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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.

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The amount of standing variation present within populations is a fundamental quantity of interest in population genetics, commonly represented by calculating the average number of differences between pairs of nucleotide sequences (nucleotide diversity, π). It is well understood that both background and positive selection can cause reductions in nucleotide diversity, but less clear how local adaptation affects it. Depending on the assumptions and parameters, some theoretical studies have emphasized how local adaptation can reduce nucleotide diversity, while others have shown that it can increase it. Here, we explore how local adaptation shapes genome-wide patterns in within-population nucleotide diversity, extending previous work to study the effects of polygenic adaptation, genotypic redundancy, and population structure. We show that local adaptation produces two very different patterns depending on the relative strengths of migration and selection, either markedly decreasing or increasing within-population diversity at linked sites at equilibrium. At low migration, regions of depleted diversity can extend large distances from the causal locus, with substantially more diversity eroded than expected with background selection. With higher migration, peaks occur over much smaller genomic distances but with much larger magnitude changes in diversity. Across spatially extended environmental gradients, both patterns can be found within a single species, with increases in diversity at the center of the range and decreases towards the periphery. Our results demonstrate that there is no universal diagnostic signature of local adaptation based on within-population nucleotide diversity, so it will not be broadly useful for explaining increased FST. However, given that neither background nor positive selection inflate diversity, when peaks are found they suggest local adaptation may be acting on a causal allele in the region.

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Melanocytes located between the anal transition zone and the dentate line of the anal canal can give rise to the uncommon malignant tumor known as anal melanoma. It has a fast-paced clinical course and can masquerade as several common anorectal symptoms, such as hemorrhoids or rectal ulcers. In melanoma, divergent differentiation is a very uncommon phenomenon. The diagnosis of melanoma is difficult with histopathology sections alone (hematoxylin and eosin, H&E). Special stains and ancillary immunohistochemistry investigations are useful in these situations. A 60-year-old female patient presented to the surgical outpatient department with complaints of anorectal bleeding. After clinical evaluation, a growth in the anorectal region was identified, and a biopsy was taken from the growth. Histopathological and subsequent immunohistochemical analysis of the biopsy material was done at the Department of Pathology. A diagnosis of amelanotic melanoma with atypical and divergent neuroendocrine differentiation involving the anorectal region was rendered. Histologically, this tumor showed extremely pleomorphic polygonal to elongated spindle cells that co-expressed neuroendocrine markers and were positive for S100, HMB-45, and Melan-A. This case presented many diagnostic challenges at both the histomorphological level and the immunohistochemical expression profile analysis. We will go into great depth regarding the diagnostic challenges in this instance and provide an outline of our approach. The immunohistochemical and prognostic importance of this case will also be covered.

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Clostridioides difficile is an intestinal pathogen of humans and animals. In community-associated infections, the environment is suggested to play a significant role in overall transmission routes. Although the prevalence of C. difficile in freshwater and soil has been widely studied, little is known about its presence in sediments. In this study, we tested 15 sediment samples collected from various freshwater sources. C. difficile was isolated from all sampled sites, yielding a total of 171 strains grouped into 26 ribotypes, with 001/072 and 014/020 being the most prevalent. Genome sequencing of 37 isolates from 17 PCR ribotypes confirmed the presence of highly related strains in the geographically distant and unlinked water samples. Eight divergent PCR ribotypes from clades C-II and C-III were found in six samples. In each sample, the unbound fraction (supernatant after sediment wash) and bound fraction (sonicated sediment sample) were subjected to enrichment. Sonication was only slightly better than washing in terms of sample positivity (14 positive samples with sonication and 11 with washing). However, sonication substantially increased the diversity of the PCR ribotypes obtained (23 in sonicated samples vs nine in washed samples). In conclusion, sediments are a rich source for investigating the diversity of environmental C. difficile, including isolates from divergent lineages. Selection of the isolation method can significantly impact the diversity of captured PCR ribotypes.IMPORTANCEClostridioides difficile, a pathogenic bacterium that can cause intestinal infections in humans and animals, thrives in the gut but also disperses widely through spores found in the environment. Clinical and environmental strains often overlap with common PCR ribotypes, which are consistently isolated worldwide. Environmental studies have mostly focused on water and soil, but sediments have been very poorly studied. In this study, we investigated the presence of C. difficile in various freshwater sediments and evaluated the effectiveness of two different isolation approaches on positivity rates and strain diversity. C. difficile was found to be highly prevalent in sediments, with an isolation rate of 100%. Sonication proved to be more effective than simple washing for capturing a greater diversity of PCR ribotypes. Overall, this study underscores the widespread presence of C. difficile in freshwater sediments and emphasizes the importance of continued surveillance and monitoring to understand its ecology and transmission dynamics.

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INTRODUCTION: Enhanced creativity is often cited as an effect of microdosing (taking repeated low doses of a psychedelic drug). There have been recent efforts to validate the reported effects of microdosing, however creativity remains a difficult construct to quantify. OBJECTIVES: The current study aimed to assess microdosing's effects on creativity using a multimodal battery of tests as part of a randomised controlled trial of microdosing lysergic acid diethylamide (LSD). METHODS: Eighty healthy adult males were given 10 µg doses of LSD or placebo every third day for six weeks (14 total doses). Creativity tasks were administered at a drug-free baseline session, at a first dosing session during the acute phase of the drug's effects, and in a drug-free final session following the six-week microdosing regimen. Creativity tasks were the Alternate Uses Test (AUT), Remote Associates Task (RAT), Consensual Assessment Technique (CAT), and an Everyday Problem-Solving Questionnaire (EPSQ). RESULTS: No effect of drug by time was found on the AUT, RAT, CAT, or EPSQ. Baseline vocabulary skill had a significant effect on AUT and RAT scores. CONCLUSIONS: Despite participants reporting feeling more creative on dose days, objective measurement found no acute or durable effects of the microdosing protocol on creativity. Possible explanations of these null findings are that laboratory testing conditions may negatively affect ability to detect naturalistic differences in creative performance, the tests available do not capture the facets of creativity that are anecdotally affected by microdosing, or that reported enhancements of creativity are placebo effects.

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Despite an established body of research characterizing how creative individuals explore their external world, relatively little is known about how such individuals navigate their inner mental life, especially in unstructured contexts such as periods of awake rest. Across two studies, the present manuscript tested the hypothesis that creative individuals are more engaged with their idle thoughts and more associative in the dynamic transitions between them. Study 1 captured the real-time conscious experiences of 81 adults as they voiced aloud the content of their mind moment-by-moment across a 10-minute unconstrained baseline period. Higher originality scores on a divergent thinking task were associated with less perceived boredom, more words spoken overall, more freely moving thoughts, and more loosely-associative (as opposed to sharp) transitions during the baseline rest period. In Study 2, across 2,612 participants, those who reported higher self-rated creativity also reported less perceived boredom during the COVID-19 pandemic, a time during which many people experienced unusually extended periods of unstructured free time. Overall, these results suggest a tendency for creative individuals to be more engaged and explorative with their thoughts when task demands are relaxed, raising implications for resting state functional MRI and societal trends to devalue idle time.

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Background: The subtype of urothelial carcinoma (SUC) has been known to possess morphological diversity for histologic subtype or divergent differentiation. However, the efficacy of avelumab against SUC remains unclear. Therefore, the effect of the treatment as well as the survival results of avelumab monotherapy were evaluated as a first-line therapeutic maintenance in patients with advanced SUC. Methods: A retrospective analysis was conducted on consecutive patients from the Uro-Oncology Group in Kyushu study population with advanced lower and upper urinary tract cancer who underwent avelumab maintenance therapy without progression after first-line platinum-based chemotherapy. Patients with pure urothelial carcinoma (PUC) and SUC were comparatively analyzed based on objective response rate (ORR), disease control rate, progression-free survival (PFS), and overall survival (OS). Results: Out of 49 recorded patients, 38 and 11 had PUC and SUC, respectively. The most common subtype element was glandular differentiation (n=5), followed by squamous differentiation (n=3), micropapillary (n=1), and plasmacytoid subtypes (n=1). The SUC and PUC groups had comparable ORR (0% vs. 2.6%, P>0.99) and disease control rates (54.5% vs. 44.7%, P=0.73). These patient groups also showed no significant difference in PFS (median 3.9 vs. 3.1 months, P=0.33) or OS (median 16.7 vs. 22.1 months, P=0.47). Conclusions: The response of SUC and PUC to avelumab was comparable in patients with advanced lower and upper urinary tract cancer, indicating that avelumab maintenance therapy is also effective for SUC.

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Subterranean and surface habitats are in stark contrast in several environmental factors. Therefore, adaptation to the subterranean environment typically impedes the (re)colonisation of surface habitats. The genus Niphargus includes amphipod crustaceans that primarily occupy subterranean habitats. All its species show typical adaptations to the subterranean environment. However, some Niphargus species occur in surface-subterranean ecotones. To understand whether (i) habitat-based phenotypic divergence is present between the cave and the ecotone species and (ii) similar phenotypes emerge independently in each ecotone, we studied morphological divergence between four cave and four ecotone Niphargus species based on 13 functional morphological traits. To account for different selection acting on the sexes, we included both males (N = 244) and females (N = 222). Nine out of 13 traits showed habitat-divergence. Traits related to feeding and crawling were shorter, while traits related to oxygenation were larger in ecotone species. Eleven out of 13 traits were sexually dimorphic. Traits related to oxygenation and crawling were larger in females, while the trait related to swimming was larger in males. We found that the extent of sexual dimorphism differs between the habitats in eight traits related to sensing, feeding, oxygenation and crawling. Additionally, we found that in certain traits related to sensing and oxygenation, habitat-related differences are only present in one sex, but not the other. We conclude that the detected differences between the cave and the ecotone species indicate divergent evolution, where similarities among the different species within habitat type indicate convergent evolution. The high degree of sexual dimorphism paired with differences in sexual dimorphism between the habitats in certain traits suggest that sexual and fecundity selections have comparable effects to environmental selection. Thus, studies of habitat-dependent adaptations investigating one sex only, or not considering sexual dimorphism, can lead to erroneous conclusions.

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Media multitasking is widespread, yet its relationship with creativity remains unclear. This study employs a combination of measures, including the media multitasking questionnaire, alternative uses task (AUT) for divergent thinking, Chinese compound remote association task (CCRAT) for convergent thinking, and a creative problem-solving task, to examine the relationship between media multitasking and creativity. Extreme values grouping [one standard deviation above or below the mean of the media multitasking index (MMI)], median value grouping, and regression analysis were used to explore the relationship between media multitasking and creativity. The results revealed the following findings: (1) across the three analysis methods, there was no significant relationship between media multitasking and performance on the AUT task. However, within the range of one standard deviation above or below the mean of the MMI, media multitasking showed a significant positive correlation with fluency, flexibility, and total scores on the AUT task. (2) Media multitasking significantly predicted the accuracy of responses on the CCRAT task positively. (3) Media multitasking significantly predicted lower scores on the applicability of creative problem-solving tasks.

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Synonymous codons were originally viewed as interchangeable, with no phenotypic consequences. However, substantial evidence has now demonstrated that synonymous substitutions can perturb a variety of gene expression and protein homeostasis mechanisms, including translational efficiency, translational fidelity, and cotranslational folding of the encoded protein. To date, most studies of synonymous codon-derived perturbations have focused on effects within a single gene. Here, we show that synonymous codon substitutions made far within the coding sequence of Escherichia coli plasmid-encoded chloramphenicol acetyltransferase (cat) can significantly increase expression of the divergent upstream tetracycline resistance gene, tetR. In four out of nine synonymously recoded cat sequences tested, expression of the upstream tetR gene was significantly elevated due to transcription of a long antisense RNA (asRNA) originating from a transcription start site within cat. Surprisingly, transcription of this asRNA readily bypassed the native tet transcriptional repression mechanism. Even more surprisingly, accumulation of the TetR protein correlated with the level of asRNA, rather than total tetR RNA. These effects of synonymous codon substitutions on transcription and translation of a neighboring gene suggest that synonymous codon usage in bacteria may be under selection to both preserve the amino acid sequence of the encoded gene and avoid DNA sequence elements that can significantly perturb expression of neighboring genes. Avoiding such sequences may be especially important in plasmids and prokaryotic genomes, where genes and regulatory elements are often densely packed. Similar considerations may apply to the design of genetic circuits for synthetic biology applications.

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Understanding the drivers of community assembly is critical for predicting the future of biodiversity and ecosystem services. Ecological selection ubiquitously shapes communities by selecting for individuals with the most suitable trait combinations. Detecting selection types on key traits across environmental gradients and over time has the potential to reveal the underlying abiotic and biotic drivers of community dynamics. Here, we present a model-based predictive framework to quantify the multidimensional trait distributions of communities (community trait spaces), which we use to identify ecological selection types shaping communities along environmental gradients. We apply the framework to over 3600 boreal forest understory plant communities with results indicating that directional, stabilizing, and divergent selection all modify community trait distributions and that the selection type acting on individual traits may change over time. Our results provide novel and rare empirical evidence for divergent selection within a natural system. Our approach provides a framework for identifying key traits under selection and facilitates the detection of processes underlying community dynamics.

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On the basis of a novel ynol-diene cyclization developed as a rapid access to tropone unit, the first divergent strategy to 17-nor-cephalotane diterpenoids has been successfully established. Combining with a bioinspired stereoselective dual hydrogenation, the divergent total synthesis of (+)-3-deoxyfortalpinoid F, (+)-harringtonolide, (-)-fortalpinoids M/N/P, and analog (-)-20-deoxocephinoid P have been achieved in 14-17 linear longest steps starting from commercially available materials.

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Inspired by the previous machine-learning study that the number of hydrogen-bonding acceptor (NHBA) is important index for the hole mobility of organic semiconductors, seven dithienobenzothiazole (DBT) derivatives 1a-g (NHBA = 5) were designed and synthesized by one-step functionalization from a common precursor. X-ray single-crystal structural analyses confirmed that the molecular arrangements of 1b (the diethyl and ethylthienyl derivative) and 1c (the di(n-propyl) and n-propylthienyl derivative) in the crystal are classified into brickwork structures with multidirectional intermolecular charge-transfer integrals, as a result of incorporation of multiple hydrogen-bond acceptors. The solution-processed top-gate bottom-contact devices of 1b and 1c had hole mobilities of 0.16 and 0.029 cm2 V-1s-1, respectively.

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Expanding the diversity of multi-macrocyclic nanocarbons, particularly those with all-benzene scaffolds, represents intriguing yet challenging synthetic tasks. Complementary to the existing synthetic approaches, here we report an efficient and modular post-functionalization strategy that employs iridium-catalyzed C-H borylation of the highly strained meta-cycloparaphenylenes (mCPPs) and an mCPP-derived catenane. Based on the functionalized macrocyclic synthons, a number of novel all-benzene topological structures including linear and cyclic chains, polycatenane, and pretzelane have been successfully prepared and characterized, thereby showcasing the synthetic utility and potential of the post-functionalization strategy.

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Strong gene flow from outcrossing relatives tends to blur species boundaries, while divergent ecological selection can counteract gene flow. To better understand how these two forces affect the maintenance of species boundaries, we focused on a species complex including a rare species, maple-leaf oak (Quercus acerifolia), which is found in only four disjunct ridges in Arkansas. Its limited range and geographic proximity to co-occurring close relatives create the possibility for genetic swamping. In this study, we gathered genome-wide single nucleotide polymorphisms (SNPs) using restriction-site-associated DNA sequencing (RADseq) from 190 samples of Q. acerifolia and three of its close relatives, Q. shumardii, Q. buckleyi, and Q. rubra. We found that Q. shumardii and Q. acerifolia are reciprocally monophyletic with low support, suggesting incomplete lineage sorting, introgression between Q. shumardii and Q. acerifolia, or both. Analyses that model allele distributions demonstrate that admixture contributes strongly to this pattern. Populations of Q. acerifolia experience gene flow from Q. shumardii and Q. rubra, but we found evidence that divergent selection is likely maintaining species boundaries: 1) ex situ collections of Q. acerifolia have a higher proportion of hybrids compared to the mature trees of the wild populations, suggesting ecological selection against hybrids at the seed/seedling stage; 2) ecological traits co-vary with genomic composition; and 3) Q. acerifolia shows genetic differentiation at loci hypothesized to influence tolerance of radiation, drought, and high temperature. Our findings strongly suggest that in maple-leaf oak, selection results in higher divergence at regions of the genome despite gene flow from close relatives.

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The default mode network (DMN) is a widely distributed, intrinsic brain network thought to play a crucial role in internally-directed cognition. The present study employs stereo-electroencephalography in 13 human patients, obtaining high resolution neural recordings across multiple canonical DMN regions during two processes that have been associated with creative thinking: spontaneous and divergent thought. We probe these two DMN-associated higher cognitive functions through mind wandering and alternate uses tasks, respectively. Our results reveal DMN recruitment during both tasks, as well as a task-specific dissociation in spatiotemporal response dynamics. When compared to the fronto-parietal network, DMN activity was characterized by a stronger increase in gamma band power (30-70 Hz) coupled with lower theta band power (4-8 Hz). The difference in activity between the two networks was especially strong during the mind wandering task. Within the DMN, we found that the tasks showed different dynamics, with the alternate uses task engaging the DMN more during the initial stage of the task, and mind wandering in the later stage. Gamma power changes were mainly driven by lateral DMN sites, while theta power displayed task-specific effects. During alternate uses task, theta changes did not show spatial differences within the DMN, while mind wandering was associated to an early lateral and late dorsomedial DMN engagement. Furthermore, causal manipulations of DMN regions using direct cortical stimulation preferentially decreased the originality of responses in the alternative uses task, without affecting fluency or mind wandering. Our results suggest that DMN activity is flexibly modulated as a function of specific cognitive processes and supports its causal role in divergent thinking. These findings shed light on the neural constructs supporting different forms of cognition and provide causal evidence for the role of DMN in the generation of original connections among concepts.

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Designers' work processes are shaped by a four-phase 'discover, define, develop, and deliver' model that alternates between divergent and convergent thinking. We suggest consideration of this conceptual scaffold in 'design sprint' workshops for graduate students in the life sciences and in design to promote creativity, interdisciplinary collaboration, and knowledge cocreation.

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RAMOSA1 (RA1) is a Cys2-His2-type (C2H2) zinc finger transcription factor that controls plant meristem fate and identity and has played an important role in maize domestication. Despite its importance, the origin of RA1 is unknown, and the evolution in plants is only partially understood. In this paper, we present a well-resolved phylogeny based on 73 amino acid sequences from 48 embryophyte species. The recovered tree topology indicates that, during grass evolution, RA1 arose from two consecutive SUPERMAN duplications, resulting in three distinct grass sequence lineages: RA1-like A, RA1-like B, and RA1; however, most of these copies have unknown functions. Our findings indicate that RA1 and RA1-like play roles in the nucleus despite lacking a traditional nuclear localization signal. Here, we report that copies diversified their coding region and, with it, their protein structure, suggesting different patterns of DNA binding and protein-protein interaction. In addition, each of the retained copies diversified regulatory elements along their promoter regions, indicating differences in their upstream regulation. Taken together, the evidence indicates that the RA1 and RA1-like gene families in grasses underwent subfunctionalization and neofunctionalization enabled by gene duplication.

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Objective This study aimed to compare the soft tissue chin (STC) thickness at different levels in patients presenting for orthodontic treatment with different vertical facial types. Materials and methods This comparative cross-sectional study was conducted at Sharif Medical & Dental College, Lahore, Pakistan, on 195 subjects. Patients presenting for orthodontic treatment, both genders, aged from 18 to 32 years, and Pakistani nationals were included. Patients with any craniofacial deformity, syndrome, cleft lip and palate, previous orthodontic or orthognathic treatment, and multiple missing teeth and prostheses in edentulous areas were excluded. Vertical facial patterns and STC thickness were recorded from pre-treatment lateral cephalograms. One-way analysis of variance (ANOVA) was applied to compare STC among various vertical facial patterns. Post-hoc analysis was done using the Tukey test. Results There were 126 females (64.62%) and 69 males (35.38%). The mean age was 21.66 ± 3.44 years. All three soft tissue chin thickness distances significantly differed among vertical facial patterns (p<0.001). Multiple comparisons show that the distance between soft and hard tissue pogonion was insignificant between low and normal angle facial heights (p=0.5). Similarly, no significant difference was observed for the distance between soft and hard tissue menton in low and normal angle subjects (p=0.4). The rest of the multiple comparisons were statistically significant (p<0.05). Conclusion The STC thickness is significantly associated with vertical facial divergence. While planning orthognathic surgery or genioplasty of the mandible, due consideration should be given to vertical divergence of the face to avoid unwanted facial changes.

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The neuroscience of creativity is built on a tacit and near universal assumption that is false. Paradoxically, this is not contentious; once made explicit, the assumption is readily conceded as false. Psychology regards creativity as made up of many complex, multifaceted, and varied cognitive and emotional processes deployed across many different domains. But we instead think of, and treat, creativity as if it were a single, separate, cohesive, and discrete thing-as in, Einstein had it. In a straightforward extension of this fallacy, cognitive neuroscientists have looked for uniquely creative cognition that (1) is distinct from all other kinds of cognition and (2) has a proprietary neural substrate. In other words, a standalone and monolithic creativity faculty in the brain that manages only creativity and all creativity. First, this paper brings into sharp focus the nature and ubiquity of this fallacy. It then outlines the alternative theoretical position that is (1) based on fundamental neural principles and (2) predicated on taking seriously the concept of creativity as complex and diverse. Like morality or secretiveness, it holds that creativity does not exist as its own, specialized entity in the brain. Instead, its neurocognitive mechanisms are distributed, embedded, and varied; that is, creativity is everywhere and multiply realizable.