary habits, by providing signatures associated to the consumption of PP-rich diets. Those signatures comprised an important proportion of metabolites that were representative of the protein package, including specific amino acids (branched-chain amino acids and their derivates, glycine, lysine), but also lipid species (lysophosphatidylcholine, phosphatidylcholine, plasmalogens) and polyphenol metabolites (catechin sulfate, conjugated valerolactones and phenolic acids).

Further studies are needed to go deeper in the identification of all metabolites making part of the specific metabolomic signatures, associated to the large range of protein package constituents and their effects on the endogenous metabolism, rather than to the protein fraction itself. The objective is to determine the bioactive metabolites, as well as the modulated metabolic pathways and the mechanisms responsible for the observed effects on cardiometabolic health.
Dynamics of Pre-Exposure (PrEP) Eligibility Because of Waxing and Waning of HIV Risk in Rakai, Uganda
Authors: Ssempijja Victor , Ssekubugu Robert , Kigozi Godfrey , Nakigozi Gertrude , Kagaayi Joseph , Ekstrom Anna Mia , Nalugoda Fred , Nantume Betty , Batte James , Kigozi Grace , Yeh Ping Teresa , Nakawooya Hadijja , Serwadda David , Quinn Thomas C. , Gray Ronald H. , Wawer Maria J. , Grabowski Kate M. , Chang Larry W. , Hoog Anja van't , Cobelens Frank , Reynolds Steven J.
Published: March 2023

Background:

We conducted a retrospective population-based study to describe longitudinal patterns of prevalence, incidence, discontinuation, resumption, and durability of substantial HIV risk behaviors (SHR) for pre-exposure prophylaxis (PrEP) eligibility.

Methods:

The study was conducted among HIV-negative study participants aged 15–49 years who participated in survey rounds of the Rakai Community Cohort Study between August 2011 and June 2018. Substantial HIV risk was defined based on the Uganda national PrEP eligibility as reporting sexual intercourse with >1 partner of unknown HIV status, nonmarital sex without a condom, having genital ulcers, or having transactional sex. Resumption of SHR meant resuming of SHR after stopping SHR, whereas persistence of SHR meant SHR on >1 consecutive visit. We used generalized estimation equations with log-binomial regression models and robust variance to estimate survey-specific prevalence ratios; Generalized estimation equations with modified Poisson regression models and robust variance to estimate incidence ratios for incidence, discontinuation, and resumption of PrEP eligibility.

Findings:

Incidence of PrEP eligibility increased from 11.4/100 person-years (pys) in the first intersurvey period to 13.9/100 pys (adjusted incidence rate ratios = 1.28; 95%CI = 1.10–1.30) and declined to 12.6/100 pys (adjusted incidence rate ratios = 1.06; 95%CI = 0.98–1.15) in the second and third intersurvey periods, respectively. Discontinuation rates of SHR for PrEP eligibility were stable (ranging 34.9/100 pys–37.3/100 pys; P = 0.207), whereas resumption reduced from 25.0/100 pys to 14.5/100 pys (P < 0.001). PrEP eligibility episodes lasted a median time of 20 months (IQR = 10–51).

Interpretation:

Pre-exposure prophylaxis use should be tailored to the dynamic nature of PrEP eligibility. Preventive-effective adherence should be adopted for assessment of attrition in PrEP programs.
Traumatic brain injury modifies adult hippocampal neural stem cell fate to promote neurogenesis at the cost of astrogliogenesis
Authors: Bielefeld P , Martirosyan A , Apresyan A , Meerhoff G , Pestana F , Poovathingal S , Reijners N , Koning W , Clement RA , Van de Veen I , Toledo E , Durá I , Hovhannisyan S. , Nilges B. , Bogdoll A. , Kashikar N. , Lucassen PJ , Belgard TG , Encinas JM , Holt MG , Fitzsimons CP
Published: March 2023

Moderate Traumatic brain injury (TBI) can result in long-lasting changes in brain function. Although frequently spared from the acute primary injury, the hippocampus becomes affected during a secondary phase that takes place hours, or even days, after TBI, contributing to cognitive deficits. The hippocampus is one of the few brain areas in the adult brain harboring native neural stem cells (NSCs) that continue to generate new neurons (neurogenesis), and to a lesser extent new astrocytes (astrogliogenesis). While deregulation of hippocampal NSCs and neurogenesis have been observed after TBI, very little is known about how TBI may affect hippocampal astrogliogenesis.

Here, we aimed to assess how TBI affects hippocampal NSCs and their subsequent commitment to the neuronal or astroglial lineages. Using a controlled cortical impact model of TBI, single cell RNA sequencing and spatial transcriptomics, we observed a cell population-specific increase in NSC-derived neuronal cells and a decrease in NSC-derived astrocytic cells. These cellular changes were associated with cell-population specific changes in gene expression and dysplasia within the dentate gyrus.

Overall, our findings support the conclusion that TBI modifies adult hippocampal NSC fate to promote neurogenesis at the cost of astrogliogenesis, and highlights specific cell populations as possible targets to counteract the changes induced by TBI in the hippocampus.
Antigen-presenting type-I conventional dendritic cells facilitate curative checkpoint blockade immunotherapy in pancreatic cancer
Authors: Mahadevan Krishnan K. , Dyevoich Allison M. , Chen Yang , Li Bingrui , Sugimoto Hikaru , Sockwell Amari M. , McAndrews Kathleen M. , Wang Huamin , Shalapour Shabnam , Watowich Stephanie S. , Kalluri Raghu
Published: March 2023

Inflammation and tissue damage associated with pancreatitis can precede or occur concurrently with pancreatic ductal adenocarcinoma (PDAC). We demonstrate that in PDAC coupled with pancreatitis (ptPDAC), antigen-presenting type-I conventional dendritic cells (cDC1s) are specifically activated. Immune checkpoint blockade therapy (iCBT) leads to cytotoxic CD8+T cell activation and eradication of ptPDAC with restoration of lifespan even upon PDAC re-challenge. Such eradication of ptPDAC was reversed following specific depletion of dendritic cells. Employing PDAC antigen-loaded cDC1s as a vaccine, immunotherapy-resistant PDAC was rendered sensitive to iCBT with a curative outcome. Analysis of the T-cell receptor (TCR) sequences in the tumor infiltrating CD8+T cells following cDC1 vaccination coupled with iCBT identified unique CDR3 sequences with potential therapeutic significance. Our findings identify a fundamental difference in the immune microenvironment and adaptive immune response in PDAC concurrent with, or without pancreatitis, and provides a rationale for combining cDC1 vaccination with iCBT as a potential treatment option.
Trophic interactions in microbiomes influence plant host population size and ecosystem function
Authors: Tan Jiaqi , Wei Na , Turcotte Martin M.
Published: March 2023

Plant microbiomes that comprise diverse microorganisms, including prokaryotes, eukaryotes, and viruses are the key determinant of plant population dynamics and ecosystem function. Despite their importance, little is known about how interactions, especially trophic interactions, between microbes from different domains modify the importance of microbiomes for plant hosts and ecosystems. Using the common duckweedLemna minor, we experimentally examined the effects of predation (by bacterivorous protozoa) and parasitism (by bacteriophage) within microbiomes on plant population size and ecosystem phosphorus removal. Our results revealed that predation increased plant population size and phosphorus removal whereas parasitism showed the opposite pattern. The structural equation modeling further pointed out that predation and parasitism affected plant population size and ecosystem function via distinct mechanisms that were both mediated by microbiomes. Our results highlight the importance of understanding microbial trophic interactions for predicting the outcomes and ecosystem impacts of plant-microbiome symbiosis.
Transcription Factor Dynamics in Cross-Regulation of Plant Hormone Signaling Pathways
Authors: Yin Lingling , Zander Mark , Huang Shao-shan Carol , Xie Mingtang , Song Liang , Guzmán J. Paola Saldierna , Hann Elizabeth , Shanbhag Bhuvana K. , Ng Sophia , Jain Siddhartha , Janssen Bart J. , Clark Natalie M. , Walley Justin W. , Beddoe Travis , Bar-Joseph Ziv , Lewsey Mathew G. , Ecker Joseph R.
Published: March 2023

Cross-regulation between hormone signaling pathways is indispensable for plant growth and development. However, the molecular mechanisms by which multiple hormones interact and co-ordinate activity need to be understood. Here, we generated a cross-regulation network explaining how hormone signals are integrated from multiple pathways in etiolated Arabidopsis (Arabidopsis thaliana) seedlings. To do so we comprehensively characterized transcription factor activity during plant hormone responses and reconstructed dynamic transcriptional regulatory models for six hormones; abscisic acid, brassinosteroid, ethylene, jasmonic acid, salicylic acid and strigolactone/karrikin. These models incorporated target data for hundreds of transcription factors and thousands of protein-protein interactions. Each hormone recruited different combinations of transcription factors, a subset of which were shared between hormones. Hub target genes existed within hormone transcriptional networks, exhibiting transcription factor activity themselves. In addition, a group of MITOGEN-ACTIVATED PROTEIN KINASES (MPKs) were identified as potential key points of cross-regulation between multiple hormones. Accordingly, the loss of function of one of these (MPK6) disrupted the global proteome, phosphoproteome and transcriptome during hormone responses. Lastly, we determined that all hormones drive substantial alternative splicing that has distinct effects on the transcriptome compared with differential gene expression, acting in early hormone responses. These results provide a comprehensive understanding of the common features of plant transcriptional regulatory pathways and how cross-regulation between hormones acts upon gene expression.
Modeling the role of the thalamus in resting-state functional connectivity: nature or structure
Authors: Cabrera-Álvarez Jesús , Doorn Nina , Maestú Fernando , Susi Gianluca
Published: March 2023

The thalamus is a central brain structure that serves as a relay station for sensory inputs from the periphery to the cortex and regulates cortical arousal. Traditionally, it has been regarded as a passive relay that transmits information between brain regions. However, recent studies have suggested that the thalamus may also play a role in shaping functional connectivity (FC) in a task-based context. Based on this idea, we hypothesized that due to its centrality in the network and its involvement in cortical activation, the thalamus may also contribute to resting-state FC, a key neurological biomarker widely used to characterize brain function in health and disease. To investigate this hypothesis, we constructed ten in-silico brain network models based on neuroimaging data (MEG, MRI, and dwMRI), and simulated them including and excluding the thalamus. and raising the noise into thalamus to represent the afferences related to the reticular activating system (RAS) and the relay of peripheral sensory inputs. We simulated brain activity and compared the resulting FC to their empirical MEG counterparts to evaluate model’s performance. Results showed that a parceled version of the thalamus with higher noise, able to drive damped cortical oscillators, enhanced the match to empirical FC. However, with an already active self-oscillatory cortex, no impact on the dynamics was observed when introducing the thalamus. We also demonstrated that the enhanced performance was not related to the structural connectivity of the thalamus, but to its higher noisy inputs. Additionally, we highlighted the relevance of a balanced signal-to-noise ratio in thalamus to allow it to propagate its own dynamics. In conclusion, our study sheds light on the role of the thalamus in shaping brain dynamics and FC in resting-state and allowed us to discuss the general role of criticality in the brain at the mesoscale level.

Author summary

Synchrony between brain regions is an essential aspect of coordinated brain function and serves as a biomarker of health and disease. The thalamus, due to its centrality and widespread connectivity with the cortex, is a crucial structure that may contribute to this synchrony by allowing distant brain regions to work together. In this study, we used computational models to investigate the thalamus’s role in generating brain synchrony at rest. Our findings suggest that the structural connectivity of the thalamus is not its primary contribution to brain synchrony. Instead, we found that the thalamus plays a critical role in driving cortical activity, and when it is not driving this activity, its impact on brain synchrony is null. Our study provides valuable insights into the thalamocortical network’s role in shaping brain dynamics and FC in resting state, laying the groundwork for further research in this area.
Transcript-specific induction of stop codon readthrough using CRISPR-dCas13 system
Authors: Manjunath Lekha E. , Singh Anumeha , Kar Debaleena , Sellamuthu Karthi , Eswarappa Sandeep M.
Published: March 2023

Stop codon readthrough (SCR) is the process where translation continues beyond a stop codon on an mRNA. Here, we describe a strategy to enhance or induce SCR in a transcript-selective manner using CRISPR-dCas13 system. Using specific guide RNAs, we targeted dCas13 to the downstream region of the canonical stop codons of mammalianAGO1andVEGFA,which are known to exhibit natural SCR. Results of readthrough assays revealed the enhancement of SCR of these mRNAs (both exogenous and endogenous) caused by dCas13. This effect was associated with ribosomal pausing, which has been reported in several SCR events. Furthermore, our results show that CRISPR-dCas13 can induce SCR across premature termination codons (PTC) in the mRNAs of green fluorescent protein andTP53. Finally, we demonstrate the utility of this strategy in the induction of readthrough across the thalassemia-causing PTC inHBBmRNA. Thus, CRISPR-dCas13 can be programmed to enhance or induce SCR in a transcript-selective and stop codon-specific manner.
Analysis of histone antibody specificity directly in sequencing data using siQ-ChIP
Authors: Kupai Ariana , Vaughan Robert M. , Rothbart Scott B. , Dickson Bradley M.
Published: March 2023

We previously developed sans spike-in quantitative chromatin immunoprecipitation sequencing (siQ-ChIP), a technique that introduces an absolute quantitative scale to ChIP-seq data without reliance on spike-in normalization approaches. The physical model of siQ-ChIP predicted that the IP step of ChIP would produce a classical binding isotherm when antibody or epitope was titrated. Here, we define experimental conditions in which this titration is observable for antibodies that recognize modified states of histone proteins. We show that minimally sequenced points along an isotherm can reveal differential binding specificities that are associated with on- and off-target epitope interactions. This work demonstrates that the interpretation of histone post-translational modification distribution from ChIP-seq data has a dependence on antibody concentration. Collectively, these studies introduce a simplified and reproducible experimental method to generate quantitative ChIP-seq data without spike-in normalization and demonstrate that histone antibody specificity can be analyzed directly in ChIP-seq experiments.
Top-down, auditory pallial regulation of the social behavior network
Authors: Spool Jeremy A. , Lally Anna P. , Remage-Healey Luke
Published: March 2023

Social encounters rely on sensory cues that carry nuanced information to guide social decision-making. While high-level features of social signals are processed in the telencephalic pallium, nuclei controlling social behaviors, called the social behavior network (SBN), reside mainly in the diencephalon. Although it is well known how mammalian olfactory pallium interfaces with the SBN, there is little information for how pallial processing of other sensory modalities can modulate SBN circuits. This is surprising given the importance of complex vocalizations, for example, for social behavior in many vertebrate taxa such as humans and birds. Using gregarious and highly vocal songbirds, female Zebra finches, we asked to what extent auditory pallial circuits provide consequential input to the SBN as it processes social sensory cues. We transiently inactivated auditory pallium of female Zebra finches during song playback and examined song-induced activation in SBN nuclei. Auditory pallial inactivation impaired responses to song specifically within the lateral ventromedial nucleus of the hypothalamus (VMHl), providing the first evidence in vertebrates of a connection between auditory pallium and the SBN. This same treatment elevated feeding behavior, which also correlated with VMHl activation. This suggests that signals from auditory pallium to VMHl can tune the balance between social attention and feeding drive. A descending influence of sensory pallium on hypothalamic circuits could therefore provide a functional connection for the integration of social stimuli with internal state to influence social decision-making.

Significance

Sensory cues such as vocalizations contain important social information. These social signals can be substantially nuanced, containing information about vocalizer identity, prior experience, valence, and emotional state. Processing these features of vocalizations necessitates processing the fast, complex sound streams in song or speech, which depends on circuits in pallial cortex. But whether and how this information is then transferred to social circuits in limbic and hypothalamic regions remains a mystery. Here, we identify a top-down influence of the songbird auditory pallium on one specific node of the social behavior network within the hypothalamus. Descending functional connections such as these may be critical for the wide range of vertebrate species that rely on intricate sensory communication signals to guide social decision-making.
The CGG triplet repeat binding protein 1 counteracts DNA secondary structure-induced transcription-replication conflicts
Authors: Ummethum Henning , Lalonde Maxime , Werner Marcel , Trauner Manuel , Chanou Anna , Weiβ Matthias , Lee Clare S. K. , Kruse Elisabeth , Ettinger Andreas , Hamperl Stephan
Published: March 2023

Short tracts of trinucleotide repeats with less than 10 repeats are found frequently throughout the genome without any apparent negative impact on DNA replication fork progression or transcription elongation. CGG binding protein 1 (CGGBP1) binds to CGG triplet repeats and has been implicated in multiple cellular processes such as transcription, replication and DNA damage. Here, we show that CGGBP1 binds to human gene promoter sites prone to G-quadruplex and R-loop secondary structure formation. Altering CGGBP1 levels results in the accumulation of R-loops and causes a defect in transcriptional elongation by RNA polymerase II, which subsequently leads to replication fork stalling and transcription-replication conflicts. Together, our work shows that short trinucleotide repeats are a source of genome-destabilizing secondary structures and cells rely on specific DNA-binding factors to maintain proper transcription and replication progression at short trinucleotide repeats.
Intragroup conflict dynamics and their linkages with horizontal power disparity configurations, upper management conflicts and coworker support
Authors: Tremblay Michel
Published: March 2023

Purpose

This study aims to examine how changes in power disparity shape in-groups and upper-level management conflict are associated with intragroup relationship and task conflict variations. It also examines how workplace conflicts relate to focal employees’ perceptions of coworker support.

Design/methodology/approach

Data were collected from 3,343 respondents for nine years, comprising measurements taken on six occasions in 47 departments and stores of a Canadian retailer. The relationships between, within and across levels were tested using multilevel structural equation modeling.

Findings

The results showed that higher levels of power concentration vested by a few members or a single person are associated wih higher levels of intragroup conflict than usual. Furthermore, higher levels of task and relationship conflicts at upper management levels are associated with higher-than-usual task and relationship conflicts between nonhierarchical employees. Additionally, a higher-than-usual intragroup task conflict level was associated with lower-than-usual coworker support, supporting the proposed multilevel dynamic model.

Research limitations/implications

An important limitation of this study is that all variables are self-reported despite using the six-wave repeated measurements, thereby increasing the possibility of inflating some observed relationships. Future research should examine the emergence of a larger spectrum of power dispersion configurations and their role on process conflict.

Practical implications

Retail managers should legitimize why a high-power concentration occurs when the equal distribution of power is not possible and find ways to minimize the trickle-down effects of conflicts at upper levels on their subordinates.

Originality/value

This study examines the effect of variability on power configurations and conflict in upper management ranks on conflict dynamic. The findings show that a high-power concentration elicits increasing conflicts, and that there is no empirical evidence that intragroup conflict is associated with positive outcomes.
Education Briefing Property capitalisation rates –benchmarking the property market
Authors: Camilleri Denis
Published: March 2023

Purpose

The aim of this Education Briefing is to comment upon the construction and role of the capitalisation rate in the valuation of property assets and how the implicit assumptions of growth are market derived and may be considered more robust than the use of growth explicit discounted cash flow (DCF) models where explicit growth assumptions can be questioned.

Design/methodology/approach

This Education Briefing will look at the role of analysing initial yields to derive market capitalisation rates, and it will look at component parts of the yield to isolate growth assumptions and compare property returns to the government bond market.

Findings

Looking at the Maltese market, the briefing shows that the valuer needs to be aware of the advantages and disadvantages of implicit and explicit valuation models.

Practical implications

The choice of valuation model is dependent upon the availability of suitable comparable information and the appropriateness of the model for the market in question. More transparent markets can benefit from the use of explicit models but where information is less available, such as the Maltese market, implicit models may be considered more robust at estimating market value.

Originality/value

This is an Education Briefing discussing the construction and applicability of implicit valuation models using a market capitalisation rate.
Predicting long‐run risk factors of stock returns: Evidence from Australia
Authors: Banerjee Rajabrata , Cavoli Tony , McIver Ron , Meng Shannon , Wilson John K.
Published: March 2023

This study utilises the stock market data provided by the Australian Equity Database to analyse the long‐run relationship between Australian stock returns and key macroeconomic variables over the period 1926–2017. To measure the diverse risk factors in the stock market, we examine the possible determinants in four main categories: real, financial, domestic and international. Our results reveal that historical stock returns are strongly connected to financial and international factors as compared to real and domestic factors. Both the 1973–1974 OPEC Oil Price Crisis and 2007–2008 Global Financial Crisis had dampening effects on stock returns. There is a positive association between the US and Australian stock markets in the long‐run. These findings on stock market dynamics and their linkages with domestic and international macroeconomic policy changes in the long‐run have important implications for traders and practitioners.
The Angelic Brethren and Everyday Sacredness: A Protestant Theologian's Journey from Berlin to Leiden in 1717*
Authors: Gard Lennart , Zuber Mike A.
Published: March 2023

In the summer of 1717, a private teacher named Jacob Michelmann travelled from Berlin to Leiden to meet the head of a Protestant community known as the Angelic Brethren. During a pivotal time in European religious and intellectual history, Johann Wilhelm Überfeld sought to inculcate in his followers, including Michelmann, a powerful sense of everyday sacredness. Überfeld criticised what he perceived as the markedness of religious speech and acts compared to unmarked everyday activities. Implicitly, this state of affairs rendered the bulk of daily life profane, that is, largely detached and irrelevant to religious life and spiritual progress. For Überfeld and his followers, however, the divine spirit could communicate even through seemingly mundane trivialities, if believers had eyes to see and ears to hear. Accordingly, they paid great attention to household chores and domestic spaces. During his journey, Michelmann successfully acquired this mindset. Yet several years later he started neglecting the lessons of his journey, which caused conflict with Überfeld. Based on the visitor's own travelogue and a wealth of other sources, this article describes Michelmann's journey from its inception to its aftermath while probing Überfeld's notion of everyday sacredness.
Beyond Performance: Does Assessed Potential Matter to Employees’ Voluntary Departure Decisions?
Authors: DELLER CAROLYN
Published: March 2023

Firms are increasingly implementing performance–potential assessment systems, whereby supervisors evaluate employees’ current performance and future‐oriented potential (i.e., promotion prospects). Whether retention is greatest for high performance–high potential (HiPo) employees under such a system is an empirical question—while the “promise” of a promotion may aid retention, these employees likely face attractive outside options. Using data from a multinational firm, I find that HiPos generally depart at a lower rate than lower performing non‐HiPos. Among shorter tenured employees, I find the strongest evidence that potential matters to departures, above and beyond performance. In several instances, the rate of departure is lower when assessed potential is higher, holding performance constant. This is the case both among higher performers, where high potential leads to HiPo status, and among lower performers where high potential affords no such status. My findings suggest that HiPo status and potential ratings may help in facilitating employees’ early sorting decisions.
Effect of ticagrelor on the function of tunneled cuffed catheter in maintenance hemodialysis patients
Authors: Shen Jianming , Deng Yanyan , Wang Liping , Zha Fei
Published: March 2023

Objective

To observe the effect of ticagrelor on the function of a tunneled cuffed catheter (TCC) in maintenance hemodialysis (MHD) patients.

Methods

Eighty MHD patients (control group: 39 cases, observation group: 41 cases) using TCC as vascular access were enrolled from January 2019 to October 2020 in this prospective study. Patients in the control group were routinely treated with aspirin for antiplatelet therapy, while patients in the observation group were treated with ticagrelor. The catheter life time, catheter dysfunction, coagulation function, and antiplatelet drug‐related adverse events of the two groups were recorded.

Results

The median life time of TCC in the control group was significantly higher than that in the observation group. Moreover, the log rank test showed that the difference was statistically significant (p < 0.001).

Conclusion

Ticagrelor may reduce the incidence of catheter dysfunction and prolong the life time of the catheter by preventing and reducing the thrombosis of TCC in MHD patients, without obvious side effects.
Longer leukocyte telomere length increases cardiovascular mortality in type 2 diabetes patients
Authors: Chen Ziwei , Shen Yao , He Jing , Shen Yang , Zhu Weida , Wu Xiaohui , Xiao Mingbing
Published: March 2023

Aims

Leukocyte telomere length (LTL), as a biomarker of biological aging, is associated with the prevalence and complications of diabetes. This study aims to investigate the associations between LTL and all‐cause and cause‐specific mortality in patients with type 2 diabetes.

Methods

All participants with baseline LTL records were included from the National Health and Nutrition Examination Survey 1999–2002. Death status and its causes were ascertained for National Death Index based on International Classification of Diseases, Tenth Revision code. Cox proportional hazards regression models were established to estimate the hazard ratios (HRs) of LTL associating with all‐cause and cause‐specific mortality.

Results

The study enrolled 804 diabetic patients with the mean follow‐up of 14.9 ± 2.59 years. There were 367 (45.6%) all‐cause deaths, 80 (10.0%) cardiovascular deaths, and 42 (5.2%) cancer‐related deaths. Longer LTL was associated with reduced all‐cause mortality, whereas this association disappeared after adjusting for other variables. Compared with the lowest tertiles of LTL, the multivariable‐adjusted hazard ratio of cardiovascular mortality was 2.11 (95% confidence interval [CI] 1.31–3.39; p < .05) in the highest tertiles. In terms of cancer mortality, the highest tertile was negatively correlated with the risk of cancer mortality (HR 0.58 [95% CI 0.37, 0.91], p < .05).

Conclusion

In conclusion, LTL was independently associated with the risk of cardiovascular mortality in patients with type 2 diabetes and was negatively correlated with the risk of cancer mortality. Telomere length may be a predictor of cardiovascular mortality in diabetes.
Mortality and prognostic factors in connective tissue disease‐associated pulmonary arterial hypertension patients complicated with right heart failure
Authors: Deng Xiaoyue , Jiang Nan , Huang Can , Zhou Shuang , Peng Linyi , Zhang Li , Liu Jinjing , Wang Li , Zhou Jiaxin , Wang Qian , Weng Li , Peng Jinmin , Zhao Jiuliang , Li Mengtao , Zeng Xiaofeng
Published: March 2023

Objective

To identify predictive factors associated with mortality in connective tissue disease‐associated pulmonary arterial hypertension (CTD‐PAH) patients who were complicated with right heart failure (RHF).

Methods

In this single‐center retrospective study, baseline demographics, clinical features, laboratory results, and hemodynamic assessments were collected. Kaplan–Meier analysis was applied to analyze all‐cause mortality. Univariate and forward stepwise multivariate Cox proportional regression analyses were performed to identify independent predictors of mortality.

Results

A total of 51 right heart catheterization‐confirmed CTD‐PAH patients complicated with RHF were consecutively enrolled in this study from 2012 to 2022. Forty‐eight (94%) enrolled patients were female and the mean age was 36.0 ± 11.8 years. Thirty‐two (61.5%) were systemic lupus erythematosus‐PAH and 33%/67% showed World Health Organization functional class III/IV, respectively. Twenty‐five (49%) of those patients died and Kaplan–Meier analysis showed the overall 1‐, 3‐, and 5‐week survival rates from the time of hospitalization as 86.28%, 60.78%, and 56.86%, respectively. RHF in CTD‐PAH patients mainly resulted from progression of PAH (n = 19) and infection (n = 5), which also contributed to the leading causes of death. Statistical analysis between survivors and non‐survivors showed that death from RHF was associated with higher levels of urea (9.66 vs 6.34 mmol/L, P = 0.002), lactate (cLac: 2.65 vs 1.9 mmol/L, P = 0.006), total bilirubin (23.1 vs 16.9 μmol/L, P = 0.018) and direct bilirubin (10.5 vs 6.5 μmol/L, P = 0.004), but with lower levels of hematocrit (33.7 vs 39, P = 0.004), cNa+ (131 vs 136 mmol/L, P = 0.003). Univariate and forward stepwise multivariate Cox proportional regression analyses indicated that the level of cLac (hazards ratio:1.297; 95% CI: 1.076–1.564; P = 0.006) was an independent risk factor for mortality.

Conclusion

The short‐term prognosis of CTD‐PAH complicated with RHF was very poor, and hyperlactic acidemia (cLac > 2.85 mmoL/L) was an independent predicting factor for mortality of CTD‐PAH patients complicated with RHF.