Peri-Alkylated Terrylenes and Ternaphthalenes Building-Blocks Towards Multi-Edge Nanographenes.

Since its first synthesis by Clar in 1948, terrylene - a fully connected ternaphthalene oligomer via naphthalene's peri-positions - has gained special focus within the rylene family, drawing interest for its unique chemical, structural, optoelectronic and single photon emission properties. In this study, we introduce a novel synthetic pathway that enhances the solubility of terrylene derivatives through complete peri-alkylation, while also facilitating extensions at the bay-positions. This approach not only broadens the scope of terrylene's chemical versatility but also opens new avenues for developing solution processable novel multi-edge nanographenes and tailoring electronic energy levels through topological edge structures. Our findings include a comprehensive structural and spectroscopic characterization along with transient absorption spectroscopy and photophysics of both the synthesized peri-alkylated terrylene and its phenylene-fused derivative.

'Snakes and ladders' in paleoanthropology: From cognitive surprise to skillfulness a million years ago.

A paradigmatic account may suffice to explain behavioral evolution in early Homo. We propose a parsimonious account that (1) could explain a particular, frequently-encountered, archeological outcome of behavior in early Homo - namely, the fashioning of a Paleolithic stone 'handaxe' - from a biological theoretic perspective informed by the free energy principle (FEP); and that (2) regards instances of the outcome as postdictive or retrodictive, circumstantial corroboration. Our proposal considers humankind evolving as a self-organizing biological ecosystem at a geological time-scale. We offer a narrative treatment of this self-organization in terms of the FEP. Specifically, we indicate how 'cognitive surprises' could underwrite an evolving propensity in early Homo to express sporadic unorthodox or anomalous behavior. This co-evolutionary propensity has left us a legacy of Paleolithic artifacts that is reminiscent of a 'snakes and ladders' board game of appearances, disappearances, and reappearances of particular archeological traces of Paleolithic behavior. When detected in the Early and Middle Pleistocene record, anthropologists and archeologists often imagine evidence of unusual or novel behavior in terms of early humankind ascending the rungs of a figurative phylogenetic 'ladder' - as if these corresponded to progressive evolution of cognitive abilities that enabled incremental achievements of increasingly innovative technical prowess, culminating in the cognitive ascendancy of Homo sapiens. The conjecture overlooks a plausible likelihood that behavior by an individual who was atypical among her conspecifics could have been disregarded in a community of Hominina (for definition see Appendix 1) that failed to recognize, imagine, or articulate potential advantages of adopting hitherto unorthodox behavior. Such failure, as well as diverse fortuitous demographic accidents, would cause exceptional personal behavior to be ignored and hence unremembered. It could disappear by a pitfall, down a 'snake', as it were, in the figurative evolutionary board game; thereby causing a discontinuity in the evolution of human behavior that presents like an evolutionary puzzle. The puzzle discomforts some paleoanthropologists trained in the natural and life sciences. They often dismiss it, explaining it away with such self-justifying conjectures as that, maybe, separate paleospecies of Homo differentially possessed different cognitive abilities, which, supposedly, could account for the presence or absence in the Pleistocene archeological record of traces of this or that behavioral outcome or skill. We argue that an alternative perspective - that inherits from the FEP and an individual's 'active inference' about its surroundings and of its own responses - affords a prosaic, deflationary, and parsimonious way to account for appearances, disappearances, and reappearances of particular behavioral outcomes and skills of early humankind.

Grape cultivars adapted to hotter, drier growing regions exhibit greater photosynthesis under hot conditions despite less drought-resistant leaves.

BACKGROUND AND AIMS: Many agricultural areas are expected to face hotter, drier conditions from climate change. Understanding the mechanisms crops use to mitigate these stresses can guide breeding for more tolerant plant material. We tested relationships between traits, physiological function under hot conditions, and historical climate associations to evaluate these mechanisms for winegrapes. We expected a more negative leaf osmotic potential at full hydration (πo), which reduces leaf turgor loss during drought, and either a metabolically cheaper or more osmoprotectant leaf chemical composition, to allow cultivars associated with hot, dry regions to maintain greater gas exchange under hot growing conditions. METHODS: We measured πo, gas exchange, and leaf chemistry for 7 commercially important winegrape cultivars that vary widely in historical climate associations. Vines were grown under common garden field conditions in a hot wine-growing region (Davis, California) and measured over the hottest period of the growing season (July - September). KEY RESULTS: □o varied significantly between cultivars, and all cultivars significantly reduced □o (osmotically adjusted) over the study period, though osmotic adjustment did not vary across cultivars. πo was correlated with gas exchange and climate associations, but in the opposite directions than expected. Photosynthesis and πo were higher in the cultivars associated with hotter, less humid regions. Leaf chemical composition varied between cultivars, but was not related to climate associations. CONCLUSIONS: These findings suggest that leaf turgor maintenance is not a primary limitation on grapevine adaptation to hot or atmospherically dry growing conditions. Thus, selecting for a more negative πo or greater osmotic adjustment is not a promising strategy to develop more climate-resilient grape varieties, contrary to findings for other crops. Future work is needed to identify the mechanisms increasing photosynthesis in the cultivars associated with hot, dry regions.

A candidate antibody drug for prevention of malaria.

Over 75% of malaria-attributable deaths occur in children under the age of 5 years. However, the first malaria vaccine recommended by the World Health Organization (WHO) for pediatric use, RTS,S/AS01 (Mosquirix), has modest efficacy. Complementary strategies, including monoclonal antibodies, will be important in efforts to eradicate malaria. Here we characterize the circulating B cell repertoires of 45 RTS,S/AS01 vaccinees and discover monoclonal antibodies for development as potential therapeutics. We generated >28,000 antibody sequences and tested 481 antibodies for binding activity and 125 antibodies for antimalaria activity in vivo. Through these analyses we identified correlations suggesting that sequences in Plasmodium falciparum circumsporozoite protein, the target antigen in RTS,S/AS01, may induce immunodominant antibody responses that limit more protective, but subdominant, responses. Using binding studies, mouse malaria models, biomanufacturing assessments and protein stability assays, we selected AB-000224 and AB-007088 for advancement as a clinical lead and backup. We engineered the variable domains (Fv) of both antibodies to enable low-cost manufacturing at scale for distribution to pediatric populations, in alignment with WHO's preferred product guidelines. The engineered clone with the optimal manufacturing and drug property profile, MAM01, was advanced into clinical development.

VALOR-CKD: A Multicenter, Randomized, Double-Blind Placebo-Controlled Trial Evaluating Veverimer in Slowing Progression of CKD in Patients with Metabolic Acidosis.

SIGNIFICANCE STATEMENT: Metabolic acidosis is a common complication of CKD and is associated with more rapid decline of kidney function, but well-powered controlled randomized trials testing the effect of treating metabolic acidosis on slowing CKD progression have not been conducted. The VALOR-CKD study randomized 1480 individuals with CKD and metabolic acidosis, across 320 sites to placebo or veverimer (a novel hydrochloric acid binder). The findings did not demonstrate the efficacy of veverimer in slowing CKD progression, but the difference in serum bicarbonate between placebo and drug arms was only approximately 1 mEq/L. Veverimer was safe and well tolerated. BACKGROUND: Metabolic acidosis is common in CKD, but whether its treatment slows CKD progression is unknown. Veverimer, a novel hydrochloric acid binder that removes acid from the gastrointestinal tract, leads to an increase in serum bicarbonate. METHODS: In a phase 3, double-blind, placebo-controlled trial, patients with CKD (eGFR of 20-40 ml/min per 1.73 m 2 ) and metabolic acidosis (serum bicarbonate of 12-20 mEq/L) from 35 countries were randomized to veverimer or placebo. The primary outcome was the composite end point of CKD progression, defined as the development of ESKD (kidney transplantation or maintenance dialysis), a sustained decline in eGFR of ≥40% from baseline, or death due to kidney failure. RESULTS: The mean (±SD) baseline eGFR was 29.2±6.3 ml/min per 1.73 m 2 , and serum bicarbonate was 17.5±1.4 mEq/L; this increased to 23.4±2.0 mEq/L after the active treatment run-in. After randomized withdrawal, the mean serum bicarbonate was 22.0±3.0 mEq/L and 20.9±3.3 mEq/L in the veverimer and placebo groups at month 3, and this approximately 1 mEq/L difference remained stable for the first 24 months. A primary end point event occurred in 149/741 and 148/739 patients in the veverimer and placebo groups, respectively (hazard ratio, 0.99; 95% confidence interval, 0.8 to 1.2; P = 0.90). Serious and overall adverse event incidence did not differ between the groups. CONCLUSIONS: Among patients with CKD and metabolic acidosis, treatment with veverimer did not slow CKD progression. The lower than expected bicarbonate separation may have hindered the ability to test the hypothesis. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: VALOR-CKD, NCT03710291 .

On some statistical and cerebral aspects of the limits of working memory capacity in anthropoid primates, with particular reference to Pan and Homo, and their significance for human evolution.

Some comparative ontogenetic data imply that effective working-memory capacity develops in ways that are independent of brain size in humans. These are interpreted better from neuroscientific considerations about the continuing development of neuronal architecture in adolescents and young adults, than from one about gross brain mass which already is reached in childhood. By contrast, working-memory capacity in Pan never develops beyond that of three- or four-year-old children. The phylogenetic divergence begs the question of whether it is any longer plausible to infer from the fossil record, that over the past two million years, an ostensibly gradual increase in endocranial volumes, assigned to the genus Homo, can be correlated in a scientifically-meaningful manner with the gradual evolution of our effective executive working memory. It is argued that whereas Pan's effective working-memory capacity is relatively similar to that of its storage working-memory, our working memory is relatively larger with deeper executive control.

LIGHTSITE III: 13-Month Efficacy and Safety Evaluation of Multiwavelength Photobiomodulation in Nonexudative (Dry) Age-Related Macular Degeneration Using the Lumithera Valeda Light Delivery System.

PURPOSE: The LIGHTSITE III study evaluated multiwavelength photobiomodulation (PBM) therapy in nonexudative (dry) age-related macular degeneration (AMD) using the LumiThera Valeda Light Delivery System. METHODS: LIGHTSITE III is a randomized, controlled trial to assess the safety and effectiveness of PBM in dry AMD. Subjects were given multiwavelength PBM (590, 660, and 850 nm) or Sham treatment delivered in a series of nine sessions over 3 to 5 weeks every four months over 24 months. Subjects were assessed for efficacy and safety outcomes. Data from the 13-month analysis are presented in this report. RESULTS: A total of 100 subjects (148 eyes) with dry AMD were randomized. LIGHTSITE III met the primary efficacy best-corrected visual acuity endpoint with a significant difference between PBM (n = 91 eyes) and Sham (n = 54 eyes) groups (Between group difference: 2.4 letters (SE 1.15), CI: -4.7 to -0.1, P = 0.02) (PBM alone: 5.4 letters (SE 0.96), CI: 3.5 to 7.3, P < 0.0001; Sham alone: 3.0 letters (SE 1.13), CI: 0.7-5.2, P < 0.0001). The PBM group showed a significant decrease in new onset geographic atrophy ( P = 0.024, Fisher exact test, odds ratio 9.4). A favorable safety profile was observed. CONCLUSION: LIGHTSITE III provides a prospective, randomized, controlled trial showing improved clinical and anatomical outcomes in intermediate dry AMD following PBM therapy.

Imitation fidelity increases with age in boys, but not in girls: An intriguing finding in a cohort of children aged 3 to 6 years.

Imitation that entails faithful reproduction of demonstrated behavior by reenacting a sequence of actions accurately is a fast and efficient way to acquire new skills as well as to conform to social norms. Previous studies reported that both culture and gender might impinge on young children's fidelity of imitation. We analyzed the imitative behavior of 87 children whose ages ranged from 3 to 6 years. An instrumental task was administered that offered partial (opaque apparatus) or total (transparent apparatus) information about causal connection between the demonstrated actions and their effect in achieving a desired reward. Imitative fidelity (imitating the actions that were demonstrated by an adult model yet were unnecessary for achieving the instrumental goal) increased as a function of age in boys, whereas no differences were found in girls. This lack of increase in girls can be ascribed to their displaying higher degrees of imitation fidelity at an earlier age.

Go with the flow: deep learning methods for autonomous viscosity estimations.

Closed-loop experiments can accelerate material discovery by automating both experimental manipulations and decisions that have traditionally been made by researchers. Fast and non-invasive measurements are particularly attractive for closed-loop strategies. Viscosity is a physical property for fluids that is important in many applications. It is fundamental in application areas such as coatings; also, even if viscosity is not the key property of interest, it can impact our ability to do closed-loop experimentation. For example, unexpected increases in viscosity can cause liquid-handling robots to fail. Traditional viscosity measurements are manual, invasive, and slow. Here we use convolutional neural networks (CNNs) as an alternative to traditional viscometry by non-invasively extracting the spatiotemporal features of fluid motion under flow. To do this, we built a workflow using a dual-armed collaborative robot that collects video data of fluid motion autonomously. This dataset was then used to train a 3-dimensional convolutional neural network (3D-CNN) for viscosity estimation, either by classification or by regression. We also used these models to identify unknown laboratory solvents, again based on differences in fluid motion. The 3D-CNN model performance was compared with the performance of a panel of human participants for the same classification tasks. Our models strongly outperformed human classification in both cases. For example, even with training on fewer than 50 videos for each liquid, the 3D-CNN model gave an average accuracy of 88% for predicting the identity of five different laboratory solvents, compared to an average accuracy of 32% for human observation. For comparison, random category selection would give an average accuracy of 20%. Our method offers an alternative to traditional viscosity measurements for autonomous chemistry workflows that might be used both for process control (e.g., choosing not to pipette liquids that are too viscous) or for materials discovery (e.g., identifying new polymerization catalysts on the basis of viscosification).

Trustworthy Data and AI Environments for Clinical Prediction: Application to Crisis-Risk in People With Depression.

Depression is a common mental health condition that often occurs in association with other chronic illnesses, and varies considerably in severity. Electronic Health Records (EHRs) contain rich information about a patient's medical history and can be used to train, test and maintain predictive models to support and improve patient care. This work evaluated the feasibility of implementing an environment for predicting mental health crisis among people living with depression based on both structured and unstructured EHRs. A large EHR from a mental health provider, Mersey Care, was pseudonymised and ingested into the Natural Language Processing (NLP) platform CogStack, allowing text content in binary clinical notes to be extracted. All unstructured clinical notes and summaries were semantically annotated by MedCAT and BioYODIE NLP services. Cases of crisis in patients with depression were then identified. Random forest models, gradient boosting trees, and Long Short-Term Memory (LSTM) networks, with varying feature arrangement, were trained to predict the occurrence of crisis. The results showed that all the prediction models can use a combination of structured and unstructured EHR information to predict crisis in patients with depression with good and useful accuracy. The LSTM network that was trained on a modified dataset with only 1000 most-important features from the random forest model with temporality showed the best performance with a mean AUC of 0.901 and a standard deviation of 0.006 using a training dataset and a mean AUC of 0.810 and 0.01 using a hold-out test dataset. Comparing the results from the technical evaluation with the views of psychiatrists shows that there are now opportunities to refine and integrate such prediction models into pragmatic point-of-care clinical decision support tools for supporting mental healthcare delivery.

Prediction and Prevention of Preterm Birth: Secondary Analysis of a Randomized Intervention Trial.

Our objective was to evaluate whether pregnancy is prolonged by the use of a proteomics-based maternal serum screening test followed by treatment interventions. This is a secondary analysis of the PREVENT-PTB randomized trial comparing screening with the PreTRM test versus no screening. The primary trial analysis found no significant between-group difference in the preterm birth rate. Rather than considering a dichotomous outcome (preterm versus term), we treated gestational age at birth as a continuous variable using survival analysis. We also evaluated between-group difference in NICU length of stay and duration of respiratory support. Results indicated that pregnancy was significantly prolonged in subjects screened with the PreTRM test compared to controls (adjusted hazard ratio 0.53, 95% confidence interval 0.36-0.78, p < 0.01). Newborns of screened subjects had significantly shorter NICU stays but no significant decrease in duration of respiratory support. In the PreTRM screen-positive group, interventions that were associated with pregnancy prolongation included care management and low-dose aspirin but not 17-hydroxyprogesterone caproate. We conclude that screening with the PreTRM test followed by interventions for screen-positive pregnancies may prolong pregnancy and reduce NICU LOS, but these observations need to be confirmed by additional research.

Food allergen analysis: A review of current gaps and the potential to fill them by matrix-assisted laser desorption/ionization.

Food allergy remains a public health, business, and regulatory challenge. Risk analysis (RA) and risk management (RM) of food allergens are of great importance and analysis for food allergens is necessary for both. The current workhorse techniques for allergen analysis (enzyme linked immunosorbent assay [ELISA] and real-time polymerase chain reaction) exhibit recognized challenges including variable and antibody specific responses and detection of species DNA rather than allergen protein, respectively. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) enables protein identification, with potential for multiplex analysis and traceability to the System of International units (SI), aiding global measurement standardization. In this review, recent literature has been systematically reviewed to assess progress in LC-MS/MS and define the potential and benefits of matrix-assisted laser desorption/ionization-time-of-flight MS (MALDI-ToF-MS) technology for allergen analysis. MALDI-ToF-MS of initially intact protein is already applied to verify in silico-derived peptide sequences for LC-MS/MS analysis. We describe the origins of MALDI and its future perspectives, including affinity bead-assisted assays coupled to MALDI. Based on the proliferation of reliable and reproducible MALDI-based clinical applications, the technique should emulate the detection capability (sensitivity) of established allergen detection techniques, whilst reducing technical support and having equivalent multiplexing potential to competing techniques, for example, LC-MS/MS and ELISA. Although unlikely to offer inherent SI traceability, MALDI-based allergen analysis will complement existing MS approaches for allergens. Affinity bead-MALDI appears capable of higher throughput at lower cost per sample than almost any existing technique, enabling repeated sub-sampling as a way to reduce representative sampling issues.

Effect of Microstructure and Dislocation Density on Material Removal and Surface Finish of Laser Powder Bed Fusion 316L Stainless Steel Subject to a Self-Terminating Etching Process.

Postprocessing of additively manufactured (AM) metal parts to remove support structures or improve the surface condition can be a manually intensive process. One novel solution is a two-step, self-terminating etching process (STEP), which achieves both support removal and surface smoothing. While the STEP has been demonstrated for laser powder bed fusion (L-PBF) 316L stainless steel, this work evaluates the impact of pre-STEP heat treatments and resulting changes in dislocation density and microstructure on the resulting surface roughness and amount of material removed. Two pre-STEP heat treatments were evaluated: stress relief at 470°C for 5 h and recrystallization-solution annealing at 1060°C for 1 h. Additionally, one set of specimens was processed without the pre-STEP heat treatment (as-printed condition). Dislocation density and phase composition were quantified using X-ray diffraction along with standard, metallurgical stain-etching techniques. This work, for the first time, highlights the mechanisms of sensitization of AM L-PBF 316L stainless steel and provides fundamental insights into selective etching of these materials. Results showed that the sensitization depth decreased with increasing dislocation density. For samples etched at a STEP bias of 540 mVSHE, material removal terminated at grain boundaries; therefore, the fine-grained stress-relieved specimen had the lowest post-STEP surface roughness. For surface roughness optimization, parts should be stress relived pre-STEP. However, to achieve more material removal, pre-STEP solution annealing should be performed.

Variation in histone configurations correlates with gene expression across nine inbred strains of mice.

The Diversity Outbred (DO) mice and their inbred founders are widely used models of human disease. However, although the genetic diversity of these mice has been well documented, their epigenetic diversity has not. Epigenetic modifications, such as histone modifications and DNA methylation, are important regulators of gene expression and, as such, are a critical mechanistic link between genotype and phenotype. Therefore, creating a map of epigenetic modifications in the DO mice and their founders is an important step toward understanding mechanisms of gene regulation and the link to disease in this widely used resource. To this end, we performed a strain survey of epigenetic modifications in hepatocytes of the DO founders. We surveyed four histone modifications (H3K4me1, H3K4me3, H3K27me3, and H3K27ac), as well as DNA methylation. We used ChromHMM to identify 14 chromatin states, each of which represents a distinct combination of the four histone modifications. We found that the epigenetic landscape is highly variable across the DO founders and is associated with variation in gene expression across strains. We found that epigenetic state imputed into a population of DO mice recapitulated the association with gene expression seen in the founders, suggesting that both histone modifications and DNA methylation are highly heritable mechanisms of gene expression regulation. We illustrate how DO gene expression can be aligned with inbred epigenetic states to identify putative cis-regulatory regions. Finally, we provide a data resource that documents strain-specific variation in the chromatin state and DNA methylation in hepatocytes across nine widely used strains of laboratory mice.

COVID-19 and mental health in 8 low- and middle-income countries: A prospective cohort study.

BACKGROUND: The Coronavirus Disease 2019 (COVID-19) pandemic and associated mitigation policies created a global economic and health crisis of unprecedented depth and scale, raising the estimated prevalence of depression by more than a quarter in high-income countries. Low- and middle-income countries (LMICs) suffered the negative effects on living standards the most severely. However, the consequences of the pandemic for mental health in LMICs have received less attention. Therefore, this study assesses the association between the COVID-19 crisis and mental health in 8 LMICs. METHODS AND FINDINGS: We conducted a prospective cohort study to examine the correlation between the COVID-19 pandemic and mental health in 10 populations from 8 LMICs in Asia, Africa, and South America. The analysis included 21,162 individuals (mean age 38.01 years, 64% female) who were interviewed at least once pre- as well as post-pandemic. The total number of survey waves ranged from 2 to 17 (mean 7.1). Our individual-level primary outcome measure was based on validated screening tools for depression and a weighted index of depression questions, dependent on the sample. Sample-specific estimates and 95% confidence intervals (CIs) for the association between COVID-19 periods and mental health were estimated using linear regressions with individual fixed effects, controlling for independent time trends and seasonal variation in mental health where possible. In addition, a regression discontinuity design was used for the samples with multiple surveys conducted just before and after the onset of the pandemic. We aggregated sample-specific coefficients using a random-effects model, distinguishing between estimates for the short (0 to 4 months) and longer term (4+ months). The random-effects aggregation showed that depression symptoms are associated with a increase by 0.29 standard deviations (SDs) (95% CI [-.47, -.11], p-value = 0.002) in the 4 months following the onset of the pandemic. This change was equivalent to moving from the 50th to the 63rd percentile in our median sample. Although aggregate depression is correlated with a decline to 0.21 SD (95% CI [-0.07, -.34], p-value = 0.003) in the period thereafter, the average recovery of 0.07 SD (95% CI [-0.09, .22], p-value = 0.41) was not statistically significant. The observed trends were consistent across countries and robust to alternative specifications. Two limitations of our study are that not all samples are representative of the national population, and the mental health measures differ across samples. CONCLUSIONS: Controlling for seasonality, we documented a large, significant, negative association of the pandemic on mental health, especially during the early months of lockdown. The magnitude is comparable (but opposite) to the effects of cash transfers and multifaceted antipoverty programs on mental health in LMICs. Absent policy interventions, the pandemic could be associated with a lasting legacy of depression, particularly in settings with limited mental health support services, such as in many LMICs. We also demonstrated that mental health fluctuates with agricultural crop cycles, deteriorating during "lean", pre-harvest periods and recovering thereafter. Ignoring such seasonal variations in mental health may lead to unreliable inferences about the association between the pandemic and mental health.

To copy or not to copy? That is the question! From chimpanzees to the foundation of human technological culture.

A prerequisite for copying innovative behaviour faithfully is the capacity of observers' brains, regarded as 'hierarchically mechanistic minds', to overcome cognitive 'surprisal' (see 2.), by maximising the evidence for their internal models, through active inference. Unlike modern humans, chimpanzees and other great apes show considerable limitations in their ability, or 'Zone of Bounded Surprisal', to overcome cognitive surprisal induced by innovative or unorthodox behaviour that rarely, therefore, is copied precisely or accurately. Most can copy adequately what is within their phenotypically habitual behavioural repertoire, in which technology plays scant part. Widespread intra- and intergenerational social transmission of complex technological innovations is not a hall-mark of great-ape taxa. 3 Ma, precursors of the genus Homo made stone artefacts, and stone-flaking likely was habitual before 2 Ma. After that time, early Homo erectus has left traces of technological innovations, though faithful copying of these and their intra- and intergenerational social transmission were rare before 1 Ma. This likely owed to a cerebral infrastructure of interconnected neuronal systems more limited than ours. Brains were smaller in size than ours, and cerebral neuronal systems ceased to develop when early Homo erectus attained full adult maturity by the mid-teen years, whereas its development continues until our mid-twenties nowadays. Pleistocene Homo underwent remarkable evolutionary adaptation of neurobiological propensities, and cerebral aspects are discussed that, it is proposed here, plausibly, were fundamental for faithful copying, which underpinned social transmission of technologies, cumulative learning, and culture. Here, observers' responses to an innovation are more important for ensuring its transmission than is an innovator's production of it, because, by themselves, the minimal cognitive prerequisites that are needed for encoding and assimilating innovations are insufficient for practical outcomes to accumulate and spread intra- and intergenerationally.

On the dependent recognition of some long zinc finger proteins.

The human genome contains about 800 C2H2 zinc finger proteins (ZFPs), and most of them are composed of long arrays of zinc fingers. Standard ZFP recognition model asserts longer finger arrays should recognize longer DNA-binding sites. However, recent experimental efforts to identify in vivo ZFP binding sites contradict this assumption, with many exhibiting short motifs. Here we use ZFY, CTCF, ZIM3, and ZNF343 as examples to address three closely related questions: What are the reasons that impede current motif discovery methods? What are the functions of those seemingly unused fingers and how can we improve the motif discovery algorithms based on long ZFPs' biophysical properties? Using ZFY, we employed a variety of methods and find evidence for 'dependent recognition' where downstream fingers can recognize some previously undiscovered motifs only in the presence of an intact core site. For CTCF, high-throughput measurements revealed its upstream specificity profile depends on the strength of its core. Moreover, the binding strength of the upstream site modulates CTCF's sensitivity to different epigenetic modifications within the core, providing new insight into how the previously identified intellectual disability-causing and cancer-related mutant R567W disrupts upstream recognition and deregulates the epigenetic control by CTCF. Our results establish that, because of irregular motif structures, variable spacing and dependent recognition between sub-motifs, the specificities of long ZFPs are significantly underestimated, so we developed an algorithm, ModeMap, to infer the motifs and recognition models of ZIM3 and ZNF343, which facilitates high-confidence identification of specific binding sites, including repeats-derived elements. With revised concept, technique, and algorithm, we can discover the overlooked specificities and functions of those 'extra' fingers, and therefore decipher their broader roles in human biology and diseases.

LIGHTSITE II Randomized Multicenter Trial: Evaluation of Multiwavelength Photobiomodulation in Non-exudative Age-Related Macular Degeneration.

INTRODUCTION: Photobiomodulation (PBM) represents a potential treatment for non-exudative age-related macular degeneration (AMD). PBM uses wavelengths of light to target components of the mitochondrial respiratory chain to improve cellular bioenergetic outputs. The aim of this study was to further investigate the effects of PBM on clinical, quality of life (QoL) and anatomical outcomes in subjects with intermediate stage non-exudative AMD. METHODS: The multicenter LIGHTSITE II study was a randomized clinical trial evaluating safety and efficacy of PBM in intermediate non-exudative AMD. The LumiThera Valeda® Light Delivery System delivered multiwavelength PBM (590, 660 and 850 nm) or sham treatment 3 × per week over 3-4 weeks (9 treatments per series) with repeated treatments at baseline (BL), 4 and 8 months. Subjects were enrolled with 20/32 to 20/100 best-corrected visual acuity (BCVA) and no central geographic atrophy (GA) within the central fovea (500 µm). RESULTS: LIGHTSITE II enrolled 44 non-exudative AMD subjects (53 eyes). PBM-treated eyes showed statistically significant improvement in BCVA at 9 months (n = 32 eyes, p = 0.02) with a 4-letter gain in the PBM-treated group versus a 0.5-letter gain in the sham-treated group (ns, p < 0.1) for patients that received all 27 PBM treatments (n = 29 eyes). Approximately 35.3% of PBM-treated eyes showed ≥ 5-letter improvement at 9 months. Macular drusen volume was not increased over time in the PBM-treated group but did show increases in the sham-treated group. While PBM and sham groups both showed GA lesion growth in the trial period, there was 20% less growth in the PBM group over 10 months, suggesting potential disease-modifying effects. No safety concerns or signs of phototoxicity were observed. CONCLUSION: These results confirm previous clinical testing of multiwavelength PBM and support treatment with Valeda as a novel therapy with a unique mechanism of action as a potential treatment for non-exudative AMD. TRIAL REGISTRATION: Clinicaltrial.Gov Registration Identifier: NCT03878420.