bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinically Meaningful Reduction in Dyspareunia Is Associated with Significant Improvements in Health-Related Quality of Life Among Women with Moderate to Severe Pain Associated with Endometriosis: A Pooled Analysis of Two Phase III Trials of Elagolix
Authors: Agarwal Sanjay K. , Soliman Ahmed M. , Pokrzywinski Robin M. , Snabes Michael C. , Coyne Karin S.
Published: September 2020

Background

Dyspareunia experienced by women diagnosed with endometriosis is associated with a decreased health-related quality of life (HRQoL).

Aim

We evaluated the relationship of clinically meaningful improvements in dyspareunia with HRQoL changes among women with endometriosis.

Methods

This was a post hoc analysis of pooled data from the phase III ELARIS-I and ELARIS-II clinical trials. Women aged 18–49 years with moderate to severe endometriosis-associated pain were randomized to placebo, elagolix 150 mg once daily, or elagolix 200 mg twice daily. HRQoL was measured using the validated Endometriosis Health Profile-30 questionnaire (EHP-30), consisting of 5 core domains and a sexual intercourse modular domain. Dyspareunia was ranked 0–3 (none, mild, moderate, or severe) or not applicable using a daily eDiary and averaged monthly. A woman with a clinically meaningful dyspareunia response (dyspareunia responder) was defined as a woman with a reduction from the baseline in dyspareunia score greater than or equal to a predetermined cutoff while maintaining stable/decreased analgesic use.

Outcomes

Dyspareunia response impact on EHP-30 scores was determined at 3 and 6 months using multivariate linear regression controlling for age, baseline EHP-30 scores, and dysmenorrhea and non-menstrual pelvic pain symptom severity.

Results

Analysis included 1,368 women with a mean age of 32.2 years. Dyspareunia responders had significant improvements vs non-responders in all adjusted mean EHP-30 domain scores at months 3 and 6 (control and powerlessness: −17.8 and −18.5; emotional well-being: −10.0 and −10.4; pain: −15.3 and −15.7; self-image: −11.4 and −12.8; social support: −14.3 and −14.0; and sexual intercourse: −18.1 and −19.7; all P < .0001).

Clinical Implications

Dyspareunia improvements are associated with both personal and psychological benefits.

Strengths & Limitations

This study involved a large sample of women from a well-defined patient population to provide statistical power in evaluating the results. As such, the findings may not be generalizable in a real-world setting. Although the perception of dyspareunia and its severity and the associated effect on HRQoL was subjective, the use of a large patient sample was used to minimize potential issues with this limitation.

Conclusion

Clinically meaningful responses in dyspareunia are associated with improvements across multiple HRQoL domains among women with endometriosis.
Selves as Solutions to Social Inequalities
Authors: Brannon Tiffany N. , Fisher Peter H. , Greydanus Abigail J.
Published: September 2020

Social disparities tied to social group membership(s) are prevalent and persistent within mainstream institutions (e.g., schools/workplaces). Accordingly, psychological science has harnessed selves - which are malleable and meaningfully shaped by social group membership(s) - as solutions to inequality. We propose and review evidence that theoretical and applied impacts of leveraging 'selves as solutions' can be furthered through the use of a stigma and strengths framework. Specifically, this framework conceptualizes selves in their fuller complexity, allowing the same social group membership to be associated with stigma, risk, and devaluation as well as strengths, resilience, and pride. We provide evidence that by enacting policies and practices that (a) reduce/minimize stigma and (b) recognize/include strengths, mainstream institutions can more fully mitigate social disparities tied to inclusion, achievement and well-being. Using social groups that vary in status/power we examine implications of this framework including the potential to foster positive, recursive, and intergroup impacts on social inequalities.
What Difference Would a Binding International Legal Instrument on Alcohol Control Make? Lessons from the World Health Organization Framework Convention on Tobacco Control’s Impact on Domestic Litigation
Authors: ZHOU Suzanne
Published: September 2020

Since the adoption of the World Health Organization (WHO) Framework Convention on Tobacco Control (FCTC) in 2003, public health professionals have debated similar conventions covering other health risks, including potentially a Framework Convention on Alcohol Control. Much of this debate has focused on the merits of binding versus non-binding instruments in terms of commitments at the international level. In this paper, I draw on lessons from the WHO FCTC to discuss instead what the difference between binding and non-binding international legal instruments might mean for domestic legal frameworks for implementing regulatory measures for alcohol control. The paper looks at possible impacts on the authority of various national authorities to implement new measures, the ability of civil society to bring cases compelling more comprehensive regulatory measures and the defence of litigation brought by commercial-sector actors to prevent, delay or weaken the implementation of laws and regulations. It reflects on what lessons these might have for alcohol control governance.
Envelopes of families of framed surfaces and singular solutions of first-order partial differential equations
Authors: Takahashi Masatomo , Yu Haiou
Published: September 2020

In order to investigate envelopes for singular surfaces, we introduce one- and two-parameter families of framed surfaces and the basic invariants, respectively. By using the basic invariants, the existence and uniqueness theorems of one- and two-parameter families of framed surfaces are given. Then we define envelopes of one- and two-parameter families of framed surfaces and give the existence conditions of envelopes which are called envelope theorems. As an application of the envelope theorems, we show that the projections of singular solutions of completely integrable first-order partial differential equations are envelopes.
Mars's Moons-Induced Time Dispersion Analysis for Solar TDOA Navigation
Authors: Li Yang-yang , Liu Jin , Ning Xiao-lin , Chen Xiao , Kang Zhi-wei
Published: September 2020

The time dispersion effect affects the accuracy of solar time difference of arrival (TDOA) navigation. In this celestial autonomous navigation, Mars's moons are reflecting celestial bodies, and their shape affects the TDOA dispersion model. In the modelling process of traditional methods, the moons of Mars (Phobos and Deimos) are regarded as points, which causes the model to be inaccurate. In order to solve these problems, we simplified the Mars's moons into ellipsoids or solid diamonds, and then established a TDOA model with the nonspherical Mars's moons as reflecting celestial bodies through differential geometry and geometric optics. Finally, we analysed the time dispersion caused by the Mars's moons in theory. Theoretical analysis and experiments show that the point model error is 5·66 km, and the 3D model error is within 70 m. Thus, the 3D TDOA model established in this paper is meaningful. In addition, the Sun–Mars-moons–spacecraft angle, solar flare, three-axis length, and attitude of the Mars's moons have a great effect on the dispersion profile, while the Mars's moons-to-spacecraft distance has a small effect.
Identity politics and hybrid tribunals
Authors: Fichtelberg Aaron
Published: September 2020

Many of the conflicts that have led to the creation of hybrid tribunals were identity-based conflicts – people who identified as members of one tribe, race, ethnicity, or religion used these distinctions as grounds to attack and persecute another group who often responded in kind. This reality means that the criminal justice processes that take place in the wake of such conflicts must take issues of identity seriously to be effective. This article uses the notion of framing contests to examine different identity-based responses to international justice. Defenders of the tribunals seek to portray them as impartial observers while critics paint them as illegitimate outsiders. Because hybrid tribunals have identity considerations as features built into them, they are better suited to promote their own legitimacy in these framing contests. These features include the personnel they use, the witnesses they call, the strategies their prosecutors deploy, and their local outreach programmes. Each of these tools can be used to frame the tribunal as a legitimate means to promote criminal justice and thereby advance the values of transitional justice.
Safety and Efficacy of CarbonCool Half-Body Vest for HAZMAT Decontamination Crews Wearing Personal Protective Equipment: A Pilot Study
Authors: Tay Pamela Jia Min , Koh Zhi Xiong , Hao Ying , Leong Mark Kwok Fai
Published: September 2020

Background:

Personal protective equipment (PPE) are essential for medical personnel responding to hazardous materials (HAZMAT) incidents. However, their impermeable design causes increased physiological strain and reduced thermoregulation, limiting work times and causing heat-related illnesses (HRI). Use of wearable cooling devices slow heat accumulation and have been shown to reduce thermal and cardiovascular strain in such situations.

Methods:

This was a prospective clinical evaluation to determine the tolerability and effectiveness of the CarbonCool cooling system – a half-body cooling vest – in participants undergoing a HAZMAT decontamination recertification. Physiological measurements (heart rate [HR], weight, temperature, and blood pressure) and participant feedback were obtained. The main outcome of interest was participants’ tolerability of the cooling vest.

Results:

A total of 23 healthy participants were recruited, with 10 randomized to the intervention group and 13 in the control group. Mean age in the control and intervention group was 35.5 years old (SD = 7.8) and 30.0 years old (SD = 6.2), respectively. Qualitative feedback obtained from participants regarding safety, mobility, and cooling efficacy was largely positive. Difference of before-after temperature and HR was 0.3°C (SD = 0.8) and 11.5bpm (SD = 13.6) in the control group compared to 0.0°C (SD = 0.5) and 0.0bpm (SD = 6.4) for the intervention group.

Conclusion:

This clinical evaluation showed that the CarbonCool cooling vest is safe and tolerable in participants wearing PPE. Further trials with sample size powered to detect physiological outcomes are needed to assess the effect of the cooling vest on a subject’s endurance to heat stress.
Dose volume histogram metrics and tumour control probability modelling in locally advanced non-small-cell lung cancer: average intensity dataset versus individual four-dimensional CT phases
Authors: Fleming Cathy , McDermott Ronan , O’Keeffe Serena , Dunne Mary , Armstrong John G. , McClean Brendan , Vintró Luis León
Published: September 2020

Aim:

This work compares dose-volume constraints (DVCs) and tumour control predictions based on the average intensity projection (AVIP) to those on each phase of the four-dimensional computed tomography.

Materials and methods:

In this prospective study plans generated on an AVIP for nine patients with locally advanced non-small-cell lung cancer were recalculated on each phase. Dose-volume histogram (DVH) metrics extracted and tumour control probabilities (TCP) were calculated. These were evaluated by Bland–Altman analysis and Pearson Correlation.

Results:

The largest difference between clinical target volume (CTV) on the individual phases and the internal CTV (iCTV) on the AVIP was seen for the smallest volume. For the planning target volume, the mean of each metric across all phases is well represented by the AVIP value. For most patients, TCPs from individual phases are representative of that on the AVIP. Organ at risk metrics from the AVIP are similar to those seen across all phases.

Findings:

Utilising traditional DVH metrics on an AVIP is generally valid, however, additional investigation may be required for small target volumes in combination with large motion as the differences between the values on the AVIP and any given phase may be significant.
Rethinking palliative care in a public health context: addressing the needs of persons with non-communicable chronic diseases
Authors: Tziraki Chariklia , Grimes Corrina , Ventura Filipa , O’Caoimh Rónán , Santana Silvina , Zavagli Veronica , Varani Silvia , Tramontano Donatella , Apóstolo João , Geurden Bart , De Luca Vincenzo , Tramontano Giovanni , Romano Maria Rosaria , Anastasaki Marilena , Lionis Christos , Rodríguez-Acuña Rafael , Capelas Manuel Luis , dos Santos Afonso Tânia , Molloy David William , Liotta Giuseppe , Iaccarino Guido , Triassi Maria , Eklund Patrik , Roller-Wirnsberger Regina , Illario Maddalena
Published: September 2020

Non-communicable chronic diseases (NCCDs) are the main cause of morbidity and mortality globally. Demographic aging has resulted in older populations with more complex healthcare needs. This necessitates a multilevel rethinking of healthcare policies, health education and community support systems with digitalization of technologies playing a central role. The European Innovation Partnership on Active and Healthy Aging (A3) working group focuses on well-being for older adults, with an emphasis on quality of life and healthy aging. A subgroup of A3, including multidisciplinary stakeholders in health care across Europe, focuses on the palliative care (PC) model as a paradigm to be modified to meet the needs of older persons with NCCDs. This development paper delineates the key parameters we identified as critical in creating a public health model of PC directed to the needs of persons with NCCDs. This paradigm shift should affect horizontal components of public health models. Furthermore, our model includes vertical components often neglected, such as nutrition, resilience, well-being and leisure activities. The main enablers identified are information and communication technologies, education and training programs, communities of compassion, twinning activities, promoting research and increasing awareness amongst policymakers. We also identified key ‘bottlenecks’: inequity of access, insufficient research, inadequate development of advance care planning and a lack of co-creation of relevant technologies and shared decision-making. Rethinking PC within a public health context must focus on developing policies, training and technologies to enhance person-centered quality life for those with NCCD, while ensuring that they and those important to them experience death with dignity.
When Does Diffusing Protest Lead to Local Organization Building? Evidence from a Comparative Subnational Study of Russia’s “For Fair Elections” Movement
Authors: Dollbaum Jan Matti
Published: September 2020

Under what conditions do nation-wide mass protests in authoritarian regimes produce new local activist organizations? Based on sixty-five interviews and over 1,000 media reports, internal documents, and social media posts, I compare the organization-building process in the “For Fair Elections” (FFE) protests of 2011–2012 across four Russian regions. I argue that mass protests are more likely to leave behind new social movement organizations (SMOs) when the local and the national interact, i.e., when long-standing activists on the ground perceive an opportunity to use the protests for their ongoing local struggles. Where new SMOs are established, their composition, activity pattern, and inner structure follow the tactical and organizational repertoires of veteran activists that were shaped by their local political environments. This argument illuminates the functioning of electoral authoritarian regimes from a subnational perspective and identifies conditions under which a bottom-up challenge to an authoritarian political system can drive local civil society development.
Diagnostische und therapeutische Nervenblockaden in der Schmerztherapie
Authors: Streitberger Konrad
Published: September 2020

Zusammenfassung. Nervenblockaden werden ausser in der Anästhesie zur Durchführung von Operationen auch in der Schmerztherapie zur Diagnostik und Therapie von lokalisierten Schmerzen eingesetzt. Zur Diagnostik wird eine minimale Menge von Lokalanästhetika direkt an den betroffenen Nerv appliziert. Die Darstellung des Nerven erfolgt dabei in der Regel mit Ultraschall. Eine für die Wirkdauer des Lokalanästhetikums anhaltende Wirkung bestätigt, dass die beschriebenen Schmerzen durch den blockierten Nerv weitergeleitet werden. In solchen Situationen können therapeutische Blockaden repetitiv mit Lokalanästhesie zur Desensibilisierung versucht werden. Eine strukturelle Läsion des Nerven mittels Hitze- oder Kälteverödung oder letztendlich operativer Durchtrennung kann zu einer länger anhaltenden Schmerzreduktion führen. Bei eher schwacher Evidenz mit wenig randomisierten kontrollierten Studien wird die Wirkung dieser Therapien allerdings kontrovers beurteilt. Zudem bestehen Risiken eines Deafferenzierungsschmerzes oder je nach Nerv von anhaltenden motorischen und sensiblen Störungen. Nicht zu unterschätzen sind bei jedem interventionellen Vorgehen Placebo- und Nocebo-Wirkungen. Berücksichtigt werden muss dabei in jedem Fall die Vorerfahrung und die Erwartung des Patienten zu der jeweiligen Intervention. Die Kenntnis dieser Wirkungen kann für Durchführung und Erfolg einer Intervention positiv genutzt werden. Problematische psychosoziale Faktoren und Hinweise zur zentralen Sensibilisierung sollten im Vorfeld erhoben werden und gegebenenfalls zur Zurückhaltung der Indikationsstellung bei sensibilisierten Patienten führen.
Neuropathische Schmerzen: Pharmakotherapie
Authors: Reisig Florian , Harnik Michael
Published: September 2020

Zusammenfassung. Die Identifizierung und Behandlung von neuropathischen Schmerzen (NP) stellt auch heute noch eine grosse Herausforderung für ein interdisziplinäres Behandlungsteam dar. Die spezifische Pharmakotherapie ist eine wichtige Säule einer multimodalen Therapiestrategie, die langfristig einem biopsychosozialen Modell folgen sollte. Die klassischen WHO-Stufe-I-Analgetika versagen jedoch bei der Behandlung des reinen NP. Dauertherapien mit Opioiden der Stufe II und III bergen nach heutigen Kenntnissen langfristig Risiken für die Patienten, die den mittelfristigen Behandlungserfolg kaum mehr rechtfertigen. Deshalb sind Kenntnisse zur Dosierung, Anwendung und Nebenwirkungen der First-Line-Medikamente wie Trizyklische Antidepressiva (TCA), Serotonin-Noradrenalin-Wiederaufnahme-Hammer (SNRI) und Gabapentinoide essenziell. Man sollte stets dem Konzept «start low, go slow» folgen, eine gute Patientenedukation ist hierbei entscheidend. Auch topische Therapieformen wie Lidocain und Ambroxol können eine sinnvolle Ergänzung des Therapieregimes sein, das vom Patienten aktiv mitgetragen wird. Die Hochdosistherapie mit Capsaicin-Pflastern (8 %) bleibt jedoch in den Händen der Schmerzspezialisten. In der perioperativen Prävention neuropathischer Schmerzen konnte für systemische Medikamentengaben bisher kein nachhaltiger Nachweis erbracht werden. Für die perineurale Medikamentenapplikation von Lokalanästhetika durch Nervenblockaden ergeben sich jedoch für Thorax- und Mammachirurgische Eingriffe sowie für die Sectio caesarea Hinweise für eine Prävention von chronischen, postoperativen Schmerzen (CPOP). Bei Systemerkrankungen wie Diabetes mellitus, aktiver Herpes zoster, Multiple Sklerose, Mangelernährung u. v. m., die eine Polyneuropathie verursachen können, hat die kausale medikamentöse Therapieoptimierung ebenfalls präventiven Charakter.
Die Rolle der rekonstruktiven Chirurgie bei neuropathischen Schmerzen
Authors: Salminger Stefan , Gstoettner Clemens , Mayer Johannes A. , Aszmann Oskar C.
Published: September 2020

Zusammenfassung. Neuropathische Schmerzen können auch in Folge iatrogener Nervenläsionen auftreten. Iatrogene oder traumatische Nervenläsionen führen häufig zu erheblichen funktionellen Beeinträchtigungen und können chronische neuropathische Schmerzen nach sich ziehen. Nur wer sich regelmässig mit der Problematik peripherer Nervenläsionen auseinandersetzt, kann auf einen ausreichend grossen diagnostischen und chirurgischen Erfahrungsschatz zurückgreifen, um rasch und effizient die richtige Diagnose und gegebenenfalls Indikation zur optimalen rekonstruktiven Therapie zu stellen. Zeit ist meist der Hauptfaktor, welcher über den Erfolg der Schadensbehebung oder zumindest -begrenzung entscheidet. Chirurgen anderer Fachdisziplinen, die nicht routinemässig, sondern rein komplikationsbedingt plötzlich mit dieser spezifischen Problemstellung konfrontiert sind, benötigen daher einen klaren Überblick über die adäquate Abklärung und Rekonstruktionsmöglichkeiten, um ihren Patienten zeitgerecht die richtige Diagnostik und Therapie zukommen zu lassen. In dieser Übersichtsarbeit sollen einerseits jene Operationen aufgelistet werden, bei denen besonders häufig iatrogene Nervenläsionen dokumentiert wurden. Des Weiteren möchten wir gemäss unseren Erfahrungen aus dem Spezialgebiet der peripheren Nervenchirurgie über die richtige und effiziente Diagnostik sowie die rekonstruktiven Möglichkeiten informieren. Mit funktionierender interdisziplinärer Zusammenarbeit und einem entsprechenden diagnostischen und therapeutischen Vorgehen lassen sich die Ergebnisse nach iatrogenen Nervenverletzungen verbessern und somit auch eventuelle juristische Konsequenzen verhindern.
Persistent Rheb-induced mTORC1 activation in spinal cord neurons induces hypersensitivity in neuropathic pain
Authors: Ma Xiaqing , Du Wenjie , Wang Wenying , Luo Limin , Huang Min , Wang Haiyan , Lin Raozhou , Li Zhongping , Shi Haibo , Yuan Tifei , Jiang Wei , Worley Paul F. , Xu Tao
Published: September 2020

The small GTPase Ras homolog enriched in the brain (Rheb) can activate mammalian target of rapamycin (mTOR) and regulate the growth and cell cycle progression. We investigated the role of Rheb-mediated mTORC1 signaling in neuropathic pain. A chronic constriction injury (CCI) model was dopted. CCI induced obvious spinal Rheb expression and phosphorylation of mTOR, S6, and 4-E-BP1. Blocking mTORC1 signal with rapamycin alleviated the neuropathic pain and restored morphine efficacy in CCI model. Immunofluoresence showed a neuronal co-localization of CCI-induced Rheb and pS6. Rheb knockin mouse showed a similar behavioral phenotype as CCI. In spinal slice recording, CCI increased the firing frequency of neurons expressing HCN channels; inhibition of mTORC1 with rapamycin could reverse the increased spinal neuronal activity in neuropathic pain. Spinal Rheb is induced in neuropathic pain, which in turn active the mTORC1 signaling in CCI. Spinal Rheb-mTOR signal plays an important role in regulation of spinal sensitization in neuropathic pain, and targeting mTOR may give a new strategy for pain management.
Tunable multiphase dynamics of arginine and lysine liquid condensates
Authors: Fisher Rachel S. , Elbaum-Garfinkle Shana
Published: September 2020

Liquid phase separation into two or more coexisting phases has emerged as a new paradigm for understanding subcellular organization, prebiotic life, and the origins of disease. The design principles underlying biomolecular phase separation have the potential to drive the development of novel liquid-based organelles and therapeutics, however, an understanding of how individual molecules contribute to emergent material properties, and approaches to directly manipulate phase dynamics are lacking. Here, using microrheology, we demonstrate that droplets of poly-arginine coassembled with mono/polynucleotides have approximately 100 fold greater viscosity than comparable lysine droplets, both of which can be finer tuned by polymer length. We find that these amino acid-level differences can drive the formation of coexisting immiscible phases with tunable formation kinetics and can be further exploited to trigger the controlled release of droplet components. Together, this work provides a novel mechanism for leveraging sequence-level components in order to regulate droplet dynamics and multiphase coexistence.
A phospho-switch controls RNF43-mediated degradation of Wnt receptors to suppress tumorigenesis
Authors: Tsukiyama Tadasuke , Zou Juqi , Kim Jihoon , Ogamino Shohei , Shino Yuki , Masuda Takamasa , Merenda Alessandra , Matsumoto Masaki , Fujioka Yoichiro , Hirose Tomonori , Terai Sayuri , Takahashi Hidehisa , Ishitani Tohru , Nakayama Keiichi I. , Ohba Yusuke , Koo Bon-Kyoung , Hatakeyama Shigetsugu
Published: September 2020

Frequent mutation of the tumour suppressor RNF43 is observed in many cancers, particularly colon malignancies. RNF43, an E3 ubiquitin ligase, negatively regulates Wnt signalling by inducing degradation of the Wnt receptor Frizzled. In this study, we discover that RNF43 activity requires phosphorylation at a triplet of conserved serines. This phospho-regulation of RNF43 is required for zebrafish development and growth of mouse intestinal organoids. Cancer-associated mutations that abrogate RNF43 phosphorylation cooperate with active Ras to promote tumorigenesis by abolishing the inhibitory function of RNF43 in Wnt signalling while maintaining its inhibitory function in p53 signalling. Our data suggest that RNF43 mutations cooperate with KRAS mutations to promote multi-step tumorigenesis via the Wnt-Ras-p53 axis in human colon cancers. Lastly, phosphomimetic substitutions of the serine trio restored the tumour suppressive activity of extracellular oncogenic mutants. Therefore, harnessing phospho-regulation of RNF43 might be a potential therapeutic strategy for tumours with RNF43 mutations.
Ultrahigh drive current and large selectivity in GeS selector
Authors: Jia Shujing , Li Huanglong , Gotoh Tamihiro , Longeaud Christophe , Zhang Bin , Lyu Juan , Lv Shilong , Zhu Min , Song Zhitang , Liu Qi , Robertson John , Liu Ming
Published: September 2020

Selector devices are indispensable components of large-scale nonvolatile memory and neuromorphic array systems. Besides the conventional silicon transistor, two-terminal ovonic threshold switching device with much higher scalability is currently the most industrially favored selector technology. However, current ovonic threshold switching devices rely heavily on intricate control of material stoichiometry and generally suffer from toxic and complex dopants. Here, we report on a selector with a large drive current density of 34 MA cm−2 and a ~106 high nonlinearity, realized in an environment-friendly and earth-abundant sulfide binary semiconductor, GeS. Both experiments and first-principles calculations reveal Ge pyramid-dominated network and high density of near-valence band trap states in amorphous GeS. The high-drive current capacity is associated with the strong Ge-S covalency and the high nonlinearity could arise from the synergy of the mid-gap traps assisted electronic transition and local Ge-Ge chain growth as well as locally enhanced bond alignment under high electric field.
Aromatic nonpolar organogels for efficient and stable perovskite green emitters
Authors: Park Jae-Man , Park Jinwoo , Kim Young-Hoon , Zhou Huanyu , Lee Younghoon , Jo Seung Hyeon , Ma Jinwoo , Lee Tae-Woo , Sun Jeong-Yun
Published: September 2020

Existing gels are mostly polar, whose nature limits their role in soft devices. The intermolecular interactions of nonpolar polymer-liquid system are typically weak, which makes the gel brittle. Here we report highly soft and transparent nonpolar organogels. Even though their elements are only carbon and hydrogen, their elastic modulus, transparency, and stretchability are comparable to common soft hydrogels. A key strategy is introducing aromatic interaction into the polymer-solvent system, resulting in a high swelling ratio that enables efficient plasticization of the polymer networks. As a proof of applicability, soft perovskite nanocomposites are synthesized, where the nonpolar environment of organogels enables stable formation and preservation of highly concentrated perovskite nanocrystals, showing high photoluminescence efficiency (~99.8%) after water-exposure and environmental stabilities against air, water, acid, base, heat, light, and mechanical deformation. Their superb properties enable the demonstration of soft electroluminescent devices that stably emit bright and pure green light under diverse deformations.
Pharmacophore hybridisation and nanoscale assembly to discover self-delivering lysosomotropic new-chemical entities for cancer therapy
Authors: Ma Zhao , Li Jin , Lin Kai , Ramachandran Mythili , Zhang Dalin , Showalter Megan , De Souza Cristabelle , Lindstrom Aaron , Solano Lucas N. , Jia Bei , Urayama Shiro , Duan Yuyou , Fiehn Oliver , Lin Tzu-yin , Li Minyong , Li Yuanpei
Published: September 2020

Integration of the unique advantages of the fields of drug discovery and drug delivery is invaluable for the advancement of drug development. Here we propose a self-delivering one-component new-chemical-entity nanomedicine (ONN) strategy to improve cancer therapy through incorporation of the self-assembly principle into drug design. A lysosomotropic detergent (MSDH) and an autophagy inhibitor (Lys05) are hybridised to develop bisaminoquinoline derivatives that can intrinsically form nanoassemblies. The selected BAQ12 and BAQ13 ONNs are highly effective in inducing lysosomal disruption, lysosomal dysfunction and autophagy blockade and exhibit 30-fold higher antiproliferative activity than hydroxychloroquine used in clinical trials. These single-drug nanoparticles demonstrate excellent pharmacokinetic and toxicological profiles and dramatic antitumour efficacy in vivo. In addition, they are able to encapsulate and deliver additional drugs to tumour sites and are thus promising agents for autophagy inhibition-based combination therapy. Given their transdisciplinary advantages, these BAQ ONNs have enormous potential to improve cancer therapy.
Light microscopy based approach for mapping connectivity with molecular specificity
Authors: Shen Fred Y. , Harrington Margaret M. , Walker Logan A. , Cheng Hon Pong Jimmy , Boyden Edward S. , Cai Dawen
Published: September 2020

Mapping neuroanatomy is a foundational goal towards understanding brain function. Electron microscopy (EM) has been the gold standard for connectivity analysis because nanoscale resolution is necessary to unambiguously resolve synapses. However, molecular information that specifies cell types is often lost in EM reconstructions. To address this, we devise a light microscopy approach for connectivity analysis of defined cell types called spectral connectomics. We combine multicolor labeling (Brainbow) of neurons with multi-round immunostaining Expansion Microscopy (miriEx) to simultaneously interrogate morphology, molecular markers, and connectivity in the same brain section. We apply this strategy to directly link inhibitory neuron cell types with their morphologies. Furthermore, we show that correlative Brainbow and endogenous synaptic machinery immunostaining can define putative synaptic connections between neurons, as well as map putative inhibitory and excitatory inputs. We envision that spectral connectomics can be applied routinely in neurobiology labs to gain insights into normal and pathophysiological neuroanatomy.
Two-photon excited deep-red and near-infrared emissive organic co-crystals
Authors: Wang Yu , Wu Huang , Li Penghao , Chen Su , Jones Leighton O. , Mosquera Martín A. , Zhang Long , Cai Kang , Chen Hongliang , Chen Xiao-Yang , Stern Charlotte L. , Wasielewski Michael R. , Ratner Mark A. , Schatz George C. , Stoddart J. Fraser
Published: September 2020

Two-photon excited near-infrared fluorescence materials have garnered considerable attention because of their superior optical penetration, higher spatial resolution, and lower optical scattering compared with other optical materials. Herein, a convenient and efficient supramolecular approach is used to synthesize a two-photon excited near-infrared emissive co-crystalline material. A naphthalenediimide-based triangular macrocycle and coronene form selectively two co-crystals. The triangle-shaped co-crystal emits deep-red fluorescence, while the quadrangle-shaped co-crystal displays deep-red and near-infrared emission centered on 668 nm, which represents a 162 nm red-shift compared with its precursors. Benefiting from intermolecular charge transfer interactions, the two co-crystals possess higher calculated two-photon absorption cross-sections than those of their individual constituents. Their two-photon absorption bands reach into the NIR-II region of the electromagnetic spectrum. The quadrangle-shaped co-crystal constitutes a unique material that exhibits two-photon absorption and near-infrared emission simultaneously. This co-crystallization strategy holds considerable promise for the future design and synthesis of more advanced optical materials.
Age and life expectancy clocks based on machine learning analysis of mouse frailty
Authors: Schultz Michael B. , Kane Alice E. , Mitchell Sarah J. , MacArthur Michael R. , Warner Elisa , Vogel David S. , Mitchell James R. , Howlett Susan E. , Bonkowski Michael S. , Sinclair David A.
Published: September 2020

The identification of genes and interventions that slow or reverse aging is hampered by the lack of non-invasive metrics that can predict the life expectancy of pre-clinical models. Frailty Indices (FIs) in mice are composite measures of health that are cost-effective and non-invasive, but whether they can accurately predict health and lifespan is not known. Here, mouse FIs are scored longitudinally until death and machine learning is employed to develop two clocks. A random forest regression is trained on FI components for chronological age to generate the FRIGHT (FrailtyInferredGeriatricHealthTimeline) clock, a strong predictor of chronological age. A second model is trained on remaining lifespan to generate the AFRAID (Analysis ofFrailty andDeath) clock, which accurately predicts life expectancy and the efficacy of a lifespan-extending intervention up to a year in advance. Adoption of these clocks should accelerate the identification of longevity genes and aging interventions.
Giant magneto-optical responses in magnetic Weyl semimetal Co3Sn2S2
Authors: Okamura Y. , Minami S. , Kato Y. , Fujishiro Y. , Kaneko Y. , Ikeda J. , Muramoto J. , Kaneko R. , Ueda K. , Kocsis V. , Kanazawa N. , Taguchi Y. , Koretsune T. , Fujiwara K. , Tsukazaki A. , Arita R. , Tokura Y. , Takahashi Y.
Published: September 2020

The Weyl semimetal (WSM), which hosts pairs of Weyl points and accompanying Berry curvature in momentum space near Fermi level, is expected to exhibit novel electromagnetic phenomena. Although the large optical/electronic responses such as nonlinear optical effects and intrinsic anomalous Hall effect (AHE) have recently been demonstrated indeed, the conclusive evidence for their topological origins has remained elusive. Here, we report the gigantic magneto-optical (MO) response arising from the topological electronic structure with intense Berry curvature in magnetic WSM Co3Sn2S2. The low-energy MO spectroscopy and the first-principles calculation reveal that the interband transitions on the nodal rings connected to the Weyl points show the resonance of the optical Hall conductivity and give rise to the giant intrinsic AHE in dc limit. The terahertz Faraday and infrared Kerr rotations are found to be remarkably enhanced by these resonances with topological electronic structures, demonstrating the novel low-energy optical response inherent to the magnetic WSM.
A shared genetic contribution to breast cancer and schizophrenia
Authors: Lu Donghao , Song Jie , Lu Yi , Fall Katja , Chen Xu , Fang Fang , Landén Mikael , Hultman Christina M. , Czene Kamila , Sullivan Patrick , Tamimi Rulla M. , Valdimarsdóttir Unnur A.
Published: September 2020

An association between schizophrenia and subsequent breast cancer has been suggested; however the risk of schizophrenia following a breast cancer is unknown. Moreover, the driving forces of the link are largely unclear. Here, we report the phenotypic and genetic positive associations of schizophrenia with breast cancer and vice versa, based on a Swedish population-based cohort and GWAS data from international consortia. We observe a genetic correlation of 0.14 (95% CI 0.09–0.19) and identify a shared locus at 19p13 (GATAD2A) associated with risks of breast cancer and schizophrenia. The epidemiological bidirectional association between breast cancer and schizophrenia may partly be explained by the genetic overlap between the two phenotypes and, hence, shared biological mechanisms.
Histone deacetylase HDA-1 modulates mitochondrial stress response and longevity
Authors: Shao Li-Wa , Peng Qi , Dong Mingyue , Gao Kaiyu , Li Yumei , Li Yi , Li Chuan-Yun , Liu Ying
Published: September 2020

The ability to detect, respond and adapt to mitochondrial stress ensures the development and survival of organisms. Caenorhabditis elegans responds to mitochondrial stress by activating the mitochondrial unfolded protein response (UPRmt) to buffer the mitochondrial folding environment, rewire the metabolic state, and promote innate immunity and lifespan extension. Here we show that HDA-1, the C. elegans ortholog of mammalian histone deacetylase (HDAC) is required for mitochondrial stress-mediated activation of UPRmt. HDA-1 interacts and coordinates with the genome organizer DVE-1 to induce the transcription of a broad spectrum of UPRmt, innate immune response and metabolic reprogramming genes. In rhesus monkey and human tissues, HDAC1/2 transcript levels correlate with the expression of UPRmt genes. Knocking down or pharmacological inhibition of HDAC1/2 disrupts the activation of the UPRmt and the mitochondrial network in mammalian cells. Our results underscore an evolutionarily conserved mechanism of HDAC1/2 in modulating mitochondrial homeostasis and regulating longevity.
Publisher Correction: ITGB3-mediated uptake of small extracellular vesicles facilitates intercellular communication in breast cancer cells
Authors: Fuentes Pedro , Sesé Marta , Guijarro Pedro J. , Emperador Marta , Sánchez-Redondo Sara , Peinado Héctor , Hümmer Stefan , Cajal Santiago Ramón y
Published: September 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Predictive factors for prognosis after gastrostomy placement in routine non-invasive ventilation users ALS patients
Authors: Hesters Adèle , Amador Maria del Mar , Debs Rabab , Le Forestier Nadine , Lenglet Timothée , Pradat Pierre-François , Salachas François , Faure Morgane , Jimenez Maria-Alejandra Galarza , Gonzalez-Bermejo Jesus , Morelot Capucine , Bruneteau Gaëlle
Published: September 2020

Due to the expanding use of non-invasive ventilation (NIV) in amyotrophic lateral sclerosis (ALS), the question of enteral nutrition is increasingly raised in NIV users ALS patients. Here, we aimed to determine the prognostic factors for survival after gastrostomy placement in routine NIV users, taking into consideration ventilator dependence. Ninety-two routine NIV users ALS patients, who underwent gastrostomy insertion for severe dysphagia and/or weight loss, were included. We used a Cox proportional hazards model to identify factors affecting survival and compared time from gastrostomy to death and 30-day mortality rate between dependent (daily use ≥ 16 h) and non-dependent NIV users. The hazard of death after gastrostomy was significantly affected by 3 factors: age at onset (HR 1.047, p = 0.006), body mass index < 20 kg/m2 at the time of gastrostomy placement (HR 2.012, p = 0.016) and recurrent accumulation of airway secretions (HR 2.614, p = 0.001). Mean time from gastrostomy to death was significantly shorter in the dependent than in the non-dependent NIV users group (133 vs. 250 days, p = 0.04). The 30-day mortality rate was significantly higher in dependent NIV users (21.4% vs. 2.8%, p = 0.03). Pre-operative ventilator dependence and airway secretion accumulation are associated with worse prognosis and should be key decision-making criteria when considering gastrostomy tube placement in NIV users ALS patients.
Defining diagnostic cutoffs in neurological patients for serum very long chain fatty acids (VLCFA) in genetically confirmed X-Adrenoleukodystrophy
Authors: Rattay Tim W. , Rautenberg Maren , Söhn Anne S. , Hengel Holger , Traschütz Andreas , Röben Benjamin , Hayer Stefanie N. , Schüle Rebecca , Wiethoff Sarah , Zeltner Lena , Haack Tobias B. , Cegan Alexander , Schöls Ludger , Schleicher Erwin , Peter Andreas
Published: September 2020

X-linked Adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene resulting in the accumulation of very long chain fatty acids (VLCFA). X-ALD is the most common peroxisomal disorder with adult patients (male and female) presenting with progressive spastic paraparesis with bladder disturbance, sensory ataxia with impaired vibration sense, and leg pain. 80% of male X-ALD patients have an adrenal failure, while adrenal dysfunction is rare in women with X-ALD. The objective of this study was to define optimal serum VLCFA cutoff values in patients with X-ALD-like phenotypes for the differentiation of genetically confirmed X-ALD and Non-X-ALD individuals. Three groups were included into this study: a) X-ALD cases with confirmed ABCD1 mutations (n = 34) and two Non-X-ALD cohorts: b) Patients with abnormal serum VCLFA levels despite negative testing for ABCD1 mutations (n = 15) resulting from a total of 1,953 VLCFA tests c) Phenotypically matching patients as Non-X-ALD controls (n = 104). Receiver operating curve analysis was used to optimize VLCFA cutoff values, which differentiate patients with genetically confirmed X-ALD and Non-X-ALD individuals. The serum concentration of C26:0 was superior to C24:0 for the detection of X-ALD. The best differentiation of Non-X-ALD and X-ALD individuals was obtained with a cutoff value of < 1.0 for the C24:0/C22:0 ratio resulting in a sensitivity of 97%, a specificity of 94.1% and a positive predictive value (PPV) of 83.8% for true X-ALD. Our findings further suggested a cutoff of < 0.02 for the ratio C26:0/C22:0 leading to a sensitivity of 90.9%, a specificity of 95.0%, and a PPV of 80.6%. Pearson correlation indicated a significant positive association between total blood cholesterol and VLCFA values. Usage of serum VLCFA are economical and established biomarkers suitable for the guidance of genetic testing matching the X-ALD phenotype. We suggest using our new optimized cutoff values, especially the two ratios (C24:0/C22:0 and C26:0/C22:0), in combination with standard lipid profiles.
Modelling the expected probability of correct assignment under uncertainty
Authors: Dvir Tom , Peres Renana , Rudnick Zeév
Published: September 2020

When making important decisions such as choosing health insurance or a school, people are often uncertain what levels of attributes will suit their true preference. After choice, they might realize that their uncertainty resulted in a mismatch: choosing a sub-optimal alternative, while another available alternative better matches their needs. We study here the overall impact, from a central planner’s perspective, of decisions under such uncertainty. We use the representation of Voronoi tessellations to locate all individuals and alternatives in an attribute space. We provide an expression for the probability of correct match, and calculate, analytically and numerically, the average percentage of matches. We test dependence on the level of uncertainty and location. We find that the overall mismatch  is considerable even for low uncertainty—a possible concern for policy makers. We further explore a commonly used practice—allocating service representatives to assist individuals’ decisions. We show that within a given budget and uncertainty level, the effective allocation is for individuals who are close to the boundary between several Voronoi cells, but are not right on the boundary.
NF-κB inhibition prevents acute shear stress-induced inflammation in the saphenous vein graft endothelium
Authors: Ward Alexander O. , Angelini Gianni D. , Caputo Massimo , Evans Paul C. , Johnson Jason L. , Suleiman M. Saadeh , Tulloh Robert M. , George Sarah J. , Zakkar Mustafa
Published: September 2020

The long saphenous vein (LSV) is commonly used as a conduit in coronary artery bypass grafting. However, long term patency remains limited by the development of vascular inflammation, intimal hyperplasia and accelerated atherosclerosis. The impact of acute exposure of venous endothelial cells (ECs) to acute arterial wall shear stress (WSS) in the arterial circulation, and the subsequent activation of inflammatory pathways, remain poorly defined. Here, we tested the hypothesis that acute exposure of venous ECs to high shear stress is associated with inflammatory responses that are regulated by NF-κB both in-vitro and ex-vivo. Analysis of the LSV endothelium revealed that activation of NF-κB occurred within 30 min after exposure to arterial rates of shear stress. Activation of NF-κB was associated with increased levels of CCL2 production and enhanced binding of monocytes in LSVECs exposed to 6 h acute arterial WSS. Consistent with this, ex vivo exposure of LSVs to acute arterial WSS promoted monocyte interactions with the vessel lumen. Inhibition of the NF-κB pathway prevented acute arterial WSS-induced CCL2 production and reduced monocyte adhesion, both in vitro and in human LSV ex vivo, demonstrating that this pathway is necessary for the induction of the acute arterial WSS-induced pro-inflammatory response. We have identified NF-κB as a critical regulator of acute endothelial inflammation in saphenous vein in response to acute arterial WSS. Localised endothelial-specific inhibition of the NF-κB pathway may be beneficial to prevent vein graft inflammation and consequent failure.
Cells from discarded dressings differentiate chronic from acute wounds in patients with Epidermolysis Bullosa
Authors: Fuentes Ignacia , Guttmann-Gruber Christina , Tockner Birgit , Diem Anja , Klausegger Alfred , Cofré-Araneda Glenda , Figuera Olga , Hidalgo Yessia , Morandé Pilar , Palisson Francis , Rebolledo-Jaramillo Boris , Yubero María Joao , Cho Raymond J. , Rishel Heather I. , Marinkovich M. Peter , Teng Joyce M. C. , Webster Timothy G. , Prisco Marco , Eraso Luis H. , Piñon Hofbauer Josefina , South Andrew P.
Published: September 2020

Impaired wound healing complicates a wide range of diseases and represents a major cost to healthcare systems. Here we describe the use of discarded wound dressings as a novel, cost effective, accessible, and non-invasive method of isolating viable human cells present at the site of skin wounds. By analyzing 133 discarded wound dressings from 51 patients with the inherited skin-blistering disease epidermolysis bullosa (EB), we show that large numbers of cells, often in excess of 100 million per day, continually infiltrate wound dressings. We show, that the method is able to differentiate chronic from acute wounds, identifying significant increases in granulocytes in chronic wounds, and we show that patients with the junctional form of EB have significantly more cells infiltrating their wounds compared with patients with recessive dystrophic EB. Finally, we identify subsets of granulocytes and T lymphocytes present in all wounds paving the way for single cell profiling of innate and adaptive immune cells with relevance to wound pathologies. In summary, our study delineates findings in EB that have potential relevance for all chronic wounds, and presents a method of cellular isolation that has wide reaching clinical application.