bluuebunny/crossref_metadata_2025 huggingface dataset:
Bacterial methyltransferases: from targeting bacterial genomes to host epigenetics
Authors: Rolando Monica , Silvestre Cristina Di , Gomez-Valero Laura , Buchrieser Carmen
Published: August 2022

Methyltransferase (MTases) enzymes transfer methyl groups particularly on proteins and nucleotides, thereby participating in controlling the epigenetic information in both prokaryotes and eukaryotes. The concept of epigenetic regulation by DNA methylation has been extensively described for eukaryotes. However, recent studies have extended this concept to bacteria showing that DNA methylation can also exert epigenetic control on bacterial phenotypes. Indeed, the addition of epigenetic information to nucleotide sequences confers adaptive traits including virulence-related characteristics to bacterial cells. In eukaryotes, an additional layer of epigenetic regulation is obtained by post-translational modifications of histone proteins. Interestingly, in the last decades it was shown that bacterial MTases, besides playing an important role in epigenetic regulations at the microbe level by exerting an epigenetic control on their own gene expression, are also important players in host–microbe interactions. Indeed, secreted nucleomodulins, bacterial effectors that target the nucleus of infected cells, have been shown to directly modify the epigenetic landscape of the host. A subclass of nucleomodulins encodes MTase activities, targeting both host DNA and histone proteins, leading to important transcriptional changes in the host cell. In this review, we will focus on lysine and arginine MTases of bacteria and their hosts. The identification and characterization of these enzymes will help to fight bacterial pathogens as they may emerge as promising targets for the development of novel epigenetic inhibitors in both bacteria and the host cells they infect.
Genomic evidence of paternal genome elimination in the globular springtailAllacma fusca
Authors: Jaron Kamil S , Hodson Christina N , Ellers Jacintha , Baird Stuart J E , Ross Laura
Published: August 2022

Paternal genome elimination—a type of reproduction in which males inherit but fail to pass on their father’s genome—evolved independently in 6–8 arthropod clades. Thousands of species, including several important for agriculture, reproduce via this mode of reproduction. While paternal genome elimination is well established in some of the clades, the evidence in globular springtails (Symphypleona) remains elusive, even though they represent the oldest and most species-rich clade putatively reproducing via paternal genome elimination. We sequenced genomic DNA from whole bodies of Allacma fusca males with high fractions (>27.5%) of sperm to conclusively confirm that all the sperm carry 1 parental haplotype only. Although it is suggestive that the single haplotype present in sperm is maternally inherited, definitive genetic proof of the parent of origin is still needed. The genomic approach we developed allows for the detection of genotypic differences between germline and soma in all species with sufficiently high fraction of germline in their bodies. This opens new opportunities for scans of reproductive modes in small organisms.
Resolution enhancement of airborne gravity data based on remove–compute–restore scheme (RCR) and downward continuation (DWC) technique
Authors: Elghrabawy Osama
Published: August 2022

This study aims to present a strategy to enhance the short wavelengths of airborne gravity signal, which attenuate due to the altitude and low-pass filtering based on remove–compute–restore (RCR) scheme and downward continuation (DWC) technique using fast Fourier transform (FFT). The airborne gravity data are measured at an altitude 1 km above the geoid using a GT-1A gravimeter. The enhancement strategy was applied in four cases. In case 1, the original airborne gravity anomaly was downward continued from 1 km to terrain level directly without applying the RCR scheme. In case 2, the XGM2019_2190 was removed from the original airborne gravity anomaly at flight level and back substituted at terrain level after applying the DWC technique. In case 3, the residual terrain model (RTM) was used instead of the XGM2019_2190 model, following the same sequence. Finally, in case 4, both regional and terrain signals were used in the same manner as applied in cases 2 and 3. The downward continued gravity anomalies were compared to the terrestrial gravity anomalies. The statistical results show that the most significant improvement was related to cases 3 and 4 in terms of the mean difference, which reveals 0.48 and 0.36 mGal, respectively. In conclusion, removing the terrain signal before applying the DWC process and back substituting it at terrain level plays a significant role in improving the resolution of the gravity signal-based airborne approach.
Cell type-specific DNA methylome signatures reveal epigenetic mechanisms for neuronal diversity and neurodevelopmental disorder
Authors: Jin Yulin , Su Kenong , Kong Ha Eun , Ma Wenjing , Wang Zhiqin , Li Yujing , Li Ronghua , Allen Emily G , Wu Hao , Jin Peng
Published: August 2022

DNA methylation plays a critical function in establishing and maintaining cell identity in brain. Disruption of DNA methylation-related processes leads to diverse neurological disorders. However, the role of DNA methylation characteristics in neuronal diversity remains underexplored. Here, we report detailed context-specific DNA methylation maps for GABAergic, glutamatergic (Glu) and Purkinje neurons, together with matched transcriptome profiles. Genome-wide mCH levels are distinguishable, while the mCG levels are similar among the three cell types. Substantial CG-differentially methylated regions (DMRs) are also seen, with Glu neurons experiencing substantial hypomethylation events. The relationship between mCG levels and gene expression displays cell type-specific patterns, while genic CH methylation exhibits a negative effect on transcriptional abundance. We found that cell type-specific CG-DMRs are informative in terms of represented neuronal function. Furthermore, we observed that the identified Glu-specific hypo-DMRs have a high level of consistency with the chromatin accessibility of excitatory neurons and the regions enriched for histone modifications (H3K27ac and H3K4me1) of active enhancers, suggesting their regulatory potential. Hypomethylation regions specific to each cell type are predicted to bind neuron type-specific transcription factors. Finally, we show that the DNA methylation changes in a mouse model of Rett syndrome, a neurodevelopmental disorder caused by the de novo mutations in MECP2, are cell type- and brain region-specific. Our results suggest that cell type-specific DNA methylation signatures are associated with the functional characteristics of the neuronal subtypes. The presented results emphasize the importance of DNA methylation-mediated epigenetic regulation in neuronal diversity and disease.
Do We All Walk the Walk? A Comparison of Walking Behaviors across Tetrapods
Authors: Struble M K , Gibb A C
Published: August 2022

Synopsis

A “walking” gait has been identified in a range of vertebrate species with different body plans, habitats, and life histories. With increased application of this broad umbrella term, it has become necessary to assess the physical characteristics, analytical approaches, definitions, and diction used to describe walks. To do this, we reviewed studies of slow-speed locomotion across a range of vertebrates to refine the parameters used to define walking, evaluate analytical techniques, and propose approaches to maximize consistency across subdisciplines of zoology. We summarize nine key parameters used to characterize walking behaviors in mammals, birds, reptiles, amphibians, and fish. After identifying consistent patterns across groups, we propose a comprehensive definition for a walking gait. A walk is a form of locomotion where the majority of the forward propulsion of the animal comes from forces generated by the appendages interacting with the ground. During a walk, an appendage must be out of phase with the opposing limb in the same girdle and there is always at least one limb acting as ground-support (no suspension phase). Additionally, walking occurs at dimensionless speeds <1 v* and the average duty factor of the limbs is always >0.5. Relative to other gaits used by the same species, the stance duration of a walk is long, the cycle frequency is low, and the cycle distance is small. Unfortunately, some of these biomechanical parameters, while effectively describing walks, may also characterize other, non-walking gaits. Inconsistent methodology likely contributes to difficulties in comparing data across many groups of animals; consistent application of data collection and analytical techniques in research methodology can improve these comparisons. Finally, we note that the kinetics of quadrupedal movements are still poorly understood and much work remains to be done to understand the movements of small, ecothermic tetrapods.
High performance evaluation of a PV/T hybrid system connected with a thermal store unit holding paraffin wax
Authors: Abbas Ehsan F , Tahseen Tahseen A , Madlol N A , Sulaiman Hulya S , Al-bonsrulah Hussein A Z , Raja Vijayanandh , Al-Bahrani Mohammed
Published: August 2022

The photovoltaic/thermal (PV/T) hybrid system combines a PV panel with a thermal collector to generate both electricity and heat energy. Several research have been conducted globally since the 1970s to increase its efficiency utilising various methodologies. One type of enhancing approach employed in this industry is phase-change materials. The current study combined a paraffin wax thermal storage unit with a typical PV/T hybrid collector (WPVT) and compared its performance with that of another comparable collector without a thermal store unit (TPVT). Both collectors were tested under actual weather circumstances from January to April 2021, with two water flow rates of 0.7 and 1.2 LPM. To analyse the rate of improvement in the PV/T system by adding a paraffin wax store unit, energy and exergy were simulated. During the trial period, the WPVT system provided the maximum efficiency flow rate of 1.2 LPM. It obtained around 60% efficiency, which was around 1.4 times that of TPVT. Furthermore, the modelling results indicated that the WPVT system’s maximum overall and exergy efficiencies were projected to be around 74.44 and 12%, respectively.
Characterization of sabatolimab, a novel immunotherapy with immuno-myeloid activity directed against TIM-3 receptor
Authors: Schwartz Stephanie , Patel Nidhi , Longmire Tyler , Jayaraman Pushpa , Jiang Xiaomo , Lu Hongbo , Baker Lisa , Velez Janelle , Ramesh Radha , Wavreille Anne-Sophie , Verneret Melanie , Fan Hong , Hu Tiancen , Xu Fangmin , Taraszka John , Pelletier Marc , Miyashiro Joy , Rinne Mikael , Dranoff Glenn , Sabatos-Peyton Catherine , Cremasco Viviana
Published: August 2022

Objectives

Sabatolimab is a humanized monoclonal antibody (hIgG4, S228P) directed against human T-cell immunoglobulin domain and mucin domain-3 (TIM-3). Herein, we describe the development and characterization of sabatolimab.

Methods

Sabatolimab was tested for binding to its target TIM-3 and blocking properties. The functional effects of sabatolimab were tested in T-cell killing and myeloid cell cytokine assays. Antibody-mediated cell phagocytosis (ADCP) by sabatolimab was also assessed.

Results

Sabatolimab was shown to (i) enhance T-cell killing and inflammatory cytokine production by dendritic cells (DCs); (ii) facilitate the phagocytic uptake of TIM-3-expressing target cells; and (iii) block the interaction between TIM-3 and its ligands PtdSer/galectin-9.

Conclusion

Taken together, our results support both direct anti-leukemic effects and immune-mediated modulation by sabatolimab, reinforcing the notion that sabatolimab represents a novel immunotherapy with immuno-myeloid activity, holding promise for the treatment of myeloid cell neoplasms.
Reference genome for the California ribbed mussel,Mytilus californianus, an ecosystem engineer
Authors: Paggeot Lisa X , DeBiasse Melissa B , Escalona Merly , Fairbairn Colin , Marimuthu Mohan P A , Nguyen Oanh , Sahasrabudhe Ruta , Dawson Michael N
Published: August 2022

The California ribbed mussel, Mytilus californianus, is an ecosystem engineer crucial for the survival of many marine species inhabiting the intertidal zone of California. Here, we describe the first reference genome for M. californianus and compare it to previously published genomes from three other Mytilus species: M. edulis, M. coruscus, and M. galloprovincialis. The M. californianus reference genome is 1.65 Gb in length, with N50 sequence length of 118 Mb, and an estimated 86.0% complete single copy genes. Compared with the other three Mytilus species, the M. californianus genome assembly is the longest, has the highest N50 value, and the highest percentage complete single copy genes. This high-quality genome assembly provides a foundation for population genetic analyses that will give insight into future conservation work along the coast of California.
Neural correlates in functional brain mapping among breast cancer survivors receiving different chemotherapy regimens: a qEEG/HEG-based investigation
Authors: Vasaghi Gharamaleki Maryam , Mousavi Seyedeh Zahra , Owrangi Maryam , Gholamzadeh Mohammad Javad , Kamali Ali-Mohammad , Dehghani Mehdi , Chakrabarti Prasun , Nami Mohammad
Published: August 2022

Background

Post-chemotherapy cognitive impairment commonly known as ‘chemobrain’ or ‘chemofog’ is a well-established clinical disorder affecting various cognitive domains including attention, visuospatial working memory, executive function, etc. Although several studies have confirmed the chemobrain in recent years, scant experiments have evaluated the potential neurotoxicity of different chemotherapy regimens and agents. In this study, we aimed to evaluate the extent of attention deficits, one of the commonly affected cognitive domains, among breast cancer patients treated with different chemotherapy regimens through neuroimaging techniques.

Methods

Breast cancer patients treated with two commonly prescribed chemotherapy regimens, Adriamycin, Cyclophosphamide and Taxol and Taxotere, Adriamycin and Cyclophosphamide, and healthy volunteers were recruited. Near-infrared hemoencephalography and quantitative electroencephalography assessments were recorded for each participant at rest and during task performance to compare the functional cortical changes associated with each chemotherapy regimen.

Results

Although no differences were observed in hemoencephalography results across groups, the quantitative electroencephalography analysis revealed increased power of high alpha/low beta in left fronto-centro-parietal regions involved in dorsal and ventral attention networks in the Adriamycin, Cyclophosphamide and Taxol-treated group compared with the Taxotere, Adriamycin and Cyclophosphamide and control group. The Adriamycin, Cyclophosphamide and Taxol-treated cases had the highest current source density values in dorsal attention network and ventral attention network and ventral attention network-related centers in 10 and 15 Hz associated with the lowest Z-scored Fast Fourier Transform coherence in the mentioned regions.

Conclusions

The negatively affected neurocognitive profile in breast cancer patients treated with the Adriamycin, Cyclophosphamide and Taxol regimen proposes presumably neurotoxic sequelae of this chemotherapy regimen as compared with the Taxotere, Adriamycin and Cyclophosphamide regimen.
The oversight of autonomous artificial intelligence: lessons from nurse practitioners as physician extenders
Authors: Morrell Walker , Shachar Carmel , Weiss Anthony P
Published: August 2022

The development of autonomous artificial intelligence (A-AI) products in health care raises novel regulatory challenges, including how to ensure their safety and efficacy in real-world settings. Supplementing a device-centered regulatory scheme with a regulatory scheme that considers A-AI products as a ‘physician extender’ may improve the real-world monitoring of these technologies and produce other benefits, such as increased access to the services offered by these products. In this article, we review the three approaches to the oversight of nurse practitioners, one type of physician extender, in the USA and extrapolate these approaches to produce a framework for the oversight of A-AI products. Under the framework, the US Food and Drug Administration would evaluate A-AI products and determine whether they are allowed to operate independently of physician oversight; required to operate under some physician oversight via a ‘collaborative protocol’ model; or required to operate under direct physician oversight via a ‘supervisory protocol’ model.
Medication Burden Among Pediatric Cancer Survivors: Analysis of a Population-Wide Electronic Database in Hong Kong
Authors: Ewig Celeste Lom-Ying , Hui Ka Ho , Lee Samantha Lai Ka , Leung Alex Wing Kwan , Wong Grace Lai-Hung , Li Chi Kong , Cheung Yin Ting
Published: August 2022

Background

Few studies have evaluated the medication burden borne by survivors of pediatric cancer. This study aimed to describe the drug utilization pattern of chronic medications in a cohort of young pediatric cancer survivors.

Methods

This was a population-based study of patients diagnosed with cancer at age 18 years or younger between 2000 and 2013 in Hong Kong and who had survived at least 5 years postdiagnosis. The primary outcome is the use of any chronic medication (medications that were prescribed for ≥30 consecutive days within a 6-month period). Multivariable log-binomial models were used to identify factors associated with chronic medication use. Kaplan-Meier analysis was used to present the cumulative proportion of survivors initiated on a chronic medication across time from cancer diagnosis.

Results

Of the 2444 survivors (median age = 22 years, interquartile range = 16-27 years), 669 (27.4%) required at least 1 chronic medication at least 5 years postdiagnosis. Survivors who developed a chronic health condition (CHC) had a 5.48 (95% confidence interval [CI] = 4.49 to 6.71) times higher risk of taking a chronic medication than those without CHC. At 10 years postdiagnosis, the cumulative proportion of survivors being initiated a chronic medication was 33.4% (95% CI = 31.1% to 35.6%) for the overall cohort. Higher cumulative proportions were observed in survivors with endocrine (74.6%, 95% CI = 68.4% to 79.6%), renal (68.8%, 95% CI = 54.2% to 78.7%), neurological (58.6%, 95% CI = 46.1% to 68.1%), and cardiovascular (54.7%, 95% CI = 44.0% to 63.4%) disorders.

Conclusion

Survivors with certain CHCs had a higher risk of starting a prescription medication in the early phase of survivorship. Future studies include examining the impact of medication burden on survivors’ functional status.
Association Between Adrenal-Restrictive HSD3B1 Inheritance and Hormone-Independent Subtypes of Endometrial and Breast Cancer
Authors: McManus Jeffrey M , Vargas Roberto , Bazeley Peter S , Schumacher Fredrick R , Sharifi Nima
Published: August 2022

Background

The germline variant rs1047303 (HSD3B1[1245A/C]), restricting or enabling production of potent androgens and estrogens from adrenal precursors, affects outcomes of castration-resistant prostate cancer and is associated with estrogen receptor positivity in postmenopausal breast cancer. Like breast cancer, endometrial cancer is another malignancy with hormone-dependent and hormone-independent subtypes. We hypothesized that adrenal-restrictive HSD3B1 genotype would associate with hormone-independent cancer subtypes.

Methods

We employed a previously described classification of tumors in The Cancer Genome Atlas into genomic clusters. We determined HSD3B1 genotype frequencies by endometrial cancer genomic cluster and calculated the odds per adrenal-restrictive A allele for the largely hormone-independent copy-number (CN) high subtype vs other subtypes. An equivalent analysis was performed for the genomically similar, hormone-independent basal breast cancer subtype. Last, we performed survival analyses for UK Biobank participants with endometrial cancer by HSD3B1 genotype. All statistical tests were 2-sided.

Results

The adrenal-restrictive HSD3B1(1245A) allele was associated with the CN-high endometrial cancer subtype (odds ratio [OR] = 1.63, 95% confidence interval [CI] = 1.14 to 2.32; P = .007). Similarly, HSD3B1(1245A) was associated with the basal breast cancer subtype (OR = 1.54, 95% CI = 1.13 to 2.08; P = .006). In the UK Biobank, endometrial cancer patients homozygous for HSD3B1(1245A) had worse overall (hazard ratio [HR] = 1.39, 95% CI = 1.16 to 1.68; P < .001) and cancer-specific (HR = 1.39, 95% CI = 1.14 to 1.70; P = .001) survival, consistent with the A allele being enriched in the more aggressive CN-high subtype.

Conclusions

These findings suggest roles for adrenal-restrictive vs adrenal-permissive steroidogenesis, by way of rs1047303 genotype, in the development of and/or outcomes from at least 3 commonly hormone-associated types of cancer: prostate, breast, and endometrial.
Comparative functional RNA editomes of neural differentiation from human PSCs
Authors: Zhang Yu , Zhang Qu , Hou Yuhong , Wang Ran , Wang Yu
Published: August 2022

RNA editing is a fundamental mechanism that constitutes the epitranscriptomic complexity. A-to-G editing is the predominant type catalyzed by ADAR1 and ADAR2 in human. Using a CRISPR/Cas9 approach to knockout ADAR1/2, we identified a regulatory role of RNA editing in directed differentiation of human embryonic stem cells (hESCs) toward neural progenitor cells (NPCs). Genome-wide landscapes of A-to-G editing in hESCs and four derivative cell lineages representing all three germ layers and the extraembryonic cell fate were profiled, with a particular focus on neural differentiation. Furthermore, a bioinformatics-guided case study identified a potential functional editing event in ZYG11B 3ʹUTR that might play a role in regulation of NPC differentiation through gain of miR6089 targeting. Collectively, our study established the functional role of A-to-G RNA editing in neural lineage differentiation; illustrated the RNA editing landscapes of hESCs and NPC differentiation; and shed new light on molecular insights thereof.
Exploring metallicity-dependent rates of Type Ia supernovae and their impact on galaxy formation
Authors: Gandhi Pratik J , Wetzel Andrew , Hopkins Philip F , Shappee Benjamin J , Wheeler Coral , Faucher-Giguère Claude-André
Published: August 2022

Type Ia supernovae are critical for feedback and elemental enrichment in galaxies. Recent surveys like the All-Sky Automated Survey for Supernova (ASAS-SN) and the Dark Energy Survey (DES) find that the specific supernova Ia rate at z ∼ 0 may be ≲20–50× higher in lower mass galaxies than at Milky Way-mass. Independently, observations show that the close-binary fraction of solar-type Milky Way stars is higher at lower metallicity. Motivated by these observations, we use the FIRE-2 cosmological zoom-in simulations to explore the impact of metallicity-dependent rate models on galaxies of $M_* \sim 10^7\!-\!10^{11}\, \rm {M}_{\odot }$. First, we benchmark our simulated star formation histories against observations, and show that the assumed stellar mass functions play a major role in determining the degree of tension between observations and metallicity-independent rate models, potentially causing ASAS-SN and DES observations to agree more than might appear. Models in which the supernova Ia rate increases with decreasing metallicity ($\propto Z^{-0.5 \,\, \rm {to} \,\, -1}$) provide significantly better agreement with observations. Encouragingly, these rate increases (≳10× in low-mass galaxies) do not significantly impact galaxy masses and morphologies, which remain largely unaffected except for our most extreme models. We explore implications for both [Fe/H] and [$\alpha /\rm {Fe}$] enrichment; metallicity-dependent rate models can improve agreement with the observed stellar mass–metallicity relations in low-mass galaxies. Our results demonstrate that a range of metallicity-dependent rate models are viable for galaxy formation and motivate future work.
Single base-pair resolution analysis of DNA binding motif with MoMotif reveals an oncogenic function of CTCF zinc-finger 1 mutation
Authors: Lebeau Benjamin , Zhao Kaiqiong , Jangal Maika , Zhao Tiejun , Guerra Maria , Greenwood Celia M T , Witcher Michael
Published: August 2022

Defining the impact of missense mutations on the recognition of DNA motifs is highly dependent on bioinformatic tools that define DNA binding elements. However, classical motif analysis tools remain limited in their capacity to identify subtle changes in complex binding motifs between distinct conditions. To overcome this limitation, we developed a new tool, MoMotif, that facilitates a sensitive identification, at the single base-pair resolution, of complex, or subtle, alterations to core binding motifs, discerned from ChIP-seq data. We employed MoMotif to define the previously uncharacterized recognition motif of CTCF zinc-finger 1 (ZF1), and to further define the impact of CTCF ZF1 mutation on its association with chromatin. Mutations of CTCF ZF1 are exclusive to breast cancer and are associated with metastasis and therapeutic resistance, but the underlying mechanisms are unclear. Using MoMotif, we identified an extension of the CTCF core binding motif, necessitating a functional ZF1 to bind appropriately. Using a combination of ChIP-Seq and RNA-Seq, we discover that the inability to bind this extended motif drives an altered transcriptional program associated with the oncogenic phenotypes observed clinically. Our study demonstrates that MoMotif is a powerful new tool for comparative ChIP-seq analysis and characterising DNA-protein contacts.
Modeling splicing outcome by combining 5′ss strength and splicing regulatory elements
Authors: Müller Lisa , Ptok Johannes , Nisar Azlan , Antemann Jennifer , Grothmann Ramona , Hillebrand Frank , Brillen Anna-Lena , Ritchie Anastasia , Theiss Stephan , Schaal Heiner
Published: August 2022

Correct pre-mRNA processing in higher eukaryotes vastly depends on splice site recognition. Beyond conserved 5′ss and 3′ss motifs, splicing regulatory elements (SREs) play a pivotal role in this recognition process. Here, we present in silico designed sequences with arbitrary a priori prescribed splicing regulatory HEXplorer properties that can be concatenated to arbitrary length without changing their regulatory properties. We experimentally validated in silico predictions in a massively parallel splicing reporter assay on more than 3000 sequences and exemplarily identified some SRE binding proteins. Aiming at a unified ‘functional splice site strength’ encompassing both U1 snRNA complementarity and impact from neighboring SREs, we developed a novel RNA-seq based 5′ss usage landscape, mapping the competition of pairs of high confidence 5′ss and neighboring exonic GT sites along HBond and HEXplorer score coordinate axes on human fibroblast and endothelium transcriptome datasets. These RNA-seq data served as basis for a logistic 5′ss usage prediction model, which greatly improved discrimination between strong but unused exonic GT sites and annotated highly used 5′ss. Our 5′ss usage landscape offers a unified view on 5′ss and SRE neighborhood impact on splice site recognition, and may contribute to improved mutation assessment in human genetics.
Nonlinear manipulation and analysis of large DNA datasets
Authors: Cui Meiying , Zhao Xueping , Reddavide Francesco V , Gaillez Michelle Patino , Heiden Stephan , Mannocci Luca , Thompson Michael , Zhang Yixin
Published: August 2022

Information processing functions are essential for organisms to perceive and react to their complex environment, and for humans to analyze and rationalize them. While our brain is extraordinary at processing complex information, winner-take-all, as a type of biased competition is one of the simplest models of lateral inhibition and competition among biological neurons. It has been implemented as DNA-based neural networks, for example, to mimic pattern recognition. However, the utility of DNA-based computation in information processing for real biotechnological applications remains to be demonstrated. In this paper, a biased competition method for nonlinear manipulation and analysis of mixtures of DNA sequences was developed. Unlike conventional biological experiments, selected species were not directly subjected to analysis. Instead, parallel computation among a myriad of different DNA sequences was carried out to reduce the information entropy. The method could be used for various oligonucleotide-encoded libraries, as we have demonstrated its application in decoding and data analysis for selection experiments with DNA-encoded chemical libraries against protein targets.
A phase I/II study of intrathecal trastuzumab in human epidermal growth factor receptor 2-positive (HER2-positive) cancer with leptomeningeal metastases: Safety, efficacy, and cerebrospinal fluid pharmacokinetics
Authors: Kumthekar Priya U , Avram Michael J , Lassman Andrew B , Lin Nancy U , Lee Eudocia , Grimm Sean A , Schwartz Margaret , Bell Burdett Kirsten L , Lukas Rimas V , Dixit Karan , Perron Isabella , Zhang Hui , Gradishar William J , Pentsova Elena I , Jeyapalan Suriya , Groves Morris D , Melisko Michelle , Raizer Jeffrey J
Published: August 2022

Background

Patients with human epidermal growth factor receptor 2-positive (HER2-positive) cancers have a high incidence of central nervous system (CNS) spread, but unfortunately systemic trastuzumab which targets the HER2 receptor has little CNS penetration. The purpose of this study was to determine the maximum-tolerated dose of intrathecal trastuzumab and its efficacy in patients with HER2-positive leptomeningeal disease (LMD).

Methods

This multicenter study enrolled 34 LMD patients in a combined phase I/II study in treating patients with intrathecal trastuzumab. Any HER2-positive histology was allowed in the phase I; the phase II was limited to HER2-positive breast cancer.

Results

Intrathecal trastuzumab was well-tolerated, with one dose limiting toxicity of grade 4 (arachnoiditis) occurring at the 80 mg twice weekly dose. The recommended phase II dose was 80 mg intrathecally twice weekly. Twenty-six patients at dose level 80 mg were included in evaluation for efficacy: partial response was seen in 5 (19.2%) patients, stable disease was observed in 13 (50.0%), and 8 (30.8%) of the patients had progressive disease. Median overall survival (OS) for phase II dose treated patients was 8.3 months (95% CI 5.2–19.6). The phase II HER2-positive breast cancer patients median OS was 10.5 months (95% CI 5.2–20.9). Pharmacokinetic (PK) studies were limited in the setting of concurrent systemic trastuzumab administration, however, did show stable cerebrospinal fluid (CSF) concentrations with repeated dosing suggest that trastuzumab does not accumulate in the CSF in toxic concentrations.

Conclusion

This study suggests promise for potentially improved outcomes of HER-positive LMD patients when treated with intrathecal trastuzumab while remaining safe and well-tolerated for patients.
Modulating glioblastoma chemotherapy response: Evaluating long non-coding RNA effects on DNA damage response, glioma stem cell function, and hypoxic processes
Authors: Yuan Edith , Liu Kristie , Lee Justin , Tsung Kathleen , Chow Frances , Attenello Frank J
Published: August 2022

Glioblastoma (GBM) is the most common and aggressive primary adult brain tumor, with an estimated annual incidence of 17 000 new cases in the United States. Current treatments for GBM include chemotherapy, surgical resection, radiation therapy, and antiangiogenic therapy. However, despite the various therapeutic options, the 5-year survival rate remains at a dismal 5%. Temozolomide (TMZ) is the first-line chemotherapy drug for GBM; however, poor TMZ response is one of the main contributors to the dismal prognosis. Long non-coding RNAs (lncRNAs) are nonprotein coding transcripts greater than 200 nucleotides that have been implicated to mediate various GBM pathologies, including chemoresistance. In this review, we aim to frame the TMZ response in GBM via exploration of the lncRNAs mediating three major mechanisms of TMZ resistance: (1) regulation of the DNA damage response, (2) maintenance of glioma stem cell identity, and (3) exploitation of hypoxia-associated responses.
Physician Payments from Pharmaceutical Companies Related to Cancer Drugs
Authors: Mitchell Aaron P , Mishra Meza Akriti , Trivedi Niti U , Bach Peter B , Gönen Mithat
Published: August 2022

Background

Drug manufacturers claim that the purpose of financial payments to physicians is to facilitate education about new drugs. This claim suggests 2 testable hypotheses: payments should not be associated with drug revenue and payments for each drug should decline over time as physicians become educated.

Materials and Methods

We used open payments data on industry payments. We included payments for cancer drugs without generic/biosimilar competitors and used federal data sources to measure Medicare spending (a proxy for overall drug revenue) and a number of prescribers. We used generalized estimating equations (GEE) to model the drug-level association between industry payments and Medicare spending. Separately, we used GEE to estimate the change in payments with respect to the duration of time since initial FDA approval.

Results

The sample included 89 drugs and 361 drug-year observations. The total value of industry payments for oncology drugs increased, from $53 333 854 in 2014 to $90 343 731 in 2018. There was no association between log-transformed mean, per-physician industry payments, and per-physician Medicare spending (estimate −0.001, 95%CI, −0.005 to 0.004). Payments for individual drugs decreased over time; estimated payments in the subsequent year for a drug with mean, per-physician payments of $1000 in the index year was: $681* for drugs 0-4 years since approval, $825 for 5-9 years, and $679* for ≥10 years (*P < .05).

Conclusions

Although industry-sponsored education may also serve marketing purposes, the absence of association between industry payments and Medicare spending and the decline in payments subsequent to approval are consistent with claims that industry payments function to facilitate physician education.
Commonalities and specialties in photosynthetic functions of PROTON GRADIENT REGULATION5 variants in Arabidopsis
Authors: Penzler Jan-Ferdinand , Marino Giada , Reiter Bennet , Kleine Tatjana , Naranjo Belen , Leister Dario
Published: August 2022

The PROTON GRADIENT REGULATION5 (PGR5) protein is required for trans-thylakoid proton gradient formation and acclimation to fluctuating light (FL). PGR5 functionally interacts with two other thylakoid proteins, PGR5-like 1 (PGRL1) and 2 (PGRL2); however, the molecular details of these interactions are largely unknown. In the Arabidopsis (Arabidopsis thaliana) pgr5-1 mutant, the PGR5G130S protein accumulates in only small amounts. In this work, we generated a knockout allele of PGR5 (pgr5-Cas) using CRISPR-Cas9 technology. Like pgr5-1, pgr5-Cas is seedling-lethal under FL, but photosynthesis and particularly cyclic electron flow, as well as chlorophyll content, are less severely affected in both pgr5-Cas and pgrl1ab (which lacks PGRL1 and PGR5) than in pgr5-1. These differences are associated with changes in the levels of 260 proteins, including components of the Calvin–Benson cycle, photosystems II and I, and the NDH complex, in pgr5-1 relative to the wild type (WT), pgr5-Cas, and pgrl1ab. Some of the differences between pgr5-1 and the other mutant lines could be tentatively assigned to second-site mutations in the pgr5-1 line, identified by whole-genome sequencing. However, others, particularly the more pronounced photosynthetic defects and PGRL1 depletion (compared to pgr5-Cas), are clearly due to specific negative effects of the amino-acid substitution in PGR5G130S, as demonstrated by complementation analysis. Moreover, pgr5-1 and pgr5-Cas plants are less tolerant to long-term exposure to high light than pgrl1ab plants. These results imply that, in addition to the previously reported necessity of PGRL1 for optimal PGR5 function, PGR5 is required alongside PGRL1 to avoid harmful effects on plant performance.
Native architecture and acclimation of photosynthetic membranes in a fast-growing cyanobacterium
Authors: Zhao Long-Sheng , Li Chun-Yang , Chen Xiu-Lan , Wang Qiang , Zhang Yu-Zhong , Liu Lu-Ning
Published: August 2022

Efficient solar energy conversion is ensured by the organization, physical association, and physiological coordination of various protein complexes in photosynthetic membranes. Here, we visualize the native architecture and interactions of photosynthetic complexes within the thylakoid membranes from a fast-growing cyanobacterium Synechococcus elongatus UTEX 2973 (Syn2973) using high-resolution atomic force microscopy. In the Syn2973 thylakoid membranes, both photosystem I (PSI)-enriched domains and crystalline photosystem II (PSII) dimer arrays were observed, providing favorable membrane environments for photosynthetic electron transport. The high light (HL)-adapted thylakoid membranes accommodated a large amount of PSI complexes, without the incorporation of iron-stress-induced protein A (IsiA) assemblies and formation of IsiA–PSI supercomplexes. In the iron deficiency (Fe−)-treated thylakoid membranes, in contrast, IsiA proteins densely associated with PSI, forming the IsiA–PSI supercomplexes with varying assembly structures. Moreover, type-I NADH dehydrogenase-like complexes (NDH-1) were upregulated under the HL and Fe− conditions and established close association with PSI complexes to facilitate cyclic electron transport. Our study provides insight into the structural heterogeneity and plasticity of the photosynthetic apparatus in the context of their native membranes in Syn2973 under environmental stress. Advanced understanding of the photosynthetic membrane organization and adaptation will provide a framework for uncovering the molecular mechanisms of efficient light harvesting and energy conversion.
Rheumatoid arthritis is associated with increased gut permeability and bacterial translocation that are reversed by inflammation control
Authors: Audo Rachel , Sanchez Pauline , Rivière Benjamin , Mielle Julie , Tan Jian , Lukas Cédric , Macia Laurence , Morel Jacques , Immediato Daien Claire
Published: August 2022

Objective

To assess how RA and DMARDs affect gut permeability.

Methods

To explore colonic mucosa integrity, tight junction proteins zonula occludens-1, occludin and claudin 2 were quantified by immunohistochemistry on colonic biopsies in 20 RA patients and 20 age- and sex-matched controls. Staining intensity was assessed by two blinded independent readers. To explore intestinal permeability, serum concentrations of lipopolysaccharide binding protein (LBP), soluble CD14 (sCD14) and zonulin-related proteins (ZRPs) were evaluated by ELISA in another cohort of 59 RA patients: 21 patients naive for DMARDs [17 before and after introduction of a conventional synthetic DMARD (csDMARD)], 38 patients with severe RA [before and after introduction of a biological DMARD (bDMARD)] and 33 healthy controls.

Results

Z0-1 protein was less expressed in the colon of RA patients than controls [mean score 1.6 (s.e.m. 0.56) vs 2.0 (0.43), P = 0.01], while no significant difference was detected for occludin and claudin-2. RA patients had higher serum LBP and sCD14 concentrations than controls. LBP and sCD14 levels were significantly correlated with the 28-joint DAS (r = 0.61, P = 0.005 and r = 0.57, P = 0.01, respectively) while ZRP did not. bDMARD responders had significantly reduced LBP and sCD14 concentrations, unlike bDMARD non-responders and patients treated with csDMARDs.

Conclusion

RA patients have altered colonic tight junction proteins and increased serum biomarkers of intestinal permeability. There was a correlation between serological markers of intestinal permeability and disease activity as well as bDMARD response. These results suggest a link between impaired gut integrity and systemic inflammation in RA.
Information in Financial Markets and Its Real Effects
Authors: Goldstein Itay
Published: August 2022

Financial markets have a central role in allocating resources in modern economies. One of the main functions of financial markets is the discovery of information. This information in turn helps guide decisions in the real side of the economy. The literature on the “feedback effect” of financial markets explores this channel. Empirical work tries to identify the informational feedback from markets to corporate decisions. Theoretical work explores implications that this feedback effect has for the equilibrium in financial markets and for economic efficiency. Current trends in information technology under the FinTech revolution change the nature of information processing in financial markets and so may change the nature of the feedback effect. In this article, I review the main themes of this developing literature and connect them to the current information revolution. I also discuss directions for future research.
Listening to and Believing Derogatory and Threatening Voices
Authors: Sheaves Bryony , Johns Louise , Loe Bao S , Bold Emily , Černis Emma ,   The McPin Hearing Voices Lived Experience Advisory Panel, Molodynski Andrew , Freeman Daniel
Published: August 2022

Background and hypothesis

A plausible cause of distress for voice hearers is listening to and believing the threats and criticisms heard. Qualitative research indicates that patients have understandable reasons to listen. This study aimed to develop the understanding of distress using this listening and believing framework. Measures were developed of listening and believing voices and the reasons, and associations with distress tested.

Study design

A cross-sectional study of patients hearing derogatory and threatening voices (N = 591). Listening and Believing–Assessment and Listening and Believing–Reasons item pools were completed, and assessments of distress. Exploratory and confirmatory factor analyses and structural equation modeling (SEM) were conducted.

Study results

52% (n = 307) of participants believed their voices most or all the time. Listening and believing had 4 factors: active listening, passive listening, believing, and disregarding. Higher levels of believing, active listening, and particularly passive listening were associated with higher levels of anxiety, depression, and voice distress. Reasons for listening and believing formed 7 factors: to better understand the threat; being too worn down to resist; to learn something insightful; being alone with time to listen; voices trying to capture attention; voices sounding like real people; and voices sounding like known people. Each type of reason was associated with active listening, passive listening, and believing. SEM showed that feeling worn down in particular accounted for listening and believing. Test–retest reliability of measures was excellent.

Conclusions

A framework of listening and believing negative voices has the potential to inform the understanding and treatment of voice distress.
Whole Genome Sequencing Suggests that “Nonpathogenicity on Banana (NPB)” Is the Ancestral State of the Ralstonia solanacearum IIB-4 Lineage
Authors: Beutler Jonathan , Holden Samuel , Georgoulis Stratton , Williams Darrielle , Norman David J. , Lowe-Power Tiffany M.
Published: August 2022

The bacterial wilt pathogens in the Ralstonia solanacearum species complex (RSSC) have broad but finite host ranges. Population genetic surveys of RSSC pathogens show that many sequevars (subspecies groups) are predominantly recovered from wilting solanaceous plants. In contrast, strains in the IIB-4 sequevar have been isolated from plants in over a dozen families. Certain IIB-4 lineages have been classified as banana-virulent versus “not pathogenic to banana (NPB).” Prior analysis suggested that the NPB lineage has diverged from the banana-virulent IIB-4 strains. To test this model, we analyzed the phenotypes and phylogeny of a diverse collection of 19 IIB-4 isolates. We used Illumina sequencing to assemble draft genomes of 12 new strains. Based on whole genome phylogenetic analysis, these IIB-4 strains clustered into five subclades. We quantified the virulence of each strain on tomato, banana, melon, and impatiens plants. Overall, the virulence patterns correlated with phylogeny. Banana virulence was restricted to the IIB-4D subclade ( N = 4/4 strains) and IIB-4E subclade ( N = 1/2 strains). Subclades IIB-4D and IIB-4E are sister subclades, and their closest relative, the IIB-4A-C subclade, lacked virulence on banana. Our data support a revised model in which banana virulence is an innovation within the IIB4D/E subclades.

[Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY 4.0 International license .
Harvard Medical School’s Sexual and Gender Minority Health Equity Initiative: Curricular and Climate Innovations in Undergraduate Medical Education
Authors: Keuroghlian Alex S. , Charlton Brittany M. , Katz-Wise Sabra L. , Williams Kesha , Jarvie E.J. , Phillips Rusty , Kremen Jessica , Guss Carly E. , Dalrymple John L. , Potter Jennifer
Published: August 2022

Problem

Sexual and gender minority (SGM) populations face numerous health disparities. Medical school curricula lack adequate educational content preparing students for serving SGM patients, and medical students typically do not experience welcoming, inclusive educational environments conducive to learning about SGM health care.

Approach

In 2018, Harvard Medical School (HMS) launched the 3-year Sexual and Gender Minority Health Equity Initiative to integrate SGM health content throughout the longitudinal core medical curriculum and cultivate an educational climate conducive for engaging students and faculty in SGM health education. The initiative employed innovative strategies to comprehensively review existing SGM health curricular content and climate; integrate content across courses and clerkships; lead with LGBTQIA+ (lesbian, gay, bisexual, transgender, queer, intersex, asexual, and all sexual and gender minorities) community engagement; adopt an intersectional approach that centers racial equity; cultivate safe, affirming educational environments for LGBTQIA+ and non-LGBTQIA+ students and staff; ensure all graduating students are prepared to care for SGM patients; enhance faculty knowledge, skills, attitudes, and confidence teaching SGM health; evaluate effectiveness and impact of SGM health curricular innovations; prioritize sustainability of curricular innovations; and publicly share and disseminate SGM health curricular products and tools.

Outcomes

Key outcomes of the initiative focused on 5 areas: development of 9 SGM health competencies, stakeholder engagement (HMS students and faculty, national SGM health experts, and LGBTQIA+ community members), student life and educational climate (increased LGBTQIA+ student matriculants, enhanced mentorship and support), curriculum development (authentic LGBTQIA+ standardized patient experiences, clerkship toolkit design), and faculty development (multimedia curriculum on content and process to teach SGM health).

Next Steps

In addition to refining curricular integration, evaluating interventions, and implementing comprehensive antiracist and gender-affirming educational policies, the next phase will involve dissemination by translating best practices into feasible approaches that any school can adopt to meet local needs with available resources.