bluuebunny/crossref_metadata_2025 huggingface dataset:
Temporal integration by multi‐level regularities fosters the emergence of dynamic conscious experience
Authors: Hu Ruichen , Li Shuo , Yuan Peijun , Wang Ying , Jiang Yi
Published: January 2024

The relationship between integration and awareness is central to contemporary theories and research on consciousness. Here, we investigated whether and how information integration over time, by incorporating the underlying regularities, contributes to our awareness of the dynamic world. Using binocular rivalry, we demonstrated that structured visual streams, constituted by shape, motion, or idiom sequences containing perceptual‐ or semantic‐level regularities, predominated over their nonstructured but otherwise matched counterparts in the competition for visual awareness. Despite the apparent resemblance, a substantial dissociation of the observed rivalry advantages emerged between perceptual‐ and semantic‐level regularities. These effects stem from nonconscious and conscious temporal integration processes, respectively, with the former but not the latter being vulnerable to perturbations in the spatiotemporal integration window. These findings corroborate the essential role of structure‐guided information integration in visual awareness and highlight a multi‐level mechanism where temporal integration by perceptually and semantically defined regularities fosters the emergence of continuous conscious experience.
Patients with a high defibrillation threshold: Approaches to management
Authors: Vidal Margenat Alejandro , Zedan Ahmed , Schubert Scott , Gopani Srushti , Hariharan Ramesh
Published: January 2024

Implantable cardioverter‐defibrillators (ICDs) have revolutionized the prognosis for patients at elevated risk of ventricular tachyarrhythmias. For safety, defibrillation should be effective with a minimum of 10 J below the device's maximum energy. While modern ICDs rarely deliver ineffective shocks in primary prevention, the surge in managing severe heart failure patients has led to an increased number of patients with high defibrillation thresholds (DFTs). This article elucidates the potential causes of high DFT, including clinical factors, lead and device placement, the presence of a Left Ventricular Assist Device (LVAD), prolonged ventricular arrhythmias, shock vectors, waveform tilt, medications, and manufacturer‐specific options. We also detail management strategies, highlighting alternative shock coil placements, practical recommendations, and case studies from our institution. Our management algorithm suggests addressing preventable causes, re‐evaluating coil positions, considering non‐invasive system modifications, upgrading to a higher‐capacity device, and adding extra coil(s).
Endo‐1,4‐beta‐xylanase 1 (MoXYL1) secreted by Magnaporthe oryzae triggers defense responses and induces cell death in rice
Authors: Lee Gi Hyun , Min Cheol Woo , Yoo Ju Soon , Jang Jeong Woo , Yoon Jinmi , Cho Lae‐Hyeon , Wang Yiming , Jeon Jong‐Seong , Gupta Ravi , Kim Sun Tae
Published: January 2024

The rice blast fungus Magnaporthe oryzae devastates cultivated rice (Oryza sativa L.), causing extensive crop losses. Despite being a major pathogen, information on this pathosystem, especially on the proteins associated with fungal pathogenicity and host defense response, is relatively scarce. Utilizing liquid chromatography‐mass spectrometry (LC–MS/MS), we identified 123 in planta‐secreted M. oryzae proteins in rice leaves and screened for their cell death‐inducing activity. Biochemical characterization of these M. oryzae proteins revealed an endo‐1,4‐beta‐xylanase (MoXYL1), which induces cell death in Nicotiana benthamiana leaves and H2O2 accumulation in rice suspension‐cultured cells. Transgenic rice plants (PDUF26::MoXYL1) expressing MoXYL1 driven by rice DOMAIN OF UNKNOWN FUNCTION PROTEIN 26 (DUF26) promoter enhanced expression of pathogen‐responsive and hormone‐related genes, and resistance to the M. oryzae and Cochliobolus miyabeanus. Data‐independent acquisition (DIA) MS‐based proteomics of wild‐type and PDUF26::MoXYL1 rice revealed 1,833 significantly modulated rice proteins upon M. oryzae infection. Among these, 219 proteins showed a significant increased abundance exclusively in PDUF26::MoXYL1 transgenic rice, while 410 proteins showed increased abundance in both wild‐type and PDUF26::MoXYL1. Notably, xylanase inhibitor proteins, pathogenesis‐related proteins, and other proteins associated with jasmonic acid biosynthesis exhibited increased abundance in response to M. oryzae. Based on these results, we proposed a putative signaling network induced by MoXYL1 and M. oryzae. In summary, our findings highlight the crucial role of MoXYL1 in inducing rice defense and in potentially enhancing rice disease resistance against fungal pathogens.
ABA‐induced interplant drought cuing
Authors: Falik Omer , Kersting Lennart , Novoplansky Ariel
Published: January 2024

Plants possess the ability to detect, integrate, and react to myriad signals and cues regarding imminent challenges and opportunities. In this study, we investigated whether unstressed plants can adaptively respond to cues emitted by neighbouring plants treated with abscisic acid (ABA) and if they can subsequently induce adaptive responses in additional unstressed neighbours. Triplets of split‐root Pisum sativum plants were grown in rows. The findings reveal that, under drought conditions, cues from ABA‐treated plants enhanced the survival of both immediately adjacent target plants and more distantly located relayed target plants. However, this cueing adversely impacted the performance of plants growing under sufficient water availability. These findings hold potential implications for our understanding of the role of interplant communication in plant interactions, as well as its effects on the survival and performance of plants in both natural and agricultural settings.
A framework for date palm (Phoenix dactylifera L.) tissue regeneration and stable transformation
Authors: Zhang Yasha , Patankar Himanshu , Aljedaani Fatima , Blilou Ikram
Published: January 2024

The date palm is a resilient, socioeconomically valuable desert fruit tree renowned for its heat, drought, and salinity tolerance. Date palm fruits are rich in nutrients and antioxidants, and their beneficial health properties can mitigate current and future food security challenges. However, it is challenging to improve date palm production through conventional breeding methods due to its slow growth. Date palm seeds do not produce true‐to‐type progeny, and commercial propagation relies on direct organogenesis from maternal tissue. Consequently, numerous economically important and valuable cultivars are lost due to tissue recalcitrance and challenges in inducing cell dedifferentiation and regeneration. Moreover, genetic engineering of date palms is currently impossible due to the lack of a stable genetic transformation protocol. This hampers the development of genetic resources in date palms.

This study established a tissue culture pipeline and a genetic transformation protocol for various commercially important date palm cultivars. We used the non‐invasive visual reporter RUBY and four morphogenic regulators to validate and improve date palm transformation potential. We found that the date palm BABY‐BOOM (PdBBM) and the WOUND INDUCED DEDIFFERENTIATION (PdWIND1) enhanced transformation efficacy. We show that PdBBM can induce embryogenesis in hormone‐free media and regenerate roots and shoots in recalcitrant varieties. On the other hand, PdWIND1 maintained embryogenic cells in their undifferentiated state. Our study provides a foundation for genetically improving date palms and a potential solution for preserving economically valuable varieties.
Low‐cost tools for large‐scale seed scarification: efficiency in two species from South American arid lands
Authors: Pérez Daniel R. , Basaez Pablo E. , Rodríguez Araujo Maria E. , Lagos Leonilda J. , Campos Damián F.
Published: January 2024

The use of native plants for arid land restoration requires the application of pre‐germination treatments to alleviate seed dormancy mechanisms. As it is known, scarification allows several valuable species to overcome the primary forms of dormancy. However, supplying large quantities of scarified seeds at a low cost represents a significant challenge. In this context, our objective was to evaluate locally constructed machines accessible to people of degraded lands in a state of poverty. The effectiveness was evaluated by comparing two native shrubs from South American arid lands, Larrea divaricata and L. cuneifolia. Four treatments were applied: control (T0), mechanical scarification with a hand drill equipped with sandpaper on its head (T1), and mechanical scarification for 15 seconds (T2) and 30 seconds (T3) with a self‐constructed machine, capable of regulating pressure and speed. For both species, the germination probability was higher with T2 (0.82 ± 0.02) compared to T0 (0.28 ± 0.03) and T1 (0.65 ± 0.03). T3 presented intermediate values (0.75 ± 0.03) but did not differ significantly from T1 and T2. Our results show the effectiveness of a locally constructed seed scarification tool to upscale seed‐based restoration in arid lands.
Peer Effects in Stock Market Participation: Evidence from Immigration
Authors: Girshina Anastasia , Mathä Thomas Y. , Ziegelmeyer Michael
Published: January 2024

This paper studies how peers' financial behavior affects individuals' own investment choices. To identify the peer effect, we exploit the composition of the Luxembourg population and use the differences in stock market participation across various immigrant groups to study the effect on stock market participation of natives. We find that stock market participation of immigrant peers has a sizable effect on that of natives and that social learning is one of the channels through which this peer effect occurs. However, social learning alone does not account for the entire effect. Social utility might, therefore, also play an important role in peer effect transmission.
‘Rules of engagement’: Does competition drive engagement in faculty development
Authors: Buckley Emily , Cooke John , Whelton Helen , Barrett Aileen
Published: January 2024

Introduction

Faculty development (FD) is integral to the implementation of educational programmes. However, attracting new faculty is challenging. Competition is a motivator for learning at an undergraduate level; however, incorporating competition to engage faculty in continued FD has not been explored. In the context of a new strategy to embed in situ simulation in postgraduate education across our healthcare group, and drawing on motivational theory, we asked ‘does competition drive engagement in new FD initiatives?’

Methods

We conducted semi‐structured interviews with nine healthcare professionals (HCPs) who had participated in an in situ simulation ‘SimStars’ competition. Guided by thematic analysis and borrowing from constructivist grounded theory, we explored participants' motivations for entering a competition, their experiences of competition throughout their education and how this process impacted on their engagement in FD.

Results

Three overarching concepts arose and challenged our understanding of the role of competition as a motivator: (1) ‘Competition is a necessary evil’; (2) ‘It really is the taking part that counts’; and (3) ‘Teamwork makes the dream work’. In contrast to previously published work, our results suggest participants view competition negatively and as a means to career progression. However, the opportunity to work as part of an (interprofessional) team towards a goal, and to develop a new skill (i.e. the process), was more motivating for participants than ‘winning’ a competition.

Conclusion

Competition may not provide a motivation for HCPs to engage in FD and may be a barrier. Providing collaboration opportunities, faculty coaching and the chance to develop new skills could enhance engagement.
Green Revolution dwarfing Rht genes negatively affected wheat floral traits related to cross‐pollination efficiency
Authors: Schierenbeck Matías , Alqudah Ahmad M. , Lantos Edit , Avogadro Evangelina G. , Simón María Rosa , Börner Andreas
Published: January 2024

Hybrid breeding is a promising strategy to quickly improve wheat yield and stability. Due to the usefulness of the Rht ‘Green Revolution’ dwarfing alleles, it is important to gain a better understanding of their impact on traits related to hybrid development. Traits associated with cross‐pollination efficiency were studied using Near Isogenic Lines carrying the different sets of alleles in Rht genes: Rht1 (semi‐dwarf), Rht2 (semi‐dwarf), Rht1 + 2 (dwarf), Rht3 (extreme dwarf), Rht2 + 3 (extreme dwarf), and rht (tall) during four growing seasons. Results showed that the extreme dwarfing alleles Rht2 + 3, Rht3, and Rht1 + 2 presented the greatest effects in all the traits analyzed. Plant height showed reductions up to 64% (Rht2 + 3) compared to rht. Decreases up to 20.2% in anther length and 33% in filament length (Rht2 + 3) were observed. Anthers extrusion decreased from 40% (rht) to 20% (Rht1 and Rht2), 11% (Rht3), 8.3% (Rht1 + 2), and 6.5% (Rht2 + 3). Positive correlations were detected between plant height and anther extrusion, anther, and anther filament lengths, suggesting the negative effect of dwarfing alleles. Moreover, the magnitude of these negative impacts depends on the combination of the alleles: Rht2 + 3 > Rht3/Rht1 + 2 > Rht2/Rht1 > rht (tall). Reductions were consistent across genotypes and environments with interactions due to magnitude effects. Our results indicate that Rht alleles are involved in multiple traits of interest for hybrid wheat production and the need to select alternative sources for reduced height/lodging resistance for hybrid breeding programs.
Iteration of Cox rings of klt singularities
Authors: Braun Lukas , Moraga Joaquín
Published: January 2024

In this article, we study the iteration of Cox rings of klt singularities (and Fano varieties) from a topological perspective. Given a klt singularity , we define the iteration of Cox rings of . The first result of this article is that the iteration of Cox rings of a klt singularity stabilizes for large enough. The second result is a boundedness one, we prove that for an ‐dimensional klt singularity , the iteration of Cox rings stabilizes for , where only depends on . Then, we use Cox rings to establish the existence of a simply connected factorial canonical (or scfc) cover of a klt singularity, with general fiber being an extension of a finite group by an algebraic torus. The scfc cover generalizes both the universal cover and the iteration of Cox rings. We prove that the scfc cover dominates any sequence of quasi‐étale finite covers and reductive abelian quasi‐torsors of the singularity. We characterize when the iteration of Cox rings is smooth and when the scfc cover is smooth. We also characterize when the spectrum of the iteration coincides with the scfc cover. Finally, we give a complete description of the regional fundamental group, the iteration of Cox rings, and the scfc cover of klt singularities of complexity one. Analogous versions of all our theorems are also proved for Fano‐type morphisms. To extend the results to this setting, we show that the Jordan property holds for the regional fundamental group of Fano‐type morphisms.
Improved Design of an Orthogonal-Axis-Type Precession Motion Ball Reducer
Authors: Terada Hidetsugu , Makino Koji , Wada Yuma , Nagai Takeshi
Published: January 2024

To realize a no-backlash reducer for a small-size orthogonal-axis output, a novel design of a precession motion ball reducer is proposed. This reducer consists of a precession-motion-generating section, a motion direction converting section of the precession motion, and a reduced output-generating section. To avoid cutting tool interference, two types of distorted spatial circular grooves are located on the outer spherical surface of a precession rotor. Furthermore, the grooves of the reduced rotation generating section are profiled on the spherical surface at the output side of the precession motion rotor, which is different from the previous precession ball reducer. In this research, the equations for the groove loci of the precession motion generation, motion direction conversion, and reduced-rotation generation, which are located on the outer spherical surfaces, are proposed. The output rotating direction can be determined using the relationship between the input and output rotation angles of the precession motion direction converting groove. The prototype reducer is confirmed to smoothly rotate. Furthermore, at the hysteresis loss characteristic test, that is better than the backlash characteristic of a general orthogonal-axis output-type speed reducer with bevel gears.
Avian ANP32A incorporated in avian influenza A virions promotes interspecies transmission by priming early viral replication in mammals
Authors: Na Lei , Sun Liuke , Yu Mengmeng , Zhang Yingzhi , Zhang Yuan , Zhang Zhenyu , Zhang Haili , Qi Ting , Guo Wei , Guo Xing , Wang Shida , Wang Jingfei , Lin Yuezhi , Wang Xiaojun
Published: January 2024

Species-specific differences in acidic nuclear phosphoprotein 32 family member A (ANP32A) determine the restriction of avian-signature polymerase in mammalian cells. Mutations that evade this restriction, such as PB2-E627K, are frequently acquired when avian influenza A viruses jump from avian hosts to mammalian hosts. However, the mechanism underlying this adaptation process is still unclear. Here, we report that host factor ANP32 proteins can be incorporated into influenza viral particles through combination with the viral RNA polymerase (vPol) and then transferred into targeted cells where they support virus replication. The packaging of the ANP32 proteins into influenza viruses is dependent on their affinity with the vPol. Avian ANP32A (avANP32A) delivered by avian influenza A virions primes early viral replication in mammalian cells, thereby favoring the downstream interspecies transmission event by increasing the total amount of virus carrying adaptive mutations. Our study clarifies one role of avANP32A where it is used by avian influenza virus to help counteract the restriction barrier in mammals.
Observation of time-reversal symmetry breaking in the band structure of altermagnetic RuO
2
Authors: Fedchenko Olena , Minár Jan , Akashdeep Akashdeep , D’Souza Sunil Wilfred , Vasilyev Dmitry , Tkach Olena , Odenbreit Lukas , Nguyen Quynh , Kutnyakhov Dmytro , Wind Nils , Wenthaus Lukas , Scholz Markus , Rossnagel Kai , Hoesch Moritz , Aeschlimann Martin , Stadtmüller Benjamin , Kläui Mathias , Schönhense Gerd , Jungwirth Tomas , Hellenes Anna Birk , Jakob Gerhard , Šmejkal Libor , Sinova Jairo , Elmers Hans-Joachim
Published: January 2024

Altermagnets are an emerging elementary class of collinear magnets. Unlike ferromagnets, their distinct crystal symmetries inhibit magnetization while, unlike antiferromagnets, they promote strong spin polarization in the band structure. The corresponding unconventional mechanism of time-reversal symmetry breaking without magnetization in the electronic spectra has been regarded as a primary signature of altermagnetism but has not been experimentally visualized to date. We directly observe strong time-reversal symmetry breaking in the band structure of altermagnetic RuO
2
by detecting magnetic circular dichroism in angle-resolved photoemission spectra. Our experimental results, supported by ab initio calculations, establish the microscopic electronic structure basis for a family of interesting phenomena and functionalities in fields ranging from topological matter to spintronics, which are based on the unconventional time-reversal symmetry breaking in altermagnets.
G3BP1-dependent condensation of translationally inactive viral RNAs antagonizes infection
Authors: Burke James M. , Ratnayake Oshani C. , Watkins J. Monty , Perera Rushika , Parker Roy
Published: January 2024

G3BP1 is an RNA binding protein that condenses untranslating messenger RNAs into stress granules (SGs). G3BP1 is inactivated by multiple viruses and is thought to antagonize viral replication by SG-enhanced antiviral signaling. Here, we show that neither G3BP1 nor SGs generally alter the activation of innate immune pathways. Instead, we show that the RNAs encoded by West Nile virus, Zika virus, and severe acute respiratory syndrome coronavirus 2 are prone to G3BP1-dependent RNA condensation, which is enhanced by limiting translation initiation and correlates with the disruption of viral replication organelles and viral RNA replication. We show that these viruses counteract condensation of their RNA genomes by inhibiting the RNA condensing function of G3BP proteins, hijacking the RNA decondensing activity of eIF4A, and/or maintaining efficient translation. These findings argue that RNA condensation can function as an intrinsic antiviral mechanism, which explains why many viruses inactivate G3BP proteins and suggests that SGs may have arisen as a vestige of this antiviral mechanism.
Rapid and accurate remethylation of DNA in
Dnmt3a-
deficient hematopoietic cells with restoration of DNMT3A activity
Authors: Li Yang , Abel Haley J. , Cai Michelle , LaValle Taylor A. , Yin Tiankai , Helton Nichole M. , Smith Amanda M. , Miller Christopher A. , Ley Timothy J.
Published: January 2024

Here, we characterize the DNA methylation phenotypes of bone marrow cells from mice with hematopoietic deficiency of
Dnmt3a
or
Dnmt3b
(or both enzymes) or expressing the dominant-negative
Dnmt3a
R878H
mutation [R882H in humans; the most common
DNMT3A
mutation found in acute myeloid leukemia (AML)]. Using these cells as substrates, we defined DNA remethylation after overexpressing wild-type (WT) DNMT3A1, DNMT3B1, DNMT3B3 (an inactive splice isoform of DNMT3B), or DNMT3L (a catalytically inactive “chaperone” for DNMT3A and DNMT3B in early embryogenesis). Overexpression of
DNMT3A
for 2 weeks reverses the hypomethylation phenotype of Dnmt3a-deficient cells or cells expressing the R878H mutation. Overexpression of DNMT3L (which is minimally expressed in AML cells) also corrects the hypomethylation phenotype of
Dnmt3a
R878H/+
marrow, probably by augmenting the activity of WT DNMT3A encoded by the residual WT allele.
DNMT3L
reactivation may represent a previously unidentified approach for restoring DNMT3A activity in hematopoietic cells with reduced DNMT3A function.
Improved immunostaining of nanostructures and cells in human brain specimens through expansion-mediated protein decrowding
Authors: Valdes Pablo A. , Yu Chih-Chieh (Jay) , Aronson Jenna , Ghosh Debarati , Zhao Yongxin , An Bobae , Bernstock Joshua D. , Bhere Deepak , Felicella Michelle M. , Viapiano Mariano S. , Shah Khalid , Chiocca E. Antonio , Boyden Edward S.
Published: January 2024

Proteins are densely packed in cells and tissues, where they form complex nanostructures. Expansion microscopy (ExM) variants have been used to separate proteins from each other in preserved biospecimens, improving antibody access to epitopes. Here, we present an ExM variant, decrowding expansion pathology (dExPath), that can expand proteins away from each other in human brain pathology specimens, including formalin-fixed paraffin-embedded (FFPE) clinical specimens. Immunostaining of dExPath-expanded specimens reveals, with nanoscale precision, previously unobserved cellular structures, as well as more continuous patterns of staining. This enhanced molecular staining results in observation of previously invisible disease marker–positive cell populations in human glioma specimens, with potential implications for tumor aggressiveness. dExPath results in improved fluorescence signals even as it eliminates lipofuscin-associated autofluorescence. Thus, this form of expansion-mediated protein decrowding may, through improved epitope access for antibodies, render immunohistochemistry more powerful in clinical science and, perhaps, diagnosis.
Myeloid and lymphoid expression of
C9orf72
regulates IL-17A signaling in mice
Authors: Limone Francesco , Couto Alexander , Wang Jin-Yuan , Zhang Yingying , McCourt Blake , Huang Cerianne , Minkin Adina , Jani Marghi , McNeer Sarah , Keaney James , Gillet Gaëlle , Gonzalez Rodrigo Lopez , Goodman Wendy A. , Kadiu Irena , Eggan Kevin , Burberry Aaron
Published: January 2024

A mutation in
C9ORF72
is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Patients with ALS or FTD often develop autoimmunity and inflammation that precedes or coincides with the onset of neurological symptoms, but the underlying mechanisms are poorly understood. Here, we knocked out murine
C9orf72
in seven hematopoietic progenitor compartments by conditional mutagenesis and found that myeloid lineage
C9orf72
prevents splenomegaly, loss of tolerance, and premature mortality. Furthermore, we demonstrated that
C9orf72
plays a role in lymphoid cells to prevent interleukin-17A (IL-17A) production and neutrophilia. Mass cytometry identified early and sustained elevation of the costimulatory molecule CD80 expressed on
C9orf72
-deficient mouse macrophages, monocytes, and microglia. Enrichment of CD80 was similarly observed in human spinal cord microglia from patients with
C9ORF72
-mediated ALS compared with non-ALS controls. Single-cell RNA sequencing of murine spinal cord, brain cortex, and spleen demonstrated coordinated induction of gene modules related to antigen processing and presentation and antiviral immunity in
C9orf72
-deficient endothelial cells, microglia, and macrophages. Mechanistically, C9ORF72 repressed the trafficking of CD80 to the cell surface in response to Toll-like receptor agonists, interferon-γ, and IL-17A. Deletion of
Il17a
in
C9orf72
-deficient mice prevented CD80 enrichment in the spinal cord, reduced neutrophilia, and reduced gut T helper type 17 cells. Last, systemic delivery of an IL-17A neutralizing antibody augmented motor performance and suppressed neuroinflammation in
C9orf72
-deficient mice. Altogether, we show that
C9orf72
orchestrates myeloid costimulatory potency and provide support for IL-17A as a therapeutic target for neuroinflammation associated with ALS or FTD.
“Deoxy” to be or “Desoxy” not to be—a century-old tale in the history of DNA nomenclature
Authors: Sharma Gaurav , Chodvadiya Jaimin , Malik Indranil
Published: January 2024

This commentary discusses a comprehensive history of the first-ever use of pertinent words directly related to DNA, such as desoxyribose, deoxyribose, desoxyribonucleic acid, and deoxyribonucleic acid. With almost 100 years of the identification and nomenclature of desoxyribose sugar and desoxyribonucleic acid, the term “desoxy” continues to see limited use. We hope that whenever young researchers come across the sporadic occurrence of “desoxy” in any published text, they will not consider it a mistake.
Inducing vulnerability to InhA inhibition restores isoniazid susceptibility in drug-resistant
Mycobacterium tuberculosis
Authors: Harrison Gregory A. , Wang Erin R. , Cho Kevin , Mreyoud Yassin , Sarkar Souvik , Almqvist Fredrik , Patti Gary J. , Stallings Christina L.
Published: January 2024

Of the approximately 10 million cases of
Mycobacterium tuberculosis
(
Mtb
) infections each year, over 10% are resistant to the frontline antibiotic isoniazid (INH). INH resistance is predominantly caused by mutations that decrease the activity of the bacterial enzyme KatG, which mediates the conversion of the pro-drug INH to its active form INH-NAD. We previously discovered an inhibitor of
Mtb
respiration, C10, that enhances the bactericidal activity of INH, prevents the emergence of INH-resistant mutants, and re-sensitizes a collection of INH-resistant mutants to INH through an unknown mechanism. To investigate the mechanism of action of C10, we exploited the toxicity of high concentrations of C10 to select for resistant mutants. We discovered two mutations that confer resistance to the disruption of energy metabolism and allow for the growth of
Mtb
in high C10 concentrations, indicating that growth inhibition by C10 is associated with inhibition of respiration. Using these mutants as well as direct inhibitors of the
Mtb
electron transport chain, we provide evidence that inhibition of energy metabolism by C10 is neither sufficient nor necessary to potentiate killing by INH. Instead, we find that C10 acts downstream of INH-NAD synthesis, causing
Mtb
to become particularly sensitive to inhibition of the INH-NAD target, InhA, without changing the concentration of INH-NAD or the activity of InhA, the two predominant mechanisms of potentiating INH. Our studies revealed that there exists a vulnerability in
Mtb
that can be exploited to render
Mtb
sensitive to otherwise subinhibitory concentrations of InhA inhibitor.

IMPORTANCE

Isoniazid (INH) is a critical frontline antibiotic to treat
Mycobacterium tuberculosis
(
Mtb
) infections. INH efficacy is limited by its suboptimal penetration of the
Mtb
-containing lesion and by the prevalence of clinical INH resistance. We previously discovered a compound, C10, that enhances the bactericidal activity of INH, prevents the emergence of INH-resistant mutants, and re-sensitizes a set of INH-resistant mutants to INH. Resistance is typically mediated by
katG
mutations that decrease the activation of INH, which is required for INH to inhibit the essential enzyme InhA. Our current work demonstrates that C10 re-sensitizes INH-resistant
katG
-hypomorphs without enhancing the activation of INH. We furthermore show that C10 causes
Mtb
to become particularly vulnerable to InhA inhibition without compromising InhA activity on its own. Therefore, C10 represents a novel strategy to curtail the development of INH resistance and to sensitize
Mtb
to sub-lethal doses of INH, such as those achieved at the infection site.
Draft genomes of two phylotype I and II
Ralstonia solanacearum
species complex (RSSC) isolates causing bacterial wilt in tomato plants from Costa Rica
Authors: Galiano-Murillo Fiorella , Salas-Lara Vidal , Echandi Carlos , Brenes-Guillén Laura , Uribe-Lorío Lorena
Published: January 2024

Bacteria from RSSC hold agricultural significance as they are the causal agents of bacterial wilt. Here, we report the draft genomes of two bacteria extracted from vascular tissues of infected tomato plants. Isolate RALF-MA was classified as
Ralstonia pseudosolanacearum
(phylotype I) and RALSA-MA as
Ralstonia solanacearum
(phylotype II).
Improving gene set enrichment analysis (GSEA) by using regulation directionality
Authors: Wang Biwen , van der Kloet Frans , Kes Mariah B. M. J. , Luirink Joen , Hamoen Leendert W.
Published: January 2024

To infer the biological meaning from transcriptome data, it is useful to focus on genes that are regulated by the same regulator, i.e., regulons. Unfortunately, current gene set enrichment analysis (GSEA) tools do not consider whether a gene is activated or repressed by a regulator. This distinction is crucial when analyzing regulons since a regulator can work as an activator of certain genes and as a repressor of other genes, yet both sets of genes belong to the same regulon. Therefore, simply averaging expression differences of the genes of such a regulon will not properly reflect the activity of the regulator. What makes it more complicated is the fact that many genes are regulated by different transcription factors, and current transcriptome analysis tools are unable to indicate which regulator is most likely responsible for the observed expression difference of a gene. To address these challenges, we developed the gene set enrichment analysis program GINtool. Additional features of GINtool are novel graphical representations to facilitate the visualization of gene set analyses of transcriptome data, the possibility to include functional categories as gene sets for analysis, and the option to analyze expression differences within operons, which is useful when analyzing prokaryotic transcriptome and also proteome data.

IMPORTANCE

Measuring the activity of all genes in cells is a common way to elucidate the function and regulation of genes. These transcriptome analyses produce large amounts of data since genomes contain thousands of genes. The analysis of these large data sets is challenging. Therefore, we developed a new software tool called GINtool that can facilitate the analysis of transcriptome data by using prior knowledge of gene sets controlled by the same regulator, the so-called regulons. An important novelty of GINtool is that it can take into account the directionality of gene regulation in these analyses, i.e., whether a gene is activated or repressed, which is crucial to assess whether a regulon or functional category is affected. GINtool also includes new graphical methods to facilitate the visual inspection of regulation events in transcriptome data sets. These and additional analysis methods included in GINtool make it a powerful software tool to analyze transcriptome data.
Transverse colon diverticulitis mimicking acute appendicitis
Authors: Vagios Ilias , Vailas Michail , Vergadis Chrysovalantis , Schizas Dimitrios
Published: January 2024

Diverticulitis in a solitary transverse colon diverticulum is uncommon, with only a handful of cases documented in the literature. There are various clinical manifestations of the disease, which make clinical and radiological diagnosis rather challenging. Herein, we present a case of a premenopausal female patient in her late 40s who presented to the emergency department, complaining of right lower quadrant abdominal pain, nausea, anorexia and fever. Following clinical, biochemical and radiological tests, the patient was prepared for surgical operation, with the presumed diagnosis of acute appendicitis. An appendicectomy was planned via a McBurney incision. Notably, no inflammation of the appendix was discovered. However, on further exploration, an inflammatory mass was identified in the transverse colon, which was subsequently excised and sent for histological examination. The histology results confirmed the presence of a ruptured solitary transverse colon diverticulum, accompanied by an adjacent mesenteric abscess. The patient’s postoperative recovery was uneventful.
Multifocal stress fractures in a patient with rheumatoid arthritis
Authors: Tong Edwin Yuen Hao , Jeong Seok Jun , Farook Mohamed Zubair , Volpin Andrea
Published: January 2024

Stress fractures are often associated to activities that requires repetitive stress such as running. However, insufficiency-type stress fractures can also occur in patients with risk factors such as rheumatoid arthritis. Diagnosis of stress fracture would require a thorough clinical evaluation along with radiological imaging. However, this may be difficult due to how it mimics other musculoskeletal problems. The case of a woman in her 60s presenting with 2 months of severe ipsilateral right knee and ankle pain is used as an example. Based on initial clinical assessment and plain radiograph, her provisional diagnosis was osteoarthritis or inflammatory arthritis secondary to rheumatoid disease. However, MRI scan revealed that she had multifocal stress fractures in her knee, ankle and foot. Hence, we hope that this case study can allow clinicians to consider multifocal stress fracture as a possible diagnosis in patients with risk factors and to have lower threshold in performing MRI scans.
Primary small intestine angiosarcoma mimicking Crohn’s disease
Authors: Thaveenthiran Prasanthan , Bae Lily , Wewelwala Chandika , Zhou Kevin
Published: January 2024

A man in his 40s presented to an emergency department after experiencing worsening abdominal pain for 2 days. Contrast-enhanced CT of the abdomen and pelvis revealed circumferential mural thickening and luminal narrowing of the distal ileum and upstream dilatation of the small intestine, indicating small intestine obstruction. This prompted emergency laparotomy, where two lesions in the distal ileum were identified as the source of his bowel obstruction and resected. Immunohistochemistry of the resected segment revealed a primary small intestine angiosarcoma acting positively for vascular markers ERG and CD31. A subsequent positron emission tomography (PET) scan revealed positive mediastinal metastatic lymphadenopathy without organ metastases.

Following his surgery, the patient recovered well and was promptly referred to an oncology unit at a specialised health centre for further treatment. Primary small intestine angiosarcoma is a rare entity in which patients present with non-specific symptoms requiring prompt tissue diagnosis to facilitate multidisciplinary management.
Chorea as an initial and solitary manifestation of systemic lupus erythematosus with antiphospholipid syndrome in an elderly man
Authors: Javed Faiza , Piranavan Paramarajan
Published: January 2024

Chorea can be an initial manifestation of systemic lupus erythematosus (SLE) or antiphospholipid syndrome (APS). It has been mostly described in younger female adults in association with other manifestations of SLE. When chorea appears as an initial and only manifestation in SLE/APS patients, the establishment of the correct diagnosis is difficult, and it may be initially attributed to a more common aetiology. Here we report an elderly man who presented with a new onset of right-sided chorea without other clinical manifestations of SLE/APS. He started on steroids a year later, however, there was no improvement. His chorea was symptomatically managed along with aspirin, and hydroxychloroquine as he refused to be on additional immunosuppression. Anticoagulation was relatively contraindicated, and also not favoured by this patient; therefore, aspirin was initiated. Even in elderly patients, once the common etiologies of chorea have been worked up, we suggest doing a rheumatological evaluation. Early diagnosis and prompt treatment can prevent persistent neurological abnormality.
Exploring malaria prediction models in Togo: a time series forecasting by health district and target group
Authors: Thomas Anne , Bakai Tchaa Abalo , Atcha-Oubou Tinah , Tchadjobo Tchassama , Rabilloud Muriel , Voirin Nicolas
Published: January 2024

Objectives

Integrating malaria prediction models into malaria control strategies can help to anticipate the response to seasonal epidemics. This study aimed to explore the possibility of using routine malaria data and satellite-derived climate data to forecast malaria cases in Togo.

Methods

Generalised additive (mixed) models were developed to forecast the monthly number of malaria cases in 40 health districts and three target groups. Routinely collected malaria data from 2013 to 2016 and meteorological and vegetation data with a time lag of 1 or 2 months were used for model training, while the year 2017 was used for model testing. Two methods for selecting lagged meteorological and environmental variables were compared: a first method based on statistical approach (‘SA’) and a second method based on biological reasoning (‘BR’). Both methods were applied to obtain a model per target group and health district and a mixed model per target group and health region with the health district as a random effect. The predictive skills of the four models were compared for each health district and target group.

Results

The most selected predictors in the models per district for the ‘SA’ method were the normalised difference vegetation index, minimum temperature and mean temperature. The ‘SA’ method provided the most accurate models for the training period, except for some health districts in children ≥5 years old and adults and in pregnant women. The most accurate models for the testing period varied by health district and target group, provided either by the ‘SA’ method or the ‘BR’ method. Despite the development of models with four different approaches, the number of malaria cases was inaccurately forecasted.

Conclusions

These models cannot be used as such in malaria control activities in Togo. The use of finer spatial and temporal scales and non-environmental data could improve malaria prediction.
Patient safety culture and satisfaction in Ghana: a facility-based cross-sectional study
Authors: Botchwey Charles Owusu-Aduomi , Boateng Agartha Afful , Ahimah Patricia Ofori , Acquah Francis , Adoma Prince Owusu , Kumah Emmanuel , Boakye Dorothy Serwaa , Boahen Ebenezer Addae , Kruh Vivian , Koomson Joseph Bob Kow
Published: January 2024

Background

Globally, one of the measures of high performing healthcare facilities is the compliance of patient safety culture, which encompasses the ability of health institutions to avoid or drastically reduce patient harm or risks. These risks or harm is linked with numerous adverse patient outcomes such as medication error, infections, unsafe surgery and diagnosis error.

Objectives

The general objective of this study was to investigate into the impact of patient safety culture practices experienced on patient satisfaction among patients who attend the Kwesimintsim Government Hospital in the Takoradi municipality.

Methods

This study was a descriptive cross-sectional study and a consecutive sampling technique was used to select 336 respondents for the study. Data was collected using a structured questionnaire and processed using Statistical Package for Social Sciences, V.21. Both descriptive and inferential statistics were carried out and result were presented using figures and tables.

Results

The study found that the overall patient safety compliance level observed by the respondents was poor (29.2%). The prevalence of adverse events experienced among the respondents was high (58%). The leading adverse events mentioned were medication errors, followed by wrong prescriptions and infections. The consequences of these adverse events encountered by the respondents were mentioned as increased healthcare costs (52%), followed by hospitalisation (43%), worsening of health conditions (41%) and contraction of chronic health conditions (22%). Patient safety cultural practices such as teamwork (β=0.17, p=0.03), response to error (β=0.16, p=0.005), communication openness (β=0.17, p=0.003) and handoffs and information exchange (β=0.17, p=0.002) were found to positively influence patient satisfaction.

Conclusion

The poor general compliance of the patient safety culture in the facility is unfortunate, and this can affect healthcare outcomes significantly. The study therefore entreats facility managers and various stakeholders to see patient safety care as an imperative approach to delivering quality essential healthcare and to act accordingly to create an environment that supports it.
Development, acceptability and usability of culturally appropriate survivor narrative videos for breast cancer treatment in Botswana: a pilot study
Authors: Martei Yehoda M , Mokokwe Lebogang , Ngwako Ngwao , Kebuang Keaobaka , Setlhako Dipho I , Gabaatlhole Goitsemang , Baaitse Bontswanetse , Segadimo Tumisang , Shulman Lawrence N , Barg Frances , Gaolebale Babe E
Published: January 2024

Objectives

Narrative communication has demonstrated effectiveness in promoting positive health behaviours, delivering support and coping with complex decision-making. Formal research evaluating this intervention for cancer treatment in Africa is lacking. We aimed to develop, and assess acceptability and usability of survivor video narrative interventions for breast cancer treatment in Botswana.

Design

A pilot study design.

Setting

Single-centre, tertiary hospital, sub-Saharan Africa.

Participants

Eight women, ≥18 years old, with stages I–III breast cancer were enrolled for the video intervention. 106 women, ≥18 years old, with stages I–IV breast cancer viewed the narrative videos and 98 completed the acceptability and usability surveys.

Intervention

Survivor narrative videos were developed using the theory of planned behaviour and using a purposive sample of Batswana, Setswana-speaking, breast cancer survivors, who had completed systemic treatment and surgery with high rates of adherence to the prescribed treatment plan.

Primary outcomes

We assessed acceptability and usability among prospectively enrolled patients presenting for routine breast cancer care at Princess Marina Hospital in Botswana, using a 13-item survey.

Results

Participants expressed high acceptability and usability of the videos, including 99% (97/98) who strongly agreed/agreed that the video presentations were easy to understand, 92% (90/98) who would recommend to other survivors and 94% (92/98) who wished there were more videos. Additionally, 89% (87/98) agreed or strongly agreed that the one-on-one instruction on how to use the tablet was helpful and 87% (85/98) that the video player was easy to use.

Conclusion

Culturally appropriate survivor video narratives have high acceptability and usability among patients with breast cancer in Botswana. There is an opportunity to leverage this intervention in routine breast cancer care for treatment support. Future studies will test the implementation and effectiveness of narrative videos on a wider scale, including for patients being treated for other cancers.
Protocol for an evaluation of the initiation of an integrated longitudinal outpatient care model for severe chronic non-communicable diseases (PEN-Plus) at secondary care facilities (district hospitals) in 10 lower-income countries
Authors: Adler Alma J , Wroe Emily B , Atzori Andrea , Bay Neusa , Bekele Wondu , Bhambhani Victoria M , Nkwiro Remy Bitwayiki , Boudreaux Chantelle , Calixte Dawson , Chiwanda Banda Jonathan , Coates Matthew M , Dagnaw Wubaye Walelgne , Domingues Katia , Drown Laura , Dusabeyezu Symaque , Fenelon Darius , Gupta Neil , Ssinabulya Isaac , Jain Yogesh , Kalkonde Yogeshwar , Kamali Innocent , Karekezi Catherine , Karmacharya Biraj Man , Koirala Bhagawan , Makani Julie , Manenti Fabio , Mangwiro Alexio , Manuel Beatriz , Masiye Jones K , Goma Fastone Mathew , Mayige Mary Theodory , McLaughlin Amy , Mensah Emmanuel , Salipa Nicole Mocumbi , Mutagaywa Reuben , Mutengerere Alvern , Ngoga Gedeon , Patiño Marta , Putoto Giovanni , Ruderman Todd , Salvi Devashri , Sesay Santigie , Taero Fameti , Tostão Emílio , Toussaint Sterman , Bukhman Gene , Mocumbi Ana Olga
Published: January 2024

Introduction

The Package of Essential Noncommunicable Disease Interventions—Plus (PEN-Plus) is a strategy decentralising care for severe non-communicable diseases (NCDs) including type 1 diabetes, rheumatic heart disease and sickle cell disease, to increase access to care. In the PEN-Plus model, mid-level clinicians in intermediary facilities in low and lower middle income countries are trained to provide integrated care for conditions where services traditionally were only available at tertiary referral facilities. For the upcoming phase of activities, 18 first-level hospitals in 9 countries and 1 state in India were selected for PEN-Plus expansion and will treat a variety of severe NCDs. Over 3 years, the countries and state are expected to: (1) establish PEN-Plus clinics in one or two district hospitals, (2) support these clinics to mature into training sites in preparation for national or state-level scale-up, and (3) work with the national or state-level stakeholders to describe, measure and advocate for PEN-Plus to support development of a national operational plan for scale-up.

Methods and analysis

Guided by Proctor outcomes for implementation research, we are conducting a mixed-method evaluation consisting of 10 components to understand outcomes in clinical implementation, training and policy development. Data will be collected through a mix of quantitative surveys, routine reporting, routine clinical data and qualitative interviews.

Ethics and dissemination

This protocol has been considered exempt or covered by central and local institutional review boards. Findings will be disseminated throughout the project’s course, including through quarterly M&E discussions, semiannual formative assessments, dashboard mapping of progress, quarterly newsletters, regular feedback loops with national stakeholders and publication in peer-reviewed journals.