bluuebunny/crossref_metadata_2025 huggingface dataset:
Values and preferences in COVID-19 public health guidelines: A systematic review
Authors: Kirsh Sarah , Ling Michael , Jassal Tanvir , Pitre Tyler , Pigott Thomas , Zeraatkar Dena
Published: March 2024

Background

Internationally accepted standards for trustworthy guidelines include the necessity to ground recommendations in values and preferences. Considering values and preferences respects the rights of citizens to participate in health decision-making and ensures that guidelines align with the needs and priorities of the communities they are intended to serve. Early anecdotal reports suggest that COVID-19 public health guidelines did not consider values and preferences.

Objective

To capture and characterize whether and how COVID-19 public health guidelines considered values and preferences.

Methods

We performed a systematic review of COVID-19 public health guidelines. We searched the eCOVID19 RecMap platform—a comprehensive international catalog of COVID-19 guidelines—up to July 2023. We included guidelines that made recommendations addressing vaccination, masking, isolation, lockdowns, travel restrictions, contact tracing, infection surveillance, and school closures. Reviewers worked independently and in duplicate to review guidelines for consideration of values and preferences.

Results

Our search yielded 129 eligible guidelines, of which 43 (33.3%) were published by national organizations, 73 (56.6%) by international organizations, and 14 (10.9%) by professional societies and associations. Twenty-six (20.2%) guidelines considered values and preferences. Among guidelines that considered values and preferences, most did so to assess the acceptability of recommendations (23; 88.5%) and by referencing published research (24; 92.3%). Guidelines only occasionally engaged laypersons as part of the guideline development group (6; 23.1%). None of the guidelines performed systematic reviews of the literature addressing values and preferences.

Conclusion

Most COVID-19 public health guidelines did not consider values and preferences. When values and preferences were considered, it was suboptimal. Disregard for values and preferences in guidelines might have partly contributed to divisive and unpopular COVID-19 policies. Given the possibility of future health emergencies, we recommend guideline developers identify efficient methods for considering values and preferences in crisis situations.
In vivo inhibition of miR-125b modulates monocyte trafficking through the CCR7 receptor and attenuates atherosclerosis
Authors: Mallén Adrian , Varela Cristian , Rotllan Noemí , Paloschi Valentina , Mäegdefessel Lars , Escolà Joan Carles , Aran Josep Maria , Navarro Estanis , Hueso Miguel
Published: March 2024

Background

Atherosclerosis (ATH) is a chronic systemic inflammatory disease affecting the vessel wall, wherein regulating non-coding RNAs play a crucial role. We previously demonstrated that miR-125b is upregulated in ATH and is a main regulator of cholesterol metabolism in macrophages. Herein we hypothesized that inhibiting miR-125b may attenuate ATH.

Methods and results

In the ApoE-/-mice model fed with a high fat diet for 14 weeks, we inhibited miR-125b using an antagomiR over a 4-week period. We observed a significant reduction in plaque size, accompanied by diminished infiltration of F4/80 macrophages and attenuation of NF-κB+activation within plaques. We explored the mechanism using a Vas-on-Chip adhesion assay using Human Aortic Endothelial Cells (HAoEC) stimulated with TNFα. We observed an impairment in the trafficking of miR-125b transfected THP-1 monocytes, accompanied by the downregulation of the CD11b/CD18 integrin and the CCR7 receptor. Furthermore, we demonstrated a direct regulation of the CCR7 receptor by miR-125b using a reporter plasmid construct (p_CCR7.WT) containing the 3’UTR region of CCR7 gene fused with a luciferase coding sequence. In addition, miR-125b transfected monocytes inhibited CCR7 cell migration induced by the CCL21 ligand but did not affect migration induced by others ligands such as MCP1. Finally, we confirmed the downregulation of CCR7 in coronary plaques in both ApoE-/-mice and patients with coronary artery disease.

Conclusions

Inhibiting miR-125b offers a novel therapeutic approach for ameliorating ATH that results in a reduction of macrophage content and plaque lesion size. This improvement occurs through the enhancement of monocyte trafficking via CCR7 that facilitates the exit of foam cells from the plaque.

CLINICAL PERSPECTIVE

What is New?

- We found evidences of a new therapeutic approach for atherosclerosis, in which miR-125b inhibition reduces macrophage content and plaque size.

- We described the molecular mechanism underlying miR-125b, which involves regulating of monocyte trafficking to plaques and the downregulation of the chemokine receptor CCR7. CCR7 plays a crucial role in facilitating the egress of macrophages and foam cells from plaques, and its downregulation contribute to progression of ATH.

- The results have been validated in a cohort of patients with coronary artery disease, where CCR7 expression was reduced in plaques.

What are the clinical implications?

- We highlight the pivotal role of monocyte trafficking in the inflammatory mechanism of atherosclerosis. Managing miR-125b/CCR7 signaling may improve the resolution of ATH promoting the exit of foam cells from plaque.

- Inhibition of miR-125b in plaque macrophages represents a novel and promising therapeutic approach for cardiovascular disease.
Pharmacogenomic synthetic lethal screens reveal hidden vulnerabilities and new therapeutic approaches for treatment of NF1-associated tumors
Authors: Williams Kyle B. , Larsson Alex T. , Keller Bryant J. , Chaney Katherine E. , Williams Rory L. , Bhunia Minu M. , Draper Garrett M. , Jubenville Tyler A. , Hudson Wendy A , Moertel Christopher L. , Ratner Nancy , Largaespada David A.
Published: March 2024

Neurofibromatosis Type 1 (NF1) is a common cancer predisposition syndrome, caused by heterozygous loss of function mutations in the tumor suppressor geneNF1. Individuals with NF1 develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage after somatic loss of the wild typeNF1allele, some of which progress further to malignant peripheral nerve sheath tumors (MPNST). There is only one FDA approved targeted therapy for symptomatic plexiform neurofibromas and none approved for MPNST. The genetic basis of NF1 syndrome makes associated tumors ideal for using synthetic drug sensitivity approaches to uncover therapeutic vulnerabilities. We developed a drug discovery pipeline to identify therapeutics for NF1-related tumors using isogeneic pairs ofNF1-proficient and deficient immortalized human Schwann cells. We utilized these in a large-scale high throughput screen (HTS) for drugs that preferentially killNF1-deficient cells, through which we identified 23 compounds capable of killingNF1-deficient Schwann cells with selectivity. Multiple hits from this screen clustered into classes defined by method of action. Four clinically interesting drugs from these classes were testedin vivousing both a genetically engineered mouse model of high-grade peripheral nerve sheath tumors and human MPNST xenografts. All drugs tested showed single agent efficacy in these models as well as significant synergy when used in combination with the MEK inhibitor Selumetinib. This HTS platform yielded novel therapeutically relevant compounds for the treatment of NF1-associated tumors and can serve as a tool to rapidly evaluate new compounds and combinations in the future.
Tau phosphorylation impedes functionality of protective tau envelopes
Authors: Siahaan Valerie , Weissova Romana , Lanska Eva , Karhanova Adela , Dostal Vojtech , Henriot Veronique , Janke Carsten , Libusova Lenka , Braun Marcus , Balastik Martin , Lansky Zdenek
Published: March 2024

Tau, an axonal microtubule-associated protein, is a critical regulator of microtubule function and stability. Tau interaction with microtubules is regulated by tau phosphorylation. Tau hyperphosphorylation is implicated in microtubule destabilization related to neurodegenerative disorders. How tau phosphorylation leads to microtubule destabilization is however unknown. Recently, it was shown that tau molecules on microtubules cooperatively assemble into cohesive layers termed envelopes. Tau envelopes protect microtubules against degradation by microtubule-severing enzymes, suggesting a functional link between envelopes and microtubule stability. Here we show that tau phosphorylation has deleterious effects on the microtubule-protective function of tau envelopes. Using reconstitution and live-cell experiments, we found that tau phosphorylation destabilizes tau envelopes and decreases their integrity, leading to reduced microtubule protection against microtubule-severing enzymes. Our data suggest that a perturbation of microtubule homeostasis linked to tau hyperphosphorylation in neurodegeneration, could be explained by the disassembly and impaired functionality of the tau envelopes.
Development of a ddPCR approach for the absolute quantification of soil microorganisms involved in atmospheric CO2fixation
Authors: Le Geay Marie , Mayers Kyle , Küttim Martin , Lauga Béatrice , Jassey Vincent E.J.
Published: March 2024

Carbon fixing microorganisms (CFMs) play a crucial role in soil carbon (C) cycling contributing to carbon uptake and sequestration through various metabolic pathways. Despite their significance, quantification of the absolute abundance of CFMs in soils remains elusive. This study employed a digital droplet PCR (ddPCR) approach to quantify the abundance of key and emerging CFM pathways in fen and bog across different depths (0-15 cm). Targeting total prokaryotes (16S rRNAgene), oxygenic phototrophs (23S rRNAgene), aerobic anoxygenic phototrophic bacteria (AAnPB,pufMgene), and chemoautotrophs (cbbLgene), we optimized ddPCR conditions to achieve absolute quantification of these genes. Overall, our results revealed that oxygenic phototrophs were the most abundant CFMs, constituting 12% of total prokaryotic abundance, followed by chemoautotrophs (10%) and AAnPBs (9%). Fen exhibited higher gene concentrations than bog. Depth variations were also observed, differing between fen and bog for all genes. Our findings highlight the abundance of oxygenic phototrophs and chemoautotrophs in peatlands, challenging previous estimations that relied solely on oxygenic phototrophs for microbial CO2fixation assessments. Incorporating absolute gene quantification is crucial for a comprehensive understanding of microbial contributions to soil processes, shedding light on the intricate mechanisms of soil functioning in peatlands.
Differential warming at crown scale impact walnut primary growth onset and secondary growth rate
Authors: Dusart Nicolas , Moulia Bruno , Saudreau Marc , Serre Christophe , Charrier Guillaume , Hartmann Félix P.
Published: March 2024

Trees are exposed to significant spatio-temporal thermal variations, which can induce intracrown discrepancies in the onset and dynamics of primary and secondary growth. In recent decades, an increase in late winter and early spring temperatures has been observed, potentially accelerating bud break, cambial activation and their potential coordination. Intracrown temperature heterogeneities could lead to asymmetric tree shapes unless there is a compensatory mechanism at the crown level.

An original warming experiment was conducted on young Juglans regia trees in a greenhouse. From February to August, the average temperature difference during the day between warmed and control parts was 4°C. The warming treatment advanced the date of budbreak significantly, by up to 14 days. Warming did not alter secondary growth resumption but increased growth rates, leading to higher xylem cell production (twice as many) and to an increase in radial increment (+80% compared to control). Meristems resumptions were asynchronous without coordination in response to temperature. Buds on warmed branches began to swell two weeks prior to cambial division, which was one week earlier than on control branches. A difference in carbon and water remobilisation at the end of bud ecodormancy was noted under warming. Overall, our results argue for a lack of compensatory mechanisms at the crown scale, which may lead to significant changes in tree architecture in response to intra-crown temperature heterogeneities.

Highlight: When tree are submitted to asymmetrical warming, it leads to early budbreak and enhanced cambial activity for warmed branches
The role of Kinesin-1 in neuronal dense core vesicle transport and lifespan regulation inC. elegans
Authors: Gavrilova Anna , Boström Astrid , Korabel Nickolay , Fedotov Sergei , Poulin Gino B. , Allan Victoria J.
Published: March 2024

Fast axonal transport is crucial for neuronal function and is driven by kinesins and cytoplasmic dynein. We investigated the role of the kinesin-1 motor complex in dense core vesicle (DCV) transport inC. elegans, using mutants in kinesin light chains (klc-1 andklc-2) and the kinesin motor subunit (unc-116) expressing anida-1::gfptransgene that labels DCVs in the ALA neuron. A reduced-functionunc-116(rf)mutation greatly impaired DCV transport in both directions. Aklc-2(rf)reduced-function mutation decreased DCV velocity in both directions and reduced the frequency of body bends during swimming. In contrast, theklc-1(-)null mutation had no effect on anterograde transport or swimming ability, but surprisingly it increased the speed of retrograde DCV transport. We also determined lifespan, finding thatklc-1(-)orklc-2(rf)single mutants were wild-type whereas theunc-116(rf),ida-1::gfpandunc-116(rf);ida-1::gfpstrains were short-lived. Strikingly, theida-1::gfptransgenic synergistically interact with eitherklcmutant to extend lifespan compared to wild-type and parental strains. Our findings suggest that kinesin-1 not only influences anterograde and retrograde DCV transport but also plays a role in regulating lifespan.
Establishing a national linked database for fetal alcohol spectrum disorder (FASD) in the UK: multi-method public and professional involvement to determine acceptability and feasibility
Authors: Harding Sarah K , Samways Beverley , Dillon Amy , Butcher Sandra , Boyd Andy , Mukherjee Raja , Cook Penny A. , McQuire Cheryl
Published: March 2024

Objective

to conduct public and professional involvement work to establish stakeholder views on the feasibility, acceptability, key purposes, and design of a national linked longitudinal research database for fetal alcohol spectrum disorder (FASD) in the UK. 

Methods

Following stakeholder-mapping, we identified contributors through collaborator networks and online searches. We consulted with stakeholders using online workshops (one for adults with FASD [and their supporters] N=5; one for caregivers of people with FASD N=7), 1:1/small-team video calls/email communication twith clinicians, policymakers, data-governance experts, third-sector representatives, and researchers [N=35]), and one hybrid clinical workshop (N=17). Discussions covered data availability, benefits, challenges, and design preferences for a national pseudonymised linked database for FASD. We derived key themes from the notes and recordings collected across all involvement activities.

Results

Our tailored, multi-method approach generated high levels of stakeholder engagement. Stakeholders expressed strong support for a pseudonymised national linked database for FASD. Key anticipated benefits were the potential for: increased awareness and understanding of FASD, leading to better support; new insights into clinical profiles, leading to greater diagnostic efficiency; facilitating international collaboration; and increased knowledge of the long-term impacts of FASD on health, social care, education, economic and criminal justice outcomes. Policymakers noted clear alignment with contemporary FASD and digital transformation priorities. Given the rich data infrastructure established in the UK, stakeholders expressed that a national linked FASD database could be world-leading. Common stakeholder concerns were around privacy and data-sharing and the importance of retaining space for clinical judgement alongside insights gained from quantitative analyses.

Conclusions

Multi-method and multidisciplinary public and professional involvement activities demonstrated the feasibility and acceptability of establishing a national linked database for FASD in the UK. Perceived benefits and challenges varied by stakeholder group, demonstrating that flexible, diverse, embedded stakeholder collaboration will be essential as we establish this database.
Sentence production and sentence repetition in autistic adolescents and young adults: Linguistic sensitivity to finiteness-marking
Authors: Girolamo Teresa , Ghali Samantha , Larson Caroline
Published: March 2024

Purpose

Despite the clinical utility of sentence production and sentence repetition to identify language impairment in autism, little is known about the extent to which these tasks are sensitive to potential dialectal variation. One promising method is strategic scoring (Oetting et al., 2016), which has good clinical utility for identifying language impairment in nonautistic school-age children across dialects of English. This report applies strategic scoring to analyze sentence repetition and sentence production in autistic adolescents and adults.

Method

Thirty-one diverse autistic adolescents and adults with language impairment (ALI;n=15) and without language impairment (ASD;n=16) completed the Formulated Sentences and Recalling Sentences subtests of the Clinical Evaluation of Language Fundamentals-5thEd (Wiig et al., 2013). Descriptive analyses and regression evaluated effects of scoring condition, group, and scoring condition by group on outcomes, as well as group differences in finiteness-marking across utterances and morphosyntactic structures.

Results

Strategic and unmodified item-level scores were essentially constant on both subtests and significantly lower in the ALI than the ASD group. Only group predicted item-level scores. Group differences were limited to: percent grammatical utterances on Formulated Sentences and percent production of overt structures combined on Sentence Repetition (ALI < ASD).

Discussion

Findings support the feasibility of strategic scoring for sentence production and sentence repetition to identify language impairment and indicate that potential dialectal variation in finiteness-marking did not confound outcomes in this sample. To better understand the clinical utility of strategic scoring, replication with a larger sample varying in age and comparisons with dialect-sensitive measures are needed.
Very Long-term Longitudinal Follow-up of Heart Failure on the REMADHE Trial
Authors: Bocchi Edimar Alcides , Guimaraes Guilherme Veiga , Romero Cristhian Espinoza , Ayub Ferreira Silvia Moreira , Biselli Bruno , Chizzola Paulo Roberto , Munhoz Robinson Tadeu , Fukushima Julia Tizue , das Dores Cruz Fátima
Published: March 2024

Background

Heart failure (HF) is associated with frequent hospitalization and worse prognosis. Prognosis factors and survival in very long-term follow-up have not been reported in HF. HF disease management programs(DMP) results are contradictory. DMP efficacy in very long-term follow-up is unknown. We studied the very long-term follow-up of up to 23.6 years and prognostic factors of HF in 412 patients under GDMT included in the REMADHE trial.

Methods

The REMADHE trial was a prospective, single-center, randomized trial comparing DMP versus usual care(C). The first patient was randomized on October 5, 1999. The primary outcome of this extended REMADHE was all-cause mortality.

Results

The all-cause mortality rate was 88.3%. HF was the first cause of death followed by death at home. Mortality was higher in the first 6-year follow-up. The predictive variables in multivariate analysis associated with mortality were age ≥52 years (P=0.015), Chagas etiology (P=0.010), LVEF <45% (P=0.008), use of digoxin (P=0.002), functional class IV (P=0.01), increase in urea (P=0.03), and reduction of lymphocytes (P=0.005). In very long-term follow-up, DMP did not affect mortality in patients under GDMT. HF as a cause of death was more frequent in the C group. Chagas disease, LVEF <45%, and renal function were associated with different modes of death.

Conclusion

DMP was not effective in reducing very-long term mortality; however, the causes of death had changed. Our findings that age, LVEF, Chagas’ disease, functional class, renal function, lymphocytes, and digoxin use were associated with poor prognosis could influence future strategies to improve HF management.
In vivo Assembly of Bacterial Partition Condensates on Circular Supercoiled and Linear DNA
Authors: Sekkouri Alaoui Hicham , Quèbre Valentin , Delimi Linda , Rech Jérôme , Debaugny-Diaz Roxanne , Labourdette Delphine , Campos Manuel , Cornet François , Walter Jean-Charles , Bouet Jean-Yves
Published: March 2024

In bacteria, faithful DNA segregation of chromosomes and plasmids is mainly mediated by ParABS systems. These systems, consisting of a ParA ATPase, a DNA binding ParB CTPase, and centromere sitesparS, orchestrate the separation of newly replicated DNA copies and their intracellular positioning. Accurate segregation relies on the assembly of a high-molecular-weight complex, comprising a few hundreds of ParB dimers nucleated fromparSsites. This complex assembles in a multi-step process and exhibits dynamic liquid-droplet properties. Despite various proposed models, the complete mechanism for partition complex assembly remains elusive. This study investigates the impact of DNA supercoiling on ParB DNA binding profilesin vivo, using the ParABS system of the plasmid F. We found that variations in DNA supercoiling does not significantly affect any steps in the assembly of the partition complex. Furthermore, physical modeling, leveraging ChIP-seq data from linear plasmids F, suggests that ParB sliding is restricted to approximately 2-Kbp fromparS, highlighting the necessity for additional mechanisms beyond ParB sliding over DNA for concentrating ParB into condensates nucleated atparS. Lastly, explicit simulations of a polymer coated with bound ParB suggest a dominant role for ParB-ParB interactions in DNA compaction within ParB condensates.
Stable and Oscillatory Hypoxia Differentially Regulate Invasibility of Breast Cancer Associated Fibroblasts
Authors: Du Wenqiang , Novin Ashkan , Liu Yamin , Afzal Junaid , Liu Shaofei , Suhail Yasir , Kshitiz
Published: March 2024

As local regions in the tumor outstrip their oxygen supply, hypoxia can develop, affecting not only the cancer cells, but also other cells in the microenvironment, including cancer associated fibroblasts (CAFs). Hypoxia is also not necessarily stable over time, and can fluctuate or oscillate. Hypoxia Inducible Factor-1 is the master regulator of cellular response to hypoxia, and can also exhibit oscillations in its activity. To understand how stable, and fluctuating hypoxia influence breast CAFs, we measured changes in gene expression in CAFs in normoxia, hypoxia, and oscillatory hypoxia, as well as measured change in their capacity to resist, or assist breast cancer invasion. We show that hypoxia has a profound effect on breast CAFs causing activation of key pathways associated with fibroblast activation, but reduce myofibroblast activation and traction force generation. We also found that oscillatory hypoxia, while expectedly resulted in a “sub-hypoxic” response in gene expression, it resulted in specific activation of pathways associated with actin polymerization and actomyosin maturation. Using traction force microscopy, and a nanopatterned stromal invasion assay, we show that oscillatory hypoxia increases contractile force generation vs stable hypoxia, and increases heterogeneity in force generation response, while also additively enhancing invasibility of CAFs to MDA-MB-231 invasion. Our data show that stable and unstable hypoxia can regulate many mechnobiological characteristics of CAFs, and can contribute to transformation of CAFs to assist cancer dissemination and onset of metastasis.
CPT1A Mediates Radiation Sensitivity in Colorectal Cancer
Authors: Chen Zhenhui , Yu Lu , Zheng Zhihao , Wang Xusheng , Guo Qiqing , Chen Yuchuan , Zhang Yaowei , Zhang Yuqin , Xiao Jianbiao , Chen Keli , Fan Hongying , Ding Yi
Published: March 2024

The prevalence and mortality rates of colorectal cancer (CRC) are increasing worldwide. Radiation resistance hinders radiotherapy, a standard treatment for advanced CRC, leading to local recurrence and metastasis. Elucidating the molecular mechanisms underlying radioresistance in CRC is critical to enhance therapeutic efficacy and patient outcomes. Bioinformatic analysis and tumour tissue examination were conducted to investigate theCPT1AmRNA and protein levels in CRC and their correlation with radiotherapy efficacy. Furthermore, lentiviral overexpression and CRISPR/Cas9 lentiviral vectors, along within vitroandin vivoradiation experiments, were used to explore the effect of CPT1A on radiosensitivity. Additionally, transcriptomic sequencing, molecular biology experiments, and bioinformatic analyses were employed to elucidate the molecular mechanisms by which CPT1A regulates radiosensitivity. CPT1A was significantly downregulated in CRC and negatively correlated with responsiveness to neoadjuvant radiotherapy. Functional studies suggested that CPT1A mediates radiosensitivity, influencing reactive oxygen species (ROS) scavenging and DNA damage response. Transcriptomic and molecular analyses highlighted the involvement of the peroxisomal pathway. Mechanistic exploration revealed that CPT1A downregulates the FOXM1-SOD1/SOD2/CAT axis, moderating cellular ROS levels after irradiation and enhancing radiosensitivity. CPT1A downregulation contributes to radioresistance in CRC by augmenting the FOXM1-mediated antioxidant response. Thus, CPT1A is a potential biomarker of radiosensitivity and a novel target for overcoming radioresistance, offering a future direction to enhance CRC radiotherapy.
Novel synthetic ecteinascidins exhibit potent anti-melanoma activity by suppressing super-enhancer-driven oncogenic transcription
Authors: Cigrang Max , Obid Julian , Nogaret Maguelone , Seno Léane , Ye Tao , Davidson Guillaume , Catez Philippe , Berico Pietro , Capelli Clara , Marechal Clara , Zachayus Amélie , Elly Clémence , Li Tsai-Kun , Compe Emmanuel , Avilés Pablo , Davidson Irwin , Egly Jean-Marc , Cuevas Carmen , Coin Frédéric
Published: March 2024

The dynamic cellular transitions exhibited by skin cutaneous melanoma (SKCM) cells present a significant challenge to current therapeutic approaches, emphasizing the critical need for innovative treatments. Lurbinectedin, a marine-derived compound belonging to the ecteinascidin family, has recently gained approval for the treatment of metastatic small-cell lung cancer (SCLC). In this study, we demonstrate the efficacy of lurbinectedin against SKCM cells, irrespective of their driver mutations or phenotypic states. Additionally, we have developed two novel derivatives of lurbinectedin, termed ecubectedin and PM54, both of which exhibit potent cytotoxic effects on SKCM cells. Moreover, these analogs demonstrate robust anti-tumor activity in melanoma xenograft models, including those resistant to current therapies, leading to prolonged animal survival. Mechanistically, our investigation reveals that these novel synthetic ecteinascidins markedly suppress oncogenic super-enhancer (SE)-mediated gene expression in SKCM cells through a multifaceted mechanism. They bind to and inhibit the activity of promoters of lineage-specific master transcription factors, as well as promoters of genes encoding ubiquitous transcription factors/coactivators, which are highly enriched at oncogenic SEs. These mechanisms likely synergize to disrupt the expression of cancer-promoting genes. Overall, our findings highlight the potential of synthetic ecteinascidins as promising therapeutics for cancers characterized by diverse transcriptional landscapes, particularly in cases where conventional therapeutic options have failed due to the heterogeneity of malignant cell population
MftG is crucial for ethanol metabolism of mycobacteria by linking mycofactocin oxidation to respiration
Authors: Graça Ana Patrícia , Nikitushkin Vadim , Ellerhorst Mark , Vilhena Cláudia , Klassert Tilman E. , Starick Andreas , Siemers Malte , Al-Jammal Walid K. , Vilotijevic Ivan , Slevogt Hortense , Papenfort Kai , Lackner Gerald
Published: March 2024

Mycofactocin is a redox cofactor essential for the alcohol metabolism of mycobacteria.. While the biosynthesis of mycofactocin is well established, the genemftG, which encodes an oxidoreductase of the glucose-methanol-choline superfamily, remained functionally uncharacterized. Here, we show that MftG enzymes are almost exclusively found in genomes containing mycofactocin biosynthetic genes and are present in 75% of organisms harboring these genes. Gene deletion experiments inMycolicibacterium smegmatisdemonstrated a growth defect of the ΔmftGmutant on ethanol as a carbon source, accompanied by an arrest of cell division reminiscent of mild starvation. Investigation of carbon and cofactor metabolism implied a defect in mycofactocin reoxidation. Cell-free enzyme assays and respirometry using isolated cell membranes indicated that MftG acts as a mycofactocin dehydrogenase shuttling electrons toward the respiratory chain. Transcriptomics studies also indicated remodeling of redox metabolism to compensate for a shortage of redox equivalents. In conclusion, this work closes an important knowledge gap concerning the mycofactocin system and adds a new pathway to the intricate web of redox reactions governing the metabolism of mycobacteria.
The 10-year health impact, economic impact, and return on investment of the South African molecular diagnostics programme for HIV, Tuberculosis and SARS-CoV-2
Authors: Nichols Brooke E. , de Nooy Alexandra , Cassim Naseem , Hans Lucia , da Silva Manuel Pedro , Chetty Kamy , Grantz Kyra H. , Han Alvin X. , Phillips Andrew N. , Jamieson Lise , Scott Lesley E. , Stevens Wendy S.
Published: March 2024

To ensure there is adequate investment into diagnostics, an understanding of the magnitude of impact and return on investment is necessary. We therefore sought to understand the health and economic impacts of the molecular diagnostic programme in South Africa, to deepen the understanding on the broad value of diagnostics and guide future healthcare investments. We calculated the 10-year (where data were available) total cost and DALYs averted associated with molecular diagnosis of molecular TB testing (2013-2022), HIV viral load monitoring (2013-2022), early infant diagnosis of HIV infection (2013-2022), and SARS-CoV-2 testing (2020-2022). We then calculated the economic value associated with those health gains and subsequent return on investment. Since the inception of the molecular diagnostics programme in South Africa, 3,035,782 DALYs have been averted as a direct consequence of this programme. This has generated an estimated $20.5 billion in economic value due to these health gains. The return on investment varied by specific diagnostic test (19.0 for tuberculosis, 1.4 for HIV viral load testing, 64.8 for early infant diagnosis of HIV, and 2.5 for SARS-CoV-2), for an average of 9.9 for the entire molecular diagnostics programme between 2013 and 2022- or $9.9 of value for each $1 invested. The molecular diagnostics programme in South Africa generated a significant amount of health gains and economic value associated with these health gains, and the return-on-investment rivals other high-impact public health interventions such as childhood vaccination. Consequently, the molecular diagnostics programme in South Africa is highly impactful, and will continue to be an excellent investment of South African public health expenditure.
Centhaquine Increases Stroke Volume and Cardiac Output in Patients with Hypovolemic Shock
Authors: Khanna Aman , Vaidya Krish , Shah Dharmesh , Ranjan Amaresh K. , Gulati Anil
Published: March 2024

Background

Centhaquine is a resuscitative agent that acts on α2B adrenergic receptors to enhance venous return in hypovolemic shock. The effect of centhaquine on cardiac output in patients with hypovolemic shock has not been reported.

Methods

Trans-thoracic echocardiography was utilized to measure stroke volume (SV), cardiac output (CO), left ventricular outflow tract-velocity time integral (LVOT-VTI), left ventricular outflow tract diameter (LVOTd), heart rate (HR), left ventricular ejection fraction (LVEF), left ventricular fractional shortening (FS) and inferior vena cava (IVC) diameter before (0 min) and after centhaquine (0.01 mg/kg, iv infusion over 60 min) treatment (60 min, 120 min, and 300 min) in 12 randomly selected patients with hypovolemic shock enrolled in a prospective, multicenter, open-label phase IV clinical study (NCT05956418) of centhaquine in patients with hypovolemic shock.

Results

A significant increase in SV (mL) was observed after 60, 120, and 300 minutes of centhaquine treatment. CO (mL/min) increased significantly at 120 and 300 min despite a decrease in HR at these times. A significant increase in IVC diameter and LVOT-VTI (mL) at these time points was observed, which indicated increased venous return. The LVEF and FS did not change, while the mean arterial pressure (MAP, mmHg) increased in patients after 120 and 300 minutes of centhaquine treatment. Positive correlations between IVC diameter and SV (R2= 0.9556) and between IVC diameter and MAP (R2= 0.8928) were observed, which indicated the effect of centhaquine mediated increase in venous return on SV, CO, and MAP.

Conclusions

Centhaquine mediated increase in venous return appears to play a critical role in enhancing SV, CO, and MAP in patients with hypovolemic shock; these changes could be pivotal for reducing shock-mediated circulatory failure, promoting tissue perfusion, and improving patient outcomes.

Trial registration

The phase IV trial reported in this study has Clinical Trials Registry, India; ctri.icmr.org.in, CTRI/2021/01/030263;clinicaltrials.gov,NCT05956418.
The Role of Cytokines in Acute and Chronic Postsurgical Pain in Pediatric Patients after Major Musculoskeletal Surgeries
Authors: Chidambaran Vidya , Duan Qing , Pilipenko Valentina , Glynn Susan M. , Sproles Alyssa , Martin Lisa J. , Lacagnina Michael J. , King Christopher D. , Ding Lili
Published: March 2024

Study Objective

To determine if baseline cytokines and their changes over postoperative days 0-2 (POD0-2) predict acute and chronic postsurgical pain (CPSP) after major surgery.

Design

Prospective, observational, longitudinal nested study.

Setting

University-affiliated quaternary children’s hospital.

Patients

Subjects (≥8 years old) with idiopathic scoliosis undergoing spine fusion or pectus excavatum undergoing Nuss procedure.

Measurements

Demographics, surgical, psychosocial measures, pain scores, and opioid use over POD0-2 were collected. Cytokine concentrations were analyzed in serial blood samples collected before and after (up to two weeks) surgery, using Luminex bead arrays. After data preparation, relationships between pre- and post-surgical cytokine concentrations with acute (% time in moderate-severe pain over POD0-2) and chronic (pain score>3/10 beyond 3 months post-surgery) pain were analyzed. After adjusting for covariates, univariate/multivariate regression analyses were conducted to associate baseline cytokine concentrations with postoperative pain, and mixed effects models were used to associate longitudinal cytokine concentrations with pain outcomes.

Main Results

Analyses included 3,164 measures of 16 cytokines from 112 subjects (median age 15.3, IQR 13.5-17.0, 54.5% female, 59.8% pectus). Acute postsurgical pain was associated with higher baseline concentrations of GM-CSF (β=0.95, SE 0.31;p=.003), IL-1β (β=0.84, SE 0.36;p=.02), IL-2 (β=0.78, SE 0.34;p=.03), and IL-12 p70 (β=0.88, SE 0.40;p=.03) and longitudinal postoperative elevations in GM-CSF (β=1.38, SE 0.57;p=.03), IFNγ (β=1.36, SE 0.6;p=.03), IL-1β (β=1.25, SE 0.59;p=.03), IL-7 (β=1.65, SE 0.7,p=.02), and IL-12 p70 (β=1.17, SE 0.58;p=.04). In contrast, CPSP was associated with lower baseline concentration of IL-8 (β= -0.39, SE 0.17;p=.02), and the risk of developing CPSP was elevated in patients with lower longitudinal postoperative concentrations of IL-6 (β= -0.57, SE 0.26;p=.03), IL-8 (β= - 0.68, SE 0.24;p=.006), and IL-13 (β= -0.48, SE 0.22;p=.03). Furthermore, higher odds for CPSP were found for females (vs.males) for IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and TNFα, and for pectus (vs.spine) surgery for IL-8 and IL-10.

Conclusion

We identified pro-inflammatory cytokines associated with increased acute postoperative pain and anti-inflammatory cytokines associated with lower CPSP risk, with potential to serve as predictive and prognostic biomarkers.
Statistical Relationship Between Bitcoin and Synthetic Opioid Mortalities: Are DEA Enforcement Actions Aligning with Trends in Drug Related Deaths?
Authors: Kang Daihun
Published: March 2024

Background

The intersection of cryptocurrency, especially Bitcoin, with public health issues, particularly synthetic opioid-related deaths, presents an emerging field of study. This research explores the statistical relationship between Bitcoin market fluctuations and synthetic opioid mortalities, against the backdrop of Drug Enforcement Administration (DEA) enforcement actions.

Methods

Utilizing data from 2009 to 2022, this study employs Pearson correlation and linear regression models to investigate the relationship between annual Bitcoin price fluctuations and synthetic opioid-related death rates, alongside DEA domestic arrest trends.

Results

A pronounced positive correlation (r = 0.92) was found between Bitcoin price changes and synthetic opioid mortality rates, with the Bitcoin price accounting for approximately 84.78% of the variance in opioid-related deaths (R² = 0.8478). The analysis also notes a disparity between increasing synthetic opioid fatalities and decreasing DEA domestic arrests.

Conclusions

The findings reveal significant correlations between Bitcoin price fluctuations and synthetic opioid-related fatalities, highlighting potential gaps in current drug enforcement strategies. This study underscores the need for an interdisciplinary approach to address the complexities introduced by cryptocurrency in the opioid crisis and suggests the necessity of integrating financial and public health strategies to combat emerging drug abuse trends.
SMYD1-mediated Mono-Methylation of Lysine K35 of the sarcomeric Myosin Heavy Chain (MHC) is fundamental for thick filament assembly in zebrafish and human iPSC-derived cardiomyocytes
Authors: Diofano Federica , Amadi Chidinma , Gahr Bernd , Weinmann Karolina , Rottbauer Wolfgang , Just Steffen
Published: March 2024

The SMYD family is a unique class of lysine methyltransferases (KMTases) known to methylate histones but also non-histone proteins. Among the five SMYD family members (1-5), SMYD1 was identified as a heart- and skeletal muscle-specific KMTase, which, together with Unc45b and Hsp90a, interacts with Myosin thereby regulating thick filament assembly. However, the process by which SMYD1 orchestrates Myosin assembly is largely unknown. Here, we found that SMYD1 physically interacts with Myosin heavy chain (Myh) at its N-terminus and that the Myh N-terminus specifically gets mono-methylated by SMYD1 at lysine 35 (K35). Accordingly, methylated Myh is properly integrated into functional sarcomeres, whereas unmethylated Myh molecules in Smyd1-deficient zebrafish are efficiently degraded by the Ubiquitin Proteasome System (UPS) leading to defective thick filament assembly. Although the inhibition of the UPS by MG132 is able to reconstitute Myosin levels in Smyd1-deficient zebrafish embryos, thick filament assembly is still blocked due to the lack of K35 Myh mono-methylation. Similar to the situation in zebrafish striated muscle cells, SMYD1-mediated MYH methylation is also critical for thick filament assembly in human cardiomyocytes, indicating cross-species conservation of this fundamental mechanism of Myosin methylation, which has been first described about 40 years ago. Further investigations will now be essential to explore the therapeutic potential of targeting this pathway in cardiomyopathies and skeletal muscle disorders.
Resource allocation in biochemically structured metabolic networks
Authors: Seeger Leon , Pinheiro Fernanda , Lässig Michael
Published: March 2024

Microbes tune their metabolism to environmental challenges by changing protein expression levels, metabolite concentrations, and reaction rates simultaneously. Here, we establish an analytical model for microbial resource allocation that integrates enzyme biochemistry and the global architecture of metabolic networks. We describe the production of protein biomass from external nutrients in pathways of Michaelis-Menten enzymes and compute the resource allocation that maximizes growth under constraints of mass conservation and metabolite dilution by cell growth. This model predicts generic patterns of growth-dependent microbial resource allocation to proteome and metabolome. In a nutrient-rich medium, optimal protein expression depends primarily on the biochemistry of individual synthesis steps, while metabolite concentrations and fluxes decrease along successive reactions in a metabolic pathway. Under nutrient limitation, individual protein expression levels change linearly with growth rate, the direction of change depending again on the enzyme’s biochemistry. Metabolite levels and fluxes show a stronger, nonlinear decline with growth rate. We identify a simple, metabolite-based regulatory logic by which cells can be tuned to near-optimal growth. Finally, our model predicts evolutionary stable states of metabolic networks, including local biochemical parameters and the global metabolite mass fraction, in tune with empirical data.
Sequential-GAM constructs the single-cell geometric 3D genome structure
Authors: Li Yongge , Wang Kaili , Shi Minglei , Zhang Michael Q. , Gao Juntao
Published: March 2024

Three-dimensional structure of the chromatin is crucial for cell identity and gene regulation. However, how genome-wide hierarchical geometric structure is organized in single cells remains elusive. Here we developed Sequential-GAM (Sequential Genome Architecture Mapping) to construct the hierarchical geometric structure and estimated the radial position of chromosomes, compartments, subcompartments, and genes in single cells by capturing contiguous thin sections of the nucleus. We found that several epigenomic features distributed gradually from the nuclear center to the periphery, including histone modifications and subcompartments. Besides, we estimated the variance of hierarchical structure and revealed the dynamic radial position of subcompartments B1 and B2. Furthermore, we defined the quasi-stable TADs set (q-stable TADs), in which TADs maintain a relatively stable distance to each other. Interestingly, q-stable TADs revealed the correlation between the stability of chromatin structure and chromatin activity. Finally, we discovered that the radial distance and the stability of radial positions for genes in single cells were negatively correlated with their expressions. Taken together, Sequential-GAM is able to estimate 3D genome’s geometric structure in single cell, and to reveal the structural stability and inter-cell heterogeneity.
Loss of the Familial Dysautonomia geneElp1in cerebellar granule cell progenitors leads to ataxia in mice
Authors: Manz Frederik , da Silva Patricia Benites Goncalves , Schouw Mackenna E. , Lukasch Chiara , Bianchini Luca , Sieber Laura , Garcia-Lopez Jesus , Ahmad Shiekh Tanveer , Li Yiran , Lin Hong , Joshi Piyush , Spänig Lisa , Radoš Magdalena , Roiuk Mykola , Sepp Mari , Zuckermann Marc , Northcott Paul A. , Patrizi Annarita , Kutscher Lena M.
Published: March 2024

Familial Dysautonomia (FD) is an autosomal recessive disorder caused by a splice site mutation in the gene ELP1, which disproportionally affects neurons. While classically characterized by deficits in sensory and autonomic neurons, neuronal defects in the central nervous system have been described. ELP1 is highly expressed in the normal developing and adult cerebellum, but its role in cerebellum development is unknown. To investigate the cerebellar function of Elp1, we knocked out Elp1 in cerebellar granule cell progenitors (GCPs) and examined the outcome on animal behavior and cellular composition. We found that GCP-specific conditional knockout of Elp1 (Elp1cKO) resulted in ataxia by 8 weeks of age. Cellular characterization showed that the animals had smaller cerebella with fewer granule cells. This defect was already apparent 7 days after birth, when Elp1cKOanimals also exhibited fewer mitotic GCPs and shorter Purkinje dendrites. Through molecular characterization, we found that loss of Elp1 was associated with an increase in apoptotic cell death and cell stress pathways in GCPs. Our study demonstrates the importance of ELP1 within the developing cerebellum, and suggests that Elp1 loss in the GC lineage may also play a role in the progressive ataxia phenotypes of FD patients.
Dynamic binding of the bacterial chaperone Trigger factor to translating ribosomes
Authors: Hävermark Tora , Metelev Mikhail , Lundin Erik , Volkov Ivan L. , Johansson Magnus
Published: March 2024

The bacterial chaperone Trigger factor (TF) binds to ribosome-nascent chain complexes (RNCs) and co-translationally aids the folding of proteins in bacteria. Decades of studies have given a broad, but often conflicting, description of the substrate specificity of TF, its RNC-binding dynamics, and competition with other RNC-binding factors, such as the Signal Recognition Particle (SRP). Previous RNC-binding kinetics experiments were conducted on stalled RNCs in reconstituted systems, and consequently, may not represent the interaction of TF with ribosomes translating mRNA in the cytoplasm of the cell. Here, we used single-particle tracking (SPT) to measure TF binding to actively translating ribosomes inside livingEscherichia coli. In cells, TF displays two distinct binding modes — long (ca 1 s) target-specific RNC binding, and shorter (ca 50 ms) sampling of non-target RNCs. RNC binding events are interrupted only by transient excursions to a freely diffusing state (ca 40 ms). We also show that TF competes with SRP for RNC bindingin vivo, and in doing so, tunes the binding selectivity of SRP.