bluuebunny/crossref_metadata_2025 huggingface dataset:
P226 Malassezia hyphae play possible roles in the pathogenesis of androgenetic alopecia
Authors: Li Juanjuan , Shi Leyao , Shi Dongmei
Published: September 2022

Poster session 2, September 22, 2022, 12:30 PM - 1:30 PM

 

Background

Androgenetic alopecia (AGA) is the most common type of hair loss that seriously affects the appearance and psychology of patients. Some studies show that Malassezia seems to participate in the development of AGA, but there is still debate on this because of absent hyphae in the alopecia area. Interestingly, M. hyphae were found in scalp alopecia area of AGA patients. Thus, we speculate that the hyphae form of Malassezia may be not causal in AGA patients, and the M. hyphae may play a possible role in AGA.

Objective

The present study aims to elucidate the correlation of M. mycelia with hair loss in AGA patients and compare the species distribution of Malassezia in scalp between AGA patients and healthy individuals.

Methods

We sampled scales from scalp alopecia area from the patients diagnosed with AGA. The specimen was stained with calcofluor white staining (CFW) and observed for Malassezia structure under light microscopy and fluorescence microscopy. In the meanwhile, the scales were used for DNA direct extraction and sequencing. The other part of the specimen was inoculated onto Modified Dixon agar and culture at 37°C for 7 days. The isolates were identified by morphological and molecular sequencing (ITS1 and ITS4).

Results

The fungal load of Malassezia was significantly increased and short club-shaped mycelia exist in AGA patients, accounting for 48.89%, The fungal load was positively correlated with the skin inflammation of the hair loss area. The skin inflammation on the hair loss scalp was relieved after the treatment with antifungal agents, accompanying the disappearance of M. hyphae and decreasing of fungal load. There is no difference in species distribution of Malassezia in both AGA patients and healthy individuals. M. globosa and M. restricta are the two most common species isolated from the hair loss area.

Conclusion

Malassezia mycelia exist in patients with mild to moderate AGA, accounting for a certain percentage. The hair loss stopped accompanied with the disappearance of M. hyphae and decreasing of fungal burden. Our data suggest that the presence of M. hyphae may contribute to the pathogenesis of AGA.
P299 A clinicomycological study of suspected mucormycosis in post-COVID patients attending a tertiary care hospital
Authors: Tak Kiran , Rastogi Vijaylatha , Verma Pushpanjali , Gehlot Vikas , Gupta Mansi , Rawat Digvijay , Prajapati Shailja , Parihar Geeta
Published: September 2022

Poster session 2, September 22, 2022, 12:30 PM - 1:30 PM

 

Objective

To study the fungal etiology, clinical, and epidemiological profile of suspected mucormycosis in post-COVID patients.

Methods

A prospective observational study was undertaken over a period of 10 months from March to December 2021. A total of 175 biopsy samples were collected from 150 suspected cases of post-COVID mucormycosis patients in sterile normal saline at the ENT department and received in the department of microbiology. MRI of brain, orbital, and paranasal sinus was done in all patients.

Tissue specimens were examined by direct KOH mount and cultures were inoculated on SDA with chloramphenicol and incubated at 22°C and 37°C for a minimum of 3-5 days and up to 4 weeks before declaring negative. The cultures were identified based on standard mycological protocols.

Results

The prevalence of mucormycosis laboratory confirmed was found to be 42.66%. Out of 150 patients, 47 were KOH positive while 33 were culture positive. The most common isolate was Rhizopus arrhizus (84.85%) followed by R.microsporus var. rhizopodiformis (9.09%), Rhizomucor pusillus (3.03%), and Saksenaea vasiformis (3.03%).

Rhino-orbital-cerebral mycormycosis was the most common clinical form (33 cases). Diabetes mellitus was the most common predisposing factor n = 112 (74.66%). Many patients had multiple symptoms like periorbital swelling (52%), headache (44.7%), fever (41.3%), loss of vision (16%), facial swelling (27.3%), and nasal pain (8.7%). Invasive fungal sinusitis was seen in MRI in 116 (77.33%) cases.

Tissue debridement was done in all positive patients along with treatment with liposomal amphotericin B (1.5-5.0 mg/kg/d) and then switched over to oral posaconazole 300 mg BD on the first day then 300 mg OD for several weeks. Inspite of rigorous treatment in 4.6% cases the prognosis was not good resulting in mortality. Also, in 40% of the patients who recovered, long-term morbidity related to vision was observed.

Conclusion

Present study determined the fungal etiology of post covid mucormycosis with R. arrhizus being the most common cause in our region compared to other studies from India. The identification of risk factors, clinical features, and laboratory findings helped in early diagnosis, leading to prompt treatment, and favorable outcomes. With diabetes mellitus being the most common predisposing factor seen, it is suggested that a holistic approach to prevent, revert and treat this condition needs to be strengthened.
P343 Novel hydrophobic binding surface proteins are instrumental for phagocytosis of Lichtheimia corymbifera by macrophages
Authors: Hassan Mohamed Abdelwahab , España Jaime David Acosta , Hea-Reung Park , Schwartze Volker U. , Schäuble Sascha , Krüger Thomas , Kniemeyer Olaf , Brakhage Axel A. , Voigt Kerstin
Published: September 2022

Poster session 3, September 23, 2022, 12:30 PM - 1:30 PM

 

Objectives

Methods

Two strains of L. corymbifera (JMRC: FSU: 09682 and JMRC: FSU: 10164) were used in this study. For phagocytosis assay, the spores were labeled with 0.1 mg/ml Fluorescein isothiocyanate (FITC) (Sigma Aldrich Chemie) in 0.1 M Na2CO3 for 30 min 146 at 30°C. Murine alveolar macrophages MH-S (ATCC:CRL-2019) were cultivated in RPMI-1640 (Sigma, 30-2001) supplemented.

Identification of the surface proteins of L. corymbifera was carried out as described before with minor modification.1 The supernatants were stored at −80°C for liquid chromatography-mass spectrometry (LC-MS/MS) analysis. Secreted proteins of L. corymbifera were determined as described in a previous study with minor modification2.

The raw files generated by the LC-MS/MS were further processed by the software Proteome Discoverer v1.4.0.288 (Thermo). Tandem mass spectra were searched against the NCBI L. corymbifera protein database.3 Approximately 10 000 MH-S cells were cultivated onto 96-well microplates (NUNC 163320) in 100 μL RPMI-1640 medium (Sigma, 30-2001). Images were acquired by the Zeiss Axio Observer 7 Spinning Disk Confocal Microscope (ZEISS, Jena, Germany) and processed with ZEN 2.1 Software (ZEISS) by 63x objective lens.

Results

Abundant surface proteins were found which serve as Candidates for secretome analysis. A total of 113 proteins were identified. Thirty proteins were confirmed to be on the spore surface based on the presence of signal peptides3. The following proteins were predominantly identified: Spore coat protein (CotH), hydrophobic surface binding protein A (HsbA), aconitase, ricin-like lectin, two transition elongation factors, multi-copper oxidase, heat shock protein 70 family (Hsp70), malate synthase, putative allergen Candidates, etc.

These proteins were heterologsly overexpressed in yeast. Successful overexpression was confirmed by LC-MS/MS. The yeast mutants were subjected to phagocytosis assays (Fig. 1). The role of surface proteins in macrophages is discussed.

Conclusion

The surface proteins are instrumental for recognition of L. corymbifera by macrophages and for intracellular survival in macrophages. The role of surface proteins is discussed in the light of evolution from environmental to human pathogenic fungus.

Sources
P404 Biofilm formation by Cryptococcus species isolated from Cerebrospinal fluid (CSF)
Authors: Ningthoujam Priyolakshmi , Sawian Robertson , Khuraijam Ranjana Devi
Published: September 2022

Poster session 3, September 23, 2022, 12:30 PM - 1:30 PM

 

Introduction

Cases of Cryptococcal meningitis have increased exponentially in the last 30 years due to the advent of AIDS, the use of immunosuppressive drugs, and chemotherapeutic agents. Among HIV-infected patients’ relapse is seen often. The ability of Cryptococcus to form biofilm may influence the clinical outcome of patients though poor adherence to ART and/or anti-fungal therapy is a known factor for relapse.

Methods

During a period of 2 years and 8 months (August 2019 to March 2022), 11 Cryptococcus sps. were isolated from 59 cerebrospinal fluids (CSF) collected from patients clinically suspected of meningitis. Samples were examined and processed by direct microscopy and fungal culture. Identification of cryptococcal isolates was carried out by conventional method and by using an automated VITEK-2 (Biomerieux) identification system. Biofilm production was estimated by XTT reduction assay. Statistical analysis was done in SPSS version 21 (IBM) and Fischer's exact was used to find an association between biofilm formation and relapse.

Results

Out of 11 Cryptococcus isolated 10 were identified as C. neoformans and one was C. gattii. Three HIV-infected patients had recurrent cryptococcal meningitis. A total of 6 (42.8%) cases reported non-adherence to ART and/or anti-fungal therapy. Biofilm was detected in 3 isolates one of which was from a patient with re-current cryptococcal meningitis but the association is not statistically significant.

Discussion

Non-adherence to HAART among HIV patients is known to increase the rate of hospitalization and mortality. Recurrence of cryptococcal meningitis has been thought to be due to drug resistance. But Illnait-zaragozí MT et al. based on STR typing technique, concluded that recurrence was due to co-infection with different strains or strains genetically modified during the long maintenance therapy. Biofilms produced by bacteria as well as fungus have been associated with more stubborn, recurrent, and persistent infections, especially among the immunocompromised population. Although biofilm production was detected in only one out of 3 isolates from recurrent cryptococcal meningitis, it may be a contributing factor along with non-adherence to treatment.

Conclusion

Non-adherence to ART and/or antifungal therapy is an important cause of relapse of cryptococcal meningitis. Biofilm production may be responsible for recurrence, especially among non-adherent patients. Further studies with a larger sample size may shed more light on the association between biofilm formation and recurrence.
P491 Scedosporium Apiospermum brain abscess in an immunocompetent host: Rare case from Southern India
Authors: Joshi Divya , Sridharan Sowmya , Gopalakrishnan Ram
Published: September 2022

Poster session 1, September 21, 2022, 12:30 PM - 1:30 PM

 

Objectives/Introduction

Scedosporium apiospermum is a filamentous fungus that causes a broad spectrum of diseases in an immunocompromised host involving the lungs, skin, bones, eyes, joints, and the central nervous system. It is a rare cause of fungal brain abscess, more so in an immunocompetent individual. Here, we report a case of brain abscess in an immunocompetent host caused by S. apiospermum.

Methods

A 78-year-old retired railway officer from Chennai, presented to our hospital on May 4, 2022, with a 3-month history of weakness, gait instability followed by difficulty in walking, and left hemiparesis. In all, 20 days before the presentation, he had an episode of generalized tonic-clonic seizure with worsening of his neurological state resulting in bed-bound status. His medical history included Pemphigus vulgaris for which he was on topical treatment, well-controlled diabetes mellitus, hypertension, and coronary artery disease.

He underwent an MRI brain which revealed a T2 heterointense intra-axial right parietal lesion with significant perilesional edema. A provisional diagnosis of a cerebral abscess and malignancy was entertained. He was subjected to craniotomy and the surgical findings were consistent with a brain abscess and the pus was evacuated and sent for microbiological analysis. The pus fungal stain was consistent with septate hyphae and the cultures grew S. apiospermum. The histopathological findings were also consistent with a brain abscess caused by septate fungi (Aspergillus like fungi).

Results/Treatment

He was started on Liposomal Amphotericin B 5 mg/kg dose IV OD and injectable voriconazole. There was an initial clinical improvement with respect to sensorium and neurological status. He subsequently developed bradycardia with worsening sensorium to which he finally succumbed.

Conclusion

Scedosporium apiospermum is an asexual form of Pseudoallescheria boydii, a fungus found in soil, contaminated water, and sewage. It is a rare cause of brain abscess in immunocompromised individuals. Near drowning or trauma may be the causative factors for immunocompetent individuals. Our patient was a well-controlled diabetic host with no apparent immunosuppression.

Scedosporium apiospermum is diagnosed on the basis of culture and microbiological examination. Due to the similarities in the clinical and histopathological presentation of Scedosporium with other similar fungi, culture becomes the gold standard tool for diagnosis.

Treatment includes surgical drainage of the abscess along with intravenous voriconazole for at least 8-12 weeks. The prognosis depends upon the immune status, surgical intervention, and medical antifungal therapy.
S5.5a Standing up FungiNet: Genomic epidemiology and surveillance of fungal diseases
Authors: Chow Nancy , Parnell Lindsay , Escandon Patricia , Govender Nelesh , Chiller Tom
Published: September 2022

S5.5 Genomic Epidemiology of Fungal Infections, September 22, 2022, 3:00 PM - 4:30 PM

 

Objectives

With the advent of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing, the public health landscape for genomic epidemiology and surveillance has transformed for a variety of pathogens. For fungal diseases, the U.S. Centers for Disease Control and Prevention (CDC) is working with global partners to stand up FungiNet, a network that aims to equip scientists with laboratory, bioinformatics, and informatics resources to harness genomic data. FungiNet partners will use genomic and epidemiologic data to detect outbreaks, identify introductions, and characterize transmission of fungal infections. In 2022, FungiNet aims to onboard nine state and local health departments in the United States and two global partners, the Instituto Nacional de Salud in Colombia and the National Institute for Communicable Diseases in South Africa, with a focus on Candida auris.

Methods

To streamline the onboarding process, CDC generated standardized operating procedures (SOPs) specific to C. auris. For DNA extraction, SOPs were created for workflows using the Zymo Research Quick-DNA™ (ZR) Fungal/Bacterial Miniprep, Qiagen Dneasy Blood and Tissue, and Epicentre (Illumina) MasterPure Yeast DNA Purification kits. For library preparation and Illumina sequencing, PulseNet methods used for foodborne pathogens were validated for C. auris. For NCBI data submissions, required data elements were defined. For SNP and phylogenetic analyses, the bioinformatics workflow MycoSNP was adapted to use Nextflow software and the Terra platform. For visualization with epidemiologic data, guidance documents and tutorials for Microreact were created. Finally, for data reporting, processes are being designed in REDCap and in laboratory information management systems to rapidly share genomic-related data.

Results

To date, 11 partners have committed to building capacity for C. auris genomic sequencing and analysis as a FungiNet partner. Of these, seven have validated methods for DNA extraction, and nine have generated high-quality sequencing data. Only one partner has installed and locally run MycoSNP, and none have submitted raw sequence data to NCBI.

Conclusions

Currently, 11 FungiNet partners are working to onboard C. auris genomic sequencing and bioinformatics analysis in 2022. This process is complex, requiring several laboratories, bioinformatics, and informatics workflows. For many partners, bioinformatics analysis and NCBI submission are the most challenging activities with the installation of MycoSNP and the ability to batch upload data to NCBI as the main barriers. Next steps will focus on the validation of informatics methods to link genomic and epidemiologic data.
S6.2d Dermatophytosis due to Trichophyton erinacei caused by contact with African hedgehogs as family pets
Authors: Bonifaz Alexandro , Araiza Javier , de la Cruz Helena Vidaurri , Morales-Peña Neredi , Treviño-Rangel Rogelio , González Gloria
Published: September 2022

S6.2 Resurgence of dermatophytic infections, September 22, 2022, 4:45 PM - 6:15 PM

 

Objective

To present a series of cases of various types of dermatophytosis caused by Trichophyton erinacei, caused by contact with African hedgehogs.

Methods

Patients with clinical suspicion of ringworm caused by T. erinacei were included in the study. Each patient underwent a mycological study, with direct examinations (KOH), cultures in Sabouraud dextrose agar medium with and without antibiotics. With the cultures obtained, molecular identification was made using the PCR technique and Matrix Assisted Laser Desorption Ionization Time of Flight (MALDI-TOF) proteomics. Once confirmed, the patients were given treatment and follow-up. When the pets (hedgehogs) were accessible, they were cultured with a cytobrush and the quills removed.

Results

In a period of 3.5 years, 16 verified cases were incorporated, 13 were females (72%) and 3 males (18%), the average age was 18.2 years, with the smallest case being 8 years old and the oldest 45 years old. The tineas manifested as follows: tinea manus 11 cases (68.7%); 2 respective cases of tinea corporis and tinea capitis (18.1 respectively) and one case of Majocchi's granuloma. The average evolution was 1.5 months with the case older than 3 months and the younger 15 days. All cases were given terbinafine at variable times and doses (according to weight and age) and clinical and mycological cure was obtained.

Discussion

Tineas can have epidemiological changes that are favored by a variety of factors, in general, pet ringworms are due to common domestic animals such as dogs and cats. Due to changing fashions, children and adolescents in recent years have changed pets such as hamsters, and recently hedgehogs, especially African variety (Atelerix albiventris) the latter may have T. erinacei as part of their skin microbiota, a similar dermatophyte or that was part of the T. mentagrophyes complex, in general of low virulence, however, its antigenic variants are little recognized by humans, which makes them present in a very inflammatory form, particularly in the hands, due to the handling of the animal, as well as the deeper inoculation (in the dermis) by the spikes left by the inoculum. So, they can generate deep tineas such as Majocchi's granuloma. In general, they respond well to systemic antifungals such as terbinafine and itraconazole, and sometimes the use of topical or systemic steroids is necessary.

Conclusions

This series of cases is a good example of how a change of habits when having pets can introduce new etiological agents that are poorly recognized antigenically, which give rise to more inflammatory and sometimes profound tineas.
Gusts in the headwind: uncertainties in direct dark matter detection
Authors: Lawrence Grace E , Duffy Alan R , Blake Chris A , Hopkins Philip F
Published: September 2022

We use high-resolution, hydrodynamic, galaxy simulations from the Latte suite of FIRE-2 simulations to investigate the inherent variation of dark matter in sub-sampled regions around the Solar Circle of a Milky Way-type analogue galaxy and its impact on direct dark matter detection. These simulations show that the baryonic back reaction, as well as the assembly history of substructures, has lasting impacts on the dark matter’s spatial and velocity distributions. These are experienced as ‘gusts’ of dark matter wind around the Solar Circle, potentially complicating interpretations of direct detection experiments on Earth. We find that the velocity distribution function in the galactocentric frame shows strong deviations from the Maxwell Boltzmann form typically assumed in the fiducial Standard Halo Model, indicating the presence of high-velocity substructures. By introducing a new numerical integration technique that removes any dependencies on the Standard Halo Model, we generate event-rate predictions for both single-element Germanium and compound Sodium Iodide detectors, and explore how the variability of dark matter around the Solar Circle influences annual modulation signal predictions. We find that these velocity substructures contribute additional astrophysical uncertainty to the interpretation of event rates, although their impact on summary statistics, such as the peak day of annual modulation, is generally low.
Harvesting the Ly α forest with convolutional neural networks
Authors: Cheng Ting-Yun , Cooke Ryan J , Rudie Gwen
Published: September 2022

We develop a machine learning based algorithm using a convolutional neural network (CNN) to identify low H i column density Ly α absorption systems (log NH i/cm−2 < 17) in the Ly α forest, and predict their physical properties, such as their H i column density (log NH i/cm−2), redshift (zH i), and Doppler width (bH i). Our CNN models are trained using simulated spectra (S/N ≃ 10), and we test their performance on high quality spectra of quasars at redshift z ∼ 2.5−2.9 observed with the High Resolution Echelle Spectrometer on the Keck I telescope. We find that ${\sim}78{{\ \rm per\ cent}}$ of the systems identified by our algorithm are listed in the manual Voigt profile fitting catalogue. We demonstrate that the performance of our CNN is stable and consistent for all simulated and observed spectra with S/N ≳ 10. Our model can therefore be consistently used to analyse the enormous number of both low and high S/N data available with current and future facilities. Our CNN provides state-of-the-art predictions within the range 12.5 ≤ log NH i/cm−2 < 15.5 with a mean absolute error of Δ(log NH i/cm−2) = 0.13, Δ(zH i) = 2.7 × 10−5, and Δ(bH i) = 4.1 km s−1. The CNN prediction costs < 3 min per model per spectrum with a size of 120 000 pixels using a laptop computer. We demonstrate that CNNs can significantly increase the efficiency of analysing Ly α forest spectra, and thereby greatly increase the statistics of Ly α absorbers.
Chandrasekhar-mass white dwarfs are the progenitors of a small fraction of Type Ia supernovae according to nucleosythesis constraints
Authors: Bravo Eduardo , Piersanti Luciano , Blondin Stéphane , Domínguez Inma , Straniero Oscar , Cristallo Sergio
Published: September 2022

The precise progenitor system of type Ia supernovae (SNe Ia), whether it is a white dwarf (WD) close to the Chandrasekhar limit or substantially less massive, has been a matter of debate for decades. Recent research by our group on the accretion and simmering phases preceding the explosion of a massive WD has shown that the central density at thermal runaway lies in the range 3.6 − 6.3 × 109 g cm−3 for reasonable choices of accretion rate on to the WD and progenitor metallicity. In this work, we have computed one-dimensional simulations of the explosion of such WDs, with special emphasis on the chemical composition of the ejecta, which in all cases is extremely rich in neutronized isotopes of chromium (54Cr) and titanium (50Ti). We show that, in order to reconcile such a nucleosynthesis with the isotopic abundances of the Solar system, Chandrasekhar-mass WDs can account for at most 26 per cent of normal-luminosity SNe Ia, or at most 20 per cent of all SNe Ia.
The Heterogeneity in the Landscape of Gene Dominance in Maize is Accompanied by Unique Chromatin Environments
Authors: Yin Liangwei , Xu Gen , Yang Jinliang , Zhao Meixia
Published: September 2022

Subgenome dominance after whole-genome duplication (WGD) has been observed in many plant species. However, the degree to which the chromatin environment affects this bias has not been explored. Here, we compared the dominant subgenome (maize1) and the recessive subgenome (maize2) with respect to patterns of sequence substitutions, genes expression, transposable element accumulation, small interfering RNAs, DNA methylation, histone modifications, and accessible chromatin regions (ACRs). Our data show that the degree of bias between subgenomes for all the measured variables does not vary significantly when both of the WGD genes are located in pericentromeric regions. Our data further indicate that the location of maize1 genes in chromosomal arms is pivotal for maize1 to maintain its dominance, but location has a less effect on maize2 homoeologs. In addition to homoeologous genes, we compared ACRs, which often harbor cis-regulatory elements, between the two subgenomes and demonstrate that maize1 ACRs have a higher level of chromatin accessibility, a lower level of sequence substitution, and are enriched in chromosomal arms. Furthermore, we find that a loss of maize1 ACRs near their nearby genes is associated with a reduction in purifying selection and expression of maize1 genes relative to their maize2 homoeologs. Taken together, our data suggest that chromatin environment and cis-regulatory elements are important determinants shaping the divergence and evolution of duplicated genes.
The high mobility group protein HMG20A cooperates with the histone reader PHF14 to modulate TGFβ and Hippo pathways
Authors: Gómez-Marín Elena , Posavec-Marjanović Melanija , Zarzuela Laura , Basurto-Cayuela Laura , Guerrero-Martínez José A , Arribas Gonzalo , Yerbes Rosario , Ceballos-Chávez María , Rodríguez-Paredes Manuel , Tomé Mercedes , Durán Raúl V , Buschbeck Marcus , Reyes José C
Published: September 2022

High mobility group (HMG) proteins are chromatin regulators with essential functions in development, cell differentiation and cell proliferation. The protein HMG20A is predicted by the AlphaFold2 software to contain three distinct structural elements, which we have functionally characterized: i) an amino-terminal, intrinsically disordered domain with transactivation activity; ii) an HMG box with higher binding affinity for double-stranded, four-way-junction DNA than for linear DNA; and iii) a long coiled-coil domain. Our proteomic study followed by a deletion analysis and structural modeling demonstrates that HMG20A forms a complex with the histone reader PHF14, via the establishment of a two-stranded alpha-helical coiled-coil structure. siRNA-mediated knockdown of either PHF14 or HMG20A in MDA-MB-231 cells causes similar defects in cell migration, invasion and homotypic cell–cell adhesion ability, but neither affects proliferation. Transcriptomic analyses demonstrate that PHF14 and HMG20A share a large subset of targets. We show that the PHF14-HMG20A complex modulates the Hippo pathway through a direct interaction with the TEAD1 transcription factor. PHF14 or HMG20A deficiency increases epithelial markers, including E-cadherin and the epithelial master regulator TP63 and impaired normal TGFβ-trigged epithelial-to-mesenchymal transition. Taken together, these data indicate that PHF14 and HMG20A cooperate in regulating several pathways involved in epithelial–mesenchymal plasticity.
Crystallographic analysis of engineered polymerases synthesizing phosphonomethylthreosyl nucleic acid
Authors: Hajjar Mohammad , Chim Nicholas , Liu Chao , Herdewijn Piet , Chaput John C
Published: September 2022

Xeno-nucleic acids (XNAs) are synthetic genetic polymers with backbone structures composed of non-ribose or non-deoxyribose sugars. Phosphonomethylthreosyl nucleic acid (pTNA), a type of XNA that does not base pair with DNA or RNA, has been suggested as a possible genetic material for storing synthetic biology information in cells. A critical step in this process is the synthesis of XNA episomes using laboratory-evolved polymerases to copy DNA information into XNA. Here, we investigate the polymerase recognition of pTNA nucleotides using X-ray crystallography to capture the post-catalytic complex of engineered polymerases following the sequential addition of two pTNA nucleotides onto the 3′-end of a DNA primer. High-resolution crystal structures reveal that the polymerase mediates Watson–Crick base pairing between the extended pTNA adducts and the DNA template. Comparative analysis studies demonstrate that the sugar conformation and backbone position of pTNA are structurally more similar to threose nucleic acid than DNA even though pTNA and DNA share the same six-atom backbone repeat length. Collectively, these findings provide new insight into the structural determinants that guide the enzymatic synthesis of an orthogonal genetic polymer, and may lead to the discovery of new variants that function with enhanced activity.
Integrated longitudinal analysis of adult grade 4 diffuse gliomas with long-term relapse interval revealed upregulation of TGF-β signaling in recurrent tumors
Authors: Kashani Elham , Schnidrig Désirée , Gheinani Ali Hashemi , Ninck Martina Selina , Zens Philipp , Maragkou Theoni , Baumgartner Ulrich , Schucht Philippe , Rätsch Gunnar , Rubin Mark A ,   SOCIBP consortium, Benjak Andrej , Bruggmann Rémy , Comoglio Federico , Kahles André , Keller Irene , K Y Ng Charlotte , Piscuoglio Salvatore , Prélot Laurie , Rätsch Gunnar , A Rubin Mark , Schnidrig Désirée , Selimovic-Hamza Senija , Thomas Tinu M , Berezowska Sabina , Ng Charlotte K Y , Vassella Erik
Published: September 2022

Background

Adult-type diffuse gliomas, CNS WHO grade 4 are the most aggressive primary brain tumors and represent a particular challenge for therapeutic intervention.

Methods

In a single-center retrospective study of matched pairs of initial and post-therapeutic glioma cases with a recurrence period greater than 1 year, we performed whole exome sequencing combined with mRNA and microRNA expression profiling to identify processes that are altered in recurrent gliomas.

Results

Mutational analysis of recurrent gliomas revealed early branching evolution in 75% of the patients. High plasticity was confirmed at the mRNA and miRNA levels. SBS1 signature was reduced and SBS11 was elevated, demonstrating the effect of alkylating agent therapy on the mutational landscape. There was no evidence for secondary genomic alterations driving therapy resistance. ALK7/ACVR1C and LTBP1 were upregulated, whereas LEFTY2 was downregulated, pointing towards enhanced Tumor Growth Factor β (TGF-β) signaling in recurrent gliomas. Consistently, altered microRNA expression profiles pointed towards enhanced Nuclear Factor Kappa B and Wnt signaling that, cooperatively with TGF-β, induces epithelial to mesenchymal transition (EMT), migration, and stemness. TGF-β-induced expression of pro-apoptotic proteins and repression of antiapoptotic proteins were uncoupled in the recurrent tumor.

Conclusions

Our results suggest an important role of TGF-β signaling in recurrent gliomas. This may have clinical implications since TGF-β inhibitors have entered clinical phase studies and may potentially be used in combination therapy to interfere with chemoradiation resistance. Recurrent gliomas show high incidence of early branching evolution. High tumor plasticity is confirmed at the level of microRNA and mRNA expression profiles.
The Short-Term and Long-Term Associations Between Receiving Tobacco Discounts or Coupons and Smoking Cessation Among U.S. Adult Cigarette Smokers With Intention to Quit
Authors: Wang Yu , Duan Zongshuan , Weaver Scott R , Self-Brown Shannon R , Ashley David L , Emery Sherry L , Huang Jidong
Published: September 2022

Introduction

To examine the associations between baseline receipt of cigarette and non-cigarette tobacco discounts or coupons and smoking cessation at follow-up among US adult cigarette smokers with the intention to quit at baseline.

Aims and Methods

Data were from the Population Assessment of Tobacco and Health (PATH) study wave 3 (October 2015–October 2016), wave 4 (December 2016–January 2018), and wave 5 (December 2018–November 2019) surveys. Two separate sets of analyses were conducted using wave 3–4 data (N = 3707) and wave 4–5 data (N = 6251). Specifically, wave 4 was used as the 1-year follow-up of wave 3 to examine the short-term association, and wave 5 was used as the 2-year follow-up of wave 4 to examine the longer-term association. Study population were current established cigarette smokers with the intention to quit (within 1 year for wave 3–4 data) at baseline. Exposure was self-reported past 12-month receipt of discounts or coupons for cigarettes and non-cigarette tobacco products at baseline, and outcome was self-reported completely quitting cigarette smoking at follow-up. Baseline single-wave weights were applied, and multivariate logistic regressions were used to estimate the adjusted associations.

Results

Participants who received cigarette discounts or coupons at baseline were less likely to quit completely for both 1-year follow-up (aOR = 0.66, 95% CI: 0.48 to 0.90) and 2-year follow-up (aOR = 0.74, 95% CI: 0.61 to 0.90). Baseline receipt of discounts or coupons for non-cigarette tobacco products were not consistently associated with cigarette smoking cessation at follow-up.

Conclusions

Receipt of cigarette discounts or coupons was associated with a reduced likelihood of successful quitting among cigarette smokers with intention to quit. Policies restricting cigarette coupons may help them quit completely.

Implications

This study found that among baseline current established cigarette smokers with intention to quit in the United States, baseline receipt of cigarette discounts or coupons was negatively associated with cigarette smoking cessation for both 1-year follow-up and 2-year follow-up. Baseline receipt of discounts or coupons for e-cigarettes, cigars, and other tobacco products were not consistently significantly associated with cigarette smoking cessation at follow-up. Our study results indicated that policies restricting cigarette coupons may help increase the likelihood of successful smoking cessation for smokers with intention to quit.
Impact of a Multistep Bundles Intervention in the Management and Outcome of Gram-Negative Bloodstream Infections: A Single-Center “Proof-of-Concept” Study
Authors: Bavaro Davide Fiore , Diella Lucia , Belati Alessandra , De Gennaro Nicolò , Fiordelisi Deborah , Papagni Roberta , Guido Giacomo , De Vita Elda , Frallonardo Luisa , Camporeale Michele , Pellegrino Carmen , Denicolò Sofia , Ranieri Enrica , Mariani Michele Fabiano , Brindicci Gaetano , Ronga Luigi , Di Gennaro Francesco , Mosca Adriana , Saracino Annalisa
Published: September 2022

Background

This is a “proof-of-concept” study aiming to evaluate the impact of a multistep bundles intervention in the management and outcomes of patients with gram-negative bloodstream infections (GN-BSIs).

Methods

This was a single-center, quasi-experimental design study. In the pre-phase (January 2019 to May 2020), patients were retrospectively enrolled. During the post-phase (June 2020 to September 2021), all patients were prospectively enrolled in a nonmandatory 3-step bundles intervention arm including (i) step 1: imaging to detect deep foci of infection, follow-up blood cultures and procalcitonin monitoring; (ii) step 2: early targeted antibiotic treatment and surgical source control; (iii) step 3: discontinuation of antibiotics within 7–10 days in case of uncomplicated BSI. Patients were followed up to 28 days from BSI onset. The primary outcome was 28-day mortality.

Results

A total of 271 patients were enrolled: 127 and 144 in the pre- vs post-phase, respectively. Full application of step 1 (67% vs 42%; P < .001), step 2 (83% vs 72%; P = .031), and step 3 (54% vs 2%; P < .001) increased in the post-phase. Overall, the intervention reduced 28-day mortality (22% vs 35%, respectively; P = .016) and the median duration of total (11 vs 15 days; P < .001) and targeted (8 vs 12 days; P = .001) antibiotic therapy. Finally, the multivariate Cox regression confirmed the independent protective effect of adherence to step 1 (adjusted hazard ratio [aHR], 0.36; 95% CI, 0.20–0.63) and step 2 (aHR, 0.48; 95% CI, 0.29–0.81) on risk of 28-day mortality.

Conclusions

Clinical management and outcomes of patients with GN-BSIs may be improved by providing a pre-established multistep bundles intervention.
KRASMutation Variants and Co-occurring PI3K Pathway Alterations Impact Survival for Patients with Pancreatic Ductal Adenocarcinomas
Authors: Diehl Adam C , Hannan Lindsay M , Zhen David B , Coveler Andrew L , King Gentry , Cohen Stacey A , Harris William P , Shankaran Veena , Wong Kit M , Green Steven , Ng Natasha , Pillarisetty Venu G , Sham Jonathan G , Park James O , Reddi Deepti , Konnick Eric Q , Pritchard Colin C , Baker Kelsey , Redman Mary , Chiorean E Gabriela
Published: September 2022

Background

KRAS variant alleles may have differential biological properties which impact prognosis and therapeutic options in pancreatic ductal adenocarcinomas (PDA).

Materials and Methods

We retrospectively identified patients with advanced PDA who received first-line therapy and underwent blood and/or tumor genomic sequencing at the University of Washington between 2013 and 2020. We examined the incidence of KRAS mutation variants with and without co-occurring PI3K or other genomic alterations and evaluated the association of these mutations with clinicopathological characteristics and survival using a Cox proportional hazards model.

Results

One hundred twenty-six patients had genomic sequencing data; KRAS mutations were identified in 111 PDA and included the following variants: G12D (43)/G12V (35)/G12R (23)/other (10). PI3K pathway mutations (26% vs. 8%) and homologous recombination DNA repair (HRR) defects (35% vs. 12.5%) were more common among KRAS G12R vs. non-G12R mutated cancers. Patients with KRAS G12R vs. non-G12R cancers had significantly longer overall survival (OS) (HR 0.55) and progression-free survival (PFS) (HR 0.58), adjusted for HRR pathway co-mutations among other covariates. Within the KRAS G12R group, co-occurring PI3K pathway mutations were associated with numerically shorter OS (HR 1.58), while no effect was observed on PFS.

Conclusions

Patients with PDA harboring KRAS G12R vs. non-G12R mutations have longer survival, but this advantage was offset by co-occurring PI3K alterations. The KRAS/PI3K genomic profile could inform therapeutic vulnerabilities in patients with PDA.
Eschatology in Christian Feminist Theologies
Authors: Ruether Rosemary Radford
Published: September 2022

Christian eschatology is a complex combination of ideas and themes that synthesizes three ancient traditions of eschatological hope: Jewish futurism, Zoroastrian apocalyptic, and the Greco-Oriental soul journey. This article examines these three historical roots of eschatology and their synthesis in Judaism and Christianity. It points out the gender and class biases found in these classical patterns of eschatology, looks at the revision of Christian eschatology in nineteenth-century progressive millennialism, and shows how early feminist theology adapted both millennialist hope and belief in personal immortality. The article then examines the critique and revision of eschatological hope in several major feminist theologians of the late twentieth and early twenty-first centuries: Marjorie Suchocki, Catherine Keller, Ivone Gebara, Delores Williams, and Rosemary Ruether. It also considers the ancient Near East roots of Christian eschatological thought, the development of Christian eschatology, crises and reinterpretation of Christian eschatology in modern Western thought, and feminist theology and eschatology in the late twentieth century.
Old Testament Eschatology and the Rise of Apocalypticism
Authors: Arnold Bill T.
Published: September 2022

Eschatology does not appear to play a prominent role in the scriptures of ancient Israel, the “Old Testament” of Christian tradition, at least not at first glance. Understood broadly enough, however, and properly associated with other formulations of Israel's theological expressions, it will become clear that eschatology eventually evolved into a prominent role indeed. Israel's theology was intensely grounded in time and space, and especially in the events of its own history. This article considers the eschatology of the Old Testament. First, it discusses the emergence and development of eschatological themes in Israel's scriptures. Second, it examines how prophecy in ancient Israel relates to that of the ancient Near East and the degree to which Israel's eschatological impulses were unique. Finally, the article assesses the complicated and disputed relationship between Old Testament eschatology and the rise of apocalypticism.
Eschatology and Theodicy
Authors: Peterson Michael L.
Published: September 2022

Eschatology and theodicy are both intimately and importantly related. The Christian creeds conclude with the affirmation of the resurrection of the dead and the life of the world to come, and classical eschatology is concerned with the doctrine of “the consummation of all things.” The inveterate problem of evil identifies basic theistic commitments—about God's knowledge, power, and goodness—that must be squared with the facts of evil in any plausible vision of the eschatological future. So, theodicy is necessary to the task of eschatology. This article examines the reciprocal relationship between eschatology and theodicy by surveying the major strands of discussion of the problem of evil in contemporary philosophy. It traces how both the argument from evil and responses to it have evolved, setting the stage for why current discussions have turned to eschatological themes. It also discusses John Hick's soul-making theodicy, Richard Swinburne's theodicy of providence, Marilyn Adams's theodicy of divine goodness, open theism's theodicy of divine risk, and theodicy and Christian hope.
Eschatology in Pop Culture
Authors: Jewett Robert , Lawrence John Shelton
Published: September 2022

Popular culture embraces diverse arenas of expression, such as mythic narratives, news story archetypes, advertising, songs, games, political campaigns, public rituals, toys, comic books, films, television series, sports, celebrities, sermons, web sites, music, and biblical commentaries for lay readers. The label “popular” carries no pejorative flavor—as it did in mid-twentieth-century discussions of “mass culture”—nor does it imply consensus about popular culture's valuation by those who experience it. Compared to more mature fields, the scholarly study of religion and popular culture lacks a single disciplinary home. Inspiration for academic study with interdisciplinary texts and courses came from the Popular Culture Association, which originated at Bowling Green State University in Ohio. This article deals with eschatology in popular culture, focusing on early forms of popular eschatology, Bible-influenced popular culture in the United States, postmillennialism in civil religion, millennialism in superheroic fictions, the millennial vision and the video game, and premillennial fictions at the turn of the century.
Eschatology in the Early Church Fathers
Authors: Daley Brian
Published: September 2022

Early Christian theology developed in a climate of strong, although fluid, eschatological expectations. The degree to which Jesus' own preaching was dominated by themes of the imminent end of human history is still hotly debated, but it is unquestionable that both his own disciples and the authors of the New Testament canon lived in a religious world animated by Jewish apocalyptic images and the hopes they implied. This article discusses patristic eschatology, not simply the use made of the apocalyptic genre by early Christian authors, but their sense of constantly living in history's final age, of facing, amid persecutions and natural disasters, the end of society and the more immediate end of individual human life. It examines Christian apocalyptic in the second century, along with early Christian homiletics, the Greek apologists, gnostic Christianity and the Orthodox response, gnostic literature, Irenaeus, Tertullian and Hippolytus, Alexandrian theology in the third century, Clement of Alexandria, Origen, fourth- and fifth-century eschatology, and later apocalypticism.
The Effects of High Frequency Oscillatory Ventilation (HFOV) with Volume Guarantee (VG) on Left Ventricular Function, Systemic and Regional Oxygenation, and Ventilation When Compared to HFOV and Conventional Mechanical Ventilation (CMV) in A Newborn Piglet Model of Respiratory Distress Syndrome (RDS)
Authors: Bhogal J , Solevag AL , O'Reilly M , Lee TF , Lu M , Joynt C , Hornberger L , Schmolzer G , Cheung PY
Published: September 2022

BACKGROUND: RDS due to surfactant deficiency is commonly seen in preterm infants. These infants often require ventilatory support such as CMV and HFOV. HFOV with VG (HFOV+VG) is an alternative mode that delivers a set tidal volume. There is limited data on either HFOV mode regarding the effects on left ventricular (LV) function, systemic and regional oxygenation, and ventilation.

OBJECTIVES: We primarily compared the effects of CMV with VG, HFOV, and HFOV+VG on cardiac index (CI). Secondary parameters included heart rate (HR), mean arterial pressure (MAP), LV ejection fraction (EF), stroke volume (SV), dP/dt max, LV end-systolic volume and pressure (ESV, ESP), end-diastolic volume and pressure (EDV, EDP), and measures of oxygenation and ventilation. Oxygenation parameters included cerebral and renal near-infrared spectroscopy (NIRS), partial pressure of arterial oxygen (PaO2), and carotid artery flow index (CAFI). Ventilation parameters included partial pressure of arterial carbon dioxide (PaCO2) and minute ventilation (MV).

DESIGN/METHODS: Piglets (1.4-2.4 kg; 1-3 days old) were acutely anesthetized and instrumented with the placement of a right femoral arterial catheter for blood gas analysis, NIRS probes (Invos®), Transonic® flow probe on right common carotid artery, and Millar® catheter in the LV. Warm saline lung lavage was performed to achieve an AaDO2 of 300-450 mmHg to simulate moderate to severe RDS. Piglets were then block-randomized to CMV, HFOV or HFOV+VG for 4 hours using a Fabian HFO ventilator (Acutronic Medical Systems AG, Switzerland)(n=8 per group). Sham-operated piglets without RDS were monitored for the same duration under CMV (n=6). Two-way repeated measures ANOVA was used to analyze the data between modes or time points.

RESULTS: Piglets developed moderately severe RDS with comparable AaDO2 and Paw along with stable hemodynamic parameters. Both HFOV and HFOV+VG groups had similar PaCO2 whereas the CMV group had elevated PaCO2 when compared to that of the Sham (p<0.01). Switching to HFOV resulted in a higher MV than its baseline. HFOV+VG but not HFOV or CMV groups had lower regional oxygenation and CAFI than its respective normoxic baseline (all p<0.01). HFOV and HFOV+VG had higher CI, EF, and SV than CMV at 4 hours of recovery (p<0.05) with similar HR, MAP, dP/dt max, ESV, ESP, EDV and EDP.

CONCLUSION: In our piglet model of RDS, HFOV shows benefits to LV function and ventilation when compared to CMV. HFOV+VG does not show benefits compared to HFOV.