bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic and Phenotypic Characterization of the Fungal Pathogen Cytospora plurivora from Western Colorado Peach Orchards and the Development of a ddPCR Assay for Detection and Quantification
Authors: Stewart Jane E. , Miller Stephan T. , Zink Frida A. , Caballero Jorge Ibarra , Tembrock Luke R.
Published: September 2021

Cytospora canker is one of the most important diseases affecting peach production in Colorado, yet previous efforts to characterize Cytospora species diversity in Colorado have relied exclusively on morphological traits. Recently, several new Cytospora species were described from peach orchards within the United States using molecular and morphological data, prompting the need to reexamine Cytospora spp. present on peach trees in Colorado. A total of 137 isolates of Cytospora spp. were collected from eight orchards in western Colorado. Isolates were sequenced at the internal transcribed spacer region and elongation factor 1-α and assessed with reference sequences in phylogenetic analyses. All isolates from western Colorado peach trees resolved with the newly described Cytospora plurivora. In addition to molecular characterization, temperature growth and virulence assays were conducted to assess phenotypic variation among the isolates from western Colorado. Variation across isolates was found both in growth at different temperatures and in virulence. Ancestral state reconstruction analyses resolved the most virulent (and most often collected) haplotypes together in a well-supported clade from which a single monophyletic origin of high virulence can be inferred. Finally, a droplet digital PCR assay was developed for use in ongoing and future studies to detect and quantify C. plurivora from field and laboratory samples.
Managing Human Subjects Research During a Global Pandemic at an Academic Center: Lessons Learned From COVID-19
Authors: Stiles Deborah F. , Ruotolo Brenda L. , Kim Helen , Cho Jane , Appelbaum Paul S. , Green Nancy S.
Published: September 2021

By March 2020, New York City became the early epicenter of the COVID-19 pandemic in the United States. Consequently, Columbia University, with its large portfolio of human subjects research, had to address the challenges of protecting thousands of research participants and research staff from potential exposure to COVID-19 while facilitating essential biomedical research, especially pandemic-related studies. The authors describe, from the perspective of Columbia’s research administration leadership, how the University and its primary teaching hospital ramped down—and later ramped up—human subjects research and reflect on lessons learned.

As the pandemic unfolded, only studies offering the prospect of direct benefit to subjects were permitted to continue with in-person contact. New in-person participant enrollment ceased, except for COVID-19 prevention or treatment studies. Centralized, frequently updated communication about policies and procedures was disseminated to the Columbia research community. Procedural efficiencies were rapidly developed and implemented for review and oversight of human subjects research and contractual agreements for clinical trials. More frequent institutional review board meetings and 24-hour support markedly reduced turnaround time for COVID-19 studies, without delaying approvals of non–COVID-19 research. Research administration worked closely with relevant principal federal agencies, whose regulatory flexibility facilitated the efficient implementation of COVID-19–related research.

Overall, the ramp-down and ramp-up of the majority of human subjects research, with specified priorities and accelerated processes, worked well. Adjustments were made to handle the increase in administrative tasks, the need to respond rapidly to added oversight responsibilities, and the management of the many new COVID-19–related research protocols. Timely, centralized communication, support for staff needs, prioritization, and collaboration were critical to successful research oversight at a large-scale academic setting in the midst of a pandemic. These perspectives may be useful to academic research centers addressing the current and future pandemics.
Advancing Social Mission Research: A Call to Action
Authors: Erikson Clese , Ziemann Margaret
Published: September 2021

Social mission efforts in health professions education are designed to advance health equity and address the health disparities of the society in which they exist. While there is growing evidence that social mission–related interventions are associated with intended outcomes such as practice in underserved communities, student diversity, and students graduating with skills and knowledge that prepare them to address societal needs, critical evidence gaps remain that limit the possibility of generalizing findings and using social mission strategically to advance health equity. At a time when COVID-19 has been laying bare health disparities related to systemic racism and maldistribution of resources, understanding how health professions training can produce the workforce needed to advance health equity becomes even more imperative. Yet, data and methods limitations are hindering progress in this critical research.

The authors present an overview of the social mission research landscape; their review of the research led them to conclude that more rigorous research and data collection are needed to determine the link between social mission activities in health professions education and advances in health equity. To accelerate understanding of how health professions education and training can advance health equity, the authors propose a social mission research road map that includes (1) creating a social mission research community by consolidating stakeholders, (2) building a solid foundation for the research through development of a consensus-driven logic framework and research agenda, and (3) laying out the data and methodological needs that are imperative to strengthening the social mission evidence base and identifying opportunities to address these needs. Core to achieving these milestones is leadership from an organizing body that can serve as a hub for social mission research and engage stakeholder groups in building the evidence base for social mission strategies that will ultimately advance health equity.
Accelerating drug access from advanced to early breast cancer: the special case of oral selective estrogen receptor degraders
Authors: Wilson Brooke E. , Cescon David W.
Published: September 2021

Purpose of review

For hormone receptor positive breast cancer, the development of endocrine resistance commonly occurs, presenting as either disease progression in the metastatic setting or recurrence during or following adjuvant endocrine therapy. Various mechanisms of resistance have been described. In order to reduce or overcome endocrine resistance, there has been substantial interest in developing potent and orally bioavailable selective estrogen receptor degraders (SERDs) for metastatic disease and select patients with early-stage estrogen receptor positive breast cancer.

Recent findings

At least 11 oral SERDs have entered clinical development. We review current studies in both the metastatic and neoadjuvant/adjuvant setting and present the available evidence of benefit and toxicity for these novel agents. Further characterization of changes to tissue-based biomarkers such as estrogen receptor, progesterone receptor and Ki67 expression and blood-based biomarkers such as ctDNA and estrogen receptor 1 mutation may help to refine therapeutic strategies, combinations, and patient selection to identify women who are most likely to benefit from these novel endocrine agents.

Although SERDs have clear therapeutic potential based on nonclinical studies and have demonstrated early signs of activity in phase I and II studies in the metastatic setting, ongoing research is needed to clarify when and in whom these agents may have greatest clinical benefit.
Improving Care Delivery: Location Timestamps to Enhance Process Measurement of a Clinical Workflow
Authors: Barrick Lindsey , Wu Danny T.Y. , Frey Theresa , Shu Derek , Abbu Ruthvik , Porter Stephen C. , Overmann Kevin M.
Published: September 2021

Introduction:

Traditional quality improvement (QI) strategies to describe workflow processes rely primarily upon qualitative methods or human-driven observations. These methods may be limited in scope and accuracy when applied to time-based workflow processes. This study sought to evaluate the utility of integrating objective time measurements to augment traditional QI strategies using procedural sedation workflow in a pediatric emergency department as an archetype.

Methods:

We applied the FOCUS-Plan-Do-Check-Act framework to reduce the time from arrival to sedation for long-bone fractures. First, we added supplementary framework-defining steps to repeat the Clarifying and Understanding steps. We then extracted objective time-based data from an electronic health record (EHR) system and a real-time locating system (RTLS). We then compared and contrasted the findings of traditional surveys with analyses of timed steps within the sedation workflow.

Results:

When identifying the source of delays, traditional survey techniques yielded ambiguous and even conflicting results based on clinical roles. The timestamps supported 5 measurable clinical role of subworkflows. By measuring the time to completion for 54 sedation cases, workflow patterns and significant bottlenecks were identified.

Conclusions:

Analyzing the time to complete individual tasks provided a more nuanced description of workflow delays and clarity when traditional survey results conflicted. Augmenting traditional QI process maps with EHR and RTLS timestamps better explained workflow bottlenecks, informing the QI team when selecting targets for subsequent Plan-Do-Check-Act work.
Initiative to Reduce Antibiotic Exposure of Asymptomatic Infants Born to Mothers with Intraamniotic Infection
Authors: Weiss Katherine J. , Song Richard S. , DeVries Nikole M. , McLean Amy L. , Moyer Laurel B.
Published: September 2021

Introduction:

Infants born to mothers with intraamniotic infection (IAI) received antibiotic treatment per the Centers for Disease Control and Prevention and American Academy of Pediatrics guidelines in our neonatal intensive care unit (NICU) for early-onset bacterial sepsis evaluation. We conducted a quality improvement project to decrease antibiotic use and NICU admission in infants born to mothers with IAI.

Methods:

We aimed to decrease the antibiotic exposure for asymptomatic infants born to mothers with IAI from 100% to 20% in 6 months. We obtained baseline data on these infants from January 2018 to January 2019, with the intervention starting in February 2019. A new standardized guideline to clinically monitor and follow laboratories on asymptomatic infants in couplet care was created with a multidisciplinary team’s help and implemented after provider education. The team reviewed data monthly and used PDSA cycles to make necessary changes, including updating order sets, more educational handouts, and real-time coaching to both nurses and physicians.

Results:

There was a dramatic decline (93%–0%) in antibiotic exposure and NICU admission after implementing this guideline. There was also a decrease in IAI diagnosis. There were no readmissions of infants for infection within 30 days of discharge, and there were no positive blood cultures.

Conclusions:

Implementing best antibiotic stewardship practices through a standardized guideline, testing, implementation of processes, and education by a multidisciplinary team limited the antibiotic exposure and NICU admissions for infants born to mothers with IAI with no known increase in readmissions.
Effect of combination therapy with neural stem cell transplantation and teramethylpyrazine in rats following acute spinal cord injury
Authors: Zhang Haocong , Huang Zijun , Guo Mingming , Meng Lingzhi , Piao Meihui , Zhang Meng , Yu Hailong
Published: September 2021

Objectives

This study was to explore the effects of teramethylpyrazine (TMP) administered in conjunction with neural stem cell transplantation on motor function, pathological lesions and the Janus kinase (JAK)2/signal transducer and activator of transcription 3 signal transduction pathway in rats following acute spinal cord injury (SCI).

Methods

Female Sprague–Dawley rats were randomly divided into sham, model, neural stem cells (NSCs) and NSCs+TMP groups. Motor function was evaluated using the Basso, Beattie, Bresnahan scale. Spinal cord neuropathies and neuron apoptosis were observed by HE and TUNEL staining. The brain-derived neurotrophic factor (BDNF), Nogo-A, JAK2 and p-JAK2 protein levels were measured by western blot analysis.

Results

NSCs+TMP significantly improved rat motor function, attenuated impaired spinal cords, and decreased cellular apoptosis, compared with NSCs therapy alone (P < 0.05). In addition, expression of BDNF protein was significantly higher in NSCs+TMP rats compared with other groups regardless of time postinjury (P < 0.05). The highest expression levels of Nogo-A protein were observed in the model group. The expression of p-JAK2 in the NSCs+TMP group was relatively lower than the model and NSCs groups (P < 0.05).

Conclusions

In rats with SCI, NSCs+TMP effectively improved motor function and offered spinal cord protection by increasing BDNF and decreasing Nogo-A levels, as well as inhibiting the JAK2/STAT3 signal transduction pathway, suggesting that TMP could be a useful agent in NSCs transplantation in the treatment of SCI.
Bicaudal-C protein, a potential antidepressant target
Authors: Han Qinghua , Jiang Jianwei , Yuan Yue , Tang Bo , Zhang Jianjun
Published: September 2021

Bicaudal-C protein is a highly conserved RNA binding protein, which contains K homology domains and sterile alpha motif domain. Genome-wide association study identified that Bicaudal-C protein was associated with depression. The expression of Bicaudal-C increased in depression patients, also increased expression of Bicaudal-C induces the behavior of depression. The decrease of synaptic plasticity plays a part in depression. Bicaudal-C protein reduces the synaptic plasticity of neurons via TrkB/mTOR/AMPA/pGluA1 pathways, Wnt pathway, or influencing some proteins related to synaptic plasticity. The decreased expression of Bicaudal-C plays an important role in the action of several antidepressants, such as ketamine, biperiden, and scopolamine. Therefore, Bicaudal-C protein may be a potential antidepressant target. Clarifying the relationship between Bicaudal-C protein and depression may help us to find new antidepressants. This review focuses on the research advances of the relationship between Bicaudal-C protein and depression.
Orbiviruses in biting midges and mosquitoes from the Zambezi region, Namibia
Authors: Guggemos Heiko D. , Fendt Matthias , Hermanns Kyra , Hieke Christian , Heyde Verena , Mfune John K. E. , Borgemeister Christian , Junglen Sandra
Published: September 2021

The genus Orbivirus includes a variety of pathogenic viruses that are transmitted by biting midges, mosquitoes and ticks. Some of the economically most relevant orbiviruses are endemic to Namibia, like the livestock-pathogenic Bluetongue and African horse sickness viruses. Here, we assessed the diversity of orbiviruses circulating in the Zambezi region of north-eastern Namibia. A total of 10 250 biting midges and 10 206 mosquitoes were collected and screened for orbivirus infections. We identified Palyam virus (PALV) in a pool of biting midges (Culicoides sp.) sampled in the Wuparo Conservancy and three strains of Corriparta virus (CORV) in Culex sp. mosquitoes sampled in Mudumu National Park and the Mashi Conservancy. This is, to our knowledge, the first detection of PALV and CORV in Namibia. Both viruses infect vertebrates but only PALV has been reported to cause disease. PALV can cause foetal malformations and abortions in ruminants. Furthermore, a novel orbivirus, related to Kammavanpettai virus from India and Umatilla virus from North America, was discovered in biting midges (Culicoides sp.) originating from Mudumu National Park and tentatively named Mudumu virus (MUMUV). Complete genomes of PALV, CORV and MUMUV were sequenced and genetically characterized. The Namibian CORV strain showed 24.3 % nucleotide divergence in its subcore shell gene to CORV strains from Australia, indicating that African CORV variants vary widely from their Australian relatives. CORV was isolated in cell culture and replicated to high titres in mosquito and duck cells. No growth was found in rodent and primate cells. The data presented here show that diverse orbiviruses are endemic to the Zambezi region. Further studies are needed to assess their effects on wildlife and livestock.
Group B streptococcal infections in infants in Iceland: clinical and microbiological factors
Authors: Baeringsdottir Birta , Erlendsdottir Helga , Bjornsdottir Erla Soffia , Martins Elisabete R. , Ramirez Mário , Haraldsson Asgeir , Thorkelsson Thordur
Published: September 2021

Introduction. Group B streptococcus (GBS) is a leading cause of invasive neonatal infections. These have been divided into early-onset disease (EOD; <7 days) and late-onset disease (LOD; 7–89 days), with different GBS clonal complexes (CCs) associated with different disease presentations.

Hypothesis. Different GBS CCs are associated with timing of infection (EOD or LOD) and clinical presentation (sepsis, meningitis or pneumonia).

Aim. To study infant GBS infections in Iceland from 1975 to 2019. Are specific GBS CCs related to disease presentation? Is CC17 overrepresented in infant GBS infections in Iceland?

Methodology. All culture-confirmed invasive GBS infections in infants (<90 days) in Iceland from 1975 to 2019 were included. Clinical information was gathered from medical records.

Results. A total of 127 invasive GBS infections in infants were diagnosed, but 105 infants were included in the study. Of these, 56 had EOD and 49 had LOD. The incidence of GBS infections declined from 2000 onwards but increased again at the end of the study period. Furthermore, there was a significant increase in LOD over the study period (P=0.0001). The most common presenting symptoms were respiratory difficulties and fever and the most common presentation was sepsis alone. Approximately one-third of the cases were caused by GBS CC17 of serotype III with surface protein RIB and pili PI-1+PI-2b or PI-2b. CC17 was significantly associated with LOD (P<0.001).

Conclusion. CC17 is a major cause of GBS infection in infants in Iceland. This clone is associated with LOD, which has been increasing in incidence. Because intrapartum antibiotic prophylaxis only prevents EOD, it is important to continue the development of a GBS vaccine in order to prevent LOD infections.
The influence of baseline clinical status and surgical strategy on early good to excellent result in spinal lumbar arthrodesis: a machine learning approach
Authors: Langella Francesco , Ventriglia Luca , Compagnone Domenico , Barletta Paolo , Huber David , Mangili Francesca , Licandro Ginevra , Galbusera Fabio , Cina Andrea , Bassani Tito , Lamartina Claudio , Scaramuzzo Laura , Bassani Roberto , Brayda-Bruno Marco , Villafañe Jorge Hugo , Berjano Pedro , Azzimonti Laura
Published: September 2021

Aims

To create, using a machine learning (ML) approach, a preoperative model from baseline demographic and health-related quality of life scores (HRQOL) to predict a good to excellent early clinical outcome.

Patients and Methods

A single spine surgery center retrospective review of prospectively collected data from January 2016 to December 2020 from the institutional registry (SpineREG) was performed. The inclusion criteria were age ≥ 18 years, both sexes, lumbar arthrodesis procedure, a complete follow up assessment (ODI, SF-36 and COMI back) and the capability to read and understand the Italian language. A delta of improvement of the ODI higher than 12.7/100 was considered a “good early outcome”. A combined target model of ODI (Δ ≥ 12.7/100), SF-36 PCS (Δ ≥ 6/100) and COMI back (Δ ≥ 2.2/10) was considered an “excellent early outcome”. The performance of the ML models was evaluated in terms of sensitivity, i.e., True Positive Rate (TPR), specificity, i.e., True Negative Rate (TNR), accuracy and area under the receiver operating characteristic curve (AUC ROC).

Results

A total of 1243 patients were included in this study. The model for predicting ODI at 6 months follow up showed a good balance between sensitivity (74.3%) and specificity (79.4%), while providing a good accuracy (75.8%) with ROC AUC = 0.842. The combined target model showed a sensitivity of 74.2% and specificity of 71.8%, with an accuracy of 72.8%, and a ROC AUC = 0.808.

Conclusion

The results of our study suggest that a machine learning approach showed high performance in predicting early good to excellent clinical results.
Modeling SARS-CoV-2 RNA Degradation in Small and Large Sewersheds
Authors: McCall Camille , Fang Zheng N. , Li Dongfeng , Czubai Andrew J. , Juan Andrew , LaTurner Zachary , Ensor Katherine , Hopkins Loren , Bedient Phil , Stadler Lauren B.
Published: September 2021

Wastewater-based epidemiology has been at the forefront of the COVID-19 pandemic, yet little is known about losses of SARS-CoV-2 in sewer networks. Here, we used advanced sewershed modeling software to simulate SARS-CoV-2 RNA loss in sewersheds across Houston, TX under various temperatures and decay rates. Moreover, a novel metric, population times travel time (PT), was proposed to identify localities with a greater likelihood of undetected COVID-19 outbreaks and to aid in the placement of upstream samplers. Findings suggest that travel time has a greater influence on viral loss across the sewershed as compared to temperature. SARS-CoV-2 viral loss at median travel times was approximately two times greater in 20°C wastewater between the small sewershed, Chocolate Bayou, and the larger sewershed, 69th Street. Lastly, placement of upstream samplers according to the PT metric can provide a more representative snapshot of disease incidence in large sewersheds. This study helps to elucidate discrepancies between SARS-CoV-2 viral load in wastewater and clinical incidence of COVID-19. Incorporating travel time and SARS-CoV-2 decay can improve wastewater surveillance efforts.
Impact of COVID-19 on the quality of life (QoL) of patients living with Sickle Cell Disorder (SCD) in Lagos, Nigeria
Authors: Akinsete Annette , Ottun Michael , Adelabu Hammed , Ajuwon Larry , Veeneman Jorden
Published: September 2021

The study aimed to assess the impact of the COVID-19 pandemic on Quality of Life (QoL) in persons living with Sickle Cell Disorder (SCD) in Lagos, Nigeria and to determine how they coped during the pandemic, particularly during the period of total lockdown with the additional “SHIELDING” measures to which they had to adhere. Data was collected using a standardized protocol PedsQL, Sickle Cell Disease Module version.3.0 designed for youth within the ages of (13-18) years, (19-35) years and their parents/Guardian if underage. The survey captured data on patients’ pain impact, hurts, management, treatments, communication with their caregivers and their Guardian’s perception. The survey was performed online, or Face-to-Face/telephone interview if online was not possible. Contacts of patients and parents were obtained from the database of Sickle Cell Foundation Nigeria. A total of 105 (80 patients and 25 parents) participants responded to the survey. The age distribution of respondents was highest at 56 % in the age bracket of 13 - 18 years old. Pain crisis were very common amongst patients. The survey revealed that the type of treatment or care received at these times determined whether or not the patients visited the hospital when they had pain crises. In addition, as patients’ reports an increase in ill-treatment they experienced in the hands of health care givers, so did the fear of accessing treatment during the COVID pandemic. It was observed that the frequency of pain crises experienced by SCD patients was proportional to the patient’s quality of life (the higher the frequency of pains, the worse the QoL). As a follow-up, a more detailed study would be required, as this study was limited in the capturing of the demographics, sex and number of participants; Considering the number of persons living with SCD that visit the Sickle Cell Foundation Nigeria, (about 3,000 patients), the number of responses in this study was low (105). It is believed that a higher number of responses would have given more information about the Sickle Cell burden and the QoL of persons living with SCD in Lagos during the COVID-19 pandemic. Lagos was the epicentre of the COVID-19 pandemic in Nigeria.
Long-term Impact of Prior Secondhand Tobacco Smoke Exposure on Respiratory Health
Authors: del Valle Fernando Diaz , Zakrajsek Jonathan K. , Min Sung-Joon , Koff Patricia B. , Bell Harold W. , Kincaid Keegan A. , Frank Daniel N. , Ramakrishnan Vijay , Ghosh Moumita , Vandivier R. William
Published: September 2021

Rationale

Ongoing secondhand tobacco smoke (SHS) exposure is associated with worsened respiratory health, but little is known about the long-term impact decades after exposure ended.

Objective

Determine the long-term consequences of SHS exposure on respiratory health.

Methods

Population-based, cohort study in subjects ≥50 years old who had >1 year versus ≤1 year of airline occupational SHS-exposure.

Measurements and Main Results

Respiratory health was the primary outcome measured by the St. George’s Respiratory Questionnaire (SGRQ). Key secondary outcomes included respiratory symptoms measured by COPD Assessment Test (CAT) and pre-bronchodilator lung function. The study enrolled 183 SHS-exposed and 59 unexposed subjects. SHS-exposed subjects were exposed to airline SHS for 16.1±9.3 years, which ended 27.5±9.4 years prior to enrollment. Prior SHS-exposure was associated with worse respiratory health based on a 6.7-unit increase in SGRQ (95% CI=[2.7, 10.7]; p=0.001) and 3-unit increase in CAT (95% CI=1.4, 4.6]; p<0.001) versus unexposed subjects, but was not associated with airflow obstruction defined by FEV1:FVC<0.7. Clinically-significant respiratory symptoms (CAT≥10) in SHS-exposed never smokers with preserved lung function (FEV1:FVC ≥0.7 and FVC ≥lower limit of normal) were associated with decreased respiratory and non-respiratory quality-of-life, reduced lung function that remained within the normal range, increased comorbidities and inhaled bronchodilator use, higher plasma CRP and SAA-1 and fewer sinonasal basal stem/progenitor cells versus asymptomatic (CAT<10) SHS-exposed subjects.

Conclusion

SHS is associated with a phenotype of impaired respiratory health almost 3 decades after exposure ended, consistent with a symptomatic form of COPD with preserved lung function recently described in smokers.
A Two-tiered Functional Screen Identifies Herpesviral Transcriptional Modifiers and their Essential Domains
Authors: Morgens David W , Nandakumar Divya , Didychuk Allison L , Yang Kevin J , Glaunsinger Britt
Published: September 2021

While traditional methods for studying large DNA viruses allow the creation of individual mutants, CRISPR/Cas9 can be used to rapidly create thousands of mutant dsDNA viruses in parallel. Here, we used this approach to study the human oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV). We designed a sgRNA library containing all possible ~22,000 guides targeting the genome of KSHV – one cut site approximately every 8 base pairs – enabling the pooled screening of the entire genome. We used this tool to phenotype all possible Cas9-targeted viruses for transcription of KSHV late genes, which is required to produce structural components of the viral capsid. By performing targeted deep sequencing of the viral genome to distinguish between knock-out and in-frame alleles created by Cas9, we discovered a novel hit, ORF46 – and more specifically its DNA binding domain – is required for viral DNA replication. Our pooled Cas9 tiling screen followed by targeted deep viral sequencing represents a two-tiered screening paradigm that may be widely applicable to dsDNA viruses.
Quantification of neuron types in the rodent hippocampal formation by data mining and numerical optimization
Authors: Attili Sarojini M. , Moradi Keivan , Wheeler Diek W. , Ascoli Giorgio A.
Published: September 2021

Quantifying the population sizes of distinct neuron types in different anatomical regions is an essential step towards establishing a brain cell census. Although estimates exist for the total neuronal populations in different species, the number and definition of each specific neuron type are still intensively investigated. Hippocampome.org is an open-source knowledge base with morphological, physiological, and molecular information for 122 neuron types in the rodent hippocampal formation. While such framework identifies all known neuron types in this system, their relative abundances remain largely unknown. This work quantitatively estimates the counts of all Hippocampome.org neuron types by literature mining and numerical optimization. We report the number of neurons in each type identified by main neurotransmitter (glutamate or GABA) and axonal-dendritic patterns throughout 26 subregions and layers of the dentate gyrus, Ammon’s horn, subiculum, and entorhinal cortex. We produce by sensitivity analysis reliable numerical ranges for each type and summarize the amounts across broad neuronal families defined by biomarkers expression and firing dynamics. Study of density distributions indicates that the number of dendritic-targeting interneurons, but not of other neuronal classes, is independent of anatomical volumes. All extracted values, experimental evidence, and related software code are released on Hippocampome.org.
The transposition rate has little influence on equilibrium copy numbers of the P-element
Authors: Kofler Robert , Nolte Viola , Schlötterer Christian
Published: September 2021

The invasion of transposable elements (TEs) in mammals and invertebrates, is likely stopped by piRNAs that emerge after insertion of the TE into a piRNA cluster (the trap model). It remains, however, still unclear which factors influence the dynamics of TE invasions. The activity of the TE (i.e. transposition rate) is one of the frequently discussed key factors. Here we take advantage of the temperature-dependent activity of the P-element, a widely studied eukaryotic TE, to test how TE activity affects the dynamics of a TE invasion. Taking advantage of the temperature-specific activity of the P-element, we monitored its invasion dynamics in experimentalDrosophila simulanspopulations at hot and cold culture conditions. Despite marked differences in transposition rates, the P-element reached very similar copy numbers at both temperatures. The reduction of the insertion rate upon approaching the copy number plateau was accompanied by the emergence of similar amounts of piRNAs against the P-element at both temperatures. Interestingly, the ping-pong cycle, which degrades TE transcripts, becomes only active after the copy number has reached the plateau. We show that the P-element abundance is an order of magnitude lower and fewer P-element insertions in piRNA clusters were observed than expected under the trap model. We conclude that the transposition rate has at the most only a minor influence on TE abundance, but other factors, such as paramutations or selection against TE insertions are shaping the TE composition of organism.
Integrated de novo Gene Prediction and Peptide Assembly of Metagenomic Sequencing Data
Authors: Thippabhotla Sirisha , Liu Ben , Yooseph Shibu , Yang Youngik , Zhang Jun , Zhong Cuncong
Published: September 2021

Metagenomics is the study of all genomic content presented in given microbial communities. Metagenomic functional analysis aims to quantify protein families and reconstruct metabolic pathways from the metagenome. It plays a central role in understanding the interaction between the microbial community and its host or environment. De novo functional analysis, which allows the discovery of novel protein families, remains challenging for high-complexity communities. There are currently three main approaches for recovering novel genes or proteins: de novo nucleotide assembly, gene calling, and peptide assembly. Unfortunately, their informational connection and dependency have been overlooked, and each has been formulated as an independent problem. In this work, we develop a sophisticated workflow called integrated Metagenomic Protein Predictor (iMPP), which leverages the informational dependencies for better de novo functional analysis. iMPP contains three novel modules: a hybrid assembly graph generation module, a graph-based gene calling module, and a peptide assembly-based refinement module. iMPP significantly improved the existing gene calling sensitivity on unassembled fragmented reads, achieving a 92% - 97% recall rate at a high precision level (>90%). iMPP further allowed for more sensitive and accurate peptide assembly, recovering more reference proteins and delivering more hypothetical protein sequences. The high performance of iMPP can provide a more comprehensive and unbiased view of the microbial communities under investigation. iMPP is freely available from https://github.com/Sirisha-t/iMPP.
Role of RALBP1 in Oxidative Stress and Mitochondrial Dysfunction in Alzheimer’s Disease
Authors: Awasthi Sanjay , Hindle Ashley , Sawant Neha A. , George Mathew , Vijayan Murali , Kshirsagar Sudhir , Morton Hallie , Bunquin Lloyd E. , Palade Philip T. , Lawrence J. Josh , Khan Hafiz , Bose Chhanda , Reddy P. Hemachandra , Singh Sharda P.
Published: September 2021

The purpose of our study is to understand the role of the Ralbp1 gene in oxidative stress (OS), mitochondrial dysfunction and cognition in Alzheimer’s disease (AD) pathogenesis. The Ralbp1 gene encodes the 76 kDa protein Rlip (aka RLIP76). Previous studies have revealed its role in OS-related cancer. However, Rlip is transcriptionally regulated by EP300, a CREB-binding protein that is important for synaptic plasticity in the brain. Rlip functions as a stress-responsive/protective transporter of glutathione conjugates (GS-E) and xenobiotic toxins. OS causes rapid cellular accumulation of Rlip and its translocation from a tubulin-bound complex to the plasma membrane, mitochondria and nucleus. Therefore, Rlip may play an important role in maintaining cognitive function in the face of OS-related injury. This study is aimed to determine whether Rlip deficiency in mice is associated with AD-like cognitive and mitochondrial dysfunction. Brain tissue obtained from cohorts of wildtype and Rlip+/- mice were analyzed for OS markers, expression of genes that regulate mitochondrial fission/fusion, and synaptic integrity. We also examined mitochondrial ultrastructure in mouse brains obtained from these mice and further analyzed the impact of Rlip deficiency on gene networks of AD, aging, inhibition of stress-activated gene expression, mitochondrial function, and CREB signaling. Our studies revealed a significant increase in the levels of OS markers and alterations in the expression of genes and proteins involved in mitochondrial biogenesis, dynamics and synapses in brain tissues of these mice. Furthermore, we compared the cognitive function of wildtype and Rlip+/- mice. Behavioral, basic motor and sensory function tests in Rlip+/- mice revealed cognitive decline, similar to AD. Gene network analysis indicated dysregulation of stress-activated gene expression, mitochondrial function, and CREB signaling genes in the Rlip+/- mouse liver. Our results suggest that the Rlip deficiency-associated increase in OS and mitochondrial dysfunction could contribute to the development of OS-related AD processes. Therefore, the restoration of Rlip activity and endogenous cytoprotective mechanisms by pharmacological interventions is a novel approach to protect against AD.
A preliminary study to evaluate white matter structural correlates of delayed visuospatial memory and one-week motor skill retention in nondemented older adults
Authors: VanGilder Jennapher Lingo , Bergamino Maurizio , Hooyman Andrew , Fitzhugh Megan , Rogalsky Corianne , Stewart Jill C. , Beeman Scott C. , Schaefer Sydney Y.
Published: September 2021

Skill retention is important for motor rehabilitation outcomes. Recent work has demonstrated that delayed visuospatial memory performance may predict motor skill retention in older and neuropathological populations. White matter integrity between parietal and frontal cortices may explain variance in upper-extremity motor learning tasks and visuospatial processes. We performed a whole-brain analysis to determine the white matter correlates of delayed visuospatial memory and one-week motor skill retention in nondemented older adults. We hypothesized that better frontoparietal tract integrity would be positively related to better behavioral performance. Nineteen participants (age>58) completed diffusion-weighted imaging, then a clinical test of delayed visuospatial memory and 50 training trials of an upper-extremity motor task; participants were retested on the motor task one week later. Principal component analysis was used to create a composite score for each participant’s behavioral data, i.e. shared variance between delayed visuospatial memory and motor skill retention, which was then entered into a voxel-based regression analysis. Behavioral results demonstrated that participants learned and retained their skill level after a week of no practice, and their delayed visuospatial memory score was positively related to the extent of skill retention. Consistent with previous work, neuroimaging results indicated that regions within bilateral anterior thalamic radiations, corticospinal tracts, and superior longitudinal fasciculi were related to better delayed visuospatial memory and skill retention. Results of this study suggest that the simple act of testing for specific cognitive impairments prior to therapy may identify older adults who will receive little to no benefit from the motor rehabilitation regimen, and that these neural regions may be potential targets for therapeutic intervention.
Mosaic Evolution of Beta Barrel Porin Encoding Genes inEscherichia coli
Authors: Chen Xiongbin , Cai Xuxia , Chen Zewei , Wu Jinjin , Hao Gaofeng , Luo Quan , Zhu Guoqiang , Koester Wolfgang , White Aaron P , Cai Yi , Wang Yejun
Published: September 2021

Bacterial porins serve as the interface interacting with extracellular environment, and are often found under positive selection to fit in different environmental stresses. Local recombination has been identified in a handful of porin genes to facilitate the rapid adaptation of bacterial cells. It remains unknown whether it is a common evolutionary mechanism in gram-negative bacteria for all or a majority of the outer membrane proteins. In this research, we investigated the β-barrel porin encoding genes inEscherichia colithat were reported under positive Darwinia selection. BesidesfhuAthat was found with ingenic local recombination predominantly previously, we identified four other genes, i.e.,lamB, ompA, ompCandompF, all showing the similar mosaic evolution patterns as infhuA. Comparative analysis of the protein sequences disclosed a list of highly variable regions in each protein family, which are mostly located in the convex of extracellular loops and coinciding with the binding sites of various bacteriophages. For each of the porin family, mosaic recombination leads to various combinations of the HVRs with different sequence patterns, generating diverse protein groups. Structure modeling further indicated the conserved global topology for various groups of each porin family, but the extracellular surface varies a lot that is formed by individual or combinatorial HVRs. The conservation of global tertiary structure ensures the channel activity while the wide diversity of HVRs may assist bacteria avoiding the invasion of phages, antibiotics or immune surveillance factors. In summary, the study identified multiple bacterial porin genes with mosaic evolution, a likely general strategy, by which outer membrane proteins could facilitate the host bacteria to both maintain normal life processes and evade the attack of unflavored environmental factors rapidly.

Importance

Microevolution studies can disclose more elaborate evolutionary mechanisms of genes, appearing especially important for genes with multifaceted function such as those encoding outer membrane proteins. However, in most cases, the gene is considered as a whole unit and the evolutionary patterns are disclosed. In this research, we reported that multiple bacterial porin proteins follow mosaic evolution, with local ingenic recombination combined with spontaneous mutations based positive Darwinia selection, and conservation for most of the other regions. It could represent a common mechanism for bacterial outer membrane proteins. The study also provides insights on development of new anti-bacterial agent or vaccines.
Nonsense-associated alternative splicing as a putative reno-protective mechanism in Pkhd1cyli/Pkhd1cyli mutant mice
Authors: Yang Chaozhe , Harafuji Naoe , Odinakachukwu Maryanne C. , Caldovic Ljubica , Boddu Ravindra , Gordish-Dressman Heather , Foreman Oded , Eicher Eva M. , Guay-Woodford Lisa M.
Published: September 2021

Autosomal recessive polycystic kidney disease (ARPKD) is a hereditary hepato-renal fibrocystic disorder and a significant genetic cause of childhood morbidity and mortality. Mutations in the Polycystic Kidney and Hepatic Disease 1 (PKHD1) gene cause all typical forms of ARPKD. Several mouse strains carrying diverse genetically engineered disruptions in the orthologous Pkhd1 gene have been generated. The current study describes a novel spontaneous mouse recessive mutation causing a cystic liver phenotype resembling the hepato-biliary disease characteristic of human ARPKD. Here we describe mapping of the cystic liver mutation to the Pkhd1 interval on Chromosome 1 and identification of a frameshift mutation within Pkhd1 exon 48 predicted to result in premature translation termination. Mice homozygous for the new mutation, symbollzed Pkhd1cyli, lack renal pathology, consistent with previously generated Pkhd1 mouse mutants that fail to recapitulate human kidney disease. We have identified a profile of alternatively spliced Pkhd1 renal transcripts that are distinct in normal versus mutant mice. The Pkhd1 transcript profile in mutant kidneys is consistent with predicted outcomes of nonsense-associated alternative splicing (NAS) and nonsense mediated decay (NMD). Overall levels of Pkhd1 transcripts in mutant mouse kidneys were reduced compared to kidneys of normal mice, and Pkhd1 encoded protein in mutant kidneys was undetectable by immunoblotting. We suggest that in Pkhd1cyli/Pkhd1cyli(cyli) mice, mutation-promoted Pkhd1 alternative splicing in the kidney yields transcripts encoding low-abundance protein isoforms lacking exon 48 encoded amino acid sequences that are sufficiently functional so as to attenuate expression of a renal cystic disease phenotype.
Synthesis, spectroscopic characterization, structural studies, thermal analysis and molecular docking ofN-(2-methyl-5-nitrophenyl)-4-(pyridin-2-yl)pyrimidin-2-amine, a precursor for drug design against chronic myeloid leukemia
Authors: Moreno-Fuquen Rodolfo , Arango-Daraviña Kevin , Kennedy Alan R.
Published: September 2021

The synthesis, crystal structure and spectroscopic and electronic properties ofN-(2-methyl-5-nitrophenyl)-4-(pyridin-2-yl)pyrimidin-2-amine (NPPA), C16H13N5O2, a potential template for drug design against chronic myelogenous leukemia (CML), is reported. The design and construction of the target molecule were carried out starting from the guanidinium nitrate salt (previously synthesized) and the corresponding enaminone. X-ray diffraction analysis and a study of the Hirshfeld surfaces revealed important interactions between the nitro-group O atoms and the H atoms of the pyridine and pyrimidine rings. A crystalline ordering in layers, by the stacking of rings through interactions of the π–π type, was observed and confirmed by a study of the shape-index surfaces and dispersion energy calculations. Quantitative electrostatic potential studies revealed the most positive value of the molecule on regions close to the N—H groups (34.8 kcal mol−1); nevertheless, steric impediments and the planarity of the molecule do not allow the formation of hydrogen bonds from this group. This interaction is however activated when the molecule takes on a new extended conformation in the active pocket of the enzyme kinase (PDB ID 2hyy), interacting with protein residues that are fundamental in the inhibition process of CML. The most negative values of the molecule are seen in regions close to the nitro group (−35.4 and −34.0 kcal mol−1). A molecular docking study revealed an energy affinity of ΔG = −10.3 kcal mol−1forNPPAwhich, despite not having a more negative value than the control molecule (Imatinib; ΔG = −12.8 kcal mol−1), shows great potential to be used as a template for new drugs against CML.
A rush to explore protein–ligand electrostatic interaction energy with Charger
Authors: Vuković Vedran , Leduc Theo , Jelić-Matošević Zoe , Didierjean Claude , Favier Frédérique , Guillot Benoît , Jelsch Christian
Published: September 2021

The mutual penetration of electron densities between two interacting molecules complicates the computation of an accurate electrostatic interaction energy based on a pseudo-atom representation of electron densities. The numerical exact potential and multipole moment (nEP/MM) method is time-consuming since it performs a 3D integration to obtain the electrostatic energy at short interaction distances. Nguyen et al. [(2018), Acta Cryst. A74, 524–536] recently reported a fully analytical computation of the electrostatic interaction energy (aEP/MM). This method performs much faster than nEP/MM (up to two orders of magnitude) and remains highly accurate. A new program library, Charger, contains an implementation of the aEP/MM method. Charger has been incorporated into the MoProViewer software. Benchmark tests on a series of small molecules containing only C, H, N and O atoms show the efficiency of Charger in terms of execution time and accuracy. Charger is also powerful in a study of electrostatic symbiosis between a protein and a ligand. It determines reliable protein–ligand interaction energies even when both contain S atoms. It easily estimates the individual contribution of every residue to the total protein–ligand electrostatic binding energy. Glutathione transferase (GST) in complex with a benzophenone ligand was studied due to the availability of both structural and thermodynamic data. The resulting analysis highlights not only the residues that stabilize the ligand but also those that hinder ligand binding from an electrostatic point of view. This offers new perspectives in the search for mutations to improve the interaction between the two partners. A proposed mutation would improve ligand binding to GST by removing an electrostatic obstacle, rather than by the traditional increase in the number of favourable contacts.