New ways for (in)validating the forest carbon neutrality hypothesis.

Over 50 years ago, Eugene Odum postulated that mature or climax forests reside in carbon neutrality. As climate change rose to prominence in the international environmental agenda, the neutrality hypothesis transformed from an ecological principle to a justification for using forest management in combating climate change. Despite persistent efforts, Odum's neutrality hypothesis has resisted both confirmation and refutation. In this opinion we show the limitations of past efforts to (in)validate Odum's neutrality hypothesis and propose new research directions for the community to permit a more general confirmation or refutation with current and near-future observations. We then demonstrate such an approach by using metabolic theory to formulate testable predictions for the total sink strength considering soil, litter, and biomass of mature or climax forests based on observations of tree biomass and individual density. In doing so, we show that ecological theory can create additional relevant, testable hypotheses to provide timely support to decision-makers seeking to address one of the world's most pressing environmental challenges.

Genomic compliance with Chargaff's second parity rule may have originated non-adaptively, but stem-loops now function adaptively.

Of Chargaff's four rules on DNA base quantity, his second parity rule (PR-2) is the most contentious. Various biometricians (e.g., Sueoka, Lobry) regarded PR-2 compliance as a non-adaptive feature of modern genomes that could be modeled through interrelations among mutation rates. However, PR-2 compliance with stem-loop potential was considered adaptively relevant by biochemists familiar with analyses of nucleic acid structure (e.g., of Crick) and of meiotic recombination (e.g., of Kleckner). Meanwhile, other biometricians had shown that PR-2 complementarity extended beyond individual bases (1-mers) to oligonucleotides (k-mers), possibly reflecting "advantageous DNA structure" (Nussinov). An "introns early" hypothesis (Reanney, Forsdyke) had suggested a primordial nucleic acid world with recombination-mediated error-correction requiring genome-wide stem-loop potential to have evolved prior to localized intrusions of protein-encoding potential (exons). Thus, a primordial genome was equivalent to one long intron. Indeed, when assessed as the base order-dependent component (correcting for local influences of GC%), modern genes, especially when evolving rapidly under positive Darwinian selection, display high intronic stem-loop potential. This suggests forced migration from neighboring exons by competing protein-encoding potential. PR-2 compliance may have first arisen non-adaptively. Primary prototypic structures were later strengthened by their adaptive contribution to recombination. Thus, contentious views may actually be in harmony.

Estimating the proportion of true null hypotheses and adaptive false discovery rate control in discrete paradigm.

Storey's estimator for the proportion of true null hypotheses, originally proposed under the continuous framework, has been modified in this work under the discrete framework. The modification results in improved estimation of the parameter of interest. The proposed estimator is used to formulate an adaptive version of the Benjamini-Hochberg procedure. Control over the false discovery rate by the proposed adaptive procedure has been proved analytically. The proposed estimate is also used to formulate an adaptive version of the Benjamini-Hochberg-Heyse procedure. Simulation experiments establish the conservative nature of this new adaptive procedure. Substantial amount of gain in power is observed for the new adaptive procedures over the standard procedures. For demonstration of the proposed method, two important real life gene expression data sets, one related to the study of HIV and the other related to methylation study, are used.

Bayesian sequential designs in studies with multilevel data.

In many studies in the social and behavioral sciences, the data have a multilevel structure, with subjects nested within clusters. In the design phase of such a study, the number of clusters to achieve a desired power level has to be calculated. This requires a priori estimates of the effect size and intraclass correlation coefficient. If these estimates are incorrect, the study may be under- or overpowered. This may be overcome by using a group-sequential design, where interim tests are done at various points in time of the study. Based on interim test results, a decision is made to either include additional clusters or to reject the null hypothesis and conclude the study. This contribution introduces Bayesian sequential designs as an alternative to group-sequential designs. This approach compares various hypotheses based on the support in the data for each of them. If neither hypothesis receives a sufficient degree of support, additional clusters are included in the study and the Bayes factor is recalculated. This procedure continues until one of the hypotheses receives sufficient support. This paper explains how the Bayes factor is used as a measure of support for a hypothesis and how a Bayesian sequential design is conducted. A simulation study in the setting of a two-group comparison was conducted to study the effects of the minimum and maximum number of clusters per group and the desired degree of support. It is concluded that Bayesian sequential designs are a flexible alternative to the group sequential design.

Bayesian evidence synthesis as a flexible alternative to meta-analysis: A simulation study and empirical demonstration.

Synthesizing results across multiple studies is a popular way to increase the robustness of scientific findings. The most well-known method for doing this is meta-analysis. However, because meta-analysis requires conceptually comparable effect sizes with the same statistical form, meta-analysis may not be possible when studies are highly diverse in terms of their research design, participant characteristics, or operationalization of key variables. In these situations, Bayesian evidence synthesis may constitute a flexible and feasible alternative, as this method combines studies at the hypothesis level rather than at the level of the effect size. This method therefore poses less constraints on the studies to be combined. In this study, we introduce Bayesian evidence synthesis and show through simulations when this method diverges from what would be expected in a meta-analysis to help researchers correctly interpret the synthesis results. As an empirical demonstration, we also apply Bayesian evidence synthesis to a published meta-analysis on statistical learning in people with and without developmental language disorder. We highlight the strengths and weaknesses of the proposed method and offer suggestions for future research.

[Bipolar disorders and multiple etiologies : a link with attachment disorders ?] / Troubles bipolaires et étiologies multiples : un lien avec les troubles de l'attachement ?

Bipolar disorders (BD) bring together different forms of mood disorders, characterized by the occurrence of depressive, manic, hypomanic and/or mixed episodes. They are recognized as the seventh cause of disability per year of life among 15 to 44 year old people by the World Health Organization (WHO). It is therefore a frequently encountered pathology. On the etiological level, the avenues currently accepted concerning BD are multiple, yet they still remain at the hypothesis stage. Each of these avenues therefore has therapeutic potential. It therefore seems interesting to address the different major hypotheses existing to date on the etiological level. We will first describe BD from historical, nosological and epidemiological points of view. We will then develop the genetic etiological aspects and the neural aspects through brain imaging research. Finally, we will propose a reflection on the specific relational etiology and the avenues of research that result from it.

Les troubles bipolaires (TB) regroupent différentes formes de troubles de l'humeur, caractérisés par la survenue d'épisodes dépressifs, maniaques, hypomanes et/ou mixtes. Ils sont reconnus comme la septième cause de handicap par année de vie parmi les personnes âgées de 15 à 44 ans par l'Organisation Mondiale de la Santé (OMS). Il s'agit donc d'une pathologie fréquemment rencontrée. Sur le plan étiologique, les pistes actuellement retenues concernant les TB sont multiples et restent encore au stade d'hypothèses. Chacune de ces pistes contribue à élargir le champ des ressources thérapeutiques possibles. Il nous semble, dès lors, intéressant d'aborder e les différentes hypothèses majeures existant à ce jour sur le plan étiologique. Nous resituerons préalablement les TB sur les plans historiques, nosologiques puis épidémiologiques. Nous développerons ensuite les aspects étiologiques génétiques et les aspects neurobiologiques à travers les recherches en imagerie cérébrale. Enfin, nous proposerons une réflexion sur l'étiologie spécifiquement relationnelle et les pistes de recherche qui en découlent.

How Do You Feel the Rhythm: Dynamic Motor-Auditory Interactions Are Involved in the Imagination of Hierarchical Timing.

Predicting and organizing patterns of events is important for humans to survive in a dynamically changing world. The motor system has been proposed to be actively, and necessarily, engaged in not only the production but the perception of rhythm by organizing hierarchical timing that influences auditory responses. It is not yet well understood how the motor system interacts with the auditory system to perceive and maintain hierarchical structure in time. This study investigated the dynamic interaction between auditory and motor functional sources during the perception and imagination of musical meters. We pursued this using a novel method combining high-density EEG, EMG, and motion capture with independent component analysis to separate motor and auditory activity during meter imagery while robustly controlling against covert movement. We demonstrated that endogenous brain activity in both auditory and motor functional sources reflects the imagination of binary and ternary meters in the absence of corresponding acoustic cues or overt movement at the meter rate. We found clear evidence for hypothesized motor-to-auditory information flow at the beat rate in all conditions, suggesting a role for top-down influence of the motor system on auditory processing of beat-based rhythms, and reflecting an auditory-motor system with tight reciprocal informational coupling. These findings align with and further extend a set of motor hypotheses from beat perception to hierarchical meter imagination, adding supporting evidence to active engagement of the motor system in auditory processing, which may more broadly speak to the neural mechanisms of temporal processing in other human cognitive functions.SIGNIFICANCE STATEMENT Humans live in a world full of hierarchically structured temporal information, the accurate perception of which is essential for understanding speech and music. Music provides a window into the brain mechanisms of time perception, enabling us to examine how the brain groups musical beats into, for example a march or waltz. Using a novel paradigm combining measurement of electrical brain activity with data-driven analysis, this study directly investigates motor-auditory connectivity during meter imagination. Findings highlight the importance of the motor system in the active imagination of meter. This study sheds new light on a fundamental form of perception by demonstrating how auditory-motor interaction may support hierarchical timing processing, which may have clinical implications for speech and motor rehabilitation.

Identifying alert concentrations using a model-based bootstrap approach.

The determination of alert concentrations, where a pre-specified threshold of the response variable is exceeded, is an important goal of concentration-response studies. The traditional approach is based on investigating the measured concentrations and attaining statistical significance of the alert concentration by using a multiple t-test procedure. In this paper, we propose a new model-based method to identify alert concentrations, based on fitting a concentration-response curve and constructing a simultaneous confidence band for the difference of the response of a concentration compared to the control. In order to obtain these confidence bands, we use a bootstrap approach which can be applied to any functional form of the concentration-response curve. This particularly offers the possibility to investigate also those situations where the concentration-response relationship is not monotone and, moreover, to detect alerts at concentrations which were not measured during the study, providing a highly flexible framework for the problem at hand.

Differential grandparental investment when maternal grandmothers are living versus deceased.

Grandparents can increase their inclusive fitness by investing time and resources in their grandchildren. However, not all grandparents make such investments equally, and between-grandparent differences in this regard can be predicted based on paternity uncertainty, lineage and grandparents' sex. Using population-based data for English and Welsh adolescents (n = 1430), we examined whether the death of the most important grandparent (in terms of investment), the maternal grandmother (MGM), changes relative support for existing hypotheses predicting differential grandparental-investment patterns. To contrast the predictions of the grandparental investment hypotheses, we used generalized order-restricted information criterion approximation. We consequently found that, when MGMs are alive, the most-supported hypothesis is 'discriminative grandparental solicitude', which ranks grandparental investment as MGMs > maternal grandfathers (MGFs) > paternal grandmothers (PGMs) > paternal grandfathers (PGFs). However, when MGMs are deceased, the paternity uncertainty hypothesis (MGFs = PGMs > PGFs) receives the most support; this is due to increased investment by PGMs. Thus, when the heaviest investors (i.e. MGMs) are deceased, PGM investments are closer to-but do not exceed-MGF investments.

The Late Stage of Abnormal Aging: Dementia.

With the growth of the aging population, more age-related diseases endanger the health of the elderly, and therefore more research attention has been put on Alzheimer's disease and dementia. Dementia does not only posing a serious threat to basic daily living in old age but also impose a greater burden on social and medical care as well as the economy. It is urgent to explore the pathogenesis of Alzheimer's disease and develop effective medicine to prevent or mitigate its onset. Currently, many related mechanisms of the pathogenesis of Alzheimer's disease have been proposed, such as beta-amyloid (A) theory, Tau protein theory, and nerve and blood vessel theory. In addition, from the perspective of improving cognitive function and controlling mental state, dementia-related therapeutic drugs were developed, such as anti-amyloid agents, amyloid vaccine, tau vaccine, and tau-aggregation inhibitor. These theories of pathogenesis and the development of drugs provide valuable experience to lift the veil of cognitive disorders in the future.

Reverse Engineering Caged Compounds: Design Principles for their Application in Biology.

Light passes through biological tissue, and so it is used for imaging biological processes in situ. Such observation is part of the very essence of science, but mechanistic understanding requires intervention. For more than 50 years a "second function" for light has emerged; namely, that of photochemical control. Caged compounds are biologically inert signaling molecules that are activated by light. These optical probes enable external instruction of biological processes by stimulation of an individual element in complex signaling cascades in its native environment. Cause and effect are linked directly in spatial, temporal, and frequency domains in a quantitative manner by their use. I provide a guide to the basic properties required to make effective caged compounds for the biological sciences.

Hypotheses in Kant's philosophy of science.

In this paper I extend the case for a necessitation account of particular laws in Kant's philosophy of science by examining the relation between reason's hypothetical use in the Appendix to the Transcendental Dialectic and the legitimate hypotheses identified in the Doctrine of Method. Building on normative accounts of reason's ideas, I argue that reason's hypothetical use does not describe the connections between objects and their grounds, which lie beyond the reach of the understanding, but merely prescribes the relations between appearances and their conditions, for which the understanding must seek. A legitimate hypothesis, I suggest, is a proposition we hold to be true that fills in one or several of those relations. The problematic character of hypotheses requires that we evaluate our reasons for holding them to be true. While natural modality is grounded in the nature of things, which cannot be fully known, our reasons for assent can and must be grounded on features of objects that are epistemically available to us.

The continuing evolution of birth cohort studies: achievements and challenges†.

Well-designed birth cohorts are able to estimate prevalence/distribution of various health events/outcomes, and to link early-life origins with adult health and function. The past two decades have seen a surge in the establishment of new birth cohorts and their accompanying research. We discussed distinct designs of current birth cohort studies, reviewed their achievements, and highlighted insights obtained from birth cohort studies, as well as challenges we are facing. Birth cohort studies are providing increasing opportunities to identify determining factors for short- and long-term health, yielding substantial evidence to uncover biological mechanisms of diseases and phenotypes, and providing further insights for public health. Dynamic monitoring, accurate measurements, long-term follow-ups, and collaborative efforts are warranted in new birth cohorts to elucidate the nature of life course relationships in contemporary generation.

Bradyrhizobium altum sp. nov., Bradyrhizobium oropedii sp. nov. and Bradyrhizobium acaciae sp. nov. from South Africa show locally restricted and pantropical nodA phylogeographic patterns.

Africa is known for its rich legume diversity with a significant number of endemic species originating in South Africa. Many of these legumes associate with rhizobial symbionts of the genus Bradyrhizobium, of which most represent new species. Yet, none of the Bradyrhizobium species from South Africa have been described. In this study, phylogenetic analysis of 16S rRNA gene sequences of fourteen strains isolated in southern Africa from root nodules of diverse legumes (i.e., from the tribes Crotalarieae, Acacieae, Genisteae, Phaseoleae and Cassieae) revealed that they belong to the Bradyrhizobium elkanii supergroup. The taxonomic position and possible novelty of these strains were further interrogated using genealogical concordance of five housekeeping genes (atpD, dnaK, glnII, gyrB and rpoB). These phylogenies consistently recovered four monophyletic groups and one singleton within Bradyrhizobium. Of these groups, two were conspecific with Bradyrhizobium brasilense UFLA 03-321T and Bradyrhizobium ivorense CI-1BT, while the remaining three represented novel taxa. Their existence was further supported with genome data, as well as metabolic and physiological traits. Analysis of nodA gene sequences further showed that the evolution of these bacteria likely involved adapting to local legume hosts and environmental conditions through the acquisition, via horizontal gene transfer, of optimal symbiotic loci. We accordingly propose the following names Bradyrhizobium acaciae sp. nov. 10BBT (SARCC 730T = LMG 31409T), Bradyrhizobium oropedii sp. nov. Pear76T (SARCC 731T = LMG 31408T), and Bradyrhizobium altum sp. nov. Pear77T (SARCC 754T = LMG 31407T) to accommodate three novel species, all of which are symbionts of legumes in South Africa.

Urban biotic homogenization: Approaches and knowledge gaps.

Urbanization is restructuring ecosystems at an unprecedented pace, with complex and profound consequences for life on Earth. One of the hypothesized trajectories of urban ecosystems and species communities is biotic homogenization, possibly leading to very similar species assemblages in cities across the globe. Urbanization can, however, also have the opposite effect: biotic diversification, with cities, at least at the local scale, becoming biologically more diverse, mainly as a consequence of high species introduction rates and habitat diversification. Applying the hierarchy-of-hypotheses approach, we systematically map and structure the comprehensive body of literature on the urban biotic homogenization (UBH) hypothesis, comprising 225 individual studies (i.e., tests of the hypothesis) retrieved from 145 publications. The UBH hypothesis is studied at multiple levels with a multitude of approaches and underlying assumptions. We show that UBH is generally used with two very different connotations: about half of the studies investigated a potential increase in community similarity across cities, whereas the other half investigated biotic homogenization within cities, the latter being supported more frequently. We also found strong research biases: (1) a taxonomic bias towards birds and plants, (2) a bias towards small and medium distances (<5000 km) in comparisons across cities, (3) a dominance of studies substituting space for time versus true temporal studies, (4) a strong focus on terrestrial versus aquatic systems, (5) more extraurban (including periurban) areas than natural or rural ecosystems for comparison to urban systems, (6) a bias towards taxonomic versus functional, phylogenetic, and temporal homogenization, and (7) more studies undertaken in Europe and North America than in other continents. The overall level of empirical support for the UBH hypothesis was mixed, with 55% of the studies reporting supporting evidence. Results significantly differed when a natural/nature reserve, an extraurban, or rural/agricultural area served as reference to infer biotic homogenization, with homogenization being detected least frequently when urban systems were compared to agricultural, i.e., other anthropogenically influenced, study sites. We provide an evidence map and a bibliographic network and identify key references on UBH with the goal to enhance accessibility and orientation for future research on this topic.

DETECTING MULTIPLE REPLICATING SIGNALS USING ADAPTIVE FILTERING PROCEDURES.

Replicability is a fundamental quality of scientific discoveries: we are interested in those signals that are detectable in different laboratories, different populations, across time etc. Unlike meta-analysis which accounts for experimental variability but does not guarantee replicability, testing a partial conjunction (PC) null aims specifically to identify the signals that are discovered in multiple studies. In many contemporary applications, for example, comparing multiple high-throughput genetic experiments, a large number M of PC nulls need to be tested simultaneously, calling for a multiple comparisons correction. However, standard multiple testing adjustments on the M PC p -values can be severely conservative, especially when M is large and the signals are sparse. We introduce AdaFilter, a new multiple testing procedure that increases power by adaptively filtering out unlikely candidates of PC nulls. We prove that AdaFilter can control FWER and FDR as long as data across studies are independent, and has much higher power than other existing methods. We illustrate the application of AdaFilter with three examples: microarray studies of Duchenne muscular dystrophy, single-cell RNA sequencing of T cells in lung cancer tumors and GWAS for metabolomics.

Improved group sequential Holm procedures for testing multiple correlated hypotheses over time.

Clinical trials can typically feature two different types of multiple inference: testing of more than one null hypothesis and testing at multiple time points. These modes of multiplicity are closely related mathematically but distinct statistically and philosophically. Regulatory agencies require strong control of the family-wise error rate (FWER), the risk of falsely rejecting any null hypothesis at any analysis. The correlations between test statistics at interim analyses and the final analysis are therefore routinely used in group sequential designs to achieve less conservative critical values. However, the same type of correlations between different comparisons, endpoints or sub-populations are less commonly used. As a result, FWER is in practice often controlled conservatively for commonly applied procedures.Repeated testing of the same null hypothesis may give changing results, when the hypothesis is rejected at an interim but accepted at the final analysis. The mathematically correct overall rejection is at odds with an inference theoretic approach and with common sense. We discuss these two issues, of incorporating correlations and how to interpret time-changing conclusions, and provide case studies where power can be increased while adhering to sound statistical principles.

A Practical Guide to Writing Quantitative and Qualitative Research Questions and Hypotheses in Scholarly Articles.

The development of research questions and the subsequent hypotheses are prerequisites to defining the main research purpose and specific objectives of a study. Consequently, these objectives determine the study design and research outcome. The development of research questions is a process based on knowledge of current trends, cutting-edge studies, and technological advances in the research field. Excellent research questions are focused and require a comprehensive literature search and in-depth understanding of the problem being investigated. Initially, research questions may be written as descriptive questions which could be developed into inferential questions. These questions must be specific and concise to provide a clear foundation for developing hypotheses. Hypotheses are more formal predictions about the research outcomes. These specify the possible results that may or may not be expected regarding the relationship between groups. Thus, research questions and hypotheses clarify the main purpose and specific objectives of the study, which in turn dictate the design of the study, its direction, and outcome. Studies developed from good research questions and hypotheses will have trustworthy outcomes with wide-ranging social and health implications.

Toward recovery in schizophrenia: Current concepts, findings, and future research directions.

Schizophrenia was initially defined as "dementia praecox" by E. Kraepelin, which implies progressive deterioration. However, recent studies have revealed that early effective intervention may lead to social and functional recovery in schizophrenia. In this review, we provide an overview of current concepts in schizophrenia and pathophysiological hypotheses. In addition, we present recent findings from clinical and basic research on schizophrenia. Recent neuroimaging and neurophysiological studies have consistently revealed specific biological differences in the structure and function of the brain in those with schizophrenia. From a basic research perspective, to determine the essential pathophysiology underlying schizophrenia, it is crucial that findings from all lines of inquiry-induced pluripotent stem cell (iPSC)-derived neural cells from patients, murine models expressing genetic mutations identified in patients, and patient clinical data-be integrated to contextualize the analysis results. However, the findings remain insufficient to serve as a diagnostic tool or a biomarker for predicting schizophrenia-related outcomes. Collaborations to conduct clinical research based on the patients' and their families' values are just beginning, and further development is expected.

Randomized p$p$ -values for multiple testing and their application in replicability analysis.

We are concerned with testing replicability hypotheses for many endpoints simultaneously. This constitutes a multiple test problem with composite null hypotheses. Traditional p$p$ -values, which are computed under least favorable parameter configurations (LFCs), are over-conservative in the case of composite null hypotheses. As demonstrated in prior work, this poses severe challenges in the multiple testing context, especially when one goal of the statistical analysis is to estimate the proportion π0$\pi _0$ of true null hypotheses. Randomized p$p$ -values have been proposed to remedy this issue. In the present work, we discuss the application of randomized p$p$ -values in replicability analysis. In particular, we introduce a general class of statistical models for which valid, randomized p$p$ -values can be calculated easily. By means of computer simulations, we demonstrate that their usage typically leads to a much more accurate estimation of π0$\pi _0$ than the LFC-based approach. Finally, we apply our proposed methodology to a real data example from genomics.