bluuebunny/crossref_metadata_2025 huggingface dataset:
Conservation education in Aotearoa-New Zealand: a values perspective
Authors: Birdsall Sally , Kelly Tim
Published: May 2022

Throughout the world, Aotearoa-New Zealand is recognised for its extraordinary biodiversity. However, many species that make up this distinctive biodiversity are under threat of extinction due to human impacts, such as the ill-considered introduction of particular animals. Many New Zealanders participate in the protection and restoration of their environment, which involves the lethal control of these introduced animals. Primary school children (5–13 years old) engage in conservation education as part of their learning, which aims to develop their abilities to take informed action to protect and restore our environment, sometimes including lethal control of introduced animals. Recently, concerns have been raised that children learning about the lethal control of introduced animals does not align with the values that should be explored and encouraged according to Aotearoa-New Zealand’s national curriculum. We argue that conservation education, including learning about the lethal control of introduced animals, encourages children to explore and encourage these values, namely valuing the diversity in their heritages, ecological sustainability, participation for the common good, equity, innovation, and respect for others.
Recent Advances in Frontotemporal Dementia
Authors: Tartaglia Maria Carmela , Mackenzie Ian R. A.
Published: May 2022

Frontotemporal dementia (FTD) is a devastating neurodegenerative condition for which there is currently no effective treatment. Although it is much less common than Alzheimer’s disease, the impact of FTD is increased by its relatively early onset and high heritability. Clinical heterogeneity and overlap with other neurodegenerative and psychiatric syndromes complicate diagnosis. However, recent advances in our understanding of the molecular basis of FTD provide a foundation for the development of much-needed biomarkers and targeted therapies. This review provides a summary of the recently revised clinical criteria for FTD, highlights diagnostic challenges, briefly summarizes recent molecular discoveries and then focuses on promising developments in biomarkers and clinical trials.
Pediatric-Specific Hazard Vulnerability Analysis: The Missing Component of Regional and Hospital-Based Preparedness
Authors: Kappy Brandon , Parish April , Barda Amie , Frost Pat , Timm Nathan
Published: May 2022

Though children comprise a large percentage of the population and are uniquely vulnerable to disasters, pediatric considerations are often omitted from regional and hospital-based emergency preparedness. Children’s absence is particularly notable in hazard vulnerability analyses (HVAs), a commonly used tool that allows emergency managers to identify a hazard’s impact, probability of occurrence, and previous mitigation efforts. This paper introduces a new pediatric-specific HVA that provides emergency managers with a quantifiable means to determine how a hazard might affect children within a given region, taking into account existing preparedness most relevant to children’s safety. Impact and preparedness categories within the pediatric-specific HVA incorporate age-based equipment and care needs, long-term developmental and mental health consequences, and the hospital and community functions most necessary for supporting children during disasters. The HVA allows emergency managers to create a more comprehensive assessment of their pediatric populations and preparatory requirements.
Effect of maternal nutrition education on early initiation and exclusive breast-feeding practices in south Ethiopia: a cluster randomised control trial
Authors: Admasu Jatani , Egata Gudina , Bassore Dereje Getahun , Feleke Fentaw Wassie
Published: May 2022

Introduction: Optimal breast-feeding practices make a major contribution to the promotion of healthy growth and development through much prevention of diarrheal and respiratory diseases which majorly cause morbidity and mortality in under-five children. However, breast-feeding practices remain suboptimality in Ethiopia. Objective: The study objective was to determine the effect of maternal nutrition education on early initiation and exclusive breast-feeding practice in the Hawela Tulla sub-city. Methods: A cluster randomised, parallel-group, single-blinded trial was used. About 310 pregnant women (155 for the intervention group and 155 for the control group) were included. Result: An early initiation of breast-feeding was significantly higher among women who received breast-feeding education than those who did not receive (104(72·7 %) v. 85(59·9 %), P = 0·022) and exclusive breast-feeding practice was also significantly higher among women who received breast-feeding education than those who did not receive (106(74·1 %) v. 86(60·6 %), P = 0·015). Breast-feeding education [AORs 1·55, 95 % CI (1·02, 2·36)], institutional delivery [AOR 2·29, 95 % CI (1·21, 4·35)], vaginal delivery [AOR 2·85, 95 % CI (1·61, 5·41)] and pre-lacteal feeding [AOR 0·47, 95 % CI (0·25, 0·85)] were predictors of early initiation of breast-feeding. Breast-feeding education [AOR 1·72, 95 % CI (1·12, 2·64)] and institutional delivery [AOR 2·36, 95 % CI (1·28, 4·33)] were also determinants of exclusive breast-feeding practices. Conclusion: Breast-feeding education improved early initiation of breast-feeding and exclusive breast-feeding practices. Providing sustained education to women regarding early initiation and exclusive breast-feeding practice should be strengthened.
In situ, broadband measurement of the radio frequency attenuation length at Summit Station, Greenland
Authors: Aguilar J. A. , Allison P. , Beatty J. J. , Besson D. , Bishop A. , Botner O. , Bouma S. , Buitink S. , Cataldo M. , Clark B. A. , Curtis-Ginsberg Z. , Connolly A. , Dasgupta P. , de Kockere S. , de Vries K. D. , Deaconu C. , DuVernois M. A. , Glaser C. , Hallgren A. , Hallmann S. , Hanson J. C. , Hendricks B. , Hornhuber C. , Hughes K. , Karle A. , Kelley J. L. , Kravchenko I. , Krebs R. , Lahmann R. , Latif U. , Mammo J. , Meyers Z. S. , Michaels K. , Mulrey K. , Nelles A. , Novikov A. , Nozdrina A. , Oberla E. , Oeyen B. , Pan Y. , Pandya H. , Plaisier I. , Punsuebsay N. , Pyras L. , Ryckbosch D. , Scholten O. , Seckel D. , Seikh M. F. H. , Smith D. , Southall D. , Torres J. , Toscano S. , Tosi D. , Van Den Broeck D. J. , van Eijndhoven N. , Vieregg A. G. , Welling C. , Williams D. R. , Wissel S. , Young R. , Zink A.
Published: May 2022

Over the last 25 years, radiowave detection of neutrino-generated signals, using cold polar ice as the neutrino target, has emerged as perhaps the most promising technique for detection of extragalactic ultra-high energy neutrinos (corresponding to neutrino energies in excess of 0.01 Joules, or 1017 electron volts). During the summer of 2021 and in tandem with the initial deployment of the Radio Neutrino Observatory in Greenland (RNO-G), we conducted radioglaciological measurements at Summit Station, Greenland to refine our understanding of the ice target. We report the result of one such measurement, the radio-frequency electric field attenuation length $L_\alpha$. We find an approximately linear dependence of $L_\alpha$ on frequency with the best fit of the average field attenuation for the upper 1500 m of ice: $\langle L_\alpha \rangle = ( ( 1154 \pm 121) - ( 0.81 \pm 0.14) \, ( \nu /{\rm MHz}) ) \,{\rm m}$ for frequencies ν ∈ [145 − 350] MHz.
Rules for Party Subsidies and Electoral Volatility in Latin America
Authors: Su Yen-Pin
Published: May 2022

Prior research has argued that public subsidies for parties matter for explaining electoral volatility, but the empirical results have been inconclusive. This article addresses this puzzle by examining how different rules for direct state funding affect different types of electoral volatility, using data from lower chamber elections in eighteen Latin American countries from 1978 through 2014. Focusing on volatility caused by new party entry and old party exit (party replacement volatility) and volatility caused by vote switching among existing parties (stable party volatility), it finds that countries with less strict eligibility thresholds for party subsidies tend to have lower levels of party replacement volatility. However, the empirical analysis does not provide sufficient evidence that the eligibility thresholds for party subsidies matter for predicting stable party volatility. Overall, this article suggests that less strict eligibility thresholds for party subsidies help produce stable party systems by reducing risks associated with party replacement volatility.
Animal Culture and Animal Welfare
Authors: Fitzpatrick Simon , Andrews Kristin
Published: May 2022

Following recent arguments that cultural practices in wild animal populations have important conservation implications, we argue that recognizing captive animals as cultural has important welfare implications. Having a culture is of deep importance for cultural animals, wherever they live. Without understanding the cultural capacities of captive animals, we will be left with a deeply impoverished view of what they need to flourish. Best practices for welfare should therefore require concern for animals’ cultural needs, but the relationship between culture and welfare is also extremely complex, requiring us to rethink standard assumptions about what constitutes and contributes to welfare.
Responsible Dissemination in Sexual Orientation Research: The Case of the AI “Gaydar”
Authors: De Block Andreas , Conix Stijn
Published: May 2022

A recent controversy about neural networks allegedly capable of detecting a person’s sexual orientation raises the question of whether all research on homosexuality should be permitted. This paper considers two arguments for limits to such research, and concludes that there are good reasons to limit at least the dissemination of applied research on the etiology of homosexuality. The paper then briefly sketches how this could work, and looks at three objections against these limitations.
Mid-Neoproterozoic magmatism in the South Qilian Belt, NE Tibetan Plateau and its tectonic implications
Authors: Qin Yu , Zhang Xiaoli , Feng Qiao , Zhang Xi , Liu Yun , Kang Yu , Chen Yan , Chu Pengju , Yang Yuexiang , Tian Lingchuan , Li Longxue
Published: May 2022

Widely distributed Mid-Neoproterozoic mafic rocks of the Qilian – Qaidam – East Kunlun region record the tectonic evolution of the northeastern Tibetan Plateau. This study presents whole-rock geochemistry, zircon U–Pb geochronology and Hf isotopes for the Xialanuoer gabbros of the central South Qilian Belt (SQB). Zircon laser ablation – inductively coupled plasma – mass spectrometry (LA-ICP-MS) U–Pb dating indicates that the gabbros were emplaced at ca. 738 Ma, indicating they are contemporaneous with mafic magmatism elsewhere in the northeastern Tibetan Plateau. The gabbros have low SiO2, Cr and Ni contents and Mg# values, are relatively enriched in light rare-earth elements (LREEs) and depleted in high-field-strength elements (HFSEs; e.g. Nb and Ta), have no positive Zr or Hf anomalies and have relatively high Nb/Ta but low Nb/La ratios. These data indicate that the Xialanuoer gabbros formed from calc-alkaline basaltic magmas that were originally generated by the partial melting of an enriched mantle of type-I (EMI-type) enriched region of the lithospheric mantle, underwent little to no crustal contamination prior to their emplacement, and have within-plate basalt geochemical affinities. Combining these data with the presence of widespread contemporaneous continental rift-related magmatism and sedimentation in the North Qilian, Central Qilian, South Qilian, Quanji, North Qaidam and East Kunlun regions suggests that the northeastern Tibetan Plateau underwent Mid-Neoproterozoic continental rifting, which also affected other Rodinian blocks (e.g. Tarim, South China, Australia, North America and Southern Africa).
Commemorative contention: The Taipei National Revolutionary Martyrs’ Shrine and the politics of death
Authors: Vu Linh D.
Published: May 2022

This article addresses the Taipei National Revolutionary Martyrs’ Shrine (Guomin geming zhonglie ci) as a site of contention over national sovereignty and belonging. The shrine originated in Sun Yat-sen's aspiration to commemorate the anti-imperial martyrs of the 1911 Republic and in the Nationalist government's attempt to marshal political allegiance in the 1920s–1940s. Upon fleeing from the mainland to Taiwan after losing to the Communist forces in 1949, the Nationalist leadership renovated the Japanese-built National Protection Shrine in Taipei, transforming it into the National Revolutionary Martyrs’ Shrine to house the displaced spirits of the national dead. Throughout the Cold War era, the spring and autumn sacrifices performed by heads of state and visits to the shrine by foreign dignities served to affirm the sovereignty of the Republic of China vis-à-vis the People's Republic of China. Even though the end of martial law in 1987 opened a new era marked by the Nationalist Party's loss of political hegemony, the shrine continued to adhere to the Nationalist Party's ideology and version of history. Far from embodying a place of remembrance and mourning for war victims, the palace-style compound is a site of contested sovereignty exaggerated by China's extraordinary growth and Taiwan's transforming identity. The enshrined dead have found a new role as both an assertion of the island's autonomy and a reflection of its dynamism. The departed, albeit silent, hold power in the malleability of their memories, and each permutation of how the past is remembered hosts its own tension.
Constitution, identity, and the Trinity: rebuttal to Leftow
Authors: Hasker William
Published: May 2022

Brian Leftow continues to argue that the metaphysical concept of constitution cannot be used to explicate the doctrine of the Trinity, as I have attempted to do. He also defends his own, distinctive view of the relation of Jesus to the Father. I maintain that he fails on both counts.
Pandemic Stories: The Voices of Older Adults
Authors: Hayden Leigh , Warren-Norton Kathryn , Chaze Ferzana , Roberts Rebecca
Published: May 2022

To document the reactions and experiences of older persons during the COVID-19 pandemic, we have conducted a qualitative study of 25 older adults (50 years of age and older) throughout the pandemic, using serial interviewing methods. This analysis reports on the data collected from the first two rounds of interviews – one conducted in the summer of 2020 and one conducted in the fall of 2020. Our thematic analysis found eight major themes: thoughts on the dangers of the pandemic, how the virus has changed daily life (including social life), health care during COVID (being a caregiver, losing a loved one, seeking health care), missing spontaneity and dealing with existential dread, the growing frustration, seeking connection through civic participation, adaptation and resilience, and the social ills that the pandemic has revealed. These stories describe both loneliness and connection, hope coupled with disappointment, but overwhelmingly, an insight into what the pandemic has shown us about the social ills that it has revealed.
Steady states of thin-film equations with van der Waals force with mass constraint
Authors: CHEN XINFU , JIANG HUIQIANG , LIU GUOQING
Published: May 2022

We consider steady states with mass constraint of the fourth-order thin-film equation with van der Waals force in a bounded domain which leads to a singular elliptic equation for the thickness with an unknown pressure term. By studying second-order nonlinear ordinary differential equation,\begin{equation*}h_{rr}+\frac{1}{r}h_{r}=\frac{1}{\alpha}h^{-\alpha}-p\end{equation*}we prove the existence of infinitely many radially symmetric solutions. Also, we perform rigorous asymptotic analysis to identify the blow-up limit when the steady state is close to a constant solution and the blow-down limit when the maximum of the steady state goes to the infinity.
Contrast Mechanisms in Secondary Electron e-Beam-Induced Current (SEEBIC) Imaging
Authors: Dyck Ondrej , Swett Jacob L , Evangeli Charalambos , Lupini Andrew R , Mol Jan , Jesse Stephen
Published: May 2022

Over the last few years, a new mode for imaging in the scanning transmission electron microscope (STEM) has gained attention as it permits the direct visualization of sample conductivity and electrical connectivity. When the electron beam (e-beam) is focused on the sample in the STEM, secondary electrons (SEs) are generated. If the sample is conductive and electrically connected to an amplifier, the SE current can be measured as a function of the e-beam position. This scenario is similar to the better-known scanning electron microscopy-based technique, electron beam-induced current imaging, except that the signal in the STEM is generated by the emission of SEs, hence the name secondary electron e-beam-induced current (SEEBIC), and in this case, the current flows in the opposite direction. Here, we provide a brief review of recent work in this area, examine the various contrast generation mechanisms associated with SEEBIC, and illustrate its use for the characterization of graphene nanoribbon devices.
Astaxanthin attenuated the stress-induced intestinal motility disorder via altering the gut microbiota
Authors: Yasuda Ritsu , Kamada Kazuhiro , Murakami Takaaki , Inoue Ryo , Mizushima Katsura , Hirose Ryohei , Inoue Ken , Dohi Osamu , Yoshida Naohisa , Katada Kazuhiro , Uchiyama Kazuhiko , Handa Osamu , Ishikawa Takeshi , Takagi Tomohisa , Konishi Hideyuki , Naito Yuji , Itoh Yoshito
Published: May 2022

Abstract: Gut microbiota and short-chain fatty acids (SCFAs) are recognized as key factors in the pathophysiology of irritable bowel syndrome. Astaxanthin is a carotenoid with strong antioxidant and anti-inflammatory activities. In this study, we examined the effects of astaxanthin on gut microbiota-, SCFAs-, and corticotropin-releasing factor (CRH)-induced intestinal hypermotility. Male Wistar rats (n=12 per group) were fed a diet with or without 0. 02% (w/w) astaxanthin for four weeks and CRH or saline was administered intravenously. The number of fecal pellets was counted 2 h after injection. Then the rats were sacrificed, and the cecal content were collected 3 h after injection. The number of feces was significantly increased by CRH injection in the control group (2.0 vs. 6.5; p=0.028), but not in the astaxanthin group (1.0 vs. 2.2; p=0.229) (n=6 per group). The cecal microbiota in the astaxanthin group was significantly altered compared with that in the control group. The concentrations of acetic acid (81.1 μmol/g vs. 103.9 μmol/g; p=0.015) and butyric acid (13.4 μmol/g vs. 39.2 μmol/g; p<0.001) in the astaxanthin group were significantly lower than that in the control group (n=12 per group). Astaxanthin attenuates CRH-induced intestinal hypermotility and alters the composition of gut microbiota and SCFAs.
Kindliche Verhaltensauffälligkeiten im ersten Lebensjahr und mütterliche Belastung in der Zeit der COVID-19-Pandemie
Authors: Tettenborn Alexandra von , Popp Lukka , Zietlow Anna-Lena , Woll Christian F. J. , Marx Anton K. G. , Nonnenmacher Nora , Kretz-Bünese Tanja , Hagl Maria , Müller Mitho , Reck Corinna
Published: May 2022

Zusammenfassung. Theoretischer Hintergrund: Die COVID-19-Pandemie stellte in vielen Bereichen eine Belastung für Familien dar, insbesondere durch die einschneidenden Beschränkungen zu Beginn. Fragestellung: Wie wirkte sich dies auf die Belastung von Müttern mit Kindern im ersten Lebensjahr und auf die kindliche Verhaltensregulation aus? Methode: In einer Online-Befragung schätzten 577 Mütter das Schrei-‍, Schlaf- und Fütter-/Essverhalten ihrer Kinder ( M = 7.3; 0 – 12 Mon., SD = 3.25) und ihre eigene Belastung ein, zudem Stresserleben, depressive Symptomatik, Partnerschaftszufriedenheit und Bonding. Ergebnisse: Schlafprobleme traten bei 21.7 %, schwer tröstbares und häufiges Schreien bei 12.3 % und exzessives Schreien bei 1.6 % der Kinder auf. Mindestens jede fünfte Mutter fühlte sich durch Schreien oder Schlafprobleme belastet. Mehr Stress, beeinträchtigtes Bonding und weniger Partnerschaftszufriedenheit erklärten 17 – 21 % der Varianz der mütterlichen Belastung durch Schrei- und Schlafverhalten. In der Zeit der stärksten Beschränkungen zeigte sich signifikant mehr Belastung in der Gruppe von Müttern, die von vermehrtem Schreien und verlängerter Einschlaflatenz berichteten, sowie mit mindestens einem weiteren Kind im Haushalt (MANOVA). Diskussion und Schlussfolgerung: Pandemiebedingt belastend für Mütter im ersten Jahr scheinen eingeschränkter Zugang zum Versorgungssystem, die Betreuung von mehr als einem Kind sowie das Alter des Kindes zu sein, während eine gute Beziehung zum Kind (Bonding) und/oder zum Partner (Partnerschaftszufriedenheit) abmildernd wirken.
Development of the Real‐Time 30‐s‐Update Big Data Assimilation System for Convective Rainfall Prediction With a Phased Array Weather Radar: Description and Preliminary Evaluation
Authors: Honda T. , Amemiya A. , Otsuka S. , Lien G.‐Y. , Taylor J. , Maejima Y. , Nishizawa S. , Yamaura T. , Sueki K. , Tomita H. , Satoh S. , Ishikawa Y. , Miyoshi T.
Published: May 2022

We present the first ever real‐time numerical weather prediction system with 30‐s update cycles at a 500‐m grid spacing for the prediction of convective precipitation in the subsequent 30 min using a new‐generation multi‐parameter phased array weather radar. The system comprises a regional atmospheric model known as the SCALE and the local ensemble transform Kalman filter (LETKF). To accelerate the SCALE‐LETKF system, data transfer between the two aforementioned components is performed using a memory copy instead of a file I/O. A complete real‐time workflow including domain nesting and observational data transfer is constructed. A real‐time test in July and August 2020 showed that the system is fast enough for a real‐time application of 30‐s forecast‐analysis cycles and 30‐min prediction. The development includes a new thinning method considering the spatially correlated observation errors in the dense radar data. This new thinning method is effective in two past case studies in the summer of 2019.
Halogen-doped phosphorescent carbon dots for grayscale patterning
Authors: Liu Yanfeng , Al-salihi Mahmoud , Guo Yong , Ziniuk Roman , Cai Songtao , Wang Luwei , Li Yuan , Yang Zhigang , Peng Dengfeng , Xi Kai , An Zhongfu , Jia Xudong , Liu Liwei , Yan Wei , Qu Junle
Published: May 2022

Flexible organic materials that exhibit dynamic ultralong room temperature phosphorescence (DURTP) via photoactivation have attracted increasing research interest for their fascinating functions of reversibly writing-reading-erasing graphic information in the form of a long afterglow. However, due to the existence of a nonnegligible activation threshold for the initial exposure dose, the display mode of these materials has thus far been limited to binary patterns. By resorting to halogen element doping of carbon dots (CDs) to enhance intersystem crossing and reduce the activation threshold, we were able to produce, for the first time, a transparent, flexible, and fully programmable DURTP composite film with a reliable grayscale display capacity. Examples of promising applications in UV photography and highly confidential steganography were constructed, partially demonstrating the broad future applications of this material as a programmable platform with a high optical information density.
Clinical outcomes in patients with relapsed/refractory FLT3-mutated acute myeloid leukemia treated with gilteritinib who received prior midostaurin or sorafenib
Authors: Perl Alexander E. , Hosono Naoko , Montesinos Pau , Podoltsev Nikolai , Martinelli Giovanni , Panoskaltsis Nicki , Recher Christian , Smith Catherine C. , Levis Mark J. , Strickland Stephen , Röllig Christoph , Groß-Langenhoff Marco , Chou Wen-Chien , Lee Je-Hwan , Yokoyama Hisayuki , Hasabou Nahla , Lu Qiaoyang , Tiu Ramon V. , Altman Jessica K.
Published: May 2022

The fms-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib is indicated for relapsed or refractory (R/R) FLT3-mutated acute myeloid leukemia (AML), based on its observed superior response and survival outcomes compared with salvage chemotherapy (SC). Frontline use of FLT3 tyrosine kinase inhibitors (TKIs) midostaurin and sorafenib may contribute to cross-resistance to single-agent gilteritinib in the R/R AML setting but has not been well characterized. To clarify the potential clinical impact of prior TKI use, we retrospectively compared clinical outcomes in patients with R/R FLT3-mutated AML in the CHRYSALIS and ADMIRAL trials who received prior midostaurin or sorafenib against those without prior FLT3 TKI exposure. Similarly high rates of composite complete remission (CRc) were observed in patients who received a FLT3 TKI before gilteritinib (CHRYSALIS, 42%; ADMIRAL, 52%) and those without prior FLT3 TKI therapy (CHRYSALIS, 43%; ADMIRAL, 55%). Among patients who received a prior FLT3 TKI in ADMIRAL, a higher CRc rate (52%) and trend toward longer median overall survival was observed in the gilteritinib arm versus the SC arm (CRc = 20%; overall survival, 5.1 months; HR = 0.602; 95% CI: 0.299, 1.210). Remission duration was shorter with prior FLT3 TKI exposure. These findings support gilteritinib for FLT3-mutated R/R AML after prior sorafenib or midostaurin.
A cancer-associated RNA polymerase III identity drives robust transcription and expression of snaR-A noncoding RNA
Authors: Van Bortle Kevin , Marciano David P. , Liu Qing , Chou Tristan , Lipchik Andrew M. , Gollapudi Sanjay , Geller Benjamin S. , Monte Emma , Kamakaka Rohinton T. , Snyder Michael P.
Published: May 2022

RNA polymerase III (Pol III) includes two alternate isoforms, defined by mutually exclusive incorporation of subunit POLR3G (RPC7α) or POLR3GL (RPC7β), in mammals. The contributions of POLR3G and POLR3GL to transcription potential has remained poorly defined. Here, we discover that loss of subunit POLR3G is accompanied by a restricted repertoire of genes transcribed by Pol III. Particularly sensitive is snaR-A, a small noncoding RNA implicated in cancer proliferation and metastasis. Analysis of Pol III isoform biases and downstream chromatin features identifies loss of POLR3G and snaR-A during differentiation, and conversely, re-establishment of POLR3G gene expression and SNAR-A gene features in cancer contexts. Our results support a model in which Pol III identity functions as an important transcriptional regulatory mechanism. Upregulation of POLR3G, which is driven by MYC, identifies a subgroup of patients with unfavorable survival outcomes in specific cancers, further implicating the POLR3G-enhanced transcription repertoire as a potential disease factor.
CRISPR/Cas9 gRNA activity depends on free energy changes and on the target PAM context
Authors: Corsi Giulia I. , Qu Kunli , Alkan Ferhat , Pan Xiaoguang , Luo Yonglun , Gorodkin Jan
Published: May 2022

A major challenge of CRISPR/Cas9-mediated genome engineering is that not all guide RNAs (gRNAs) cleave the DNA efficiently. Although the heterogeneity of gRNA activity is well recognized, the current understanding of how CRISPR/Cas9 activity is regulated remains incomplete. Here, we identify a sweet spot range of binding free energy change for optimal efficiency which largely explains why gRNAs display changes in efficiency at on- and off-target sites, including why gRNAs can cleave an off-target with higher efficiency than the on-target. Using an energy-based model, we show that local gRNA-DNA interactions resulting from Cas9 “sliding” on overlapping protospacer adjacent motifs (PAMs) profoundly impact gRNA activities. Combining the effects of local sliding for a given PAM context with global off-targets allows us to better identify highly specific, and thus efficient, gRNAs. We validate the effects of local sliding on gRNA efficiency using both public data and in-house data generated by measuring SpCas9 cleavage efficiency at 1024 sites designed to cover all possible combinations of 4-nt PAM and context sequences of 4 gRNAs. Our results provide insights into the mechanisms of Cas9-PAM compatibility and cleavage activation, underlining the importance of accounting for local sliding in gRNA design.
Wireless implantable optical probe for continuous monitoring of oxygen saturation in flaps and organ grafts
Authors: Guo Hexia , Bai Wubin , Ouyang Wei , Liu Yihan , Wu Changsheng , Xu Yameng , Weng Yang , Zang Hao , Liu Yiming , Jacobson Lauren , Hu Ziying , Wang Yihang , Arafa Hany M. , Yang Quansan , Lu Di , Li Shuo , Zhang Lin , Xiao Xun , Vázquez-Guardado Abraham , Ciatti Joanna , Dempsey Elizabeth , Ghoreishi-Haack Nayereh , Waters Emily A. , Haney Chad R. , Westman Amanda M. , MacEwan Matthew R. , Pet Mitchell A. , Rogers John A.
Published: May 2022

Continuous, real-time monitoring of perfusion after microsurgical free tissue transfer or solid organ allotransplantation procedures can facilitate early diagnosis of and intervention for anastomotic thrombosis. Current technologies including Doppler systems, cutaneous O2-sensing probes, and fluorine magnetic resonance imaging methods are limited by their intermittent measurements, requirements for skilled personnel, indirect interfaces, and/or their tethered connections. This paper reports a wireless, miniaturized, minimally invasive near-infrared spectroscopic system designed for uninterrupted monitoring of local-tissue oxygenation. A bioresorbable barbed structure anchors the probe stably at implantation sites for a time period matched to the clinical need, with the ability for facile removal afterward. The probe connects to a skin-interfaced electronic module for wireless access to essential physiological parameters, including local tissue oxygenation, pulse oxygenation, and heart rate. In vitro tests and in vivo studies in porcine flap and kidney models demonstrate the ability of the system to continuously measure oxygenation with high accuracy and sensitivity.
Open-source personal pipetting robots with live-cell incubation and microscopy compatibility
Authors: Dettinger Philip , Kull Tobias , Arekatla Geethika , Ahmed Nouraiz , Zhang Yang , Schneiter Florin , Wehling Arne , Schirmacher Daniel , Kawamura Shunsuke , Loeffler Dirk , Schroeder Timm
Published: May 2022

Liquid handling robots have the potential to automate many procedures in life sciences. However, they are not in widespread use in academic settings, where funding, space and maintenance specialists are usually limiting. In addition, current robots require lengthy programming by specialists and are incompatible with most academic laboratories with constantly changing small-scale projects. Here, we present the Pipetting Helper Imaging Lid (PHIL), an inexpensive, small, open-source personal liquid handling robot. It is designed for inexperienced users, with self-production from cheap commercial and 3D-printable components and custom control software. PHIL successfully automates pipetting (incl. aspiration) for e.g. tissue immunostainings and stimulations of live stem and progenitor cells during time-lapse microscopy using 3D printed peristaltic pumps. PHIL is cheap enough to put a personal pipetting robot within the reach of most labs and enables users without programming skills to easily automate a large range of experiments.
Brightening of a dark monolayer semiconductor via strong light-matter coupling in a cavity
Authors: Shan Hangyong , Iorsh Ivan , Han Bo , Rupprecht Christoph , Knopf Heiko , Eilenberger Falk , Esmann Martin , Yumigeta Kentaro , Watanabe Kenji , Taniguchi Takashi , Klembt Sebastian , Höfling Sven , Tongay Sefaattin , Antón-Solanas Carlos , Shelykh Ivan A. , Schneider Christian
Published: May 2022

Engineering the properties of quantum materials via strong light-matter coupling is a compelling research direction with a multiplicity of modern applications. Those range from modifying charge transport in organic molecules, steering particle correlation and interactions, and even controlling chemical reactions. Here, we study the modification of the material properties via strong coupling and demonstrate an effective inversion of the excitonic band-ordering in a monolayer of WSe2 with spin-forbidden, optically dark ground state. In our experiments, we harness the strong light-matter coupling between cavity photon and the high energy, spin-allowed bright exciton, and thus creating two bright polaritonic modes in the optical bandgap with the lower polariton mode pushed below the WSe2 dark state. We demonstrate that in this regime the commonly observed luminescence quenching stemming from the fast relaxation to the dark ground state is prevented, which results in the brightening of this intrinsically dark material. We probe this effective brightening by temperature-dependent photoluminescence, and we find an excellent agreement with a theoretical model accounting for the inversion of the band ordering and phonon-assisted polariton relaxation.
A lncRNA signature associated with tumor immune heterogeneity predicts distant metastasis in locoregionally advanced nasopharyngeal carcinoma
Authors: Liang Ye-Lin , Zhang Yuan , Tan Xi-Rong , Qiao Han , Liu Song-Ran , Tang Ling-Long , Mao Yan-Ping , Chen Lei , Li Wen-Fei , Zhou Guan-Qun , Zhao Yin , Li Jun-Yan , Li Qian , Huang Sheng-Yan , Gong Sha , Zheng Zi-Qi , Li Zhi-Xuan , Sun Ying , Jiang Wei , Ma Jun , Li Ying-Qin , Liu Na
Published: May 2022

Increasing evidence has revealed the roles of long noncoding RNAs (lncRNAs) as tumor biomarkers. Here, we introduce an immune-associated nine-lncRNA signature for predicting distant metastasis in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). The nine lncRNAs are identified through microarray profiling, followed by RT–qPCR validation and selection using a machine learning method in the training cohort (n = 177). This nine-lncRNA signature classifies patients into high and low risk groups, which have significantly different distant metastasis-free survival. Validations in the Guangzhou internal (n = 177) and Guilin external (n = 150) cohorts yield similar results, confirming that the signature is an independent risk factor for distant metastasis and outperforms anatomy-based metrics in identifying patients with high metastatic risk. Integrative analyses show that this nine-lncRNA signature correlates with immune activity and lymphocyte infiltration, which is validated by digital pathology. Our results suggest that the immune-associated nine-lncRNA signature can serve as a promising biomarker for metastasis prediction in LA-NPC.
Medication availability and economic barriers to adherence in asthma and COPD patients in low-resource settings
Authors: Tabyshova Aizhamal , Sooronbaev Talant , Akylbekov Azamat , Mademilov Maamed , Isakova Aida , Erkinbaeva Aidai , Magdieva Kamila , Chavannes Niels H. , Postma Maarten J. , van Boven Job F. M.
Published: May 2022

Inhaled medication is essential to control asthma and COPD, but availability and proper adherence are challenges in low-middle income countries (LMIC). Data on medication availability and adherence in Central Asia are lacking. We aimed to investigate the availability of respiratory medication and the extent of financially driven non-adherence in patients with COPD and asthma in Kyrgyzstan. A cross-sectional study was conducted in two regions of Kyrgyzstan. Patients with a physician- and spirometry confirmed diagnosis of asthma and/or COPD were included. The main outcomes were (1) availability of respiratory medication in hospitals and pharmacies, assessed by a survey, and (2) medication adherence, assessed by the Test of Adherence to Inhalers (TAI). Logistic regression analyses were used to identify predictors for adherence. Of the 300 participants (COPD: 264; asthma: 36), 68.9% were buying respiratory medication out-of-pocket. Of all patients visiting the hospital, almost half reported medication not being available. In pharmacies, this was 8%. Poor adherence prevailed over intermediate and good adherence (80.7% vs. 12.0% and 7.3%, respectively). Deliberate and erratic non-adherence behavior patterns were the most frequent (89.7% and 88.0%), followed by an unconscious non-adherent behavioral pattern (31.3%). In total, 68.3% reported a financial reason as a barrier to proper adherence. Low BMI was the only factor significantly associated with good adherence. In this LMIC population, poor medication availability was common and 80% were poorly adherent. Erratic and deliberate non-adherent behaviors were the most common pattern and financial barriers play a role in over two-thirds of the population.
CRISPRi chemical genetics and comparative genomics identify genes mediating drug potency in Mycobacterium tuberculosis
Authors: Li Shuqi , Poulton Nicholas C. , Chang Jesseon S. , Azadian Zachary A. , DeJesus Michael A. , Ruecker Nadine , Zimmerman Matthew D. , Eckartt Kathryn A. , Bosch Barbara , Engelhart Curtis A. , Sullivan Daniel F. , Gengenbacher Martin , Dartois Véronique A. , Schnappinger Dirk , Rock Jeremy M.
Published: May 2022

Mycobacterium tuberculosis (Mtb) infection is notoriously difficult to treat. Treatment efficacy is limited by Mtb’s intrinsic drug resistance, as well as its ability to evolve acquired resistance to all antituberculars in clinical use. A deeper understanding of the bacterial pathways that influence drug efficacy could facilitate the development of more effective therapies, identify new mechanisms of acquired resistance, and reveal overlooked therapeutic opportunities. Here we developed a CRISPR interference chemical-genetics platform to titrate the expression of Mtb genes and quantify bacterial fitness in the presence of different drugs. We discovered diverse mechanisms of intrinsic drug resistance, unveiling hundreds of potential targets for synergistic drug combinations. Combining chemical genetics with comparative genomics of Mtb clinical isolates, we further identified several previously unknown mechanisms of acquired drug resistance, one of which is associated with a multidrug-resistant tuberculosis outbreak in South America. Lastly, we found that the intrinsic resistance factor whiB7 was inactivated in an entire Mtb sublineage endemic to Southeast Asia, presenting an opportunity to potentially repurpose the macrolide antibiotic clarithromycin to treat tuberculosis. This chemical-genetic map provides a rich resource to understand drug efficacy in Mtb and guide future tuberculosis drug development and treatment.
ColabFold: making protein folding accessible to all
Authors: Mirdita Milot , Schütze Konstantin , Moriwaki Yoshitaka , Heo Lim , Ovchinnikov Sergey , Steinegger Martin
Published: May 2022

ColabFold offers accelerated prediction of protein structures and complexes by combining the fast homology search of MMseqs2 with AlphaFold2 or RoseTTAFold. ColabFold’s 40−60-fold faster search and optimized model utilization enables prediction of close to 1,000 structures per day on a server with one graphics processing unit. Coupled with Google Colaboratory, ColabFold becomes a free and accessible platform for protein folding. ColabFold is open-source software available at https://github.com/sokrypton/ColabFold and its novel environmental databases are available at https://colabfold.mmseqs.com.
Identifying amyloid-related diseases by mapping mutations in low-complexity protein domains to pathologies
Authors: Murray Kevin A. , Hughes Michael P. , Hu Carolyn J. , Sawaya Michael R. , Salwinski Lukasz , Pan Hope , French Samuel W. , Seidler Paul M. , Eisenberg David S.
Published: May 2022

Proteins including FUS, hnRNPA2, and TDP-43 reversibly aggregate into amyloid-like fibrils through interactions of their low-complexity domains (LCDs). Mutations in LCDs can promote irreversible amyloid aggregation and disease. We introduce a computational approach to identify mutations in LCDs of disease-associated proteins predicted to increase propensity for amyloid aggregation. We identify several disease-related mutations in the intermediate filament protein keratin-8 (KRT8). Atomic structures of wild-type and mutant KRT8 segments confirm the transition to a pleated strand capable of amyloid formation. Biochemical analysis reveals KRT8 forms amyloid aggregates, and the identified mutations promote aggregation. Aggregated KRT8 is found in Mallory–Denk bodies, observed in hepatocytes of livers with alcoholic steatohepatitis (ASH). We demonstrate that ethanol promotes KRT8 aggregation, and KRT8 amyloids co-crystallize with alcohol. Lastly, KRT8 aggregation can be seeded by liver extract from people with ASH, consistent with the amyloid nature of KRT8 aggregates and the classification of ASH as an amyloid-related condition.
California wildfire spread derived using VIIRS satellite observations and an object-based tracking system
Authors: Chen Yang , Hantson Stijn , Andela Niels , Coffield Shane R. , Graff Casey A. , Morton Douglas C. , Ott Lesley E. , Foufoula-Georgiou Efi , Smyth Padhraic , Goulden Michael L. , Randerson James T.
Published: May 2022

Changing wildfire regimes in the western US and other fire-prone regions pose considerable risks to human health and ecosystem function. However, our understanding of wildfire behavior is still limited by a lack of data products that systematically quantify fire spread, behavior and impacts. Here we develop a novel object-based system for tracking the progression of individual fires using 375 m Visible Infrared Imaging Radiometer Suite active fire detections. At each half-daily time step, fire pixels are clustered according to their spatial proximity, and are either appended to an existing active fire object or are assigned to a new object. This automatic system allows us to update the attributes of each fire event, delineate the fire perimeter, and identify the active fire front shortly after satellite data acquisition. Using this system, we mapped the history of California fires during 2012–2020. Our approach and data stream may be useful for calibration and evaluation of fire spread models, estimation of near-real-time wildfire emissions, and as means for prescribing initial conditions in fire forecast models.
Viability, task switching, and fall avoidance of the simplest dynamic walker
Authors: Patil Navendu S. , Dingwell Jonathan B. , Cusumano Joseph P.
Published: May 2022

Walking humans display great versatility when achieving task goals, like avoiding obstacles or walking alongside others, but the relevance of this to fall avoidance remains unknown. We recently demonstrated a functional connection between the motor regulation needed to achieve task goals (e.g., maintaining walking speed) and a simple walker’s ability to reject large disturbances. Here, for the same model, we identify the viability kernel—the largest state-space region where the walker can step forever via at least one sequence of push-off inputs per state. We further find that only a few basins of attraction of the speed-regulated walker’s steady-state gaits can fully cover the viability kernel. This highlights a potentially important role of task-level motor regulation in fall avoidance. Therefore, we posit an adaptive hierarchical control/regulation strategy that switches between different task-level regulators to avoid falls. Our task switching controller only requires a target value of the regulated observable—a “task switch”—at every walking step, each chosen from a small, predetermined collection. Because humans have typically already learned to perform such goal-directed tasks during nominal walking conditions, this suggests that the “information cost” of biologically implementing such controllers for the nervous system, including cognitive demands in humans, could be quite low.
Behavioral and inflammatory sex differences revealed by celecoxib nanotherapeutic treatment of peripheral neuroinflammation
Authors: Deal Brooke , Reynolds Laura M. , Patterson Charles , Janjic Jelena M. , Pollock John A.
Published: May 2022

Neuropathic pain affects millions of people worldwide, yet the molecular mechanisms of how it develops and persists are poorly understood. Given that males have historically been utilized as the primary sex in preclinical studies, less is known about the female neuroinflammatory response to injury, formation of pain, or response to pain-relieving therapies. Macrophages contribute to the development of neuroinflammatory pain via the activation of their cyclooxygenase-2 (COX-2) enzyme, which leads to the production of prostaglandin E2 (PGE2). PGE2 activates nociception and influences additional leukocyte infiltration. Attenuation of COX-2 activity decreases inflammatory pain, most commonly achieved by nonsteroidal anti-inflammatory drugs (NSAIDs), yet NSAIDs are considered ineffective for neuropathic pain due to off target toxicity. Using chronic constriction injury of the rat sciatic nerve, we show that males and females exhibit quantitatively the same degree of mechanical allodynia post injury. Furthermore, a low-dose nanotherapeutic containing the NSAID celecoxib is phagocytosed by circulating monocytes that then naturally accumulate at sites of injury as macrophages. Using this nanotherapeutic, we show that treated males exhibit complete reversal of hypersensitivity, while the same dose of nanotherapeutic in females provides an attenuated relief. The difference in behavioral response to the nanotherapy is reflected in the reduction of infiltrating macrophages at the site of injury. The observations contained in this study reinforce the notion that female neuroinflammation is different than males.
A noble extended stochastic logistic model for cell proliferation with density-dependent parameters
Authors: Roy Trina , Ghosh Sinchan , Saha Bapi , Bhattacharya Sabyasachi
Published: May 2022

Cell proliferation often experiences a density-dependent intrinsic proliferation rate (IPR) and negative feedback from growth-inhibiting molecules in culture media. The lack of flexible models with explanatory parameters fails to capture such a proliferation mechanism. We propose an extended logistic growth law with the density-dependent IPR and additional negative feedback. The extended parameters of the proposed model can be interpreted as density-dependent cell-cell cooperation and negative feedback on cell proliferation. Moreover, we incorporate further density regulation for flexibility in the model through environmental resistance on cells. The proposed growth law has similarities with the strong Allee model and harvesting phenomenon. We also develop the stochastic analog of the deterministic model by representing possible heterogeneity in growth-inhibiting molecules and environmental perturbation of the culture setup as correlated multiplicative and additive noises. The model provides a conditional maximum sustainable stable cell density (MSSCD) and a new fitness measure for proliferative cells. The proposed model shows superiority to the logistic law after fitting to real cell culture datasets. We illustrate both conditional MSSCD and the new cell fitness for a range of parameters. The cell density distributions reveal the chance of overproliferation, underproliferation, or decay for different parameter sets under the deterministic and stochastic setups.