bluuebunny/crossref_metadata_2025_split huggingface dataset:
With Our Powers Combined
Authors: Kasherman Lawrence , Karakasis Katherine , Oza Amit M. 
Published: December 2021

Abstract
The use of poly(ADP-ribose) polymerase inhibitors and immune checkpoint inhibitor therapies has seen substantial clinical success in oncology therapeutic development. Although multiple agents within these classes have achieved regulatory approval globally—in several malignancies in early and advanced stages—drug resistance remains an issue. Building on preclinical evidence, several early trials and late-phase studies are underway. This review explores the therapeutic potential of combination poly(ADP-ribose) polymerase inhibitors and immune checkpoint inhibitor therapy in solid tumors, including the scientific and therapeutic rationale, available clinical evidence, and considerations for future trial and biomarker development across different malignancies using ovarian and other solid cancer subtypes as key examples.
DNA Damage Repair Inhibitors—Combination Therapies
Authors: Smith Gabriella , Alholm Zachary , Coleman Robert L. , Monk Bradley J. 
Published: December 2021

Abstract
DNA damage response and repair (DDR) is responsible for ensuring genomic integrity. It is composed of intricate, complex pathways that detect various DNA insults and then activate pathways to restore DNA fidelity. Mutations in this network are implicated in many malignancies but can also be exploited for cancer therapies. The advent of inhibitors of poly(ADP-ribose) polymerase has led to the investigation of other DDR inhibitors and combinations to address high unmet needs in cancer therapeutics. Specifically, regimens, often in combination with chemotherapy, radiation, or other DDR inhibitors, are being investigated. This review will focus on 4 main DDR pathways—ATR/CHK1, ATM/CHK2, DNA-PKcs, and polymerase θ—and the current state of clinical research and use of the inhibitors of these pathways with other DDR inhibitors.
Epidural Anesthesia and Arterial Maximal Flow Velocity of Free Flap in Patients Having Microvascular Lower Extremity Reconstruction: A Randomized Controlled Trial
Authors: Park Jun-Young , Suh Hyunsuk Peter , Kwon Jin Geun , Yu Jihion , Lee Joonho , Hwang Jai-Hyun , Hong Joon Pio , Kim Young-Kug 
Published: December 2021

Background:
One of the critical factors for free flap survival is to maintain adequate perfusion. The authors evaluated the effect of epidural anesthesia on arterial maximal flow velocity of the free flap in microvascular lower extremity reconstruction.

Methods:
This is a prospective randomized study where patients were allocated to receive either combined general-epidural anesthesia (epidural group, n = 26) or general anesthesia alone (control group, n = 26). After injecting epidural ropivacaine 10 ml in the epidural group, the effect on arterial maximal flow velocity of the free flap was analyzed using ultrasonography. The primary outcome measurement was the arterial maximal flow velocity 30 minutes after establishing the baseline. Intraoperative hemodynamics and postoperative outcomes such as postoperative pain, opioid requirements, surgical complications, intensive care unit admission, and hospital length of stay were also assessed.

Results:
The arterial maximal flow velocity 30 minutes after the baseline measurement was significantly higher in the epidural group (35.3 ± 13.9 cm/second versus 23.5 ± 8.4 cm/second; p = 0.001). The pain score at 1 hour postoperatively and opioid requirements at 1 and 6 hours postoperatively were significantly lower in the epidural group [3.0 (interquartile range, 2.0 to 5.0) versus 5.0 (interquartile range, 3.0 to 6.0), p = 0.019; 0.0 μg (interquartile range, 0.0 to 50.0 μg) versus 50.0 μg (interquartile range, 0.0 to 100.0 μg), p = 0.005; and 46.9 μg (interquartile range, 0.0 to 66.5 μg) versus 96.9 μg (interquartile range, 41.7 to 100.0 μg), p = 0.014, respectively]. There were no significant differences in intraoperative hemodynamics or other postoperative outcomes between the two groups.

Conclusion:
Epidural anesthesia increased the arterial maximal flow velocity of the free flap and decreased postoperative pain and opioid requirements in microvascular lower extremity reconstruction.

CLINICAL QUESTION/LEVEL OF EVIDENCE:
Therapeutic, I.
Beyond the Scalpel: Attracting and Nurturing Surgeon-Scientists in Plastic Surgery
Authors: Baker Nusaiba F. , Colazo Juan M. , Gosain Arun K. 
Published: December 2021

Summary:
With plastic surgery being at the forefront of innovation and discovery in multiple research disciplines, plastic surgery is poised for M.D./Ph.D. and research-focused M.D. trainees to be attracted to this field. Surprisingly, recent reports have shown that the number of surgeon-scientists pursuing research is on the decline, with these declines being even more pronounced within plastic surgery. It is essential that plastic surgery remains a leader in translational research by cultivating a group of individuals who have been trained in basic research and are thereby competitive to obtain extramural grant funding. To address this need, the authors review data elucidating why the research-oriented trainee may forego pursuing a career in plastic surgery. Although much of the existing literature is speculative, the authors identified the current number of M.D./Ph.D.s in plastic surgery using data obtained from the American Society of Plastic Surgeons and investigated number of grants in plastic surgery compared to other medical and surgical fields using the National Institutes of Health Research Portfolio Online Reporting Tools Expenditures and Results. The authors hypothesize that economic constraints and difficulty securing protected research time may be contributing to fewer trainees pursuing plastic surgery. The purpose of this article is (1) to discuss potential reasons deterring research-oriented trainees from pursuing careers as surgeon-scientists within plastic surgery; (2) to propose solutions that may attract more trainees interested in careers as surgeon-scientists to the field of plastic surgery; (3) to highlight the lack of quantitative data regarding surgeon-scientist training in plastic surgery; and (4) to propose and encourage future research avenues to help attract and nurture surgeon-scientists in plastic surgery.
Identification of novel Ebola virus inhibitors using biologically contained virus
Authors: Vanmechelen Bert , Stroobants Joren , Chiu Winston , Schepers Joost , Marchand Arnaud , Chaltin Patrick , Vermeire Kurt , Maes Piet 
Published: December 2021

AbstractDespite recent advancements in the development of vaccines and monoclonal antibody therapies for Ebola virus disease, treatment options remain limited. Moreover, management and containment of Ebola virus outbreaks is often hindered by the remote nature of the locations in which the outbreaks originate. Small-molecule compounds offer the advantage of being relatively cheap and easy to produce, transport and store, making them an interesting modality for the development of novel therapeutics against Ebola virus disease. Furthermore, the repurposing of small-molecule compounds, previously developed for alternative applications, can aid in reducing the time needed to bring potential therapeutics from bench to bedside. For this purpose, the Medicines for Malaria Venture provides collections of previously developed small-molecule compounds for screening against other infectious diseases. In this study, we used biologically contained Ebola virus to screen over 4,200 small-molecule drugs and drug-like compounds provided by the Medicines for Malaria Venture (i.e., the Pandemic Response Box and the COVID Box) and the Centre for Drug Design and Discovery (CD3, KU Leuven, Belgium). In addition to confirming known Ebola virus inhibitors, illustrating the validity of our screening assays, we identified eight novel selective Ebola virus inhibitors. Although the inhibitory potential of these compounds remains to be validated in vivo, they represent interesting compounds for the study of potential interventions against Ebola virus disease and might serve as a basis for the development of new therapeutics.
Extreme drought triggers transition to an alternative soil microbial state
Authors: Cordero Irene , Leizeaga Ainara , Hicks Lettice C. , Rousk Johannes , Bardgett Richard D. 
Published: December 2021

SUMMARYSoil microbial communities play a pivotal role in regulating ecosystem functioning1but they are increasingly threatened by human-driven perturbations, including climate extremes, which are predicted to increase in frequency and intensity with climate change2. It has been demonstrated that soil microbial communities are sensitive to climate extremes, such as drought3,4, and that effects can be long-lasting5,6. However, considerable uncertainties remain concerning the response of soil microbial communities to increases in the intensity and frequency of climate extremes, and their potential to trigger transitions to alternative, and potentially deleterious, taxonomic and functional states7. Here we demonstrate that extreme, frequent drought induces a shift to an alternative soil microbial state characterised by strongly altered bacterial and fungal community structure of reduced complexity and functionality. Moreover, we found that this drought-induced alternative microbial state persisted after returning soil to its previous moisture status. However, bacterial communities were able to adapt by increasing their growth capacity, despite being of reduced diversity. Abrupt transitions to alternative states are well documented in aquatic and terrestrial plant communities in response to human-induced perturbations, including climate extremes8,9. Our results provide experimental evidence that such transitions also occur in soil microbial communities in response to extreme drought with potentially deleterious consequences for soil health.
Developing an empirical model for spillover and emergence: Orsay virus host range in Caenorhabditis
Authors: Shaw Clara L. , Kennedy David A. 
Published: December 2021

ABSTRACTA lack of tractable experimental systems in which to test hypotheses about the ecological and evolutionary drivers of disease spillover and emergence has limited our understanding of these processes. Here we introduce a promising system: Caenorhabditis hosts and Orsay virus, a positive-sense single-stranded RNA virus that naturally infects C. elegans. We assayed the susceptibility of species across the Caenorhabditis tree and found 21 of 84 wild strains belonging to 14 of 44 species to be susceptible to Orsay virus. Confirming patterns documented in other systems, we detected effects of host phylogeny on susceptibility. We then tested whether susceptible strains were capable of transmitting Orsay virus by transplanting exposed hosts and determining whether they transmitted infection to conspecifics during serial passage. We found no evidence of transmission in 10 strains (virus undetectable after passaging), evidence of low-level transmission in 5 strains (virus lost between passage 1 and 5), and evidence of sustained transmission in 6 strains (including all 3 experimental C. elegans strains). Transmission was associated with host phylogeny and with viral amplification in exposed populations. Variation in Orsay virus susceptibility and transmission among Caenorhabditis species suggests that the system could be powerful for studying spillover and emergence.
Brain regulatory program predates central nervous system evolution
Authors: Faltine-Gonzalez Dylan , Havrilak Jamie , Layden Michael J 
Published: December 2021

AbstractUnderstanding if bilaterian centralized nervous systems (CNS) evolved once or multiple times has been debated for over a century. Recent efforts determined that the nerve chords found in bilaterian CNSs likely evolved independently, but the origin(s) of brains remains debatable. Developing brains are regionalized by stripes of gene expression along the anteroposterior axis. Gene homologs are expressed in the same relative order in disparate species, which has been interpreted as evidence for homology. However, regionalization programs resemble anteroposterior axial patterning programs, which supports an alternative model by which conserved expression in brains arose convergently through the independent co-option of deeply conserved axial patterning programs. To begin resolving these hypotheses, we sought to determine when the neurogenic role for axial programs evolved. Here we show that the nerve net in the cnidarian Nematostella vectensis and bilaterian brain are regionalized by the same molecular programs, which indicates nervous system regionalization predates the emergence of bilaterians and CNSs altogether. This argues that shared regionalization mechanisms are insufficient to support the homology of brains and supports the notion that axial programs were able to be co-opted multiple times during evolution of brains.
Genome-wide Association Study identifies two novel loci for Gilles de la Tourette Syndrome
Authors: Tsetsos Fotis , Topaloudi Apostolia , Jain Pritesh , Yang Zhiyu , Yu Dongmei , Kolovos Petros , Tumer Zeynep , Rizzo Renata , Hartmann Andreas , Depienne Christel , Worbe Yulia , Müller-Vahl Kirsten R. , Cath Danielle C. , Boomsma Dorret I. , Wolanczyk Tomasz , Zekanowski Cezary , Barta Csaba , Nemoda Zsofia , Tarnok Zsanett , Padmanabhuni Shanmukha S. , Buxbaum Joseph D. , Grice Dorothy , Glennon Jeffrey , Stefansson Hreinn , Hengerer Bastian , Yannaki Evangelia , Stamatoyannopoulos John A. , Benaroya-Milshtein Noa , Cardona Francesco , Hedderly Tammy , Heyman Isobel , Huyser Chaim , Mir Pablo , Morer Astrid , Mueller Norbert , Münchau Alexander , Plessen Kerstin J. , Porcelli Cesare , Roessner Veit , Walitza Susanne , Schrag Anette , Martino Davide ,   The TSAICG,   The TSGeneSEE initiative,   The EMTICS collaborative group,   The TS-EUROTRAIN network,   The TIC Genetics collaborative group, Tischfield Jay A. , Heiman Gary A. , Willsey A. Jeremy , Dietrich Andrea , Davis Lea K. , Crowley James , Mathews Carol A. , Scharf Jeremiah M. , Georgitsi Marianthi , Hoekstra Pieter J. , Paschou Peristera 
Published: December 2021

AbstractTourette Syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture, characterized by multiple motor tics and at least one vocal tic persisting for more than one year. We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6,133 TS individuals and 13,565 ancestry-matched controls. We identified a genome-wide significant locus on chromosome 5q15 and one array-wide significant locus on chromosome 2q24.2. Integration of eQTL, Hi-C and GWAS data implicated the NR2F1 gene and associated lncRNAs within the 5q15 locus, and the RBMS1 gene within the 2q24.2 locus. Polygenic risk scoring using previous GWAS results demonstrated statistically significant ability to predict TS status in the novel cohort. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring on brain volume data identified statistically significant associations with right and left putamen volumes. Our work presents novel insights in the neurobiology of TS opening up new directions for future studies.
Symptoms persisting after hospitalization for COVID-19: 12 months interim results of the COFLOW study
Authors: Bek L.M. , Berentschot J.C. , Heijenbrok-Kal M.H. , Huijts S. , van Genderen M.E. , Vlake J.H. , van Bommel J. , Aerts J.G.J.V. , Ribbers G.M. , van den Berg-Emons H.J.G. , Hellemons M.E. 
Published: December 2021

ABSTRACTIntroductionA large proportion of patients experiences a wide range of sequelae after acute COVID-19 infection, especially after severe illness. The long-term health sequelae need to be assessed. Our objective was to longitudinally assess persistence of symptoms and clusters of symptoms up to 12 months after hospitalization for COVID-19, and to assess determinants of the main persistent symptoms.MethodsIn this multicenter prospective cohort study patients with COVID-19 are followed up for 2 years with measurements at 3, 6, 12, and 24 months after hospital discharge. Here, we present interim results regarding persistent symptoms up to 12 months. Symptoms were clustered into physical, respiratory, cognitive and fatigue symptoms.ResultsWe included 492 patients; mean age was 60.2±10.7 years, 335 (68.1%) males, median length of hospital stay 11 (6.0-27.0) days. At 3 months after discharge 97.0% of the patients had at least 1 persisting symptom, this declined to 95.5% and 92.0% at 6 and 12 months, respectively (p=0.010). Muscle weakness, exertional dyspnea, fatigue, and memory and concentration problems were the most prevalent symptoms with rates over 50% during follow-up. Over time, muscle weakness, hair loss, and exertional dyspnea decreased significantly (p<0.001), while other symptoms, such as fatigue, concentration and memory problems, anosmia, and ageusia persisted. Symptoms from the physical and respiratory cluster declined significantly over time, in contrast to symptoms from the fatigue and cognitive clusters. Female gender was the most important predictor of persistent symptoms and co-occurrence of symptoms from all clusters. Shorter hospital stay and treatment with steroids were related with decreased muscle weakness; comorbidity and being employed were related with increased fatigue; and shorter hospital stay and comorbidity were related with memory problems.ConclusionThe majority of patients experienced COVID-19 sequelae up to 12 months after hospitalization. Whereas physical and respiratory symptoms showed slow gradual decline, fatigue and cognitive symptoms did not evidently resolve over time. This finding stresses the importance of finding the underlying causes and effective treatments for post-COVID condition, beside adequate COVID-19 prevention.
Ubiquitin proteomics uncovers RNA polymerase I as a critical target of the Nse1 RING domain
Authors: Ibars Eva , Codina-Fabra Joan , Bellí Gemma , Casas Celia , Tarrés Marc , Solé-Soler Roger , Lorite Neus P. , Ximénez-Embún Pilar , Muñoz Javier , Colomina Neus , Torres-Rosell Jordi 
Published: December 2021

ABSTRACTUbiquitination controls numerous cellular processes, and its deregulation is associated to many pathologies. The Nse1 subunit in the Smc5/6 complex contains a RING domain with ubiquitin E3 ligase activity and essential functions in genome integrity. However, Nse1-dependent ubiquitin targets remain largely unknown. Here, we use label-free quantitative proteomics to analyse the nuclear ubiquitinome of nse1-C274A RING mutant cells. Our results show that Nse1 impacts on the ubiquitination of several proteins involved in DNA damage tolerance, ribosome biogenesis and metabolism that, importantly, extend beyond canonical functions of the Smc5/6 complex in chromosome disjunction. In addition, our analysis uncovers an unexpected connection between Nse1 and RNA polymerase I (RNAP I) ubiquitination. Specifically, Nse1 and the Smc5/6 complex promote the ubiquitination of K408 and K410 in the clamp domain of Rpa190, a modification that induces its degradation in response to blocks in transcriptional elongation. We propose that this mechanism contributes to Smc5/6-dependent segregation of the rDNA array, the locus transcribed by RNAP I.
Passive inertial damping improves high-speed gaze stabilization in hoverflies
Authors: Hardcastle Ben J , Bierig Karin , Heras Francisco JH , Longden Kit D , Schwyn Daniel A , Krapp Holger G 
Published: December 2021

SUMMARYGaze stabilization reflexes reduce motion blur and simplify the processing of visual information by keeping the eyes level. These reflexes typically depend on estimates of the rotational motion of the body, head, and eyes, acquired by visual or mechanosensory systems. During rapid movements, there can be insufficient time for sensory feedback systems to estimate rotational motion, requiring additional mechanisms. Solutions to this common problem are likely to be adapted to an animal’s behavioral repertoire. Here, we examine gaze stabilization in three families of dipteran flies, each with distinctly different flight behaviors. Through frequency response analysis based on tethered-flight experiments, we demonstrate that fast roll oscillations of the body lead to a stable gaze in hoverflies, whereas the reflex breaks down at the same speeds in blowflies and horseflies. Surprisingly, the high-speed gaze stabilization of hoverflies does not require sensory input from the halteres, their low-latency balance organs. Instead, we show how the behavior is explained by a hybrid control system that combines a sensory-driven, active stabilization component mediated by neck muscles, and a passive component which exploits physical properties of the animal’s anatomy—the mass and inertia of its head. This adaptation requires hoverflies to have specializations of the head-neck joint that can be employed during flight. Our comparative study highlights how species-specific control strategies have evolved to support different visually-guided flight behaviors.SIGNIFICANCE STATEMENTAcross the animal kingdom, reflexes are found which stabilize the eyes to reduce the impact of motion blur on vision—analogous to the image stabilization functions found in modern cameras. These reflexes can be complex, often combining predictions about planned movements with information from multiple sensory systems which continually measure self-motion and provide feedback. The processing of this information in the nervous system incurs time delays which impose limits on performance when fast stabilization is required. Hoverflies overcome the limitations of sensory-driven stabilization reflexes by exploiting the passive stability provided by the head during roll perturbations with particularly high rotational kine-matics. Integrating passive and active mechanisms thus extends the useful range of vision and likely facilitates distinctive aspects of hoverfly flight.
Neural mechanisms to exploit positional geometry for collision avoidance
Authors: Tanaka Ryosuke , Clark Damon A. 
Published: December 2021

SummaryVisual motion provides rich geometrical cues about the three-dimensional configuration the world. However, how brains decode the spatial information carried by motion signals remains poorly understood. Here, we study a collision avoidance behavior in Drosophila as a simple model of motion-based spatial vision. With simulations and psychophysics, we demonstrate that walking Drosophila exhibit a pattern of slowing to avoid collisions by exploiting the geometry of positional changes of objects on near-collision courses. This behavior requires the visual neuron LPLC1, whose tuning mirrors the behavior and whose activity drives slowing. LPLC1 pools inputs from object- and motion-detectors, and spatially biased inhibition tunes it to the geometry of collisions. Connectomic analyses identified circuitry downstream of LPLC1 that faithfully inherits its response properties. Overall, our results reveal how a small neural circuit solves a specific spatial vision task by combining distinct visual features to exploit universal geometrical constraints of the visual world.