bluuebunny/crossref_metadata_2025 huggingface dataset:
Breast Implant Surgery: An Overview of the Risks and Health Complications
Authors: Prothe Jessica , Rozovics Paul , Sykes Robyn , Taccona Michael
Published: March 2023

We present an overview of the risks and health complications associated with breast implant surgery with a focus on breast implant illness (BII), breast implant–associated anaplastic large cell lymphoma (BIA-ALCL), and breast implant–associated squamous cell carcinoma (BIA-SCC). BII is a constellation of systemic symptoms that can occur after breast implant devices are surgically implanted into the human body. BIA-ALCL is a T-cell lymphoma associated with the implantation of textured breast implant devices. BIA-SCC is a potentially aggressive epithelial-based tumor that can occur following implantation with smooth or textured breast implant devices. Nurses may lack awareness and knowledge regarding BII, BIA-ALCL, and BIA-SCC, and this can negatively affect patient safety. Therefore, it is essential that all nurses, especially members of the plastic and aesthetic nursing community, understand these disease processes. Currently, it is not standard practice to screen every patient for the presence of an implantable device at every health care encounter. However, by not doing so, health care professionals may miss the opportunity to identify illness, disease, or cancer that could be related to an implanted device; therefore, practice changes to increase patient safety are both necessary and warranted. To identify those individuals at greatest risk for implant-related illness, disease, or cancer, we propose implementing universal screening of all individuals for implantable devices. We define universal screening for implantable devices as assessing all patients for the presence or absence of an implantable device at every health care encounter. We recommend using the IOWA model to guide our proposed evidence-based practice update.
Prediction of Malignant Thyroid Nodules Using 18F-FDG PET/CT–Based Radiomics Features in Thyroid Incidentalomas
Authors: Ko Woo Seog , Kim Seong-Jang
Published: March 2023

Objective

The purpose of the current study was to evaluate the diagnostic performances of 18F-FDG PET/CT–based radiomics features for prediction of malignant thyroid nodules (TNs) in thyroid incidentaloma (TI).

Methods

PubMed, Cochrane database, and EMBASE database, from the earliest available date of indexing through December 31, 2022, were searched for studies evaluating diagnostic performance of 18F-FDG PET/CT–based radiomics features for prediction of malignant TNs in TI. We determined the sensitivities and specificities across studies, calculated positive and negative likelihood ratios (LRs; positive and negative LRs), and estimated pooled area under the curve.

Results

Across 5 studies (518 patients), the pooled sensitivity of 18F-FDG PET/CT was 0.77 (95% confidence interval [CI], 0.67–0.84), and a pooled specificity was 0.67. Likelihood ratio syntheses gave an overall positive LR of 2.3 (95% CI, 1.5–3.6) and negative LR of 0.35 (95% CI, 0.26–0.47). The pooled diagnostic odds ratio was 7 (95% CI, 4–12). The pooled area under the curve of fixed effects was 0.763 (95% CI, 0.736–0.791), and that of random effects was 0.763 (95% CI, 0.721–0.805).

Conclusion

18F-FDG PET/CT–based radiomics features showed a good diagnostic performance for prediction of malignant TNs in TI.
An insight into seroepidemiology and dynamics of circulating serotypes of Dengue virus over a four year period from western Uttar Pradesh, India
Authors: MUSTAFA ZEESHAN , KHAN HARIS MANZOOR , AZAM MOHD , SAMI HIBA , ALI SYED GHAZANFAR , AHMAD ISLAM , RAZA ADIL , KHAN MOHAMMAD AZAM
Published: March 2023

An important public health problem in India is dengue infection, and every year there is an increase in the number of dengue cases. Dengue affects all individuals irrespective of their gender and age, but still, the infection rate was higher among males and younger ones. Despite low severity in general, the dengue virus can cause severe health conditions in some individuals. Genetic characterization of the circulating endemic dengue virus (DENV) serotypes plays a significant role in establishing epidemiological knowledge and subsequent vaccine development. In the present study over a 4-yr period, we tried to figure out the dengue virus transmission dynamics in major regions of western Uttar Pradesh in North India. ELISA tests were used to diagnose dengue, and PCRs were used to determine the circulating serotype. We found that dengue infection peaks after the rainy season and affects all sexes and ages. A total of 1277 individual are found positive for dengue, among them 61.7% are males and 38.3% are females, DEN-1 was found in 23.12%, DEN-2 in 45%, DEN-3 in 29.06%, and DEN-4 in 1.5% of the dengue infected individuals. All four dengue virus serotypes are circulating in the study area, and dengue virus serotype-2 (DEN-2) is the most prevalent serotype.
Roseobacter insulae sp. nov. and Loktanella gaetbuli sp. nov., isolated from tidal flats in the Yellow Sea in Korea
Authors: Lee Eun Bee , Park Sooyeon , Kim Wonyong , Yoon Jung-Hoon
Published: March 2023

Two bacterial strains (designated as YSTF-M11T and TSTF-M6T) were isolated from tidal flat sediments of the Yellow Sea, Republic of Korea, and taxonomically characterized. A neighbour-joining phylogenetic tree based on 16S rRNA gene sequences showed that strain YSTF-M11T clusters with the type strains of

Roseobacter

species and strain TSTF-M6T clusters with the type strains of

Loktanella salsilacus

,

Loktanella fryxellensis

and

Loktanella atrilutea

. Strains YSTF-M11T and TSTF-M6T exhibited 16S rRNA gene sequence similarity values of 97.5–98.9 % and 94.1–97.2 % to the type strains of four

Roseobacter

species and to the type strains of four

Loktanella

species, respectively. An UBCG tree based on genomic sequences and a tree based on AAI showed that strains YSTF-M11T and TSTF-M6T form a cluster with the type strains of

Roseobacter

species and with the type strains of

L. salsilacus

,

L. fryxellensis

and

L. atrilutea

, respectively. The ANI and dDDH values between genomic sequences of strain YSTF-M11T and the type strains of four

Roseobacter

species and between those of strain TSTF-M6T and the type strains of the three

Loktanella

species were in ranges of 74.0–75.9 and 18.2–19.7 % and 74.7–75.5 and 18.8–19.3 %, respectively. The DNA G+C contents of strains YSTF-M11T and TSTF-M6T were 60.3 and 61.9 % based on their genomic sequences. Both strains contained Q-10 as the predominant ubiquinone and C18 : 1
 ω7c as the major fatty acid. Strains YSTF-M11T and TSTF-M6T were separated from recognized

Roseobacter

species and

L. salsilacus

,

L. fryxellensis

and

L. atrilutea

, respectively, by their phenotypic properties together with the phylogenetic and genetic distinctiveness. Based on data presented in this study, strains YSTF-M11T (=KACC 21642T =NBRC 115155T) and TSTF-M6T (=KACC 21643T =NBRC 115154T) are considered to represent novel species of the genera

Roseobacter

and

Loktanella

, respectively, for which the names Roseobacter insulae sp. nov. and Loktanella gaetbuli sp. nov. are proposed.
Factors Shaping Network Emergence: A Cross-Country Comparison of Quality of Care Networks in Bangladesh, Ethiopia, Malawi, and Uganda
Authors: Shawar Yusra Ribhi , Djellouli Nehla , Akter Kohenour , Payne Will , Kinney Mary , Mwaba Kasonde , Seruwagi Gloria , English Mike , Marchant Tanya ,   The QCN Evaluation Group, Shiffman Jeremy , Colbourn Tim
Published: March 2023

The Quality Care Network (QCN) was conceptualized by the World Health Organisation (WHO) and other global partners to facilitate learning on and improve quality of care for maternal and newborn health within and across low and middle-income countries. However, there was significant variance in the speed and extent in which QCN formed in the involved countries. This paper investigates the factors that shaped QCN’s differential emergence in Bangladesh, Ethiopia, Malawi, and Uganda. Drawing on network scholarship, we conducted a replicated case study of the four country cases and triangulated several sources of data, including a document review, observations of national-level and district level meetings, and key informant interviews in each country and at the global level. Thematic coding was performed in NVivo 12. We find that QCN emerged most quickly and robustly in Bangladesh, followed by Ethiopia, then Uganda, and slowest and with least institutionalization in Malawi. Factors connected to the policy environment and network features explained variance in network emergence. With respect to the policy environment, pre-existing resources and initiatives dedicated to maternal and newborn health (MNH) and quality improvement, strong data and health system capacity, and national commitment to advancing on synergistic goals were crucial drivers to QCN’s emergence. With respect to the features of the network itself, the embedding of QCN leadership in powerful agencies with pre-existing coordination structures and trusting relationships with key stakeholders, inclusive network membership, and effective individual national and local leadership were also crucial in explaining QCN’s speed and quality of emergence across countries. Studying QCN emergence provides critical insights as to why some well- intentioned top-down global health networks don’t materialize in some country contexts and have relatively quick uptake in others, and has implications for a network’s perceived legitimacy and ultimate effectiveness in producing stated objectives.
Natural antibodies as “eat-me” signals for phagocytosis of necrotic cell debris at sites of tissue injury
Authors: Mattos Matheus Silvério , Vandendriessche Sofie , Schuermans Sara , Feyaerts Lars , Hövelmeyer Nadine , Waisman Ari , Marques Pedro Elias
Published: March 2023

Natural antibodies (NAbs) are circulating polyreactive immunoglobulins that bind endogenous and exogenous antigens. Here, we investigated the role of NAbs in driving the clearance of necrotic cell debris from injury sites. Using mouse models of liver injury, we observed that IgM and IgG NAbs opsonize necrotic debrisin vivoby recognizing common self-molecules such as histones, actin, phosphoinositides and cardiolipin, but not phosphatidylserine. Importantly, mice lacking NAbs presented impaired recovery from liver injury, which was correlated to sustained presence of necrotic debris in the tissue, prolonged inflammation and reduced hepatocellular proliferation. Mechanistically, necrotic debris phagocytosis was dependent on NAbsin vitroandin vivo, and restitution with total immunoglobulins rescued the defective recovery from liver injury in immunodeficient mice. In summary, we showed that NAbs opsonize necrotic cell debris and act as “eat-me” signals for engulfment through FcγRs and CD11b, driving the recovery from tissue injury.

Highlights

Natural antibodies opsonize exposed self-antigens upon necrotic cell death.

The phagocytosis of necrotic cell debris requires natural antibodies, FcγRs and CD11b.

Natural antibodies drive cellular proliferation and tissue regeneration after liver injury.

Treatment with natural antibodies improves the recovery from liver injury in both immunodeficient and immunocompetent mice.

Graphical abstract
An atlas and database of neuropeptide gene expression in the adult zebrafish forebrain
Authors: Hiraki-Kajiyama Towako , Miyasaka Nobuhiko , Ando Reiko , Wakisaka Noriko , Itoga Hiroya , Onami Shuichi , Yoshihara Yoshihiro
Published: March 2023

Zebrafish is a useful model organism in neuroscience; however, its gene expression atlas in the adult brain is not well developed. In the present study, we examined the expression of 38 neuropeptides, and glutamatergic neuron marker gene mix (slc17a6a, slc17a6b, slc17a7a,andslc17a7b) in the adult zebrafish brain usingin situhybridization. The results are summarized as an expression atlas in 19 coronal planes of the forebrain. Furthermore, the scan data of all sections were made publicly available as a database. Based on these data, we performed detailed neuroanatomical analyses of the hypothalamus. By scrutinizing and comparing the expression patterns of neuropeptides, we found that several regions described as one nucleus in the reference zebrafish brain atlas contain two or more subregions with significantly different neuropeptide/neurotransmitter expression profiles, and we proposed them as novel subnuclei. Subsequently, the expression data obtained in this study were compared with those in mice, and a cluster analysis was performed to examine the similarities. As a result, several nuclei in zebrafish and mice were clustered in close vicinity: zebrafish ventral part of the anterior part of the parvocellular preoptic nucleus (PPav)/magnocellular preoptic nucleus (PM) and mouse paraventricular hypothalamic nucleus (Pa), zebrafish posterior part of the parvocellular preoptic nucleus (PPp) and mouse medial preoptic area (MPA), zebrafish dorsal part of the ventral zone of periventricular hypothalamus (Hvd)/anterior tuberal nucleus (ATN) and mouse ventromedial hypothalamic nucleus (VMN). The present expression atlas, database, and anatomical findings will contribute to future neuroscientific research using zebrafish.

Key points

The expression of 38 neuropeptides and GABAergic/glutamatergic neuronal marker genes in adult zebrafish forebrain was examined and compiled as an atlas.

All scanned brain section data were published as a database.

Based on the expression data obtained, multiple subnuclei in the zebrafish hypothalamus were proposed, and comparisons with the mouse hypothalamus were conducted.
Colocalization of blood cell traits GWAS associations and variation in PU.1 genomic occupancy prioritizes causal noncoding regulatory variants
Authors: Jeong Raehoon , Bulyk Martha L.
Published: March 2023

Genome-wide association studies (GWAS) have uncovered numerous trait-associated loci across the human genome, most of which are located in noncoding regions, making interpretations difficult. Moreover, causal variants are hard to statistically fine-map at many loci because of widespread linkage disequilibrium. To address this challenge, we present a strategy utilizing transcription factor (TF) binding quantitative trait loci (bQTLs) for colocalization analysis to identify trait associations likely mediated by TF occupancy variation and to pinpoint likely causal variants using motif scores. We applied this approach to PU.1 bQTLs in lymphoblastoid cell lines and blood cell traits GWAS data. Colocalization analysis revealed 69 blood cell trait GWAS loci putatively driven by PU.1 occupancy variation. We nominate PU.1 motif-altering variants as the likely shared causal variants at 51 loci. Such integration of TF bQTL data with other GWAS data may reveal transcriptional regulatory mechanisms and causal noncoding variants underlying additional complex traits.
Caenorhabditis elegansSEL-5/AAK1 regulates cell migration and cell outgrowth independently of its kinase activity
Authors: Knop Filip , Zounarová Apolena , Šabata Vojtěch , Middelkoop Teije Corneel , Macůrková Marie
Published: March 2023

DuringCaenorhabditis elegansdevelopment multiple cells migrate long distances or extend processes to reach their final position and/or attain proper shape. Wnt signalling pathway stands out as one of the major coordinators of cell migration or cell outgrowth along the anterior-posterior body axis. Wnt signalling outcome is fine-tuned by various mechanisms including endocytosis. In this study, we show that SEL-5, theC. elegansorthologue of mammalian AP2-associated kinase AAK1, acts together with the retromer complex as a positive regulator of EGL-20/Wnt signalling during the migration of QL neuroblast daughter cells. At the same time, SEL-5 in cooperation with the retromer complex is also required during excretory canal cell outgrowth. Importantly, SEL-5 kinase activity is not required for its role in either neuronal migration or excretory cell outgrowth and neither of these processes is dependent on DPY-23/AP2M1 phosphorylation. We further establish that Wnt proteins CWN-1 and CWN-2 together with Frizzled receptor CFZ-2 positively regulate excretory cell outgrowth, while LIN-44/Wnt and LIN-17/Frizzled together generate a stop signal inhibiting its extension.
Plant cellulose synthase membrane protein isolation directly fromPichia pastorisprotoplasts, liposome reconstitution, and its enzymatic characterization
Authors: Jayachandran Dharanidaran , Banerjee Shoili , Chundawat Shishir P. S.
Published: March 2023

The most abundant renewable biopolymer on earth, viz., cellulose, acts as carbon storage reserve in plant and microbial cell walls that could potentially be converted into biofuels or other valuable bioproducts. Cellulose is synthesized by a plant cell membrane-integrated processive glycosyltransferase (GT) called cellulose synthase (CesA). Since only a few of these plant CesAs have been purified and characterized to date, there are huge gaps in our mechanistic understanding of these enzymes. Furthermore, the coordination between different CesAs involved in primary and secondary cell wall formation is yet to be unveiled. The biochemistry and structural biology studies of CesAs are currently hampered by challenges associated with their expression and extraction at high yields. To aid in understanding CesA reaction mechanisms and to provide a more efficient CesA extraction method, two putative plant CesAs – PpCesA5 fromPhyscomitrella patensand PttCesA8 fromPopulus tremula x tremuloidesthat are involved in primary and secondary cell wall formation in plants were expressed usingPichia pastorisas an expression host. We developed a protoplast-based membrane protein extraction approach to directly isolate both these membrane-bound enzymes for purification, as detected by immunoblotting and mass spectrometry-based analyses. Our method results in a higher purified protein yield by 3-4-fold than the standard cell homogenization protocol. Our purified CesAs were reconstituted into liposomes to yield active enzymes that gave similar biochemical characteristics (e.g., substrate utilization and cofactor requirements, no primer needed to initiate polymerization reaction) as enzymes isolated using the standard protocol. This method resulted in reconstituted CesA5 and CesA8 with similar Michaelis-Menten kinetic constants, Km= 167 μM, 108 μM and Vmax= 7.88×10−5μmol/min, 4.31×10−5μmol/min, respectively, in concurrence with the previous studies. Taken together, these results suggest that CesAs involved in primary and secondary cell wall formation can be expressed and purified using a simple and more efficient extraction method. This could potentially help unravel the mechanism of native and engineered cellulose synthase complexes involved in plant cell wall biosynthesis.
A method to improve the reproducibility of findings from epigenome- and transcriptome-wide association studies
Authors: van den Oord Edwin JCG , Guintivano Jerry D , Aberg Karolina A.
Published: March 2023

Reproducibility is a cornerstone of scientific progress. In epigenome- and transcriptome-wide association studies (E/TWAS) failure to reproduce may be the result of false discoveries. Whereas multiple methods exist to control false discoveries due to sampling error, minimizing false discoveries due to outliers and other data artefacts remains challenging. We propose a robust E/TWAS approach that outperforms alternative methods to improve reproducibility such as split-half replication. Furthermore, robust E/TWAS results in only a minor loss of power if there are no outliers and can in the presence of outliers, likely a more realistic scenario, even be more powerful than regular E/TWAS.
Structural Covariance of the Duplicated Heschl’s Gyrus: A Sulcal/Gyral Template Morphology Approach
Authors: Eckert Mark A. ,   Dyslexia Data Consortium
Published: March 2023

Heschl’s gyrus (HG) can occur as a single gyrus or with a completely duplicated posterior HG that has been related to a variety of abilities and disorders. Voxel-based studies typically involve the normalization of these qualitatively different HG types, thus making it difficult to evaluate the contribution of sulcal/gyral variability to voxel-based effects and perhaps obscuring some effects. To examine the structural covariance of single and duplicated HG, templates were created for the left single and duplicated HG. Structural covariance analysis with a Jacobian measure of volumetric displacement demonstrated consistent spatial covariance with homologous structure in the right hemisphere across qualitatively different HG morphology. These results suggest that HG duplication is aptly named with respect to cortical structure variation and demonstrate a multi-template approach for studying qualitatively unique brain function and structure linked to perceptual and cognitive functions.

Highlights

Qualitatively unique sulcal/gyral features can affect voxel-based analyses.

Heschl’s gyrus is highly variable across people.

Morphology-specific templates were created to study Heschl’s gyrus structural covariance.

Single and duplicated Heschl’s gyrus exhibited a similar pattern of covariance.
Feature-specific salience maps in human cortex
Authors: Thayer Daniel D. , Sprague Thomas C.
Published: March 2023

Priority maps are representations of visual space that determine the relative importance of scene locations. Computational theories suggest that priority maps identify salient locations based on individual feature dimensions (e.g., color, motion), which are integrated into an aggregate priority map. While widely accepted, a core assumption of this framework—the existence of independent feature dimension maps in visual cortex—remains untested. Here, we tested the hypothesis that feature-selective retinotopic regions in human cortex act as neural feature dimension maps, indexing salience based on their preferred feature. We used fMRI activation patterns to reconstruct spatial maps while participants viewed stimuli with salient regions defined by color or motion direction. Reconstructed spatial maps selectively represented salient locations defined by each region’s preferred feature. These findings identify spatially organized feature dimension maps that characterize the salience of scene locations based on a specific visual feature, confirming a key prediction of priority map theory.
Kaposi’s sarcoma-associated herpesvirus ORF67.5 functions as a component of the terminase complex
Authors: Iwaisako Yuki , Watanabe Tadashi , Suzuki Youichi , Nakano Takashi , Fujimuro Masahiro
Published: March 2023

Kaposi’s sarcoma-associated herpesvirus (KSHV) is a double-stranded DNA gammaherpesvirus, with a poorly characterized lytic replication cycle. However, the lytic replication cycle of the alpha- and betaherpesviruses are well characterized. During lytic infection of alpha- and betaherpesviruses, the viral genome is replicated as a precursor form, which contains tandem genomes linked via terminal repeats (TRs). One genomic unit of the precursor form is packaged into a capsid and is cleaved at the TR by the terminase complex. While the alpha- and betaherpesvirus terminases are well characterized, the KSHV terminase remains poorly understood. KSHV ORF7, ORF29, and ORF67.5 are presumed to be components of the terminase complex based on their homology to other terminase proteins. We previously reported that ORF7-deficient KSHV formed numerous immature soccer ball-like capsids and failed to cleave the TRs. ORF7 interacted with ORF29 and ORF67.5, however ORF29 and ORF67.5 did not interact with each other. While these results suggested that ORF7 is important for KSHV terminase function and capsid formation, the function of ORF67.5 was completely unknown. Therefore, to analyze the function of ORF67.5, we constructed ORF67.5-deficient BAC16. ORF67.5-deficient KSHV failed to produce infectious virus, failed to cleave the TRs, and numerous soccer ball-like capsids were observed in ORF67.5-deficient KSHV-harboring cells. Furthermore, ORF67.5 promoted the interaction between ORF7 and ORF29, and ORF29 increased the interaction between ORF67.5 and ORF7. Thus, our data indicated that ORF67.5 functions as a component of the KSHV terminase complex by contributing to TR cleavage, terminase complex formation, capsid formation, and virus production.

IMPORTANCE

Although the formation and function of the alpha- and betaherpesvirus terminase complexes are well understood, the KSHV terminase complex is still largely uncharacterized. This complex presumably contains KSHV ORF7, ORF29, and ORF67.5. We were the first to report the presence of soccer ball-like capsids in ORF7-deficient KSHV-harboring lytic-induced cells. Here, we demonstrated that ORF67.5-deficient KSHV also formed the soccer ball-like capsids in lytic-induced cells. Moreover, ORF67.5 was required for TR cleavage, infectious virus production, and enhancement of the interaction between ORF7 and ORF29. ORF67.5 has several highly conserved regions among its human herpesviral homologs. These regions were necessary for virus production and for the interaction of ORF67.5 with ORF7, which was supported by the AI-predicted structure model. Importantly, our results provide the first evidence showing that ORF67.5 is essential for terminase complex formation and TR cleavage.
Auditory Complications among Childhood Cancer Survivors and Health-related Quality of Life: A PanCareLIFE study
Authors: Strebel Sven , Baust Katja , Grabow Desiree , Byrne Julianne , Langer Thorsten , Zehnhoff-Dinnesen Antoinette am , Kuonen Rahel , Weiss Annette , Kepak Tomas , Kruseova Jarmila , Berger Claire , Calaminus Gabriele , Sommer Grit , Kuehni Claudia E.
Published: March 2023

Auditory complications are potential side effects from childhood cancer treatment. Yet, limited evidence exists about the impact of auditory complications—particularly tinnitus—on health-related quality of life (HRQoL) among childhood cancer survivors (CCS). We determined the prevalence of hearing loss and tinnitus in the large European PanCareLIFE cohort of CCS and examined its effect on HRQoL. We included CCS from four European countries who were diagnosed at age ≤ 18 years; survived ≥ 5 years; and aged 25–44 years at study. We assessed HRQoL (Short Form 36), hearing loss, and tinnitus using questionnaires. We used multivariable linear regression to examine associations between these two auditory complications and HRQoL adjusting for socio-demographic and clinical factors. Our study population consisted of 6,318 CCS (53% female; median age at cancer diagnosis 9 years interquartile range [IQR] 5–13 years) with median age at survey of 31 years (IQR 28–35 years). Prevalence was 7.5% (confidence interval [CI]: 6.9–8.2) for hearing loss and 7.6% (CI: 6.4–9.0) for tinnitus. CCS with hearing loss had impaired physical (coefficient [coef.] - 4.3, CI: -7.0 to -1.6) and mental (coef. -3.2, CI: -5.5 to -0.8) HRQoL when compared with CCS with normal hearing. Tinnitus was also associated with impaired physical (coef. -8.2, CI: -11.8 to -4.7) and mental (coef. -5.9, CI: -8.8 to -3.1) HRQoL. We observed the lowest HRQoL among CCS with both hearing loss and tinnitus. Our findings indicate timely treatment of hearing loss and tinnitus may contribute to quality of life of survivors.
Viral and Host Mediators of Non-Suppressible HIV-1 Viremia
Authors: Mohammadi Abbas , Etemad Behzad , Zhang Xin , Li Yijia , Bedwell Gregory J. , Sharaf Radwa , Kittilson Autumn , Melberg Meghan , Wong Colline , Fajnzylber Jesse , Worrall Daniel P. , Rosenthal Alex , Jordan Hannah , Jilg Nikolaus , Kaseke Clarety , Giguel Francoise , Lian Xiaodong , Deo Rinki , Gillespie Elisabeth , Chishti Rida , Abrha Sara , Adams Taylor , Siagian Abigail , Anderson Peter L. , Deeks Steven G. , Lederman Michael M. , Yawetz Sigal , Kuritzkes Daniel R. , Lichterfeld Mathias D. , Tsibris Athe , Carrington Mary , Brumme Zabrina L. , Castillo-Mancilla Jose R. , Engelman Alan N. , Gaiha Gaurav D. , Li Jonathan Z.
Published: March 2023

Non-suppressible HIV-1 viremia (NSV) can occur in persons with HIV despite adherence to combination antiretroviral therapy (ART) and in the absence of significant drug resistance. Here, we show that plasma NSV sequences are comprised primarily of large clones without evidence of viral evolution over time. We defined proviruses that contribute to plasma viremia as “producer”, and those that did not as “non-producer”. Compared to ART-suppressed individuals, NSV participants had a significantly larger producer reservoir. Producer proviruses were enriched in chromosome 19 and in proximity to the activating H3K36me3 epigenetic mark. CD4+cells from NSV participants demonstrated upregulation of anti-apoptotic genes and downregulation of pro-apoptotic and type I/II interferon-related pathways. Furthermore, NSV participants showed no elevation in HIV-specific CD8+cell responses and producer proviruses were enriched for HLA escape mutations. We identified critical host and viral mediators of NSV that represent potential targets to disrupt HIV persistence and promote viral silencing.
Participant perspectives to improve tenofovir adherence in the prevention of mother-to-child transmission of hepatitis B virus in Kinshasa, DRC
Authors: Morgan Camille E , Thahir Sahal , Ngimbi Patrick , Mwandagalirwa Kashamuka , Ntambua Sarah , Matondo Jolie , Tabala Martine , Mbendi Nlombi Charles , Kaba Didine , Yotebieng Marcel , Parr Jonathan , Banek Kristin , Thompson Peyton
Published: March 2023

Prevention of mother-to-child transmission (PMTCT) programs for hepatitis B virus (HBV) are critical to reach the World Health Organization's 2030 HBV elimination goals. Despite demonstrated feasibility utilizing HIV infrastructure, HBV PMTCT programs are not implemented in many African settings, including in the Democratic Republic of Congo (DRC). In a previous pilot of HBV PMTCT implementation in DRC's capital, Kinshasa, we observed low TDF metabolite levels at delivery among women with high-risk HBV who were given tenofovir disoproxil fumarate (TDF) antiviral therapy. As such, we conducted qualitative interviews with women who received TDF to understand facilitators and barriers of medication adherence. We used a modified Information-Motivation-Behavioral Skills model (IMB+) as a framework for thematic content analysis. We found that trust in healthcare workers, familial support, and improved awareness of the disease and treatment options were important facilitators of TDF adherence; pill size, social stigma, and low HBV knowledge were barriers to adherence. While overall acceptance of TDF was high in this pilot, improved TDF adherence is needed in order to reach efficacious levels for preventing transmission from mothers to newborns. We suggest ongoing HBV sensitization within existing maternity and HIV care infrastructure would address gaps in knowledge and stigma identified here. Additionally, given the trust women have towards maternity center staff and volunteers, scaled HBV PMTCT interventions should include specific sensitization and education for healthcare affiliates, who currently receive no HBV prevention or information in DRC. This study is timely as TDF, particularly future long-acting formulations, could be considered as an alternate rather than adjuvant to birth-dose vaccination for HBV PMTCT in sub-Saharan Africa.
Tumor-specific activity of precision medicines in the NCI-MATCH trial
Authors: Zhou Ivvone , Plana Deborah , Palmer Adam C.
Published: March 2023

Structured Abstract

Background

NCI-MATCH is a precision medicine basket trial designed to test the effectiveness of treating cancers based on specific genetic changes in patients’ tumors, regardless of cancer type. Multiple subprotocols have each tested different targeted therapies matched to specific genetic aberrations. Most subprotocols exhibited low rates of tumor shrinkage as evaluated across all tumor types enrolled. We hypothesized that these results may arise because these precision cancer therapies have tumor type-specific efficacy, as is common among other cancer therapies.

Methods

To test the hypothesis that certain tumor types are more sensitive to specific therapies than other tumor types, we applied permutation testing to tumor volume change and progression-free survival data from ten published NCI-MATCH subprotocols (together n=435 patients). False discovery rate was controlled by the Benjamini-Hochberg procedure.

Results

Six of ten subprotocols exhibited statistically significant evidence of tumor-specific drug sensitivity, four of which were previously considered negative based on response rate across all tumors. This signal-finding analysis highlights potential uses of FGFR tyrosine kinase inhibition in urothelial carcinomas with actionableFGFRaberrations, MEK inhibition in lung cancers withBRAFnon-V600Emutations, and MEK inhibition in cholangiocarcinomas withNRASmutations.

Conclusions

These findings support the value of basket trials because even when precision medicines do not have tumor-agnostic activity, basket trials can identify tumor-specific activity for future study.
The Role of Sacubitril/Valsartan and Gliflozins in Heart Failure with Reduced Ejection Fraction after Cardiac Resynchronization Therapy
Authors: Fonderico Celeste , Pergola Valerio , Faccenda Daniele , Comparone Gianluigi , Marrese Aldo , Salucci Alfonsomaria , Ammirati Giuseppe , Cocchiara Luigi , Varriale Alfonso , Esposito Giovanni , Rapacciuolo Antonio , Strisciuglio Teresa
Published: March 2023

BACKGROUND

The angiotensin receptor-neprilysin inhibitor (ARNi) and the sodium- glucose co-transporter 2 inhibitors (SGLT2i) have improved the outcome of patients with heart failure and reduced ejection fraction (HFrEF). However, data characterizing their effectiveness after cardiac resynchronization therapy (CRT) implant are relatively scarce. This study investigated the impact of ARNi and SGLT2i treatment 1) on CRT response at 12 months 2) on the cardiac function and the clinical functional status (NYHA class) at mid- and long-term follow-up 3) on the cardiac and overall survival at long-term follow-up.

METHODS AND RESULTS

HFrEF patients referred for CRT implant were enrolled in the study and were grouped by the ARNi/SGLT2i therapy. A first analysis investigated the synergistic impact of these drugs started at implant on 1-year CRT response and included all 172 patients enrolled. In order to evaluate whether the time of ARNi/SGLT2i initiation after CRT response assessment is meaningful, a second analysis considered 100 patients with a follow-up ≥ 24 months. The median follow-up was 63.1 (confidence interval [CI] 95%, 52.7 - 73.8) months.

At 1-year follow-up, 40 of 51 (78.4%) patients in ARNi or SGLT2i group and 66 of 121 (54.5%) in the no treatment group were classified as responders (p = 0.006). In multivariable analysis, ARNi/SGLT2i use was an independent predictor of CRT response (odds ratio, 5.38; CI 95%, 2-16.2; p = 0.001). At mid-term follow-up (median time [interquartile range, IQR] 40.6 [25.2; 58.3] months), 61 patients started to assume these drugs. NYHA functional class improved in 23 (37.7%) patients and decreased in only 2 (3.3%) in ARNi/SGLT2i patients vs 13 (33.3%) in no treatment group (p < 0.001). ARNi and SGLT2i improved significantly also the Δ LVEF, with a median [IQR] increase of 4 [2; 8] % compared to the no treatment group - 1.8 [-4; 0.2] % (p < 0.001) and were independently associated with a NYHA functional class II or I at long-term (hazard ratio [HR], 3.67; CI 95%, 1.37-10.2; p < 0.001). Their estimated effectiveness was consistent over the entire follow-up period (Schoenfeld residuals test, p = 0.10), although without reaching statistical significance effects on cardiovascular survival (HR, 0.61; CI 95%, 0.25-1.50; p = 0.22).

CONCLUSIONS

The ARNi and SGLT2i treatment in CRT patients improves the clinical and echocardiographic response at 12-month and long-term follow-up, independently from the time of initiation. These drugs also confer benefit on survival, however further studies are needed to confirm these data.
Deep Learning using Susceptibility-Weighted MR Sequence to Detect Microbleeds and Classify Cerebral Small Vessel Disease
Authors: Wu Ruizhen , Liu Huaqing , Li Hao , Chen Lifen , Wei Lei , Huang Xuehong , Liu Xu , Men Xuejiao , Li Xidan , Han Lanqing , Lu Zhengqi , Qin Bing
Published: March 2023

Background

Microbleeds (CMBs) serve as neuroimaging biomarkers to assess risk of intracerebral hemorrhage and diagnose cerebral small vessel disease (CSVD). Therefore, detecting CMBs can evaluate the risk of intracerebral hemorrhage and use its presence to support CSVD classification, both are conducive to optimizing CSVD management. This study aimed to develop and test a deep learning (DL) model based on susceptibility-weighted MR sequence (SWS) to detect CMBs and classify CSVD to assist neurologists in optimizing CSVD management.

Methods

Patients with arteriolosclerosis (aSVD), cerebral amyloid angiopathy (CAA), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) treated at three centers were enrolled between January 2017 and May 2022 in this retrospective study. The SWSs of patients from two centers were used as the development set, and the SWSs of patients from the remaining center were used as the external test set. The DL model contains a Mask R-CNN for detecting CMBs and a multi-instance learning (MIL) network for classifying CSVD. The metrics for model performance included intersection over union (IoU), Dice score, recall, confusion matrices, receiver operating characteristic curve (ROC) analysis, accuracy, precision, and F1-score.

Results

A total of 364 SWS were recruited, including 336 in the development set and 28 in the external test set. IoU for the model was 0.523 ± 0.319, Dice score 0.627 ± 0.296, and recall 0.706 ± 0.365 for CMBs detection in the external test set. For CSVD classification, the model achieved a weighted-average AUC of 0.908 (95% CI: 0.895-0.921), accuracy of 0.819 (95% CI: 0.768-0.870), weighted-average precision of 0.864 (95% CI: 0.831-0.897), and weighted-average F1-score of 0.829 (95% CI: 0.782-0.876) in the external set, outperforming the performance of the neurologist group.

Conclusion

The DL model based on SWS can detect CMBs and classify CSVD, thereby assisting neurologists in optimizing CSVD management.
ThePlasmodium falciparumartemisinin resistance-associated protein Kelch 13 is required for formation of normal cytostomes
Authors: Tutor Madel V. , Shami Gerald J. , Siddiqui Ghizal , Creek Darren J. , Tilley Leann , Ralph Stuart A.
Published: March 2023

Artemisinin (ART) is a quick-killing and effective antimalarial activated by the haem derived from haemoglobin digestion. Mutations in the parasite’s Kelch 13 (K13) protein compromise the efficacy of this drug. Recent studies indicate an undefined role for K13 in haemoglobin uptake. Here, we show that K13 is associated with the collar that constricts cytostomal invaginations required for the parasite to ingest host cytosol. Induced mislocalisation of K13 led to the formation of atypical invaginations lacking the cytostomal ring and constricted neck normally associated with cytostomes. Moreover, the levels of haemoglobin degradation products, haem and haemozoin, are decreased when K13 is inactivated. Our findings demonstrate that K13 is required for normal formation and/or stabilisation of the cytostome, and thereby the parasite’s uptake of haemoglobin. This is consistent with perturbation of K13 function leading to decreased activation of ART and consequently, reduced killing.

Significance Statement

Artemisinin-resistant parasites contain mutations in the gene encoding the Kelch 13 protein (K13). How K13 mutations result in artemisinin resistance is unclear. Here, we present evidence that normal K13 is required for the formation of the cytostome, a specialised parasite feeding apparatus used to endocytose host cell haemoglobin. Our results suggest that artemisinin resistance is due to a decrease in artemisinin activation brought about by a decrease in efficiency of haemoglobin uptake and consequently reduced production of haem.
Medial Prefrontal Cortex Serotonin Input Regulates Cognitive Flexibility in Mice
Authors: Morgan Ashlea A. , Alves Nuno D. , Stevens Gregory S. , Yeasmin Tamanna T. , Mackay Alexandra , Power Saige , Sargin Derya , Hanna Carla , Adib Arwa L. , Ziolkowski-Blake Annette , Lambe Evelyn K. , Ansorge Mark S.
Published: March 2023

The medial prefrontal cortex (mPFC) regulates cognitive flexibility and emotional behavior. Neurons that release serotonin project to the mPFC, and serotonergic drugs influence emotion and cognition. Yet, the specific roles of endogenous serotonin release in the mPFC on neurophysiology and behavior are unknown. We show that axonal serotonin release in the mPFC directly inhibits the major mPFC output neurons. In serotonergic neurons projecting from the dorsal raphe to the mPFC, we find endogenous activity signatures pre-reward retrieval and at reward retrieval during a cognitive flexibility task.In vivooptogenetic activation of this pathway during pre-reward retrieval selectively improved extradimensional rule shift performance while inhibition impaired it, demonstrating sufficiency and necessity for mPFC serotonin release in cognitive flexibility. Locomotor activity and anxiety-like behavior were not affected by either optogenetic manipulation. Collectively, our data reveal a powerful and specific modulatory role of endogenous serotonin release from dorsal raphe-to-mPFC projecting neurons in cognitive flexibility.
Adaptation mechanisms ofListeria monocytogenesto quaternary ammonium compounds
Authors: Schulz Lisa Maria , Dreier Fabienne , de Sousa Miranda Lisa Marie , Rismondo Jeanine
Published: March 2023

Listeria monocytogenesis ubiquitously found in nature and can easily enter food-processing facilities due to contaminations of raw materials. Several countermeasures are used to combat contamination of food products, for instance the use of disinfectants that contain quaternary ammonium compounds, such as benzalkonium chloride (BAC) and cetyltrimethylammonium bromide (CTAB). In this study, we assessed the potential of the commonly used wildtype strain EGD-e to adapt to BAC and CTAB under laboratory growth conditions. All BAC-tolerant suppressors exclusively carried mutations infepRor its promoter region likely resulting in the overproduction of the efflux pump FepA. In contrast, CTAB- tolerance was associated with mutations insugR, which regulates the expression of the efflux pumps SugE1 and SugE2.L. monocytogenesstrains lacking either FepA or SugE1/2 could still acquire tolerance towards BAC and CTAB. Genomic analysis revealed that the overproduction of the remaining efflux system could compensate for the deleted one. Even in the absence of both efflux systems, tolerant strains could be isolated, which all carried mutations in the diacylglycerol kinase encoding genelmo1753(dgkB). DgkB converts diacylglycerol to phosphatidic acid, which is subsequently re-used for the synthesis of phospholipids suggesting that alterations in membrane composition could be the third adaptation mechanism.

Originality-Significance Statement

Survival and proliferation ofListeria monocytogenesin the food industry is an ongoing concern, and while there are various countermeasures to combat contamination of food products, the pathogen still successfully manages to withstand the harsh conditions present in food-processing facilities, resulting in reoccurring outbreaks, subsequent infection, and disease. To counteract the spread ofL. monocytogenesit is crucial to understand and elucidate the underlying mechanism that permit their successful evasion. We here present various adaptation mechanisms ofL. monocytogenesto withstand two important quaternary ammonium compounds.
Specificity and mechanism of 1,6 hexanediol-induced disruption of nuclear transport
Authors: Barrientos Elizabeth C. Riquelme , Otto Tegan A. , Mouton Sara N. , Steen Anton , Veenhoff Liesbeth M.
Published: March 2023

Selective transport through the nuclear pore complex (NPC) depends on the dynamic binding of the intrinsically disordered components of the NPC, the FG-nups, with each other and with nuclear transport receptors (NTRs). Hydrophobic interactions with the phenylalanines of FG-nups are critical for this dynamic binding. 1,6-hexanediol (1,6HD), is an aliphatic alcohol that interferes with hydrophobic interactions. Here we assessed the specificity and mechanism by which 1,6HD disrupts the permeability barrier of NPCs in live baker’s yeast cells. Exposure to 1,6HD (10 min, 0-5%) leads to gradual loss of the NPC permeability. This is likely a direct effect on the nuclear transport machinery as cell viability, the pH and ATP levels in the cytosol, as well as the appearance of mitochondria, Golgi, peroxisomes, ER, vacuoles, plasma membrane, nucleolus, secretory pathway and stress granules are not notably changed. There are however effects on the cytoskeleton and Hsp104 to be noted. While 1,6HD treatment does not lead to dissociation or degradation of NPC subunits, a massive relocation of multiple NTRs from NPCs does occur. This displacement quantitatively correlates with the increased passive permeability of NPCs. The loss of NTRs and associated cargo will present a major change in the macromolecular crowding and composition and hence the physicochemical properties of the central channel. We conclude that 1,6HD provides a surprisingly specific intervention to temporarily permeate NPCs and we present evidence that the mechanism includes release of NTRs from the NPCs.
Structural basis for activation of glutaminase
Authors: Guo Chen-Jun , Wang Zi-Xuan , Liu Ji-Long
Published: March 2023

Glutaminase is a rate-limiting enzyme in glutaminolysis, which produces glutamate from glutamine and enters the TCA cycle[1]. In addition, it plays a key role in redox homeostasis[2], autophagy[3], immune system regulation[4], central nervous system maintenance[5], and senolysis[6]. Therefore, the allosteric regulation of glutaminase is a fascinating topic that has broad implications for our understanding of glutamine metabolism and related diseases[7–9]. Phosphate was discovered as a natural agonist for glutaminase in 1947[10], but the structural basis and mechanism for this regulation remains unclear. Using cryo-electron microscopy, here we determine the structure of human glutaminase with phosphate. This structure allows us to capture phosphate binding at the dimer-dimer interface at near atomic resolution, revealing an allosteric activation mechanism by remodelling the catalytic pocket. Surprisingly, we find that phosphate antagonizes BPTES (a classical antagonist) and CB-839 (the current subject of several phase II clinical trials). Accurate identification of phosphate binding sites lays the foundation for the design of glutaminase agonists and antagonists with broad pharmaceutical significance.