bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of Next-Generation Poly(ADP-Ribose) Polymerase 1–Selective Inhibitors
Authors: Ngoi Natalie Y.L. , Leo Elisabetta , O'Connor Mark J. , Yap Timothy A.
Published: December 2021

Poly(ADP-ribose) polymerase (PARP) inhibitors have transformed the therapeutic landscape for advanced ovarian cancer and expanded treatment options for other tumor types, including breast, pancreas, and prostate cancer. Yet, despite the success of PARP inhibitors in our current therapeutic armamentarium, not all patients benefit because of primary resistance, whereas different acquired resistance mechanisms can lead to disease progression on therapy. In addition, the toxicity profile of PARP inhibitors, primarily myelosuppression, has led to adverse events in a proportion of patients as monotherapy, and has limited the use of PARP inhibitors for certain rational combination strategies, such as chemotherapy and targeted therapy regimens. Currently approved PARP inhibitors are essentially equipotent against PARP1 and PARP2 enzymes. In this review, we describe the development of next-generation PARP1-selective inhibitors that have entered phase I clinical trials. These inhibitors have demonstrated increased PARP1 inhibitory potency and exquisitely high PARP1 selectivity in preclinical studies—features that may lead to improved clinical efficacy and a wider therapeutic window. First-in-human clinical trials seeking to establish the safety, tolerability, and recommended phase II dose, as well as antitumor activity of these novel agents, have commenced. If successful, this next-generation of PARP1-selective agents promises to build on the succeses of current PARP inhibitor treatment paradigms in cancer medicine.
With Our Powers Combined
Authors: Kasherman Lawrence , Karakasis Katherine , Oza Amit M.
Published: December 2021

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

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

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.
Comparing hospital-resource utilization by an enhanced pneumonia surveillance programme for COVID-19 with pre-pandemic pneumonia admissions – a Singaporean hospital’s experience
Authors: Huang Wenhui , Chai Gin Tsen , Thong Bernard Yu-Hor , Chan Mark , Ang Brenda , Chow Angela
Published: December 2021

Introduction. During the early days of coronavirus disease 2019 (COVID-19) in Singapore, Tan Tock Seng Hospital implemented an enhanced pneumonia surveillance (EPS) programme enrolling all patients who were admitted from the Emergency Department (ED) with a diagnosis of pneumonia but not meeting the prevalent COVID-19 suspect case definition.

Hypothesis/Gap Statement. There is a paucity of data supporting the implementation of such a programme.

Aims. To compare and contrast our hospital-resource utilization of an EPS programme for COVID-19 infection detection with a suitable comparison group.

Methodology. We enrolled all patients admitted under the EPS programme from TTSH’s ED from 7 February 2020 (date of EPS implementation) to 20 March 2020 (date of study ethics application) inclusive. We designated a comparison cohort over a similar duration the preceding year. Relevant demographic and clinical data were extracted from the electronic medical records.

Results. There was a 3.2 times higher incidence of patients with an admitting diagnosis of pneumonia from the ED in the EPS cohort compared to the comparison cohort (P<0.001). However, there was no significant difference in the median length of stay of 7 days (P=0.160). Within the EPS cohort, stroke and fluid overload occur more frequently as alternative primary diagnoses.

Conclusions. Our study successfully evaluated our hospital-resource utilization demanded by our EPS programme in relation to an appropriate comparison group. This helps to inform strategic use of hospital resources to meet the needs of both COVID-19 related services and essential ‘peace-time’ healthcare services concurrently.
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

Despite 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

Soil 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

A 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

Understanding 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

Tourette 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

Introduction

A 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.

Methods

In 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.

Results

We 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.

Conclusion

The 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

Ubiquitination 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

Gaze 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 STATEMENT

Across 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

Visual 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.
Video-Based Deep Learning to Detect Dyssynergic Defecation with 3D High-Definition Anorectal Manometry
Authors: Levy Joshua J. , Navas Christopher M. , Chandra Joan A. , Christensen Brock C. , Vaickus Louis J. , Curley Michael , Chey William D. , Baker Jason R. , Shah Eric D.
Published: December 2021

BACKGROUND AND AIMS

Evaluation for dyssynergia is the most common reason that gastroenterologists refer patients for anorectal manometry, because dyssynergia is amenable to biofeedback by physical therapists. High-definition anorectal manometry (3D-HDAM) is a promising technology to evaluate anorectal physiology, but adoption remains limited by its sheer complexity. We developed a 3D-HDAM deep learning algorithm to evaluate for dyssynergia.

METHODS

Spatial-temporal data were extracted from consecutive 3D-HDAM studies performed between 2018-2020 at a tertiary institution. The technical procedure and gold standard definition of dyssynergia were based on the London consensus, adapted to the needs of 3D-HDAM technology. Three machine learning models were generated: (1) traditional machine learning informed by conventional anorectal function metrics, (2) deep learning, and (3) a hybrid approach. Diagnostic accuracy was evaluated using bootstrap sampling to calculate area-under-the-curve (AUC). To evaluate overfitting, models were validated by adding 502 simulated defecation maneuvers with diagnostic ambiguity.

RESULTS

302 3D-HDAM studies representing 1,208 simulated defecation maneuvers were included (average age 55.2 years; 80.5% women). The deep learning model had comparable diagnostic accuracy (AUC=0.91 [95% confidence interval 0.89-0.93]) to traditional (AUC=0.93[0.92-0.95]) and hybrid (AUC=0.96[0.94-0.97]) predictive models in training cohorts. However, the deep learning model handled ambiguous tests more cautiously than other models; the deep learning model was more likely to designate an ambiguous test as inconclusive (odds ratio=4.21[2.78-6.38]) versus traditional/hybrid approaches.

CONCLUSIONS

By considering complex spatial-temporal information beyond conventional anorectal function metrics, deep learning on 3D-HDAM technology may enable gastroenterologists to reliably identify and manage dyssynergia in broader practice.
Immunogenic epitope panel for accurate detection of non-cross-reactive T cell response to SARS-CoV-2
Authors: Titov Aleksei , Shaykhutdinova Regina , Shcherbakova Olga V. , Serdyuk Yana , Sheetikov Savely A. , Zornikova Ksenia V. , Maleeva Alexandra V. , Khmelevskaya Alexandra , Dianov Dmitry V. , Shakirova Naina T. , Malko Dmitry B. , Shkurnikov Maxim , Nersisyan Stepan , Tonevitsky Alexander , Khamaganova Ekaterina , Ershov Anton V. , Osipova Elena Y. , Nikolaev Ruslan V. , Pershin Dmitry E. , Vedmedskia Viktoria A. , Maschan Mikhail , Ginanova Victoria , Efimov Grigory A.
Published: December 2021

The ongoing COVID-19 pandemic calls for more effective diagnostic tools, and T cell response assessment can serve as an independent indicator of prior COVID-19 exposure while also contributing to a more comprehensive characterization of SARS-CoV-2 immunity. In this study, we systematically assessed the immunogenicity of 118 epitopes with immune cells collected from multiple cohorts of vaccinated, convalescent, and healthy unexposed and SARS-CoV-2 exposed donors. We identified seventy-five immunogenic epitopes, 24 of which were immunodominant. We further confirmed HLA restriction for 49 epitopes, and described association with more than one HLA allele for 14 of these. After excluding two cross-reactive epitopes that generated a response in pre-pandemic samples, we were left with a 73-epitope set that offers excellent diagnostic specificity without losing sensitivity compared to full-length antigens, which evoked a robust cross-reactive response. We subsequently incorporated this set of epitopes into an in vitro diagnostic ‘Corona-T-test’ which achieved a diagnostic accuracy of 95% in a clinical trial. When applied to a cohort of asymptomatic seronegative individuals with a history of prolonged SARS-CoV-2 exposure, this test revealed a lack of specific T cell response combined with strong cross-reactivity to full-length antigens, indicating that abortive infection had occurred in these individuals.
Stabilization of Microbial Communities by Responsive Phenotypic Switching
Authors: Haas Pierre A. , Gutierrez Maria A. , Oliveira Nuno M. , Goldstein Raymond E.
Published: December 2021

Clonal microbes can switch between different phenotypes and recent theoretical work has shown that stochastic switching between these subpopulations can stabilize microbial communities. This phenotypic switching need not be stochastic, however, but could also be in response to environmental factors, both biotic and abiotic. Here, motivated by the bacterial persistence phenotype, we explore the ecological effects of such responsive switching by analyzing phenotypic switching in response to competing species. We show that the stability of microbial communities with responsive switching differs generically from that of communities with stochastic switching only. To understand the mechanisms by which responsive switching stabilizes coexistence, we go on to analyze simple two-species models. Combining exact results and numerical simulations, we extend the classical stability results for the competition of two species without phenotypic variation to the case in which one species switches, stochastically and responsively, between two phenotypes. In particular, we show that responsive switching can stabilize coexistence even when stochastic switching on its own does not affect the stability of the community.
Antimicrobial resistance determinants in silage
Authors: Nagy Sára Ágnes , Gréta Tóth Adrienn , Papp Márton , Kaplan Selçuk , Solymosi Norbert
Published: December 2021

Animal products may play a role in developing and spreading antimicrobial resistance in several ways. On the one hand, residues of antibiotics not adequately used in animal farming can enter the human body via food. But resistant bacteria may also be present in animal products, which can transfer the antimicrobial resistance genes (ARG) to the bacteria in the consumer’s body by horizontal gene transfer. As previous studies have shown that fermented foods have a meaningful ARG content, it is indicated that such genes may also be present in silage used as mass feed in the cattle sector. In our study, we aspired to answer what ARGs occur in silage and what mobility characteristics they have? For this purpose, we have analyzed bioinformatically 52 freely available deep sequenced silage samples from shotgun metagenome next-generation sequencing. A total of 17 perfect matched ARGs occurred 55 times in the samples. More than half of these ARGs are mobile because they can be linked to integrative mobile genetic elements, prophages or plasmids. Our results point to a neglected but substantial ARG source in the food chain.
Continual reelin signaling by the prime neurogenic niche of the adult brain
Authors: Pérez-Martínez F. Javier , Cifuentes Manuel , Luque Juan M.
Published: December 2021

During development reelin sets the pace of neocortical neurogenesis enabling in turn newborn neurons to migrate, but whether and, if so, how reelin signaling affects the adult neurogenic niches remains uncertain. We show that reelin signaling, resulting in Dab1 phosphorylation, occurs in the ependymal-subependymal zone (EZ/SEZ) of the lateral ventricles where, along with its associated rostral migratory stream (RMS), the highest density of functional ApoER2 accumulates. Mice deficient for reelin, ApoER2 or Dab1 exhibit enlarged ventricles and dysplastic RMS. Moreover, while the conditional ablation of Dab1 in neural progenitor cells (NPCs) enlarges the ventricles and impairs neuroblasts clearance from the SEZ, the transgenic misexpression of reelin in NPCs of reelin-deficient mice normalizes the ventricular lumen and the density of ependymal cilia, ameliorating in turn neuroblasts migration; consistently, intraventricular infusion of reelin reroutes neuroblasts. These results demonstrate that reelin signaling persists sustaining the germinal niche of the lateral ventricles and influencing neuroblasts migration in the adult brain.
Structural models of SARS-CoV-2 Omicron variant in complex with ACE2 receptor or antibodies suggest altered binding interfaces
Authors: Lubin Joseph H. , Markosian Christopher , Balamurugan D. , Pasqualini Renata , Arap Wadih , Burley Stephen K. , Khare Sagar D.
Published: December 2021

There is enormous ongoing interest in characterizing the binding properties of the SARS-CoV-2 Omicron Variant of Concern (VOC) (B.1.1.529), which continues to spread towards potential dominance worldwide. To aid these studies, based on the wealth of available structural information about several SARS-CoV-2 variants in the Protein Data Bank (PDB) and a modeling pipeline we have previously developed for tracking the ongoing global evolution of SARS-CoV-2 proteins, we provide a set of computed structural models (henceforth models) of the Omicron VOC receptor-binding domain (omRBD) bound to its corresponding receptor Angiotensin-Converting Enzyme (ACE2) and a variety of therapeutic entities, including neutralizing and therapeutic antibodies targeting previously-detected viral strains. We generated bound omRBD models using both experimentally-determined structures in the PDB as well as machine learningbased structure predictions as starting points. Examination of ACE2-bound omRBD models reveals an interdigitated multi-residue interaction network formed by omRBD-specific substituted residues (R493, S496, Y501, R498) and ACE2 residues at the interface, which was not present in the original Wuhan-Hu-1 RBD-ACE2 complex. Emergence of this interaction network suggests optimization of a key region of the binding interface, and positive cooperativity among various sites of residue substitutions in omRBD mediating ACE2 binding. Examination of neutralizing antibody complexes for Barnes Class 1 and Class 2 antibodies modeled with omRBD highlights an overall loss of interfacial interactions (with gain of new interactions in rare cases) mediated by substituted residues. Many of these substitutions have previously been found to independently dampen or even ablate antibody binding, and perhaps mediate antibody-mediated neutralization escape (e.g., K417N). We observe little compensation of corresponding interaction loss at interfaces when potential escape substitutions occur in combination. A few selected antibodies (e.g., Barnes Class 3 S309), however, feature largely unaltered or modestly affected protein-protein interfaces. While we stress that only qualitative insights can be obtained directly from our models at this time, we anticipate that they can provide starting points for more detailed and quantitative computational characterization, and, if needed, redesign of monoclonal antibodies for targeting the Omicron VOC Spike protein. In the broader context, the computational pipeline we developed provides a framework for rapidly and efficiently generating retrospective and prospective models for other novel variants of SARS-CoV-2 bound to entities of virological and therapeutic interest, in the setting of a global pandemic.
Optimizing the energy bandwidth for transmission full-field X-ray microscopy experiments
Authors: Storm Malte , Döring Florian , Marathe Shashidhara , Cipiccia Silvia , David Christian , Rau Christoph
Published: December 2021

Full-field transmission X-ray microscopy (TXM) is a very potent high-resolution X-ray imaging technique. However, it is challenging to achieve fast acquisitions because of the limited efficiency of the optics. Using a broader energy bandwidth, for example using a multilayer monochromator, directly increases the flux in the experiment. The advantage of more counts needs to be weighed against a deterioration in achievable resolution because focusing optics show chromatic aberrations. This study presents theoretical considerations of how much the resolution is affected by an increase in bandwidth as well as measurements at different energy bandwidths (ΔE/E = 0.013%, 0.27%, 0.63%) and the impact on achievable resolution. It is shown that using a multilayer monochromator instead of a classical silicon double-crystal monochromator can increase the flux by an order of magnitude with only a limited effect on the resolution.
Scaling up Sirohi: can women empowerment and sustainability drive a luxury brand?
Authors: Sondhi Neena , Basu Rituparna
Published: December 2021

Learning outcomes

The case offers a unique opportunity to understand the market dynamics of a young luxury brand that aspires to empower women and pursue the broader goal of marketing sustainability in an emerging market. The discussion would enable learners to conduct environmental analysis and assess implications of crisis (current pandemic) on business, understand the marketing mix implications for a firm with societal orientation, learn to design effective brand positioning strategies and plan social and market driven brand strategies to ensure sustainable growth.

Case overview/synopsis

Gauri Malik, an investment banker-turned-social entrepreneur, forayed into the luxury home décor and furniture market with Sirohi, in 2019. In a market driven by exclusivity and design appeal, the brand had sustainability at its core. Malik worked with 200 women, from a conservative rural base in India to create traditional products that were hand-made with recycled natural fibres and upcycled plastic wastes. Driven by the goal of securing the livelihood for a larger group of women artisans, Malik wanted to scale up from 350 to 5000 products in the next five years. Hence, for materializing her ambitious plans she sought answers to- Could her home-trained women artisans deliver the promise of quality and finesse to support Sirohi scale up as a luxury brand? While it was extremely critical for Sirohi to have an articulated image-she wondered if the parallel focus on the up-market luxury brand image and sustainability-create competitive advantage or lead to diffused positioning?

Complexity academic level

Classified as MODERATE in terms of difficulty level, the case can be effectively used in post-graduate programmes for foundation courses on Marketing Management, elective courses on Brand Management or Sustainability Marketing.

Supplementary materials

Teaching notes are available for educators only.

Subject code

CSS 8: Marketing.
Research on strengthening stone arch bridge with CFRP rebars
Authors: Zhang Kexin , Li Dachao , Shen Xinyuan , Hou Wenyu , Li Yanfeng , Xue Xingwei
Published: December 2021

Purpose

This paper aims to describe carbon fiber reinforced plastics (CFRP) bars as a way to strengthen a 40-year-old stone arch bridge. To investigate effectiveness of the strengthening method, fielding-load tests were carried out before and after strengthening.

Design/methodology/approach

High-strength CFRP bars with minor radius, high tensile strain and good corrosion resistance were used in this reinforcement. The construction process for strengthening with CFRP bars – including CFRP bars cutting, crack grouting, original structural surface treatment, implant drilling, CFRP bars installation and pouring mortar – was described. Ultimate bearing capacity of the bridge after strengthening was discussed.

Findings

The results of concrete stress and deflection show that the strength and stiffness of the strengthened bridge are improved. The strengthened way with CFRP bars is feasible and effective.

Originality/value

This paper describes CFRP bars as a way to strengthen a 40-year-old stone arch bridge.
A dual-branch balance saliency model based on discriminative feature for fabric defect detection
Authors: Liu Zhoufeng , Wang Menghan , Li Chunlei , Ding Shumin , Li Bicao
Published: December 2021

Purpose

The purpose of this paper is to focus on the design of a dual-branch balance saliency model based on fully convolutional network (FCN) for automatic fabric defect detection, and improve quality control in textile manufacturing.

Design/methodology/approach

This paper proposed a dual-branch balance saliency model based on discriminative feature for fabric defect detection. A saliency branch is firstly designed to address the problems of scale variation and contextual information integration, which is realized through the cooperation of a multi-scale discriminative feature extraction module (MDFEM) and a bidirectional stage-wise integration module (BSIM). These modules are respectively adopted to extract multi-scale discriminative context information and enrich the contextual information of features at each stage. In addition, another branch is proposed to balance the network, in which a bootstrap refinement module (BRM) is trained to guide the restoration of feature details.

Findings

To evaluate the performance of the proposed network, we conduct extensive experiments, and the experimental results demonstrate that the proposed method outperforms state-of-the-art (SOTA) approaches on seven evaluation metrics. We also conduct adequate ablation analyses that provide a full understanding of the design principles of the proposed method.

Originality/value

The dual-branch balance saliency model was proposed and applied into the fabric defect detection. The qualitative and quantitative experimental results show the effectiveness of the detection method. Therefore, the proposed method can be used for accurate fabric defect detection and even surface defect detection of other industrial products.
Gulf property damage, housing price trends and US bankruptcy filings
Authors: Brotman Billie Ann , Katzman Brett
Published: December 2021

Purpose

This paper aims to examine potential causes of bankruptcy as they relate to hurricane damage. Investigate whether hurricanes result in personal bankruptcy filings due to real property damages. Strengthen existing descriptive results by using fully modified ordinary least squares (FMOLS).

Design/methodology/approach

Lagged FMOLS model is used with data from states that suffered hurricane damage between 2000 through 2020. FMOLS controls for various financial distresses that can cause bankruptcy filings.

Findings

Bankruptcy is usually filed for within one year of a hurricane. Changes in house prices and hurricane severity were significant indicators of bankruptcy filings. However, the divorce rate, commonly thought of as a primary reason for bankruptcy, is insignificant.

Research limitations/implications

Data was available on a state level for the independent variables. Hurricane damage needed to be financially significant enough for inland flooding to be measurable and influential.

Practical implications

Establishes that financial distress comes from several sources, not just home damage. Financial distress is highly correlated with whether a home was insured. Divorce does not cause bankruptcy filings.

Social implications

Federal flood insurance programs should be reexamined. Having a broader all-risk homeowner policy could reduce the number of households that file for bankruptcy after a hurricane.

Originality/value

Existing research uses descriptive statistics and obtains mixed findings regarding the association between hurricane damage and bankruptcy filings. The FMOLS approach provides clarity about this association.
Assessing the macro and micro elements of the Akbarieh World Heritage Garden using participant observer method in a continuous/stop-motion
Authors: Khalilnezhad Mohammad Reza , Kopec Dak
Published: December 2021

Purpose

This study aims to assess each of the seven segments of the Akbarieh Garden as the World Heritage Cultural Landscape. First, we wanted to identify the macro elements that dominated one's perception within each area. Then, we wanted to identify the micro elements that support the vista in its entirety.

Design/methodology/approach

To acquire data, we used a Participant Observer (PO) method as part of a Continuous/Stop-Motion (CSM) procedure. The identification of macro elements came from retrospective recollections derived from the continuous walk method—the stop-walk method allowed for the identification of micro elements. The data gained from this method is then used to understand how one interprets and responds to large—multi-segmented sites such as the Akbarieh Garden.

Findings

The results of this study show the Continuous/Stop-Motion method yielded predictable results with macro elements and elements of interest being easily recalled. However, the use of photographing for the stop-walk method revealed a similar focus on the macro element. We had hypothesized that the micro elements would be the elements of fascination and discovered when the person remained in the area to photograph scenes of interest. However, the PO photographed the macro elements. It wasn't until the post photo analysis that the PO identified some of the micro elements would be the elements of fascination and discovered when the person remained in the area to photograph scenes of interest. However, the PO photographed the macro elements. It wasn't until the post photo analysis that the PO identified some of the micro elements. The post photo discoveries suggest that real-time experience of micro elements is undervalued.

Originality/value

There is no general discussion on this topic yet amongst professionals. The initiative of the Participant Observer (PO) method as a tool for perception the historic gardens and landscapes identified that gap and its related necessity to provide guidance. As is true for exploratory studies, these results provide a foundation for further study. The use of the Continuous/Stop-Motion method was ideal for this study.