bluuebunny/crossref_metadata_2025 huggingface dataset:
Experiences With Counterfeit Aesthetic Medical Devices and Injectables: A National Survey
Authors: Wang Jordan V. , Hattier Georgette , Rohrer Thomas , Zachary Christopher B. , Saedi Nazanin
Published: December 2019

BACKGROUND

Counterfeit medical devices and injectables have recently garnered interest in the field of aesthetics. Unlike their original counterparts, these counterfeit products have neither been tested nor verified using certified quality control measures.

OBJECTIVE

Our study investigated the pervasiveness of counterfeit products in the field as well as the experiences and attitudes of practitioners.

MATERIALS AND METHODS

An online survey was distributed to current members of the American Society for Dermatologic Surgery (ASDS) and the American Society for Laser Medicine and Surgery (ASLMS).

RESULTS

For medical devices, 37.4% have encountered counterfeits and 20.1% have experienced patients with adverse events from them. For injectables, 41.1% have encountered counterfeits and 39.7% have experienced patients with adverse events from them. Compared with their original, most respondents believe that counterfeits are worse in terms of reliability, safety, and effectiveness. The majority also believe that counterfeits are either very or extremely endangering to patient safety.

CONCLUSION

Counterfeit medical devices and injectables are not uncommonly encountered. Overall, practitioners believe counterfeits are endangering patient safety and result in adverse events and think that either stricter rules and regulations or better enforcement of existing regulations is necessary.
Identifying the Most Stable State of a Foam Sclerosant for Foam Sclerotherapy
Authors: Zhang Han-Shu , Yang Ai-Jun , Liu Shaohua
Published: December 2019

BACKGROUND

Foam sclerotherapy is an effective treatment strategy for vascular malformations, and its sclerosing power depends on foam stability. Twenty quick passages have been widely used as an indicator of the most stable state of sclerosants, but the universality of their effectiveness has not been proven yet.

OBJECTIVE

We aimed to identify simple and objective indicators of the most stable state of commonly used sclerosants and provide practitioners with suggestions to judge when foam producing is completed in sclerotherapy.

MATERIALS AND METHODS

The universality of the effectiveness of 20 passages was tested by producing bleomycin foam with different passages. Further study was performed by testing modified bleomycin, polidocanol, and sodium tetradecylsulfate foam.

RESULTS

The bleomycin foam became denser as passages were added, and the sound of each passage became almost silent after 40 passages. The almost silent sound can be an indicator of foam stability for most sclerosants. It has a different application range compared with 20 quick passages.

CONCLUSION

We suggest that practitioners choose a different indicator depending on the foam used.
The contribution of orexin receptors within the ventral tegmental area to modulation of antinociception induced by chemical stimulation of the lateral hypothalamus in the animal model of orofacial pain in the rats
Authors: Safari-Sandiani Emad , Rahimitabar Niloofar , Rezaee Laleh , Behnaz Mohammad , Haghparast Abbas
Published: December 2019

Involvement of the ventral tegmental area (VTA) and the lateral hypothalamus (LH) in the modulation of formalin-induced nociception is well documented. In this study, we investigated the role of orexin 1 (OX1) and orexin 2 (OX2) receptors within the VTA in modulation of the LH-induced antinociception during both phases of orofacial formalin test. Male adult Wistar rats weighing 230–250 g were unilaterally implanted with two stainless steel guide cannulae in the VTA and LH. In two separate supergroups, animals received SB334867 (OX1 receptor antagonist) or TCS OX2 29 (OX2 receptor antagonist), at the doses of 3, 10, and 30 nM/rat into the VTA before intra-LH microinjection of carbachol (250 nM/rat) as a nonselective cholinergic receptor agonist for chemical stimulation of orexinergic neurons in this region. Rats were subcutaneously injected with 1% formalin (50 µl; s) into the orofacial region, 5 min after intra-LH microinjection of carbachol or saline. The blockade of both orexin receptors in the VTA reduced intra-LH carbachol-induced antinociception. However, this effect was greater during the late phases of the orofacial formalin test. The blockade of the OX1 but not OX2 receptors in the VTA affect the pain-related behaviors during the early phase, and also, the contribution of OX2 receptor to modulate the LH-induced antinociceptive responses was greater than OX1 receptor during the late phase of orofacial formalin test. The results indicated the neural pathway projected from the LH to the VTA contributes to the modulation of formalin-induced orofacial pain. Orexinergic drugs might be considered as therapeutic agents for inflammatory pain treatment.
Implant-based Breast Reconstruction Outcomes Comparing Freeze-dried Aseptic Alloderm and Sterile Ready-to-use Alloderm
Authors: Widmyer Anna S. , Mirhaidari Shayda J. , Wagner Douglas S.
Published: December 2019

Background:

The use of acellular dermal matrix has revolutionized implant-based breast reconstruction in the 21st century. There have been a number of different dermal matrices introduced to clinical use and their equivalence has been debated. The purpose of this study is to examine a sequential series of acellular dermal matrix assisted implant-based breast reconstructions by a single surgeon and to compare the outcomes between a freeze-dried (FD) Alloderm cohort and a sterile ready to use Alloderm cohort.

Methods:

After institutional review board approval, all consecutive implant-based breast reconstructions of a single surgeon (D.S.W.) from January 2009 to June 2016 were examined. Two hundred thirty-six patients received either FD Alloderm in the first 151 breasts reconstructed or sterile ready-to-use Alloderm in the last 227 breasts.

Results:

The FD Alloderm patients had more tissue expander reconstructions performed and were all subpectoral placement. The ready-to-use Alloderm patients had more direct-to-implant procedures and some prepectoral placements. The complication rates were similar for seroma, hematoma, skin necrosis, and dehiscence. There were more infections, implant losses, and unexpected reoperations in the FD Alloderm group.

Conclusion:

The rate of infection, explantation, and unexpected reoperation was lower in the sterile ready-to-use Alloderm group versus the FD Alloderm group.
Comparison of Fasciocutaneous and Muscle-based Free Flaps for Soft Tissue Reconstruction of the Upper Extremity
Authors: Koepple Christoph , Kallenberger Ann-Katrin , Pollmann Lukas , Hundeshagen Gabriel , Schmidt Volker J. , Kneser Ulrich , Hirche Christoph
Published: December 2019

Background:

Soft tissue free flap reconstruction of upper extremities has proven to be reliable and essential for limb salvage and function. Nevertheless, comparative data regarding flap outcome are still lacking. The present study aimed to compare procedural features and individual complication rates of different free flaps used for upper extremity reconstruction.

Methods:

The authors evaluated retrospectively the results of 164 free flaps in 149 patients with upper extremity defects. Chart reviews were performed from April 2000 to June 2014, analyzing flap choices, complication, and success rate assessment for patients >18 years old, with a soft tissue defect of the upper extremity. Chosen flap types were classified as fasciocutaneous (including adipocutaneous) and muscle-based, respectively. We comparatively analyzed total flap loss, flap survival after microsurgical revisions, and susceptibility rates for thromboses rates and partial flap necrosis.

Results:

Defect size was larger when muscle-based flaps were used (231 ± 38.6 versus 164 ± 13.7 cm2,P< 0.05). Outcome analysis revealed a tendency towards higher arterial thrombosis rates for muscle flaps (10.2% versus 4.3%) and venous thrombosis rates for fasciocutaneous flaps (2% versus 7%). Total flap loss (6.1% versus 7.8%) and flap survival after vascular revisions (75% versus 70.6%) showed comparable rates. Partial flap necrosis was generally higher in muscle-based flaps (22.4% versus 8.6%,P= 0.02) with impact on patients’ hospital stay (37.2 ± 4.69 and 27.11 ± 1.62 days, n = 115,P= 0.01), while no differences in partial necrosis rates were noted in flaps larger than 300 cm2(25% versus 10%,P= 0.55). There was a trend over time towards using fasciocutaneous-based flaps more frequently with a final overall percentage of 83.7% between 2012 and 2014.

Conclusions:

Microsurgical tissue transfer to the upper extremity is safe and reliable, but flap-type specific procedural and measures should be taken into consideration. Total flap loss as well as flap survival after microsurgical revisions are not altered between these flaps. They differ, however, in their susceptibilities for thromboses rates, partial flap necrosis and thus require individual risk stratification and flap placement.
Application of Orbital Septum Fat Flap Stuffing to Correct Inferior Orbital Sulcus Deformities
Authors: Jiang Ling , Deng Ying , Li Wei
Published: December 2019

The inferior orbitopalpebral sulcus deformity is challenging during lower eyelid blepharoplasty. Plastic surgeons are currently addressing each case individually, depending on the patient’s unique circumstances. Nevertheless, patients with large orbital grooves often complain that the inferior orbitopalpebral sulcus is not sufficiently improved. Altogether, 189 patients underwent transcutaneous blepharoplasty. According to their local anatomy, 98 underwent transcutaneous blepharoplasty surgery only, 59 had it combined with arcus marginalis release, and 32 had it combined with orbital septum fat flap stuffing. For the latter 32 patients, the orbital fat was trimmed and flipped to roll over the edge 10 mm from the infraorbital rim to form a base to repair the tear trough deformity and palpebromalar groove. Excessive dermatochalasis was removed, excrescent bulging fat was released, and the sulcus deformity was flattened using the orbital fat flap. The cosmetic results were satisfactory. Releasing the orbital septal fat helped restructure the deformity. The lower eyelid bags and lower orbital sulcus deformities were well corrected, allowing recovery with a convex-type facial contour. Using an orbital fat flap to treat a tear trough deformity and palpebromalar groove is effective and safe. Careful performances by surgeons can avoid serious complications. This operation satisfies both patients and surgeons.
Regular Statin Use and Incidence of Postendoscopic Retrograde Cholangiopancreatography Pancreatitis
Authors: Hakuta Ryunosuke , Nakai Yousuke , Hamada Tsuyoshi , Suzuki Yukari , Inokuma Akiyuki , Oyama Hiroki , Kanai Sachiko , Nakamura Tomoka , Sato Tatsuya , Ishigaki Kazunaga , Saito Kei , Saito Tomotaka , Takahara Naminatsu , Mizuno Suguru , Kogure Hirofumi , Tada Minoru , Koike Kazuhiko
Published: December 2019

Goals and Background:

Endoscopic retrograde cholangiopancreatography is widely utilized to diagnose and treat various pancreaticobiliary diseases, but postendoscopic retrograde cholangiopancreatography pancreatitis (PEP) can be a fatal adverse event. Evidence suggests that statins may exhibit suppressive effects on inflammation in the pancreas. We carried out an observational cohort study to examine the protective effect of statins on PEP.

Study:

We retrospectively identified consecutive patients who underwent endoscopic retrograde cholangiopancreatography at a tertiary care center in Japan between January 2010 and January 2019. The incidences of PEP were compared between regular and nonregular statin users. Using the multivariable logistic regression model, we examined the association of regular statin use with the incidence of PEP controlling for potential risk factors for PEP.

Results:

We included 2664 patients (328 regular statin users and 2336 nonregular users). The incidence of PEP did not differ by statin use status (P=0.52): 8.8% in regular statin users and 7.9% in nonregular users. The multivariable-adjusted odds ratio for PEP comparing regular statin use with nonregular use was 1.08 (95% confidence interval, 0.67-1.72; P=0.76). When we examined specific statin types (hydrophilic and lipophilic statins), we consistently observed the null association: 6.8% of 132 hydrophilic statin users and 10% of 196 lipophilic statin users (P=0.74 and 0.27, respectively, compared with nonregular users).

Conclusions:

Regular statin use was not shown to be protective against PEP. A further investigation is warranted before this medication is tested in prospective randomized trials.
Long-term Outcome in Severe Left Ventricular Primary Graft Dysfunction Post Cardiac Transplantation Supported by Early Use of Extracorporeal Membrane Oxygenation
Authors: Connolly Sophie , Granger Emily , Hayward Christopher , Huang David , Kerr Stephen , McCanny Peter , Buscher Hergen
Published: December 2019

Background.

Severe primary graft dysfunction (PGD) is the leading cause of early death following cardiac transplantation. The early use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) may facilitate graft rescue. However, the additional risks of its use are unknown.

Methods.

We retrospectively reviewed the medical records of all adult patients who underwent cardiac transplantation from January 2009 to February 2016 at St Vincent’s Hospital, Sydney, to evaluate risk factors for the use of VA-ECMO and related morbidity and long-term survival.

Results.

One hundred ninety-two transplanted patients were identified, 49 (25%) of whom developed left or biventricular PGD requiring VA-ECMO. The total operation time (median 495 [interquartile range 139.8] versus 412.8 [132] min, P < 0.001), cardiopulmonary bypass time (220 [63] versus 176 [73] min, P < 0.001) and the presence of a previous sternotomy (29 [59%] versus 51 [36%], P = 0.019) were associated with the use of VA-ECMO. One-year survival in the VA-ECMO cohort was 71%. After a median follow-up time of 696 days (interquartile range 1201 d), survival was significantly higher in the non-ECMO group (P = 0.004) but not when conditioned on hospital survival (P = 0.34). Patients with shorter than median ECMO runtime (<108 h) had a similar long-term survival to patients who did not require ECMO (P = 0.559). In the ECMO cohort, multivariable logistic regression revealed baseline creatinine in µmol/L (odds ratio 0.99 [95% confidence interval 0.99-1.00], P = 0.019) and duration of ECMO support in days (odds ratio 0.65 [95% confidence interval 0.44-0.97], P = 0.034) were inversely and independently associated with 1-year survival.

Conclusions.

Short- and long-term survival of PGD supported with VA-ECMO was better than previously described. Early recovery of PGD on VA-ECMO support negates its negative impact on short- and long-term survival.
The co-stimulatory activity of Tim-3 requires Akt and MAPK signaling and immune synapse recruitment
Authors: Kataoka Shunsuke , Manandhar Priyanka , Lee Judong , Workman Creg J. , Banerjee Hridesh , Szymczak-Workman Andrea L. , Kvorjak Michael , Lohmueller Jason , Kane Lawrence P.
Published: December 2019

Expression of the transmembrane protein Tim-3 is increased on dysregulated T cells undergoing chronic T cell activation, including in chronic infection and solid tumors. We and others previously reported that Tim-3 exerts apparently paradoxical co-stimulatory activity in T cells (and other cells), including enhancement of ribosomal S6 protein phosphorylation (pS6). Here we examined the upstream signaling pathways that control Tim3-mediated increases in pS6 in T cells. We have also defined the localization of Tim-3 relative to the T cell immune synapse and impacts on downstream signaling. Recruitment of Tim-3 to the immune synapse was mediated exclusively by the transmembrane domain, replacement of which impaired Tim-3 co-stimulation of pS6. Strikingly, enforced localization of the Tim-3 cytoplasmic domain to the immune synapse in the context of a chimeric antigen receptor still allowed for robust T cell activation. Our findings are consistent with a model whereby Tim-3 enhances TCR-proximal signaling under acute conditions.

One Sentence Summary

Here we define elements of signaling and localization associated with Tim-3 co-stimulatory function in T cells.
Higher cognitive reserve is associated with better neural efficiency in the cognitive performance of young adults. An event-related potential study
Authors: Velasco Gabriela Gutiérrez-Zamora , Fernández Thalía , Silva-Pereyra Juan , Alcántara Vicenta Reynoso
Published: December 2019

To examine the effects of cognitive reserve (CR) and working memory (WM) load on the cognitive performance of young adults, we performed two event-related potential (ERP) experiments. The first experiment aims to show how high CR influences young adult performance as a function of two levels of working memory load (high vs. low) during a Sternberg task. For both positive and negative probes, participants with high and low CR showed larger P300 amplitudes to low WM loads than to high WM loads. Both CR groups showed a longer P300 latency to high WM loads than to low WM loads, but this difference was greater for the low CR group than for the high CR group. The high CR group displayed larger P300 amplitudes for every experimental condition compared to the low CR group. The second experiment analyzed grammatical gender agreement in sentence processing when CR and WM load were manipulated. Sentences varied according to the gender agreement of the noun and adjective, where the gender of the adjective either agreed or disagreed with that of the noun (agreement), and with regard to the number of words between the noun and the adjective in the sentence (WM load). Participants with high CR showed greater modulation of left anterior negativity (LAN) and P600a effects as WM increased than that observed in participants with low CR. The findings together suggest that higher levels of cognitive reserve improve neural efficiency, which may result in better working memory performance and sentence processing.
Phloem-mediated spreading of SIGS-derived non-coding RNAs inHordeum vulgare
Authors: Biedenkopf D , Will T , Knauer T , Jelonek L , Furch ACU , Busche T , Koch A
Published: December 2019

Small (s)RNA molecules are crucial factors in the communication between hosts and their interacting pathogens/pests that can modulate both host defense and microbial virulence/pathogenicity known as cross-kingdom RNA interference (ckRNAi). Consistent with this, sRNAs and their double-stranded (ds)RNA precursors have been adopted to control plant diseases through exogenously applied RNA biopesticides, known as spray-induced gene silencing (SIGS). While RNA spray proved to be effective, the mechanisms underlying the transfer and uptake of SIGS-associated RNAs are inadequately understood. Moreover, the use of the SIGS-technology as a biopesticide will require the systemic spreading of dsRNA/siRNA signals. Our results strongly support the notion of phloem-mediated long-distance movement of SIGS-associated dsRNA and/or siRNA. These findings are significant contributions to our mechanistic understanding of RNA spray technology, as our previous data indicate that SIGS requires the processing of dsRNAs by the fungal RNAi machinery. In summary, our findings support the model that SIGS involves: (i) uptake of sprayed dsRNA by the plant (via stomata); (ii) transfer of apoplastic dsRNAs into the symplast (DCL processing into siRNAs); (iii) systemic translocation of siRNA or unprocessed dsRNA via the vascular system (phloem/xylem); (iv) uptake of apoplastic dsRNA or symplastic dsRNA/siRNA depending on the lifestyle/feeding behavior of the pathogen/pest.
Comparative proteomics of octocoral and scleractinian skeletomes and the evolution of coral calcification
Authors: Conci Nicola , Lehmann Martin , Vargas Sergio , Wörheide Gert
Published: December 2019

Corals are ecosystem engineers of the coral reefs, one of the most biodiverse but severely threatened marine ecosystems. The ability of corals to form the three dimensional structure of reefs depends on the precipitation of calcium carbonate under biologically control. However, the exact mechanisms underlying this biologically controlled biomineralization remain to be fully unelucidated, for example whether corals employ a different molecular machinery for the deposition of different calcium carbonate (CaCO3) polymorphs (i.e., aragonite or calcite). Here we used tandem mass spectrometry (MS/MS) to compare skeletogenic proteins, i.e., the proteins occluded in the skeleton of three octocoral and one scleractinian species:Tubipora musicaandSinulariacf.cruciata, both forming calcite sclerites, the blue coralHeliopora coeruleawith an aragonitic rigid skeleton, and the scleractinian aragoniticMontipora digitata. We observed extremely low overlap between aragonitic and calcitic species, while a core set of proteins is shared between octocorals producing calcite sclerites. However, the same carbonic anhydrase (CruCA4) is employed for the formation of skeletons of both polymorphs. Similarities could also be observed between octocorals and scleractinians, including the presence of a galaxin-like protein. Additionally, as in scleractinians, some octocoral skeletogenic proteins, such as acidic proteins and scleritin, appear to have been secondarily co-opted for calcification and likely derive from proteins playing different extracellular functions. InH. coerulea, co-option was characterized by aspartic acid-enrichment of proteins. This work represents the first attempt to identify the molecular basis underlying coral skeleton polymorph diversity, providing several new research targets and enabling both future functional and evolutionary studies aimed at elucidating the origin and evolution of biomineralization in corals.
Global redistribution and local migration in semi-discrete host-parasitoid population dynamic models
Authors: Emerick Brooks , Singh Abhyudai
Published: December 2019

Host-parasitoid population dynamics is often probed using a semi-discrete/hybrid modeling framework. Here, the update functions in the discrete-time model connecting year-to-year changes in the population densities are obtained by solving ordinary differential equations that mechanistically describe interactions when hosts become vulnerable to parasitoid attacks. We use this semi-discrete formalism to study two key spatial effects: local movement (migration) of parasitoids between patches during the vulnerable period; and yearly redistribution of populations across patches outside the vulnerable period. Our results show that in the absence of any redistribution, constant density-independent migration and parasitoid attack rates are unable to stabilize an otherwise unstable host-parasitoid population dynamics. Interestingly, inclusion of host redistribution (but not parasitoid redistribution) before the start of the vulnerable period can lead to stable coexistence of both species. Next, we consider a Type-III functional response (parasitoid attack rate increases with host density), where the absence of any spatial effects leads to a neutrally stable host-parasitoid equilibrium. As before, density-independent parasitoid migration by itself is again insufficient to stabilize the population dynamics and host redistribution provides a stabilizing influence. Finally, we show that a Type-III functional response combined with density-dependent parasitoid migration leads to stable coexistence, even in the absence of population redistributions. In summary, we have systematically characterized parameter regimes leading to stable/unstable population dynamics with different forms of spatial heterogeneity coupled to the parasitoid’s functional response using mechanistically formulated semi-discrete models.
Kirrel3-mediated synapse formation is attenuated by disease-associated missense variants
Authors: Taylor Matthew R. , Martin E. Anne , Sinnen Brooke , Trilokekar Rajdeep , Ranza Emmanuelle , Antonarakis Stylianos E. , Williams Megan E.
Published: December 2019

Missense variants in Kirrel3 are repeatedly identified as risk factors for autism spectrum disorder and intellectual disability but it has not been reported if or how these variants disrupt Kirrel3 function. Previously, we studied Kirrel3 loss-of-function using knockout mice and showed that Kirrel3 is a synaptic adhesion molecule necessary to form one specific type of hippocampal synapse in vivo. Here, we developed a new gain-of-function assay for Kirrel3 and find that wild-type Kirrel3 induces synapse formation selectively between Kirrel3-expressing cells via homophilic, trans-cellular binding. We tested six disease-associated Kirrel3 missense variants and find that five attenuate this synaptogenic function. All variants tested traffic to the cell surface and localize to synapses similar to wild-type Kirrel3. Two tested variants lack homophilic trans-cellular binding, which likely accounts for their reduced synaptogenic function. Interestingly, we also identified variants that bind in trans but cannot induce synapses, indicating Kirrel3 trans-cellular binding is necessary but not sufficient for its synaptogenic function. Collectively, these results suggest Kirrel3 functions as a synaptogenic, cell-recognition molecule, and this function is attenuated by missense variants associated with autism spectrum disorder and intellectual disability. Thus, we provide critical insight to Kirrel3 function in typical brain development and the consequences of missense variants associated with autism spectrum disorder and intellectual disability.

SIGNIFICANCE STATEMENT

Here, we advance our understanding of mechanisms mediating target-specific synapse formation by providing evidence that Kirrel3 trans-cellular interactions mediate contact recognition and signaling to promote synapse development. Moreover, this is the first study to test the effects of disease-associated Kirrel3 missense variants on synapse formation, and thereby, provides a framework to understand the etiology of complex neurodevelopmental disorders arising from rare missense variants in synaptic genes.
The pattern of Nodal morphogen signaling is shaped by co-receptor expression
Authors: Lord Nathan D. , Carte Adam N. , Abitua Philip B. , Schier Alexander F.
Published: December 2019

Embryos must communicate instructions to their constituent cells over long distances. These instructions are often encoded in the concentration of signals called morphogens. In the textbook view, morphogen molecules diffuse from a localized source to form a concentration gradient, and target cells adopt fates by measuring the local morphogen concentration. However, natural patterning systems often incorporate numerous co-factors and extensive signaling feedback, suggesting that embryos require additional mechanisms to generate signaling patterns. Here, we examine the mechanisms of signaling pattern formation for the mesendoderm inducer Nodal during zebrafish embryogenesis. We find that Nodal signaling activity spans a normal range in the absence of signaling feedback, suggesting that diffusion is sufficient for Nodal gradient formation. We further show that the range of endogenous Nodal ligands is set by the EGF-CFC co-receptor Oep: in the absence of Oep, Nodal ligands spread to form a nearly uniform distribution throughout the embryo. In turn, increasing Oep levels sensitizes cells to Nodal ligands. We recapitulate these experimental results with a computational model in which Oep regulates the diffusive spread of Nodal ligands by setting the rate of capture by target cells. This model predicts, and we confirmin vivo, the surprising observation that a failure to replenish Oep during patterning transforms the Nodal signaling gradient into a travelling wave. These results reveal that patterns of Nodal morphogen signaling are shaped by co-receptor-mediated restriction of ligand spread and cell sensitization.
Influenza H3 and H1 hemagglutinins have different genetic barriers for resistance to broadly neutralizing stem antibodies
Authors: Wu Nicholas C. , Thompson Andrew J. , Lee Juhye M. , Su Wen , Arlian Britni M. , Xie Jia , Lerner Richard A. , Yen Hui-Ling , Bloom Jesse D. , Wilson Ian A.
Published: December 2019

In the past decade, the discovery and characterization of broadly neutralizing antibodies (bnAbs) to the highly conserved stem region of influenza hemagglutinin (HA) have provided valuable insights for development of a universal influenza vaccine. However, the genetic barrier for resistance to stem bnAbs has not been thoroughly evaluated. Here, we performed a series of deep mutational scanning experiments to probe for resistance mutations. We found that the genetic barrier to resistance to stem bnAbs is generally very low for the H3 subtype but substantially higher for the H1 subtype. Several resistance mutations in H3 cannot be neutralized by stem bnAbs at the highest concentration tested, do not reducein vitroviral fitness andin vivopathogenicity, and are often present in circulating strains as minor variants. Thus, H3 HAs have a higher propensity than H1 HAs to escape major stem bnAbs and creates a potential challenge in the development of abona fideuniversal influenza vaccine.

ONE SENTENCE SUMMARY

Acquisition of resistance by influenza virus to broadly neutralizing hemagglutinin stem antibodies varies tremendously depending on subtype.
Capturing multiple timescales of adaptation to second-order statistics with generalized linear models: gain scaling and fractional differentiation
Authors: Latimer Kenneth W. , Fairhall Adrienne L.
Published: December 2019

Single neurons can dynamically change the gain of their spiking responses to account for shifts in stimulus variance. Moreover, gain adaptation can occur across multiple timescales. Here, we examine the ability of a simple statistical model of spike trains, the generalized linear model (GLM), to account for these adaptive effects. The GLM describes spiking as a Poisson process whose rate depends on a linear combination of the stimulus and recent spike history. The GLM successfully replicates gain scaling observed in Hodgkin-Huxley simulations of cortical neurons that occurs when the ratio of spike-generating potassium and sodium conductances approaches one. Gain scaling in the GLM depends on the length and shape of the spike history filter. Additionally, the GLM captures adaptation that occurs over multiple timescales as a fractional derivative of the stimulus variance, which has been observed in neurons that include long timescale after hyperpolarization conductances. Fractional differentiation in GLMs requires long spike history that span several seconds. Together, these results demonstrate that the GLM provides a tractable statistical approach for examining single-neuron adaptive computations in response to changes in stimulus variance.
Meta-Learning Biologically Plausible Semi-Supervised Update Rules
Authors: Gu Keren , Greydanus Sam , Metz Luke , Maheswaranathan Niru , Sohl-Dickstein Jascha
Published: December 2019

The question of how neurons embedded in a network update their synaptic weights to collectively achieve behavioral goals is a longstanding problem in systems neuroscience. Since Hebb’s hypothesis [10] that cells that fire together strengthen their connections, cellular studies [6] have shed light on potential synaptic mechanisms underlying learning. These mechanisms have directly driven the careful hand design of biologically plausible models of learning and memory in computational neuroscience [1]. However, these hand designed rules have yet to achieve satisfying success training large neural networks, and are dramatically outperformed by biologically implausible approaches such as backprop. We propose an alternative paradigm for designing biologically plausible learning rules: using meta-learning tolearna parametric synaptic update rule which is capable of training deep networks. We demonstrate this approach by meta-learning an update rule for semi-supervised tasks, where sparse labels are provided to a deep network but the majority of inputs are unlabeled. The meta-learned plasticity rule integrates bottom-up, top-down, and recurrent inputs to each neuron, and generates weight updates as the product of pre- and post- synaptic neuronal outputs. The way in which the inputs to each neuron are combined to produce a learning signal, however, is itself ameta-learnedfunction, parameterized by a neural network. Critically, the meta-learned update rule integrates only neuron-local information when proposing updates–that is, our learning rule is spatially localized to individual neurons. After meta-learning, the resulting synaptic update rule is capable of driving task-relevant learning for semi-supervised tasks. We demonstrate this capability on two simple classification problems. In general, we believe meta-learning to be a powerful approach to finding more effective synaptic plasticity rules, which will motivate new hypotheses for biological neural networks, and new algorithms for artificial neural networks.
A possible coding for experience: ripple-like events and synaptic diversity
Authors: Ishikawa J , Tomokage T , Mitsushima D
Published: December 2019

The hippocampal CA1 is necessary to maintain experienced episodic memory in many species, including humans. To monitor the temporal dynamics of processing, we recorded multiple-unit firings of CA1 neurons in male rats experiencing one of four episodes for 10 min: restraint stress, social interaction with a female or male, or observation of a novel object. Before an experience, the neurons mostly exhibited sporadic firings with some synchronized (≈ 50 ms) ripple-like firing events in habituated home cage. After experience onset, restraint or social interaction with other rats induced spontaneous high-frequency firings (super bursts) intermittently, while object observation induced the events inconsistently. Minutes after experience initiation, CA1 neurons frequently exhibited ripple-like firings with less-firing silent periods. The number of ripple-like events depended on the episode experienced and correlated with the total duration of super bursts. Experience clearly diversified multiple features of individual ripple-like events in an episode-specific manner, sustained for more than 30 min in the home cage.

Ex vivopatch clamp analysis further revealed experience-promoted synaptic plasticity. Compared with unexposed controls, animals experiencing the female, male, or restraint episodes showed cell-dependently increased AMPA- or GABAAreceptor– mediated postsynaptic currents, whereas contact with a novel object increased only GABAergic currents. Multivariate ANOVA in multi-dimensional virtual space revealed experience-specific super bursts with subsequent ripple-like events and synaptic plasticity, leading us to hypothesize that these factors are responsible for creating experience-specific memory. It is possible to decipher encrypted experience through the deep learning of the orchestrated ripple-like firings and synaptic plasticity in multiple CA1 neurons.
Corticosterone as a potential confounding factor in delineating mechanisms underlying ketamine’s rapid antidepressant actions
Authors: Wegman-Points Lauren , Pope Brock , Zobel Allison , Semke Lori , Wauson Eric , Duric Vanja , Yuan Li-Lian
Published: December 2019

Although ketamine represents a new line of antidepressants with unique clinical advantages, its use as a long-term treatment has limitations, particularly its dissociative/psychotomimetic effects and abuse potential. In rats, we observed that a subanesthetic dose of ketamine (10mg/kg) induced a 3-fold increase in corticosterone (CORT) levels in both serum and brain tissue, within an hour of administration. This increase took place in both male and female rats, in both naïve and stressed animals. However, no CORT increase was detected in rats injected with (2R, 6R)-hydroxynorketamine (HNK), an active metabolite of ketamine, that is believed to contribute to ketamine’s antidepressant effect. In response to the release in CORT, ketamine injected animals displayed a significant increase in the expression ofsgk1, a downstream effector of glucocorticoid receptor signaling, in the hippocampus indicating the initiation of a transcriptional program. We hypothesized this surge in CORT release was a manifestation of stress experienced by the rat in response to ketamine’s psychotropic effects. When sensory perception was blocked under isoflurane anesthesia, administration of ketamine did not increase circulating CORT levels as compared to animals injected with saline. Taken together, ketamine administration triggers a behavioral stress response that has downstream molecular consequences. The resulting CORT release, virtually concurrent with the timing of ketamine’s rapid-acting antidepressant actions, necessitates the consideration of this pathway’s potential involvement when trying to dissect out the relevant molecular mechanisms underlying ketamine’s action.
Valeriana Officinalis Crude Extracts Impair Hair Cell Regeneration in Larval Zebrafish Lateral Line
Authors: Rodríguez-Morales Roberto , Santana-Cruz Alexis , Tossas-Deida Tiffany , Torrado-Tapias Aranza , Behra Martine
Published: December 2019

Irreversible hair cell (HC) loss in the inner ear is the leading cause for hearing and balance disorders. Discovery of therapeutic molecules preventing HC death and promoting regeneration, which does not occur in mammals like it does in lower vertebrates, is of major interest. In fish, HCs are also found in a superficial mechano-sensory organ called the lateral line (LL). LL-HCs are exposed to surrounding waters and are accessible to waterborne molecules providing a potent mean to study in vivo HC stability and regeneration. Commercial small molecule libraries were tested in screens for HC survival and regeneration in zebrafish, but ethnobotanical pharmacopeias remain totally unexplored because of the challenge that such complex mixtures represent. A rapid and cost-effective first-pass assay informing about the regenerative potential of an extract is therefore critical before embarking on cumbersome purification steps. We chose to test Valerian crude root extracts (Val), which are typically composed of more than 150 different components, amongst which is a main and abundant compound: valeric acid (VA). VA discovery and purification led to the commercialization of a synthetic analog: Valproic acid (VPA) which is a first-line drug for epilepsy and bipolar disorders that was also shown to significantly hamper LL-HC regeneration. We reasoned that if Val is not toxic, it would elicit effects like VPA. Thus, we synchronously ablated HCs in 5-day post-fertilization (dpf) larvae and monitored regeneration over the following 3 days in the presence of Val at the highest well-tolerated concentration (Val1 = 1mg/ml), or VPA (= 150μM) as previously published. Both treatments significantly decreased HC regeneration without affecting HC-survival suggesting a similar mode of action. Furthermore, Val application as early as 3dpf and prolonged for up to 4 days did not affect larval survival, indicating that reduced HC-regeneration was not due to overall toxicity. Taken together, Val and VPA-treatments displayed a comparable response in a simple and up-scalable HC-regeneration assay which is an in-first-pass potent approach for drug discovery.
Evaluating the worth of nascent old vine cues for South African wines
Authors: Priilaid David , Steyn Jonathan
Published: December 2019

Purpose

In increasingly competitive markets, opportunities exist to meaningfully differentiate product offerings by cue signalling the claims of emergent categories. Therefore, and within the context of wine sales, the purpose of this study models the supply-led price importance of nascent, extrinsic old vine (OV) cues for South African wines to establish whether to what extent and how producers prioritise such nascent cues relative to more established extrinsic cues of worth.

Design/methodology/approach

A data set was compiled of 159 South African wines with OV category cues signalled on front labels, back labels or via marketing material. The play of contending cue variables was computed through an ordinary least square hedonic pricing model.

Findings

In addition to the contribution of established cues such as aggregated critic ratings, grape varieties and area of origin, this study confirms that vineyard age contributes significantly to wine price, particularly when signalled on back labels.

Practical implications

In price setting and positional models, such as brand extensions, the findings prove useful in understanding the inherent value of nascent cues and specifically vineyard age, relative to competing established wine cues of worth.

Originality/value

This study extends the wine pricing theory by validating the viability of nascent OV cues in the modelling of a wine’s value.
A comprehensive framework to rank cloud-based e-learning providers using best-worst method (BWM)
Authors: Pour Mona Jami , Mesrabadi Javad , Hosseinzadeh Mahnaz
Published: December 2019

Purpose

Today, the high cost of e-learning systems’ implementation and the difficulty of managing the infrastructures motivate educational institutions toward application of cloud-based e-learning systems. This new system should be aligned with the academics’ aims and pedagogical principles to be beneficial for learners and instructors. Therefore, the vendor selection of learning systems is one of the most important processes to migrate toward cloud-based e-learning. The purpose of this paper is to develop a new framework to facilitate the vendor selection of cloud-based e-learning systems in the cloud market.

Design/methodology/approach

To identify the initial criteria as to the vendor selection of cloud-based e-learning services, a literature review is done. To enrich the initial criteria, a focus group of experts is investigated, and the framework developed; then, a survey analysis is conducted to validate the proposed framework. The extracted criteria and sub-criteria are weighted and prioritized using best-worst method (BWM).

Findings

The results indicate that the main dimensions of vendor selection framework as regards cloud-based e-learning systems are managerial, technological and pedagogical factors. The rank orders and weights of the mentioned aspects and their sub-criteria are calculated using the BWM.

Practical implications

The proposed framework helps managers to get a big picture of requirements as to cloud-based e-learning and more effectively to select appropriate vendors in this initiative. In the vendor selection process, managers must pay attention to technological issues as well as managerial and pedagogical considerations.

Originality/value

Cloud-based e-learning systems are getting increasingly essential to offer training courses more efficiently in educational institutions. Although the intersection between cloud computing and e-learning has increasingly grown in both practical and academic contexts, there are little studies on how educational institutions and organizations could be able to select appropriate cloud-based e-learning systems. This paper explores the ignored but critically important subject of cloud-based e-learning. The main contribution of this paper is to propose a novel and integrated framework containing the important aspects of vendor selection in cloud-based e-learning services. The proposed framework comprises managerial, technological and pedagogical aspects simultaneously as well as sub-criteria denoting each aspect.
Algorithmic equity in the hiring of underrepresented IT job candidates
Authors: Yarger Lynette , Cobb Payton Fay , Neupane Bikalpa
Published: December 2019

Purpose

The purpose of this paper is to offer a critical analysis of talent acquisition software and its potential for fostering equity in the hiring process for underrepresented IT professionals. The under-representation of women, African-American and Latinx professionals in the IT workforce is a longstanding issue that contributes to and is impacted by algorithmic bias.

Design/methodology/approach

Sources of algorithmic bias in talent acquisition software are presented. Feminist design thinking is presented as a theoretical lens for mitigating algorithmic bias.

Findings

Data are just one tool for recruiters to use; human expertise is still necessary. Even well-intentioned algorithms are not neutral and should be audited for morally and legally unacceptable decisions. Feminist design thinking provides a theoretical framework for considering equity in the hiring decisions made by talent acquisition systems and their users.

Social implications

This research implies that algorithms may serve to codify deep-seated biases, making IT work environments just as homogeneous as they are currently. If bias exists in talent acquisition software, the potential for propagating inequity and harm is far more significant and widespread due to the homogeneity of the specialists creating artificial intelligence (AI) systems.

Originality/value

This work uses equity as a central concept for considering algorithmic bias in talent acquisition. Feminist design thinking provides a framework for fostering a richer understanding of what fairness means and evaluating how AI software might impact marginalized populations.