bluuebunny/crossref_metadata_2025 huggingface dataset:
In Memoriam: A Memoir for Our Fallen “Heroes”
Authors: Chaurasia Bipin , Deora Harsh , El-Ghandour Nasser M F , Oyesiku Nelson M , Chaurasia Raushan Kumar , Schulder Michael , Soriano Sanchez Jose Antonio , Teo Mario , Hernesniemi Juha , Linzey Joseph Raynor , Schwartz Theodore H , Cohen-Gadol Aaron A , Lawton Michael , Umana Giuseppe , Mura Jorge , Grotenhuis Andre , Sinha Ajit K , Schroeder Henry W S , Natarajan Sabareesh , Sughrue Michael E , Spetzler Robert F , Drummond Katharine , Tanikawa Rokuya , Seixo Kadri Paulo Abdo do , Kato Yoko , Teo Charles , Suri Ashish , Tomasi Santino Ottavio , Winkler Peter A , Scalia Gianluca , Sampron Nicolas , Rasulic Lukas , Cappabianca Paolo , Fontanella Marco M , Laws Edward R
Published: June 2020

Even though neurosurgeons exercise these enormous and versatile skills, the COVID-19 pandemic has shaken the fabrics of the global neurosurgical family, jeopardizing human lives, and forcing the entire world to be locked down. We stand on the shoulders of the giants and will not forget their examples and their teachings. We will work to the best of our ability to honor their memory. Professor Harvey Cushing said: “When to take great risks; when to withdraw in the face of unexpected difficulties; whether to force an attempted enucleation of a pathologically favorable tumor to its completion with the prospect of an operative fatality, or to abandon the procedure short of completeness with the certainty that after months or years even greater risks may have to be faced at a subsequent session—all these require surgical judgment which is a matter of long experience.” It is up to us, therefore, to keep on the noble path that we have decided to undertake, to accumulate the surgical experience that these icons have shown us, the fruit of sacrifice and obstinacy. Our tribute goes to them; we will always remember their excellent work and their brilliant careers that will continue to enlighten all of us.
Supplementation with vitamin D in the COVID-19 pandemic?
Authors: Hadizadeh Fatemeh
Published: June 2020

The coronavirus disease 2019 (COVID-19) pandemic was declared a public health emergency of international concern by the World Health Organization. COVID-19 has high transmissibility and could result in acute lung injury in a fraction of patients. By counterbalancing the activity of the renin-angiotensin system, angiotensin-converting enzyme 2, which is the fusion receptor of the virus, plays a protective role against the development of complications of this viral infection. Vitamin D can induce the expression of angiotensin-converting enzyme 2 and regulate the immune system through different mechanisms. Epidemiologic studies of the relationship between vitamin D and various respiratory infections were reviewed and, here, the postulated mechanisms and clinical data supporting the protective role of vitamin D against COVID-19–mediated complications are discussed.
SARS-CoV-2 Screening Test for Japanese Returnees From Wuhan, China, January 2020
Authors: Kutsuna Satoshi , Suzuki Tadaki , Hayakawa Kayoko , Tsuzuki Shinya , Asai Yusuke , Suzuki Tetsuya , Ide Satoshi , Nakamura Keiji , Moriyama Yuki , Kinoshita Noriko , Hosokawa Naoto , Osawa Ryosuke , Yamamuro Ryosuke , Akiyama Yutaro , Miyazato Yusuke , Nomoto Hidetoshi , Nakamoto Takato , Ota Masayuki , Saito Sho , Ishikane Masahiro , Morioka Shinichiro , Yamamoto Kei , Ujiie Mugen , Terada Mari , Nakamura-Uchiyama Fukumi , Sahara Toshinori , Sano Masahiro , Imamura Akifumi , Sekiya Noritaka , Fukushima Kazuaki , Kawana Akihiko , Fujikura Yuji , Sano Tomoya , Suematsu Ryohei , Sakamoto Naoya , Nagata Kaoru , Kato Tomoyuki , Katano Harutaka , Wakita Takaji , Sugiyama Haruhito , Kokudo Norihiro , Ohmagari Norio
Published: June 2020

Background

Severe acute respiratory syndrome–related coronavirus 2 (SARS-CoV-2) was found to be the causative microorganism of coronavirus disease 2019 (COVID-19), which started to spread in Wuhan, China. This study was to evaluate the effectiveness of questionnaire, symptoms-based screening, and polymerase chain reaction (PCR) screening of returnees from COVID-19-endemic areas on a chartered flight, to examine the proportion of infected persons and the proportion of asymptomatic persons among infected persons who returned from Wuhan.

Methods

A retrospective cohort study was done in 7 tertiary medical institutions in Japan. A total of 566 Japanese who returned from Wuhan participated in the study.

Results

Overall, 11 of the 566 passengers had a positive SARS-CoV-2 PCR result for pharyngeal swabs and 6 were asymptomatic. Only fever differed between SARS-CoV-2-positive and -negative individuals (P < .043). Six of the 11 PCR-positive individuals were asymptomatic; 4 remained positive on day 10, and 1 asymptomatic person tested positive up to day 27. Two of the 11 were negative on the first PCR test and positive on the second.

Conclusions

Our results will be important insights on screening returnees from locked-down cities, as well as providing important data on the proportion of asymptomatic individuals infected with SARS-CoV-2. A 13-day observation period and a second round of PCR may be effective to screen patients, including asymptomatic infections.
Primary Care Physicians’ Attitudes and Perceptions Towards Antibiotic Resistance and Antibiotic Stewardship: A National Survey
Authors: Zetts Rachel M , Garcia Andrea M , Doctor Jason N , Gerber Jeffrey S , Linder Jeffrey A , Hyun David Y
Published: June 2020

Background

Outpatient antibiotic stewardship is needed to reduce inappropriate prescribing and minimize the development of resistant bacteria. We assessed primary care physicians’ perceptions of antibiotic resistance, antibiotic use, and the need for stewardship activities.

Methods

We conducted a national online survey of 1550 internal, family, and pediatric medicine physicians in the United States recruited from an opt-in panel of healthcare professionals. Descriptive statistics were generated for respondent demographics and question responses. Responses were also stratified by geographic region and medical specialty, with a χ 2 test used to assess for differences.

Results

More respondents agreed that antibiotic resistance was a problem in the United States (94%) than in their practice (55%) and that inappropriate antibiotic prescribing was a problem in outpatient settings (91%) than in their practice (37%). In addition, 60% agreed that they prescribed antibiotics more appropriately than their peers. Most respondents (91%) believed that antibiotic stewardship was appropriate in office-based practices, but they ranked antibiotic resistance as less important than other public health issues such as obesity, diabetes, opioids, smoking, and vaccine hesitancy. Approximately half (47%) believed they would need a lot of help to implement stewardship. Respondents indicated that they were likely to implement antibiotic stewardship efforts in response to feedback or incentives provided by payers or health departments.

Conclusions

Primary care physicians generally did not recognize antibiotic resistance and inappropriate prescribing as issues in their practice. This poses a challenge for the success of outpatient stewardship. Healthcare stakeholders will need to explore opportunities for feedback and incentive activities to encourage stewardship uptake.
Alignment With Market Forces: The “Re-Whithering” of Infectious Diseases
Authors: Spellberg Brad
Published: June 2020

Given constant emergence of new infectious threats, infectious diseases (ID) should be one of the most attractive medical specialties to students and trainees. Yet, ID Fellowship programs continue to not fill in the match, and ID remains among the lowest paid specialties. Approximately 35 years after Dr. Petersdorf first asked the question, we find ourselves once again wondering, “Whither Infectious Diseases?” To answer this question, and align with predominant US market forces, ID experts should push for the following: (1) restrictions regarding utilization of ID diagnostics and antimicrobial agents; (2) pay-for-performance measures regarding antimicrobial prescribing rates; and (3) healthcare reform as called for by the American College of Physicians to move away from fee-for-service medicine. Einstein said, “Continuing to do the same thing over and over and expecting a different result is the definition of insanity.” We must move towards alignment with market forces, to benefit our patients, society, and our colleagues.
The Babies of Mortgage Market Deregulation
Authors: Hacamo Isaac
Published: June 2020

This paper documents that mortgage market deregulation helps mitigate the risk of population aging by affecting a foundational family-level decision: the choice to have children. Using a U.S. federal regulator ruling, I show that young households fully exposed to mortgage market deregulation increase their probability of purchasing a home and having a child by 6 percentage points. Supplemental tests reject alternative hypotheses based on income or housing wealth growth and, instead, suggest that access to space is the relevant economic mechanism. Collectively, the evidence indicates that increased access to mortgage credit affects the total number of children in the economy.
Neural Responses to Reward in a Gambling Task: Sex Differences and Individual Variation in Reward-Driven Impulsivity
Authors: Li Guangfei , Zhang Sheng , Le Thang M , Tang Xiaoying , Li Chiang-Shan R
Published: June 2020

Previous work suggests sex differences in reward sensitivity. However, it remains unclear how men and women differ in the neural processes of reward-driven impulsivity. With a data set of 968 subjects (502 women) curated from the Human Connectome Project, we investigated sex differences in regional activations to reward and to punishment in a gambling task. Individual variations in reward-driven impulsivity were quantified by the difference in reaction time between reward and punishment blocks in the gambling task, as well as by a behavioral measure of delay discounting. At a corrected threshold, men and women exhibited significant differences in regional activations to reward and to punishment. Longer reaction times during reward versus punishment blocks, indicative of more cautious responding, were associated with left-hemispheric lateral prefrontal cortical activation to reward in men but not women. Steeper discounting was associated with higher activation to reward in the right-hemispheric dorsal anterior cingulate cortex and angular gyrus in women but not men. These sex differences were confirmed in slope tests. Together, the results highlight the sex-specific neural processes of reward-driven impulsivity with left-hemispheric prefrontal cortex supporting impulse control in men and right-hemispheric saliency circuit playing a more important role in diminished impulse control in women.
TDIF regulates auxin accumulation and modulates auxin sensitivity to enhance both adventitious root and lateral root formation in poplar trees
Authors: Yue Jing , Yang Heyu , Yang Shaohui , Wang Jiehua
Published: June 2020

Of six TRACHEARY ELEMENT DIFFERENTIATION INHIBITORY FACTOR (TDIF)-encoding genes in poplar, PtTDIF1 is predominantly expressed in adventitious roots (ARs), and the other five PtTDIFs are preferentially expressed in lateral roots (LRs). Upon auxin application, expression of all PtTDIFs declined in ARs but transiently increased in LRs. Both exogenous TDIF peptides and overexpression of PtTDIFs in poplar positively regulated the initiation and elongation of LRs, and overexpression of PtTDIFs also increased the number of ARs. As visualized by the auxin-responsive marker DR5:GUS, TDIF had differential impacts on the auxin signaling activity in ARs and LRs, which was corroborated by the free indole-3-acetic acid (IAA) measurements in them. Shoot tips of PtTDIF2- and PtTDIFL2-overexpressing (together as PtTDIFsOE) trees revealed an enhanced IAA biosynthetic capacity, and removal of the aerial tissues dramatically diminished the root phenotypes of micro-propagated PtTDIFsOE trees. Furthermore, PtTDIFsOE poplars displayed an increased sensitivity for exogenous IAA, and N-1-naphthylphthalamic acid (NPA) completely blocked the TDIF-induced AR and LR formation. In PtTDIFsOE roots, several auxin-related LR initiation markers such as GATA23, LBD16 and LBD29 were transcriptionally upregulated, further supporting that TDIF regulates LR organogenesis by strengthening the spatiotemporal auxin cues and that dynamic interplays between hormones govern root branching and developmental plasticity in tree species.
What is the Real Rate of Radial Nerve Injury After Humeral Nonunion Surgery?
Authors: Koh Justin , Tornetta Paul , Walker Brock , Jones Clifford , Sharmaa Tayseer , Sems Stephen , Ringenbach Kathleen , Boateng Henry , Bellevue Kate , Firoozabadi Reza , Spitler Clay , Saxena Sharul , Cannada Lisa , Borade Amrut , Horwitz Daniel , Buck J. Stewart , Bosse Michael , Westberg Jerald R. , Schmidt Andrew , Kempton Laurence , Newcomb Emily , Marcantonio Andrew , Delarosa Matthew , Krause Peter , Gudeman Andrew , Mullis Brian , Alhoukail Amro , Leighton Ross , Cortez Abigail , Morshed Saam , Tieszer Christina , Sanders David , Patel Shaan , Mir Hassan R.
Published: June 2020

Objectives:

To determine the radial nerve palsy (RNP) rate and predictors of injury after humeral nonunion repair in a large multicenter sample.

Design:

Consecutive retrospective cohort review.

Setting:

Eighteen academic orthopedic trauma centers.

Patients/Participants:

Three hundred seventy-nine adult patients who underwent humeral shaft nonunion repair. Exclusion criteria were pathologic fracture and complete motor RNP before nonunion surgery.

Intervention:

Humeral shaft nonunion repair and assessment of postoperative radial nerve function.

Main Outcome:

Measurements: Demographics, nonunion characteristics, preoperative and postoperative radial nerve function and recovery.

Results:

Twenty-six (6.9%) of 379 patients (151 M, 228 F, ages 18–93 years) had worse radial nerve function after nonunion repair. This did not differ by surgical approach. Only location in the middle third of the humerus correlated with RNP (P= 0.02). A total of 15.8% of patients with iatrogenic nerve injury followed for a minimum of 12 months did not resolve. For those who recovered, resolution averaged 5.4 months. On average, partial/complete palsies resolved at 2.6 and 6.5 months, respectively. Sixty-one percent (20/33) of patients who presented with nerve injury before their nonunion surgery resolved.

Conclusion:

In a large series of patients treated operatively for humeral shaft nonunion, the RNP rate was 6.9%. Among patients with postoperative iatrogenic RNP, the rate of persistent RNP was 15.8%. This finding is more generalizable than previous reports. Midshaft fractures were associated with palsy, while surgical approach was not.

Level of Evidence:

Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
Sleep Disturbance in Scleroderma
Authors: Figueiredo Fernanda Pirajá , Aires Gabriela Diniz , Nisihara Renato , Skare Thelma L.
Published: June 2020

Introduction

Sleep quality may be impaired in systemic scleroderma (SSc) patients and contribute to loss of life quality.

Aim

The aims of this study were to study the prevalence of sleep disturbance in SSc patients and its possible association with epidemiological, clinical and laboratory data, treatment used, and depression, and to verify the association of sleep disturbance and quality of life in this group of patients.

Methods

This is a cross-sectional study including 60 SSc patients. Epidemiological, clinical, laboratory, and treatment data were extracted from the medical records. To evaluate sleep quality, the PSQI (Pittsburgh Sleep Quality Index) was used; to evaluate depression, the CES-D (Center for Epidemiological Scale–Depression) was used; and to evaluate quality of life, SF-12 (12-Item Short-Form Health Survey) was used. Disease severity was evaluated by the Medsger index and the degree of cutaneous involvement by the modified Rodnan index.

Results

The prevalence of patients with sleep disturbance was 73.3%. Sleep disturbance was associated with esophageal involvement (p = 0.03), Medsger index with higher disease severity (p = 0.01), and more depressive mood (p = 0.002). Patients with poor quality of sleep had worse quality of life by the SF-12 in mental (p = 0.001) and physical domains (p = 0.0008). No associations were found with epidemiological, serological, and treatment variables (all P's = nonsignificant).

Conclusions

There is a high prevalence of sleep disturbance in patients with SSc that is associated with esophageal involvement, severity of disease, depression, and worse quality of life.
Holistic Treatment of Fibromyalgia Based on Physiopathology
Authors: Martínez-Lavín Manuel
Published: June 2020

Patients suffering from fibromyalgia have many vexing symptoms; in contrast, physicians do not have a logical physiopathological framework to explain the multiple complaints. The objective of this writing is to discuss a patient-centered holistic fibromyalgia therapy based on a coherent physiopathological model.

The rationale proposing fibromyalgia as stress-related sympathetically maintained neuropathic pain syndrome has solid research foundations. Autoimmunity is evident in a subset of fibromyalgia cases. Dorsal root ganglia are likely the crucial sympathetic-nociceptive short circuit sites. Skin biopsy and corneal confocal microscopy have demonstrated small nerve fiber pathology in fibromyalgia cases.

Patient empowerment through information and symptom validation is the first step for a successful fibromyalgia therapy.

Points to Highlight

Fibromyalgia is a genuine painful neuropathic pain syndrome. In fibromyalgia stress becomes pain. Autonomic (sympathetic) dysfunction explains the multiplicity of fibromyalgia symptoms.

The well-informed patient (and her/his family) must take on the leading role in her/his own rehabilitation. Fibromyalgia treatment often requires important lifestyle changes. Physicians and allied health care personnel facilitate this adjustment. Specific fibromyalgia drivers are discussed. Common modern bad habits alter autonomic nervous system balance and worsen fibromyalgia symptoms. Currently used drugs for fibromyalgia are rudimentary and with low retention rates. Autoimmune fibromyalgia requires focused therapeutic approach.

Conclusion

A patient-centered holistic therapy aimed to regain autonomic nervous system resilience remains the most effective fibromyalgia therapy.

Future Directions

Corneal confocal microscopy will likely become an objective fibromyalgia diagnostic and follow-up procedure. More specific analgesic antineuropathic medications for fibromyalgia are on the horizon.
Trade-offs of managing Arctic predator harvest instability in fluctuating oceans
Authors: Goto Daisuke , Filin Anatoly A. , Howell Daniel , Bogstad Bjarte , Kovalev Yury , Gjøsæter Harald
Published: June 2020

Sustainable human exploitation of marine living resources stems from a delicate balance between short-term yield stability and long-term population persistence to achieve socioeconomic and conservation goals. However, imperfect knowledge of how oscillations in ecosystem processes regulate fluctuations in exploited populations can obscure the risk of missing management targets. We illustrate how the harvest policy to suppress short-term yield fluctuation inadvertently disrupts population cycles and yield stability of exploited, long-lived predators under stochastically fluctuating environmental forces (food availability and regional climate) using Northeast Arctic (NEA) cod (Gadus morhua, an apex predatory fish) as a case study. We use a stochastic, empirically parameterized multispecies model to simulate NEA cod population dynamics through life-history processes; Barents Sea capelin (Mallotus villosus, a pelagic forage fish) modulates cod productivity through density-dependent cannibalism–predation dynamics, whereas sea temperature regulates cod consumption, growth, and recruitment. We first test how capelin and sea temperature fluctuations regulate patterns in cod yield fluctuation and then quantitatively assess how fishing pattern designed to limit yield between-year variance (within 50–5%) perturbs cod population–catch dynamics. Simulations suggest that capelin and temperature interactively contribute to shifting cyclic patterns in cod yield fluctuation primarily through cod cannibalism–predation dynamics. Wavelet analyses further show that muffling yield variance (30 % or less) reshapes the cyclicity (shorter period and greater amplitude) of cod population size and demography, thereby becoming progressively unsynchronized with fishing pressure. Our work reveals unintended consequences of managing transient dynamics of fished populations: the interworking of population cycle destabilized by inadvertently intensifying fishing pressure, amplifying yield fluctuation and, in turn, elevating overharvest risk when not accounting for compounded effects of stochasticity in ecologically connected processes. These policy implications underscore the need for an ecosystem approach to designing ecologically sound management measures to safely harvest shared living resources while achieving socioeconomic security in increasingly more dynamic oceans in the Arctic and elsewhere.
One-shot learning with spiking neural networks
Authors: Scherr Franz , Stöckl Christoph , Maass Wolfgang
Published: June 2020

Understanding how one-shot learning can be accomplished through synaptic plasticity in neural networks of the brain is a major open problem. We propose that approximations toBPTTin recurrent networks of spiking neurons (RSNNs) such ase-propcannot achieve this because their local synaptic plasticity is gated by learning signals that are rather ad hoc from a biological perspective: Random projections of instantaneously arising losses at the network outputs, analogously as in Broadcast Alignment for feedforward networks. In contrast, synaptic plasticity is gated in the brain by learning signals such as dopamine, which are emitted by specialized brain areas, e.g. VTA. These brain areas have arguably been optimized by evolution to gate synaptic plasticity in such a way that fast learning of survival-relevant tasks is enabled. We found that a corresponding model architecture, where learning signals are emitted by a separate RSNN that is optimized to facilitate fast learning, enables one-shot learning via local synaptic plasticity in RSNNs for large families of learning tasks. The same learning approach also supports fast spike-based learning of posterior probabilities of potential input sources, thereby providing a new basis for probabilistic reasoning in RSNNs. Our new learning approach also solves an open problem in neuromorphic engineering, where on-chip one-shot learning capability is highly desirable for spike-based neuromorphic devices, but could so far not be achieved. Our method can easily be mapped into neuromorphic hardware, and thereby solves this problem.
Biological invasions alter environmental microbiomes: a meta-analysis
Authors: Malacrinò Antonino , Sadowski Victoria A. , Martin Tvisha K. , de Oliveira Nathalia Cavichiolli , Brackett Ian J. , Feller James D. , Harris Kristian J. , Heredia Orlando Combita , Vescio Rosa , Bennett Alison E.
Published: June 2020

Biological invasions impact both agricultural and natural systems. The damage can be quantified in terms of both economic loss and reduction of biodiversity. Although the literature is quite rich about the impact of invasive species on plant and animal communities, their impact on environmental microbiomes is underexplored. Here, we re-analyze publicly available data using a common framework to create a global synthesis of the effects of biological invasions on environmental microbial communities. Our findings suggest that non-native species are responsible for the loss of microbial diversity and shifts in the structure of microbial populations. Therefore, the impact of biological invasions on native ecosystems might be more pervasive than previously thought, influencing both macro- and micro-biomes. We also identified gaps in the literature which encourage research on a wider variety of environments and invaders, and the influence of invaders across seasons and geographical ranges.
Exaggerated postnatal surge of orexin and the effects of elimination of excess orexin on blood pressure in spontaneously hypertensive rats in postnatal development
Authors: Barnett Savannah , Dong Ruhong , Briggs Logan , Moushey Alexander , Li Aihua
Published: June 2020

It has been established that an overactive orexin (OX) system is associated with neurogenic hypertension in spontaneously hypertensive rats (SHRs). However, the chronology and mechanism of such association between orexin system and hypertension is unclear. We hypothesized that an aberrant surge of OX neurons in SHRs precedes the aberrant increase of arterial blood pressure (ABP) during postnatal development, which was primarily contributed by the exaggerated postnatal OX neurogenesis. We found that (1) SHRs experienced a greater surge in the number of orexin neurons than normotensive Wistar-Kyoto (WKY) rats before P16, which led to significantly more OX neurons than age-matched controls by P15-16 (3680±219 vs 2407±182, respectively, P=0.002). (2) Exaggerated OX neurogenesis, marked by bromodeoxyuridine (BrdU), was the primary contributor to excessive OX neurons in SHRs during development. (3) In contrast, SHRs and normotensive control rats have similar mean arterial blood pressure (ABP) at P15, and a significantly higher ABP in SHR than WKY emerges at P20 (74.8 ± 2.5 vs 66.9 ± 4.4 mmHg in wakefulness, respectively, P<0.05), a few days following the surge of OX activity. (4) Selectively eliminating excess (∼30%) orexin neurons, via a targeted neurotoxin, in SHRs between P30 and P40 results in a significantly lowered ABP compared to non-lesioned SHRs at P40. We suggest that the postnatal surge of OX neurons, primarily attributed to the exaggerated postnatal OX neurogenesis, may be necessary for the development of higher ABP in SHRs, and modulation of the overactive OX system may have a preventative effect during the pre-hypertensive period.

New Findings

What is the central question of this study?

Excess orexin neurons have been associated with hypertension in spontaneously hypertensive rats, however, the association and mechanism between developing excess orexin neurons and high blood pressure are unknown.

What is the main finding and its importance?

Using spontaneously hypertensive rats in anatomical and physiological studies, we provided evidence showing that the excess OX neurons, primarily via exaggerated OX neurogenesis, may be necessary in developing a higher ABP in SHRs during development, and modulation of the overactive orexin system may be beneficial in treating hypertension.
Integrated Stress Response Inhibition Provides Sex-Dependent Protection Against Noise-Induced Cochlear Synaptopathy
Authors: Rouse Stephanie L. , Matthews Ian R. , Li Jiang , Sherr Elliott H. , Chan Dylan K.
Published: June 2020

Noise-induced hearing loss (NIHL) is a common health concern with significant social, psychological, and cognitive implications. Moderate levels of acoustic overstimulation associated with tinnitus and impaired speech perception cause cochlear synaptopathy, characterized physiologically by reduction in wave I of the suprathreshold auditory brainstem response (ABR) and reduced number of synapses between sensory hair cells and auditory neurons. The unfolded protein response (UPR), an endoplasmic reticulum stress response pathway, has been implicated in the pathogenesis and treatment of NIHL as well as neurodegeneration and synaptic damage in the brain. In this study, we used the small molecule UPR modulator ISRIB (Integrated Stress Response InhiBitor) to treat noise-induced cochlear synaptopathy in a mouse model. Mice pretreated with ISRIB prior to noise-exposure were protected against noise-induced synapse loss. Male, but not female, mice also exhibited ISRIB-mediated protection against noise-induced suprathreshold ABR wave-I amplitude reduction. Female mice had higher baseline wave-I amplitudes but greater sensitivity to noise-induced wave-I reduction. Our results suggest that the UPR is implicated in noise-induced cochlear synaptopathy, and can be targeted for treatment.
SARS-CoV-2 assays to detect functional antibody responses that block ACE2 recognition in vaccinated animals and infected patients
Authors: Walker Susanne N. , Chokkalingam Neethu , Reuschel Emma L. , Purwar Mansi , Xu Ziyang , Gary Ebony N. , Kim Kevin Y. , Schultheis Katherine , Walters Jewell , Ramos Stephanie , Smith Trevor R.F. , Broderick Kate E. , Tebas Pablo , Patel Ami , Weiner David B. , Kulp Daniel W.
Published: June 2020

SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) has caused a global pandemic of COVID-19 resulting in cases of mild to severe respiratory distress and significant mortality. The global outbreak of this novel coronavirus has now infected >8 million people worldwide with >2 million cases in the US (June 17th, 2020). There is an urgent need for vaccines and therapeutics to combat the spread of this coronavirus. Similarly, the development of diagnostic and research tools to determine infection and vaccine efficacy are critically needed. Molecular assays have been developed to determine viral genetic material present in patients. Serological assays have been developed to determine humoral responses to the spike protein or receptor binding domain (RBD). Detection of functional antibodies can be accomplished through neutralization of live SARS-CoV2 virus, but requires significant expertise, an infectible stable cell line, a specialized BioSafety Level 3 (BSL-3) facility. As large numbers of people return from quarantine, it is critical to have rapid diagnostics that can be widely adopted and employed to assess functional antibody levels in the returning workforce. This type of surrogate neutralization diagnostic can also be used to assess humoral immune responses induced in patients from the large number of vaccine and immunotherapy trials currently on-going. Here we describe a rapid serological diagnostic assay for determining antibody receptor blocking and demonstrate the broad utility of the assay by measuring the antibody functionality of sera from small animals and non-human primates immunized with an experimental SARS-CoV-2 vaccine and using sera from infected patients.
Multiomics Characterization of Potential Therapeutic Vulnerabilities in Low-grade Serous Ovarian Carcinoma
Authors: Shrestha Raunak , Fernandez Marta Llaurado , Dawson Amy , Hoenisch Joshua , Volik Stanislav , Lin Yen-Yi , Anderson Shawn , Kim Hannah , Haegert Anne , Colborne Shane , McConeghy Brian , Bell Robert H. , Brahmbhatt Sonal , DiMattia Gabriel E. , Le Bihan Stephane , Morin Gregg B. , Collins Colin C. , Carey Mark S.
Published: June 2020

Background

Low-grade serous ovarian carcinoma (LGSOC) is a rare tumor subtype with high case fatality rates. As such, there is a pressing need to develop more effective treatments using newly available preclinical models for therapeutic discovery and drug evaluation. Here, we use a multiomics approach to interrogate a collection of LGSOC patient-derived cell lines to elucidate novel biomarkers and therapeutic vulnerabilities.

Methods

Fourteen LGSOC cell lines were interrogated using whole exome sequencing, RNA sequencing, and mass spectrometry-based proteomics. Somatic mutation, copy-number aberrations, gene and protein expression were analyzed and integrated using different computational approaches. LGSOC cell line data was compared to publicly available LGSOC tumor data (AACR GENIE cohort), and also used for predictive biomarker identification of MEK inhibitor (MEKi) efficacy. Protein interaction databases were evaluated to identify novel therapeutic targets.

Results

KRASmutations were exclusively found in MEKi-sensitive andNRASmutations mostly in MEKi-resistant cell lines. Analysis of COSMIC mutational signatures revealed distinct patterns of nucleotide substitution mutations in MEKi-sensitive and MEKi-resistant cell lines. Deletions ofCDKN2A/BandMTAPgenes (chromosome 9p21) were much more frequent in cell lines than tumor samples and possibly represent key driver events in the absence of KRAS/NRAS/BRAF mutations. Forin-vitroMEKi efficacy prediction, proteomic data provided better discrimination than gene expression data. Condensin, MCM, and RFC protein complexes were identified as potential treatment targets in MEKi-resistant cell lines.

Conclusions

Our LGSOC cell lines are representative models of the most common molecular aberrations found in LGSOC tumors. This study highlights the importance of using proteomic data in multiomics assessment of drug prediction and identification of potential therapeutic targets. CDKN2A/B and MTAP deficiency offer an opportunity to find synthetically lethal candidates for novel treatments. Multiomics approaches are crucial to improving our understanding of the molecular aberrations in LGSOC, establishing effective drug prediction programs and identifying novel therapeutic targets in LGSOC.
A system for phenotype harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program
Authors: Stilp Adrienne M. , Emery Leslie S. , Broome Jai G. , Buth Erin J. , Khan Alyna T. , Laurie Cecelia A. , Wang Fei Fei , Wong Quenna , Chen Dongquan , D’Augustine Catherine M. , Heard-Costa Nancy L. , Hohensee Chancellor R. , Johnson William Craig , Juarez Lucia D. , Liu Jingmin , Mutalik Karen M. , Raffield Laura M. , Wiggins Kerri L. , de Vries Paul S. , Kelly Tanika N. , Kooperberg Charles , Natarajan Pradeep , Peloso Gina M. , Peyser Patricia A. , Reiner Alex P. , Arnett Donna K. , Aslibekyan Stella , Barnes Kathleen C. , Bielak Lawrence F. , Bis Joshua C. , Cade Brian E. , Chen Ming-Huei , Correa Adolfo , Cupples L. Adrienne , de Andrade Mariza , Ellinor Patrick T. , Fornage Myriam , Franceschini Nora , Gan Weiniu , Ganesh Santhi K. , Graffelman Jan , Grove Megan L. , Guo Xiuqing , Hawley Nicola L. , Hsu Wan-Ling , Jackson Rebecca D. , Jaquish Cashell E. , Johnson Andrew D. , Kardia Sharon LR , Kelly Shannon , Lee Jiwon , Mathias Rasika A. , McGarvey Stephen T. , Mitchell Braxton D. , Montasser May E. , Morrison Alanna C. , North Kari E. , Nouraie Seyed Mehdi , Oelsner Elizabeth C. , Pankratz Nathan , Rich Stephen S. , Rotter Jerome I. , Smith Jennifer A. , Taylor Kent D. , Vasan Ramachandran S. , Weeks Daniel E. , Weiss Scott T. , Wilson Carla G. , Yanek Lisa R. , Psaty Bruce M. , Heckbert Susan R. , Laurie Cathy C.
Published: June 2020

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institute’s Trans-Omics for Precision Medicine (TOPMed) program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 TOPMed studies per phenotype. We discuss the challenges faced in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include (1) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.
The early adolescent brain on music: analysis of functional dynamics reveals engagement of orbitofrontal cortex reward system
Authors: Fasano M. C. , Cabral J. , Stevner A. , Vuust P. , Cantou P. , Brattico E. , Kringelbach M. L.
Published: June 2020

Music listening plays a pivotal role for children and adolescents, yet surprisingly few neuroimaging studies have studied the underlying functional dynamics. We used functional magnetic resonance imaging to scan 17 preadolescents aged 10-11 years old while listening to music. We subsequently tracked the occurrence of functional brain networks over time by using a recent method that detects recurrent BOLD phase-locking states: the Leading Eigenvector Dynamics Analysis (LEiDA). In particular, we compared the probabilities of occurrence and switching profiles of different patterns of BOLD phase-locking between music and no music. Moreover, we used an adapted version of the Barcelona Music Reward Questionnaire (BMRQ) to measure the music reward sensitivity of the participants. Our results showed significantly increased occurrence of a BOLD phase-locking pattern during music listening compared to no music, characterized by a phase-shift in the BOLD signals of the medial orbitofrontal and ventromedial prefrontal cortices – a brain subsystem associated to reward processing – from the rest of the brain. Moreover, we observed a significantly higher probability of switching to this pattern while listening to music. We also found a positive correlation between the individual musical reward sensitivity and the tendency to switch to this reward state during music. Our findings highlight the involvement of a brain subsystem involved in hedonic processing during music listening in the early adolescent brain. These results offer novel insight into the neural underpinnings of musical reward in early adolescence and may help us to understand the importance of music at this delicate age.
“Acute Respiratory Distress and Cytokine Storm in Aged, SARS-CoV-2 Infected African Green Monkeys, but not in Rhesus Macaques”
Authors: Blair Robert V. , Vaccari Monica , Doyle-Meyers Lara A. , Roy Chad J , Russell-Lodrigue Kasi , Fahlberg Marissa , Monjure Chris J. , Beddingfield Brandon , Plante Kenneth S. , Plante Jessica A. , Weaver Scott C. , Qin Xuebin , Midkiff Cecily C. , Lehmicke Gabrielle , Golden Nadia , Threeton Breanna , Penney Toni , Allers Carolina , Barnes Mary B , Pattison Melissa , Datta Prasun K , Maness Nicholas J , Birnbaum Angela , Fischer Tracy , Bohm Rudolf P. , Rappaport Jay
Published: June 2020

SARS-CoV-2 induces a wide range of disease severity ranging from asymptomatic infection, to a life-threating illness, particularly in the elderly and persons with comorbid conditions. Among those persons with serious COVID-19 disease, acute respiratory distress syndrome (ARDS) is a common and often fatal presentation. Animal models of SARS-CoV-2 infection that manifest severe disease are needed to investigate the pathogenesis of COVID-19 induced ARDS and evaluate therapeutic strategies. Here we report ARDS in two aged African green monkeys (AGMs) infected with SARS-CoV-2 that demonstrated pathological lesions and disease similar to severe COVID-19 in humans. We also report a comparatively mild COVID-19 phenotype characterized by minor clinical, radiographic and histopathologic changes in the two surviving, aged AGMs and four rhesus macaques (RMs) infected with SARS-CoV-2. We found dramatic increases in circulating cytokines in three of four infected, aged AGMs but not in infected RMs. All of the AGMs showed increased levels of plasma IL-6 compared to baseline, a predictive marker and presumptive therapeutic target in humans infected with SARS-CoV-2 infection. Together, our results show that both RM and AGM are capable of modeling SARS-CoV-2 infection and suggest that aged AGMs may be useful for modeling severe disease manifestations including ARDS.
T4SE-XGB: interpretable sequence-based prediction of type IV secreted effectors using eXtreme gradient boosting algorithm
Authors: Chen Tianhang , Wang Xiangeng , Chu Yanyi , Wei Dong-Qing , Xiong Yi
Published: June 2020

Type IV secreted effectors (T4SEs) can be translocated into the cytosol of host cells via type IV secretion system (T4SS) and cause diseases. However, experimental approaches to identify T4SEs are time- and resource-consuming, and the existing computational tools based on machine learning techniques have some obvious limitations such as the lack of interpretability in the prediction models. In this study, we proposed a new model, T4SE-XGB, which uses the eXtreme gradient boosting (XGBoost) algorithm for accurate identification of type IV effectors based on optimal features based on protein sequences. After trying 20 different types of features, the best performance was achieved when all features were fed into XGBoost by the 5-fold cross validation in comparison with other machine learning methods. Then, the ReliefF algorithm was adopted to get the optimal feature set on our dataset, which further improved the model performance. T4SE-XGB exhibited highest predictive performance on the independent test set and outperformed other published prediction tools. Furthermore, the SHAP method was used to interpret the contribution of features to model predictions. The identification of key features can contribute to improved understanding of multifactorial contributors to host-pathogen interactions and bacterial pathogenesis. In addition to type IV effector prediction, we believe that the proposed framework can provide instructive guidance for similar studies to construct prediction methods on related biological problems. The data and source code of this study can be freely accessed athttps://github.com/CT001002/T4SE-XGB.
α-Synuclein facilitates endocytosis by elevating the steady-state levels of phosphatidylinositol 4,5-bisphosphate
Authors: Meir Schechter , Merav Atias , Suaad Abd Elhadi , Dana Davidi , Daniel Gitler , Ronit Sharon
Published: June 2020

α-Synuclein (α-Syn) is a protein implicated in the pathogenesis of Parkinson’s disease (PD). It is an intrinsically disordered protein that binds acidic phospholipids. Growing evidence supports a role for α-Syn in membrane trafficking, including, mechanisms of endocytosis and exocytosis, although the exact role of α-Syn in these mechanisms is currently unclear. Here we have investigated the role of α-Syn in membrane trafficking through its association with acidic phosphoinositides (PIPs), such as phosphatidylinositol 4,5-bisphosphate (PI4,5P2) and phosphatidylinositol 3,4-bisphosphate (PI3,4P2). Our results show that α-Syn colocalizes with PIP2and the phosphorylated active form of the clathrin adaptor AP2 at clathrin-coated pits. Using endocytosis of transferrin, an indicator of clathrin mediated endocytosis (CME), we find that α-Syn involvement in endocytosis is specifically mediated through PI4,5P2levels. We further show that the rate of synaptic vesicle (SV) endocytosis is differentially affected by α-Syn mutations. In accord with their effects on PI4,5P2levels at the plasma membrane, the PD associated E46K and A53T mutations further enhance SV endocytosis. However, neither A30P mutation, nor Lysine to Glutamic acid substitutions at the KTKEGV repeat domain of α-Syn, that interfere with phospholipid binding, affect SV endocytosis. This study provides evidence for a critical involvement of PIPs in α-Syn-mediated membrane trafficking.

Significance Statement

α-Synuclein (α-Syn) protein is known for its causative role in Parkinson’s disease. α-Syn is normally involved in mechanisms of membrane trafficking, including endocytosis, exocytosis and synaptic vesicles cycling. However, a certain degree of controversy regarding the exact role of α-Syn in these mechanisms persists. Here we show that α-Syn acts to increase plasma membrane levels PI4,5P2and PI3,4P2to facilitate clathrin mediated and synaptic vesicles endocytosis. Based on the results, we suggest that α-Syn interactions with the acidic phosphoinositides facilitate a shift in their homeostasis to support endocytosis.
Endogenous neural stem cells modulate microglia and protect from demyelination
Authors: Brousse Béatrice , Magalon Karine , Daian Fabrice , Durbec Pascale , Cayre Myriam
Published: June 2020

In response to corpus callosum (CC) demyelination, subventricular zone-derived neural progenitors (SVZdNP) are mobilized and generate new myelinating oligodendrocytes. Here, we examine the putative immunomodulatory properties of endogenous SVZdNP during demyelination in the cuprizone model. We observed that SVZdNP density is higher in the lateral and rostral CC regions that show weaker demyelination and is inversely correlated with activated microglia density and pro-inflammatory cytokines levels. Single-cell RNA-sequencing further revealed CC areas with high SVZdNP mobilization are enriched in a microglial cell subpopulation with immunomodulatory signature. We identified ligand/receptor couple MFGE8 (milk fat globule-epidermal growth factor-8)/integrin β3 as a ligand/receptor couple implicated in SVZdNP/microglia dialog. MFGE8 is highly enriched in immature SVZdNP mobilized to the demyelinated CC and promotes myelin debris phagocytosis in vitro. Altogether these results demonstrate that beyond their cell replacement capacity endogenous progenitors display immunomodulatory properties highlighting a new role for endogenous SVZdNP in myelin regeneration.
Tau amyloidogenesis begins with a loss of its conformational polymorphism
Authors: del Carmen Fernández-Ramírez María , Hervás Rubén , Menéndez Margarita , Laurents Douglas V. , Carrión-Vázquez Mariano
Published: June 2020

Knowledge on the molecular bases of early amyloid assembly is fundamental to understand its structure-dysfunction relationship during disease progression. Tauopathies, a well-defined set of neurodegenerative disorders that includes Alzheimer’s disease, are characterized by the pathological amyloid aggregation of tau. However, the underlying molecular mechanisms that trigger tau aggregation and toxicity are poorly understood. Here, using a single-molecule approach, AFM-based single molecule-force spectroscopy (AFM-SMFS), combined with a protein-engineering mechanical protection strategy, we have analyzed the fluctuations of the conformational space of tau during the start of its pathological amyloid assembly. Specifically, we have analyzed the region that includes the four tau microtubule-binding repeats, known to play a key role on tau aggregation. We find that, unlike other amyloid-forming proteins, tau aggregation is accompanied by a decrease of conformational polymorphism, which is driven by amyloid-promoting factors, such as the Δ280K and P301L mutations, linked to Frontotemporal Dementia-17, or by specific chemical conditions. Such perturbations have distinct effects and lead to different tau (aggregate) structures. In addition to providing insight into how tau aggregates in a context dependent manner, these findings may help delve into how protein aggregation-based diseases, like Alzheimer’s, might be treated using monomer fluctuations as a pharmacological target.

Abstract Figure