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Brain-computer interfaces (BCIs) that reconstruct and synthesize speech using brain activity recorded with intracranial electrodes may pave the way toward novel communication interfaces for people who have lost their ability to speak, or who are at high risk of losing this ability, due to neurological disorders. Here, we report online synthesis of intelligible words using a chronically implanted brain-computer interface (BCI) in a man with impaired articulation due to ALS, participating in a clinical trial (ClinicalTrials.gov, NCT03567213) exploring different strategies for BCI communication. The 3-stage approach reported here relies on recurrent neural networks to identify, decode and synthesize speech from electrocorticographic (ECoG) signals acquired across motor, premotor and somatosensory cortices. We demonstrate a reliable BCI that synthesizes commands freely chosen and spoken by the participant from a vocabulary of 6 keywords previously used for decoding commands to control a communication board. Evaluation of the intelligibility of the synthesized speech indicates that 80% of the words can be correctly recognized by human listeners. Our results show that a speech-impaired individual with ALS can use a chronically implanted BCI to reliably produce synthesized words while preserving the participant's voice profile, and provide further evidence for the stability of ECoG for speech-based BCIs.

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Homozygosity for the ε4 allele of APOE increases the odds of developing Alzheimer's by 12 to 15 times relative to the most common ε3;ε3 genotype, and its association with higher plaque loads comports with evidence that APOEε4 compromises autophagy. The ApoE4 protein specifically binds a cis element ("CLEAR") in the promoters of several autophagy genes to block their transcription. We used a multifaceted approach to identify a druggable site in ApoE4, and virtual screening of lead-like compounds identified small molecules that specifically bind to this site to impede ApoE4::DNA binding. We validated these molecules both in vitro and in vivo with models expressing ApoE4, including ApoE4 targeted-replacement mice. One compound was able to significantly restore transcription of several autophagy genes and protected against amyloid-like aggregation in a C. elegans AD model. Together, these findings provide proof-of-principle evidence for pharmacological remediation of lysosomal autophagy by ApoE4 via ApoE4-targeted lead molecules that represent a novel tack on neurodegenerative disorders.

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Brain-computer interfaces (BCIs) can be used to control assistive devices by patients with neurological disorders like amyotrophic lateral sclerosis (ALS) that limit speech and movement. For assistive control, it is desirable for BCI systems to be accurate and reliable, preferably with minimal setup time. In this study, a participant with severe dysarthria due to ALS operates computer applications with six intuitive speech commands via a chronic electrocorticographic (ECoG) implant over the ventral sensorimotor cortex. Speech commands are accurately detected and decoded (median accuracy: 90.59%) throughout a 3-month study period without model retraining or recalibration. Use of the BCI does not require exogenous timing cues, enabling the participant to issue self-paced commands at will. These results demonstrate that a chronically implanted ECoG-based speech BCI can reliably control assistive devices over long time periods with only initial model training and calibration, supporting the feasibility of unassisted home use.

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Recent studies have shown that speech can be reconstructed and synthesized using only brain activity recorded with intracranial electrodes, but until now this has only been done using retrospective analyses of recordings from able-bodied patients temporarily implanted with electrodes for epilepsy surgery. Here, we report online synthesis of intelligible words using a chronically implanted brain-computer interface (BCI) in a clinical trial participant (ClinicalTrials.gov, NCT03567213) with dysarthria due to amyotrophic lateral sclerosis (ALS). We demonstrate a reliable BCI that synthesizes commands freely chosen and spoken by the user from a vocabulary of 6 keywords originally designed to allow intuitive selection of items on a communication board. Our results show for the first time that a speech-impaired individual with ALS can use a chronically implanted BCI to reliably produce synthesized words that are intelligible to human listeners while preserving the participants voice profile.

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Glial fibrillary acidic protein (GFAP) is an intermediate filament structural protein involved in cytoskeleton assembly and integrity, expressed in high abundance in activated glial cells. GFAP is neuroprotective, as knockout mice are hypersensitive to traumatic brain injury. GFAP in cerebrospinal fluid is a biomarker of Alzheimer's disease (AD), dementia with Lewy bodies, and frontotemporal dementia (FTD). Here, we present novel evidence that GFAP is markedly overexpressed and differentially phosphorylated in AD hippocampus, especially in AD with the apolipoprotein E [ε4, ε4] genotype, relative to age-matched controls (AMCs). Kinases that phosphorylate GFAP are upregulated in AD relative to AMC. A knockdown of these kinases in SH-SY5Y-APPSw human neuroblastoma cells reduced amyloid accrual and lowered protein aggregation and associated behavioral traits in C. elegans models of polyglutamine aggregation (as observed in Huntington's disease) and of Alzheimer's-like amyloid formation. In silico screening of the ChemBridge structural library identified a small molecule, MSR1, with stable and specific binding to GFAP. Both MSR1 exposure and GF AP-specific RNAi knockdown reduce aggregation with remarkably high concordance of aggregate proteins depleted. These data imply that GFAP and its phosphorylation play key roles in neuropathic aggregate accrual and provide valuable new biomarkers, as well as novel therapeutic targets to alleviate, delay, or prevent AD.

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We conduct a consequential lifecycle analysis (LCA) of greenhouse gas (GHG) emissions from North American liquefied natural gas (LNG) export projects, estimating the change in global natural gas and coal use resulting from the market effects of increased LNG trade. We estimate that building a 2.1 billion cubic feet per day (Bcfd) LNG export facility, equivalent to one of the larger LNG projects under development in the US today, will change global GHG emissions -39 to 11 Mt CO2e (90% range) with a median value of -8 Mt CO2e. Previous attributional LCA methods for electricity generation with LNG replacing coal find a much larger benefit of LNG exports, a median value of -36 Mt CO2e for this size project. The smaller decrease in GHGs is attributable to higher domestic coal use and a smaller decrease in international coal use than assumed by previous methods. Net global emission change estimates are most sensitive to the uncertainty in economic elasticities outside of North America. Given the scale of planned and proposed LNG export terminals, project regulators and policymakers must account for market effects to more accurately estimate the global net change in GHG emissions.

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Research has identified treatment-responsive and treatment-resistant subtypes of automatically maintained self-injurious behavior (ASIB) based on patterns of responding in the functional analysis (FA) reflecting its sensitivity to disruption by alternative reinforcement, and the presence of self-restraint. Rooker et al. (2019) unexpectedly observed reductions in treatment-resistant self-injury while participants performed an operant task. The current study further examined this in nine participants with treatment-resistant ASIB in an example of discovery-based research. An operant task engendering high rates of responding (switch-pressing) to produce food, reduced self-injury across all participants, and eliminated self-injury for some participants under certain schedules. Although this finding must be replicated and evaluated over longer time periods, it provides some evidence that alternative reinforcement can disrupt self-injury in these treatment-resistant subtypes under some conditions. Reinforcer and response competition are discussed as possible mechanisms underlying these disruptive effects, as are the potential implications of these findings regarding treatment.

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Partial melting of mantle peridotites at spreading ridges is a continuous global process that forms the oceanic crust and refractory, positively buoyant residues (melt-depleted mantle peridotites). In the modern Earth, these rocks enter subduction zones as part of the oceanic lithosphere. However, in the early Earth, the melt-depleted peridotites were 2-3 times more voluminous and their role in controlling subduction regimes and the composition of the upper mantle remains poorly constrained. Here, we investigate styles of lithospheric tectonics, and related dynamics of the depleted mantle, using 2-D geodynamic models of converging oceanic plates over the range of mantle potential temperatures (Tp = 1300-1550 °C, ∆T = T - Tmodern = 0-250 °C) from the Archean to the present. Numerical modeling using prescribed plate convergence rates reveals that oceanic subduction can operate over this whole range of temperatures but changes from a two-sided regime at ∆T = 250 °C to one-sided at lower mantle temperatures. Two-sided subduction creates V-shaped accretionary terrains up to 180 km thick, composed mainly of highly hydrated metabasic rocks of the subducted oceanic crust, decoupled from the mantle. Partial melting of the metabasic rocks and related formation of sodic granitoids (Tonalite-Trondhjemite-Granodiorite suites, TTGs) does not occur until subduction ceases. In contrast, one sided-subduction leads to volcanic arcs with or without back-arc basins. Both subduction regimes produce over-thickened depleted upper mantle that cannot subduct and thus delaminates from the slab and accumulates under the oceanic lithosphere. The higher the mantle temperature, the larger the volume of depleted peridotites stored in the upper mantle. Extrapolation of the modeling results reveals that oceanic plate convergence at ∆T = 200-250 °C might create depleted peridotites (melt extraction of > 20%) constituting more than half of the upper mantle over relatively short geological times (~ 100-200 million years). This contrasts with the modeling results at modern mantle temperatures, where the amount of depleted peridotites in the upper mantle does not increase significantly with time. We therefore suggest that the bulk chemical composition of upper mantle in the Archean was much more depleted than the present mantle, which is consistent with the composition of the most ancient lithospheric mantle preserved in cratonic keels.

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Variation in dispersal ability among taxa affects community assembly and biodiversity maintenance within metacommunities. Although fungi and bacteria frequently coexist, their relative dispersal abilities are poorly understood. Nectar-inhabiting microbial communities affect plant reproduction and pollinator behavior, and are excellent models for studying dispersal of bacteria and fungi in a metacommunity framework. Here, we assay dispersal ability of common nectar bacteria and fungi in an insect-based dispersal experiment. We then compare these results with the incidence and abundance of culturable flower-inhabiting bacteria and fungi within naturally occurring flowers across two coflowering communities in California across two flowering seasons. Our microbial dispersal experiment demonstrates that bacteria disperse via thrips among artificial habitat patches more readily than fungi. In the field, incidence and abundance of culturable bacteria and fungi were positively correlated, but bacteria were much more widespread. These patterns suggest shared dispersal routes or habitat requirements among culturable bacteria and fungi, but differences in dispersal or colonization frequency by thrips, common flower visitors. The finding that culturable bacteria are more common among nectar sampled here, in part due to superior thrips-mediated dispersal, may have relevance for microbial life history, community assembly of microbes, and plant-pollinator interactions.

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Contingent positive reinforcement has proven more effective in treating escape-maintained problem behavior than contingent negative reinforcement, particularly when problem behavior continues to produce escape. However, this research has overwhelmingly used distributed-reinforcement arrangements, where tasks and reinforcer access are interspersed throughout the work period. An alternative to interspersal involves allowing the individual to accumulate and then receive a larger quantity of reinforcement once work requirements are completed; this is known as an accumulated-reinforcement arrangement. The current study examined the efficacy of, and preference for positive (food) and negative (break) reinforcement contingencies delivered in accumulated and distributed arrangements in the treatment of escape-maintained problem behavior. In Experiment 1, accumulated break was preferred for 4 of 5 participants and accumulated food was preferred for 3 of 5. In Experiment 2, accumulated break was similarly effective to distributed break for 3 of 5 participants and accumulated and distributed food were equally effective for 4 participants.

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Porphyromonas gingivalis (Pg) is a primary oral pathogen in the widespread biofilm-induced "chronic" multi-systems inflammatory disease(s) including Alzheimer's disease (AD). It is possibly the only second identified unique example of a biological extremophile in the human body. Having a better understanding of the key microbiological and genetic mechanisms of its pathogenesis and disease induction are central to its future diagnosis, treatment, and possible prevention. The published literature around the role of Pg in AD highlights the bacteria's direct role within the brain to cause disease. The available evidence, although somewhat adopted, does not fully support this as the major process. There are alternative pathogenic/virulence features associated with Pg that have been overlooked and may better explain the pathogenic processes found in the "infection hypothesis" of AD. A better explanation is offered here for the discrepancy in the relatively low amounts of "Pg bacteria" residing in the brain compared to the rather florid amounts and broad distribution of one or more of its major bacterial protein toxins. Related to this, the "Gingipains Hypothesis", AD-related iron dyshomeostasis, and the early reduced salivary lactoferrin, along with the resurrection of the Cholinergic Hypothesis may now be integrated into one working model. The current paper suggests the highly evolved and developed Type IX secretory cargo system of Pg producing outer membrane vesicles may better explain the observed diseases. Thus it is hoped this paper can provide a unifying model for the sporadic form of AD and guide the direction of research, treatment, and possible prevention.

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Researchers have examined factors of authors such as sex of author, gender identity, and seniority within the field of behavior analysis to determine if any biases towards a certain group existed. Most recently, Kranak et al. (2020) found that women and new authors are well-represented in the Journal of Applied Behavior Analysis (JABA). However, that analysis included only published manuscripts. Thus, the degree to which these subpopulations are proportionally represented is unknown, because that analysis was unable to determine how often these subpopulations are submitting manuscripts. Therefore, the purpose of the current investigation was to extend Kranak et al. and analyze all accepted and rejected manuscripts submitted to JABA from 2015 - 2019. Results indicated that women and men had nearly identical acceptance rates during this time period, whereas veteran authors' acceptance rate was nearly 2.5 times greater than that of new authors. Implications for publishing, reviewing, and research mentorship practices are discussed.

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Individuals with intellectual and developmental disabilities who exhibit problem behavior often receive behavioral assessment and treatment in specialized inpatient and outpatient clinics. However, problem behavior sometimes reemerges as a function of changes in contexts and stimulus conditions, such as returning to the home environment. This reemergence is called renewal. Recently, Muething et al. (2020) found that renewal occurred in over half (67%) of cases from an outpatient clinic. Their sample was obtained exclusively from an outpatient setting and despite the applied relevance of renewal, its clinical prevalence in other populations is unknown. Accordingly, we replicated Muething et al.'s procedures and analyzed renewal in 37 inpatient treatment applications across 34 cases via consecutive-controlled case series. Renewal was present in 59% of cases; however, we found that renewal occurred in only 24% of context changes compared to 42% reported by Muething et al. Various factors related to the prevalence of renewal were evaluated.

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Individuals with intellectual and developmental disabilities are at an increased risk for engaging in severe problem behavior, which is often preceded by less intense precursor behaviors. These precursor behaviors may be a viable option as target behaviors for functional analyses in situations where evoking severe problem behavior is not ideal. We identified precursor behaviors through a correlational analysis and confirmed their membership in the same response class as more severe problem behavior through an experimental analysis.

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The ancient cores of continents (cratons) are underlain by mantle keels-volumes of melt-depleted, mechanically resistant, buoyant and diamondiferous mantle up to 350 kilometres thick, which have remained isolated from the hotter and denser convecting mantle for more than two billion years. Mantle keels formed only in the Early Earth (approximately 1.5 to 3.5 billion years ago in the Precambrian eon); they have no modern analogues1-4. Many keels show layering in terms of degree of melt depletion5-7. The origin of such layered lithosphere remains unknown and may be indicative of a global tectonics mode (plate rather than plume tectonics) operating in the Early Earth. Here we investigate the possible origin of mantle keels using models of oceanic subduction followed by arc-continent collision at increased mantle temperatures (150-250 degrees Celsius higher than the present-day values). We demonstrate that after Archaean plate tectonics began, the hot, ductile, positively buoyant, melt-depleted sublithospheric mantle layer located under subducting oceanic plates was unable to subduct together with the slab. The moving slab left behind craton-scale emplacements of viscous protokeel beneath adjacent continental domains. Estimates of the thickness of this sublithospheric depleted mantle show that this mechanism was efficient at the time of the major statistical maxima of cratonic lithosphere ages. Subsequent conductive cooling of these protokeels would produce mantle keels with their low modern temperatures, which are suitable for diamond formation. Precambrian subduction of oceanic plates with highly depleted mantle is thus a prerequisite for the formation of thick layered lithosphere under the continents, which permitted their longevity and survival in subsequent plate tectonic processes.

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Barnard-Brak, Richman, Little, and Yang (Behaviour Research and Therapy, 102, 8-15, 2018) developed a structured-criteria metric, fail-safe k, which quantifies the stability of data series within single-case experimental designs (SCEDs) using published baseline and treatment data. Fail-safe k suggests the optimal point in time to change phases (e.g., move from Phase B to Phase C, reverse back to Phase A). However, this tool has not been tested with clinical data obtained in the course of care. Thus, the purpose of the current study was to replicate the procedures described by Barnard-Brak et al. with clinical data. We also evaluated the correspondence between the fail-safe k metric with outcomes obtained via dual-criteria and conservative-dual criteria methods, which are empirically supported methods for evaluating data-series trends within SCEDs. Our results provide some degree of support for use of this approach as a research tool with clinical data, in particular when evaluating small or medium treatment effect sizes, but further research is needed before this can be used widely by practitioners.

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Competing stimulus assessments (CSAs) are designed to identify stimuli that, when made freely available, reduce problem behavior. Although CSAs have demonstrated utility, identifying competing stimuli can be difficult for some individuals. The current study describes outcomes from an augmented CSA (A-CSA) for 6 consecutively encountered cases with treatment-resistant subtypes of automatically maintained problem behavior. When test stimuli were made freely available, only between 0 and 1 effective competing stimuli were identified for each case. Prompting and response blocking were temporarily employed in succession to promote engagement with stimuli and disrupt problem behavior. When those procedures were withdrawn and stimuli made freely available, the number of effective competing stimuli increased in all 6 cases. Findings suggest that procedures designed to promote engagement and disrupt problem behavior may allow the A-CSA to be a platform not only for identifying competing stimuli, but also for actively establishing competing stimuli.

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The Journal of Applied Behavior Analysis (JABA) is considered the flagship journal for the discipline of applied behavior analysis. Thus, popular research topics and other publication trends within JABA reflect the current cultural and scientific contingencies governing the field of behavior analysis. Researchers have previously quantified a number of authorship trends in JABA (and other behavior-analytic journals) across a number of variables, such as gender identity and sex of author, country of origin, or seniority within the field (Dunlap et al., 1998) to examine demographic and organizational factors associated with successful publication in JABA. These analyses ought to be conducted continuously to monitor trends and detect any potential biases (e.g., sexism). Accordingly, the purpose of the present investigation was to replicate previous research in this area (e.g., Dymond et al., 2000) and provide an update of current publication trends within JABA. Implications for future research and publishing practices are discussed.

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Scheithauer et al. (2020) recently demonstrated that differences in the source of baseline data extracted from a functional analysis (FA) may not affect subsequent clinical decision-making in comparison to a standard baseline. These outcomes warrant additional quantitative examination, as correspondence of visual analysis has sometimes been reported to be unreliable. In the current study, we quantified the occurrence of false positives within a dataset of FA and baseline data using the dual-criteria (DC) and conservative dual-criteria (CDC) methods. Results of this quantitative analysis suggest that false positives were more likely when using FA data (rather than original baseline data) as the initial treatment baseline. However, both sources of baseline data may have acceptably low levels of false positives for practical use. Overall, the findings provide preliminary quantitative support for the conclusion that determinations of effective treatment may be easily obtained using different sources of baseline data.

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