bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epidemiology of Clefts in Kwazulu Natal: Comparison With Systematic Review Analysis, Similarities, and Differences
Authors: Madaree Anil 
Published: August 2022

Preamble:
The incidence and accuracy of cleft epidemiology is variable depending on geographical region, population group, and country being assessed. Confounding factors are rendered more accurate if consecutive patients seen in a unit over a prolonged period are reported.

Materials and Methods:
Plastic surgery charts at Inkosi Albert Luthuli Central Hospital (IALCH) were reviewed from 2003 to 2019. Appropriate International Classification of Diseases (ICD) cleft codes were used to obtain a cleft database of all cleft patients. The review revealed 1487 cleft patients. Data extracted included sex, race, extent of cleft lip or palate, laterality, and birth month.

Results:
Overall, there was an almost equivalent sex distribution with 745 females and 742 males. There were 390 cleft lip only (26%), 505 cleft lip with palate (CLP) (34%), and 592 cleft palate only (40%). In the cleft lip only group, Black females were affected in 54% and males in 46%, whereas in the Asian group, females were affected in 33% and males in 67% (P=0.022). In the CLP group, Asian and Colored females were affected more (56% and 60%, respectively), while in the Black and White groups, females were less affected (40% and 26%, respectively). Cleft palate only was the most common category in Black (44%) and Colored (55%), while the CLP category was most common in Asian (49%) and White (42%).

Conclusions:
Demographics of cleft lip and palate in KwaZulu Natal is different from other series in certain aspects. In addition, there are differences in the race groups when analyzing certain aspects. The differences may be based on genetic or environmental factors and warrants further investigation.
70 Years of Human Cingulate Cortex Stimulation. Functions and Dysfunctions Through the Lens of Electrical Stimulation
Authors: Pelliccia Veronica , Del Vecchio Maria , Avanzini Pietro , Revay Martina , Sartori Ivana , Caruana Fausto 
Published: August 2022

Summary:In this review, we retrace the results of 70 years of human cingulate cortex (CC) intracerebral electrical stimulation and discuss its contribution to our understanding of the anatomofunctional and clinical aspects of this wide cortical region. The review is divided into three main sections. In the first section, we report the results obtained by the stimulation of the anterior, middle, and posterior CC, in 30 studies conducted on approximately 1,000 patients from the 1950s to the present day. These studies show that specific manifestations can be reliably associated with specific cingulate subfields, with autonomic, interoceptive, and emotional manifestations clustered in the anterior cingulate, goal-oriented motor behaviors elicited from the anterior midcingulate and a variety of sensory symptoms characterizing the posterior cingulate regions. In the second section, we compare the effect of CC intracerebral electrical stimulation with signs and manifestations characterizing cingulate epilepsy, showing that the stimulation mapping of CC subfields provides precious information for understanding cingulate epileptic manifestations. The last section tackles the issue of the discrepancy emerging when comparing the results of clinical (electrical stimulation, epilepsy) studies—revealing the quintessential affective and motor nature of the CC—with that reported by neuroimaging studies—which focus on high-level cognitive functions. Particular attention will be paid to the hypothesis that CC hosts a “Pain Matrix” specifically involved in pain perception, which we will discuss in the light of the fact that the stimulation of CC (as well as cingulate epileptic seizures) does not induce nociceptive effects.
Systematic Review and Meta-Analysis of the Effect of Adverse Childhood Experiences (ACEs) on Brain-Derived Neurotrophic Factor (BDNF) Levels
Authors: Vyas Neha , Wimberly Courtney E. , Beaman M. Makenzie , Kaplan Samantha J. , Rasmussen Line J.H. , Wertz Jasmin , Gifford Elizabeth J. , Walsh Kyle M. 
Published: August 2022

AbstractThere is continued interest in identifying dysregulated biomarkers that mediate associations between adverse childhood experiences (ACEs) and negative long-term health outcomes. However, little is known regarding how ACE exposure modulates neural biomarkers to influence poorer mental health outcomes in ACE-exposed children. To address this, we performed a systematic review and meta-analysis of the impact of ACE exposure on Brain Derived Neurotrophic Factor (BDNF) levels - a neural biomarker associated with the onset of mood disorders. Twenty-two studies were selected for inclusion within the systematic review, ten of which were included in meta-analysis. Most included studies retrospectively assessed impacts of childhood maltreatment in clinical populations. Sample size, BDNF protein levels in ACE-exposed and unexposed subjects, and standard deviations were extracted from ten publications to estimate the BDNF ratio of means (ROM) across exposure categories. Overall, no significant difference was found in BDNF protein levels between ACE-exposed and unexposed groups (ROM: 1.05; 95% CI: 0.91-1.22). Non-significant elevation of BDNF levels in ACE-exposed subjects was observed among studies specifically investigating childhood maltreatment and among studies measuring BDNF in serum, but these analyses were limited by high between-study heterogeneity. Studies that measured BDNF levels in subjects prior to age 20 revealed elevated levels in the ACE-exposed group, which was not observed in studies measuring BDNF levels later in life. These results support continued investigation into the impact of ACE exposure on neural biomarkers and highlight the potential importance of analyte type and timing of sample collection on study results.
A randomized, double-blind, Phase 1 study of IN-006, an inhaled antibody treatment for COVID-19
Authors: Moench Thomas R. , Botta Lakshmi , Farrer Brian , Lickliter Jason D. , Kang Hyunah , Park Yoona , Kim Cheolmin , Hoke Marshall , Brennan Miles , McSweeney Morgan D. , Richardson Zachary , Whelan John B. , Cho Jong Moon , Lee Soo Young , Faurot Frances , Hutchins Jeff , Lai Samuel K. 
Published: August 2022

AbstractRationaleAlthough COVID-19 is predominantly a respiratory tract infection, current antibody treatments are administered by systemic dosing. We hypothesize that inhaled delivery of a muco-trapping monoclonal antibody would provide a more effective and convenient treatment for COVID-19.ObjectiveWe investigated the safety, tolerability, and pharmacokinetics of IN-006, a reformulation of regdanvimab, an approved intravenous treatment for COVID-19, for nebulized delivery by a handheld nebulizer.MethodsA Phase 1 study was conducted in healthy volunteers. Study staff and participants were blinded to treatment assignment, except for pharmacy staff preparing the study drug. The primary outcomes were safety and tolerability. Exploratory outcomes were pharmacokinetic measurements of IN-006 in nasal fluid and serum.ResultsTwenty-three participants were enrolled and randomized across two single dose and one multiple dose cohorts. There were no serious adverse events (SAEs). All enrolled participants completed the study without treatment interruption or discontinuation. All treatment-emergent adverse events were transient, non-dose dependent, and were graded mild to moderate in severity. Nebulization was well tolerated and completed in a mean of 6 minutes in the high dose group. Mean nasal fluid concentrations of IN-006 in the multiple dose cohort were 921 µg/g of nasal fluid at 30 minutes after dosing and 5.8 µg/g at 22 hours. Mean serum levels in the multiple dose cohort peaked at 0.55 µg/mL at 3 days after the final dose.ConclusionsIN-006 was well-tolerated and achieved concentrations in the respiratory tract orders of magnitude above its inhibitory concentration. These data support further clinical development of IN-006.RegistrationAustralian New Zealand Clinical Trials Registry: ACTRN12621001235897
Non-contact microfluidic analysis of the stiffness of single large extracellular vesicles from IDH1-mutated glioblastoma cells
Authors: Jeong Mi Ho , Im Hyungsoon , Dahl Joanna B. 
Published: August 2022

AbstractIn preparation for leveraging extracellular vesicles (EVs) for disease diagnostics and therapeutics, fundamental research is being done to understand EV biological, chemical, and physical properties. Most published studies investigate nanoscale EVs and focus on EV biochemical content. There is much less understanding of large microscale EV characteristics and EV mechanical properties. We recently introduced a non-contact microfluidic technique that measures the stiffness of large EVs (>1 μm diameter). This study probes the sensitivity of the microfluidic technique to distinguish between EV populations by comparing stiffness distributions of large EVs derived from glioblastoma cell lines. EVs derived from cells expressing the IDH1 mutation, a common glioblastoma mutation known to disrupt lipid metabolism, were significantly stiffer than those expressed from wild-type cells. A supporting lipidomics analysis shows that the IDH1 mutation increases the amount of saturated lipids in EVs. Taken together, these data suggest that high-throughput microfluidics is capable of distinguishing between large EV populations that differ in biomolecular composition and therefore structure. These findings advance the understanding of EV biomechanics, in particular for the less studied microscale EVs, and demonstrate microfluidics to be a promising technique to perform clinical EV mechanophenotyping.
Extreme sex chromosome differentiation, likely driven by inversion, contrasts with mitochondrial paraphyly between species of crowned sparrows
Authors: McCallum Quinn , Askelson Kenneth , Fogarty Finola , Natola Libby , Nikelski Ellen , Huang Andrew , Irwin Darren 
Published: August 2022

AbstractSympatric species pairs provide researchers with the opportunity to study patterns of genomic differentiation during the late stages of speciation and to identify the genomic regions underlying reproductive isolation. The Golden-crowned Sparrow (Zonotrichia atricapilla) and the White-crowned Sparrow (Zonotrichia leucophrys) are broadly sympatric songbirds found in western North America. These sister species are phenotypically differentiated and largely reproductively isolated despite possessing similar mitochondrial genomes, likely due to recent mitochondrial introgression. We used a genotyping-by-sequencing (GBS) approach to determine the structure of nuclear genomic differentiation between these species and also between two hybridizing subspecies of Z. leucophrys, across more than 45,000 single nucleotide polymorphisms (SNPs). The two Z. leucophrys subspecies showed moderate levels of relative differentiation, as well as patterns consistent with a history of recurrent selection in both ancestral and daughter populations. Z. leucophrys and Z. atricapilla show high levels of relative differentiation and strong heterogeneity in the level of differentiation among different chromosomal regions, with a large portion of the Z chromosome showing highly elevated differentiation. Patterns of relative and absolute differentiation and linkage disequilibrium suggest a large inversion on the Z chromosome, with inversion haplotypes that segregate between Z. atricapilla and Z. leucophrys. While mitochondrial DNA differentiation is often emphasized in studies of speciation, differentiation between these Zonotrichia sparrows appears to have occurred first in the Z chromosome and secondarily in autosomes, followed by mitochondrial introgression. This putative inversion has implications for reproductive isolation between these species and adds to a growing body of evidence for the importance of inversions and the Z chromosome in speciation.
Structures of BIRC6-Client Complexes Provide Mechanism of Smac-Mediated Release of Caspases
Authors: Hunkeler Moritz , Jin Cyrus Y. , Fischer Eric S. 
Published: August 2022

SummaryApoptosis is tightly regulated and essential for metazoan development1, 2. Excessive apoptosis contributes to neurodegenerative disease, while diminished apoptosis can lead to inflammation and cancer3. Inhibitor of apoptosis (IAP) proteins are the principal actors that restrain apoptotic activity and are thus attractive therapeutic targets4. IAPs in turn are regulated by mitochondria-derived pro-apoptotic factors such as Smac and HtrA24. Here, through a series of cryo-electron microscopy (cryo-EM) structures of full-length baculoviral IAP repeat-containing protein 6 (BIRC6) bound to Smac, caspase-3, caspase-7 and HtrA2, we provide the molecular basis for BIRC6-mediated caspase inhibition and its release by Smac. We demonstrate that BIRC6 cooperates preferentially with the non-canonical E1 enzyme UBA6 to ubiquitylate caspases and that caspase ubiquitylation is effectively inhibited by Smac through near-irreversible interactions. The dimeric arrangement of BIRC6 resolves the long-standing question of how the evolutionarily conserved single-BIR domain IAPs sequester caspases and how Smac binding antagonizes IAPs. This collection of BIRC6 structures provides critical insights into IAP-mediated apoptosis regulation, relevant for the development of current and future apoptosis-targeting cancer therapeutics.
In vitro and in vivo activity of Gepotidacin against drug-resistant mycobacterial infections
Authors: Ahmad Mohammad Naiyaz , Garg Tanu , Singh Shriya , Shukla Richa , Ramya VK , Kaur Parvinder , Chopra Sidharth , Dasgupta Arunava 
Published: August 2022

AbstractMycobacterial pathogens including Non-tuberculous mycobacteria (NTM) and M. tuberculosis (Mtb), are pathogens of significant worldwide interest owing to inherent drug resistance to a wide variety of FDA-approved drugs as well as causing a broad range of serious infections. Identifying new antibiotics active against mycobacterial pathogens is an urgent unmet need, especially those antibiotics that can bypass existing resistance mechanisms. In this study, we demonstrate that Gepotidacin, a first-in-class triazaacenapthylene topoisomerase inhibitor, shows potent activity against Mtb and M. fortuitum as well as against other NTMs species, including fluoroquinolone-resistant M. abscessus. Furthermore, Gepotidacin exhibits concentration-dependent bactericidal activity against various mycobacterial pathogens, synergizes with several drugs utilized for their treatment, and reduces bacterial load in macrophages in the intracellular killing assay comparable to amikacin. Additionally, M. fortuitum ATCC 6841 was unable to generate resistance to Gepotidacin in vitro. When tested in a murine neutropenic M. fortuitum infection model, Gepotidacin caused a significant reduction in bacterial load in various organs at 10 fold lower concentration than amikacin. Taken together, Gepotidacin possesses a potentially new mechanism of action that enables it to escape existing resistance mechanisms. Thus, it can be projected as a potent novel lead for the treatment of mycobacterial infections, particularly for NTM, where present therapeutic interventions are very limited.
Phat queens emerge fashionably late: body size and condition predict timing of spring emergence for queen bumble bees
Authors: Keaveny Ellen C. , Dillon Michael E. 
Published: August 2022

AbstractFor insects, the timing of many life history events (phenology) depends on temperature cues. Body size is a critical mediator of insect responses to temperature, so may also influence phenology. The determinants of spring emergence of bumble bee queens are not well understood, but body size is likely important for several reasons. In fall, queens accumulate energy stores to fuel overwinter survival. Accumulation of fat stores prior to and depletion of fat stores during overwintering are likely size-dependent: larger queens can accumulate more lipids and have lower mass-specific metabolic rates. Therefore, larger queens and queens in relatively better condition may have delayed depletion of energy stores, allowing for later spring emergence. To test whether timing of spring emergence is associated with body size and condition, we captured 295Bombus huntiiqueens in Laramie, WY, during the 2020 and 2021 growing seasons, weighed them, and measured intertegular width (a size metric unaffected by variation in feeding and hydration state). Early emerging queens were smaller than later emerging queens across years. Mass relative to intertegular width increased as the season progressed suggesting, as predicted, that body condition influences the timing of spring emergence for these crucial pollinators.
Evaluation of KRASG12C Inhibitor Responses in Novel Murine KRASG12C Lung Cancer Cell Line Models
Authors: Sisler Daniel J , Hinz Trista K , Le Anh T , Kleczko Emily K , Nemenoff Raphael A , Heasley Lynn E 
Published: August 2022

AbstractThe KRAS(G12C) mutation is the most common genetic mutation in North American lung adenocarcinoma patients. Recently, direct inhibitors of the KRASG12C protein have been developed and demonstrate clinical response rates of 37-43%. Importantly, these agents fail to generate durable therapeutic responses with median progression-free survival of ~6.5 months. To provide models for further preclinical improvement of these inhibitors, we generated three novel murine KRASG12C-driven lung cancer cell lines. The co-occurring NRASQ61L mutation in KRASG12C-positive LLC cells was deleted and the KRASG12V allele in CMT167 cells was edited to KRASG12C with CRISPR/Cas9 methods. Also, a novel murine KRASG12C line, mKRC.1, was established from a tumor generated in a genetically-engineered mouse model. The three lines exhibit similar in vitro sensitivities to KRASG12C inhibitors (MRTX-1257, AMG-510), but distinct in vivo responses to MRTX-849 ranging from progressive growth with orthotopic LLC-NRAS KO tumors to marked shrinkage with mKRC.1 tumors. All three cell lines exhibited synergistic in vitro growth inhibition with MRTX-1257 and the SHP2 inhibitor, RMC-4550 and the MRTX-849/RMC-4550 combination yielded tumor shrinkage in orthotopic LLC-NRAS KO tumors propagated in syngeneic mice. Notably, this synergistic combination response was lost in athymic nu/nu mice, supporting a growing literature demonstrating a role for adaptive immunity in the response to this class of drugs. These new models of murine KRASG12C mutant lung cancer should prove valuable for identifying improved therapeutic combination strategies with KRASG12C inhibitors.Contribution to the Field StatementThe development of KRASG12C inhibitors has not impacted treatment of lung cancers bearing the KRASG12C mutation to the degree that tyrosine kinase inhibitors have changed the treatment outcomes for patients bearing oncogenic mutations in receptor tyrosine kinases. Thus, the field is now exploring combination strategies with KRASG12C inhibitors that may enhance their clinical benefit. Moreover, published findings indicate that host immunity contributes to efficacy of oncogene-directed inhibitors including KRASG12C inhibitors. Thus, these novel murine KRASG12C-driven lung cancer cell lines will provide valuable models for preclinical evaluation of novel drug combinations in immune competent hosts.
Resolving deleterious and near-neutral effects requires different pooled fitness assay designs
Authors: Limdi Anurag , Baym Michael 
Published: August 2022

AbstractPooled sequencing-based fitness assays are a powerful and widely used approach to quantifying fitness of thousands of genetic variants in parallel. Despite the throughput of such assays, they are prone to biases in fitness estimates, and errors in measurements are typically larger for deleterious fitness effects, relative to neutral effects. In practice, designing pooled fitness assays involves tradeoffs between the number of timepoints, the sequencing depth, and other parameters to gain as much information as possible within a feasible experiment. Here, we combined theory, simulations, and reanalysis of an existing experimental dataset to explore how assay parameters impact measurements of near-neutral and deleterious fitness effects. We found that sequencing multiple timepoints at relatively modest depth improved estimates of near-neutral fitness effects, but systematically biased measurements of deleterious effects. We identified a theoretical lower bound for estimates from bulk fitness assays, and showed that increasing sequencing depth, and reducing number of timepoints improved resolution of deleterious fitness effects. Our results highlight a tradeoff between measurement of deleterious and near-neutral effect sizes for a fixed amount of data and suggest that fitness assay design should be tuned for fitness effects that are relevant to the specific biological question.
Meiotic gene transcription programs are mediated by A-MYB and BRDT-dependent RNA polymerase II pause release during mammalian prophase I
Authors: Alexander Adriana K. , Rice Edward J. , Barshad Gilad , Zhu Lina , Cohen Paula E , Danko Charles G. 
Published: August 2022

AbstractDuring meiotic prophase I, germ cells must balance transcriptional activation with meiotic recombination and chromosome synapsis, biological processes requiring extensive changes to chromatin state and structure. Here we explored the interplay between chromatin accessibility and transcription across a detailed time-course of murine male meiosis by measuring genome-wide patterns of chromatin accessibility, nascent transcription, and processed mRNA. To understand the relationship between these parameters of gene regulation and recombination, we integrated these data with maps of double-strand break formation. Maps of nascent transcription show that Pol II is loaded on chromatin and maintained in a paused state early during prophase I. In later stages of prophase I, paused Pol II is released in a coordinated transcriptional burst resulting in ∼3-fold increase in transcription. Release from pause is mediated by the transcription factor A-MYB and the testis-specific bromodomain protein, BRDT. The burst of transcriptional activity is both temporally and spatially segregated from key steps of meiotic recombination: double strand breaks show evidence of chromatin accessibility earlier during prophase I and at distinct loci from those undergoing transcriptional activation, despite shared chromatin marks. Our findings reveal the mechanism underlying chromatin specialization in either transcription or recombination in meiotic cells.