The cellular function of ROP GTPase prenylation is important for multicellularity in the moss Physcomitrium patens.

A complete picture of how signaling pathways lead to multicellularity is largely unknown. Previously, we generated mutations in a protein prenylation enzyme, GGB, and showed that it is essential for maintaining multicellularity in the moss Physcomitrium patens. Here, we show that ROP GTPases act as downstream factors that are prenylated by GGB and themselves play an important role in the multicellularity of P. patens. We also show that the loss of multicellularity caused by the suppression of GGB or ROP GTPases is due to uncoordinated cell expansion, defects in cell wall integrity and the disturbance of the directional control of cell plate orientation. Expressing prenylatable ROP in the ggb mutant not only rescues multicellularity in protonemata but also results in development of gametophores. Although the prenylation of ROP is important for multicellularity, a higher threshold of active ROP is required for gametophore development. Thus, our results suggest that ROP activation via prenylation by GGB is a key process at both cell and tissue levels, facilitating the developmental transition from one dimension to two dimensions and to three dimensions in P. patens.

Protein-protein interactions between tenascin-R and RPTPζ/phosphacan are critical to maintain the architecture of perineuronal nets.

Neural plasticity, the ability to alter the structure and function of neural circuits, varies throughout the age of an individual. The end of the hyperplastic period in the central nervous system coincides with the appearance of honeycomb-like structures called perineuronal nets (PNNs) that surround a subset of neurons. PNNs are a condensed form of neural extracellular matrix that include the glycosaminoglycan hyaluronan and extracellular matrix proteins such as aggrecan and tenascin-R (TNR). PNNs are key regulators of developmental neural plasticity and cognitive functions, yet our current understanding of the molecular interactions that help assemble them remains limited. Disruption of Ptprz1, the gene encoding the receptor protein tyrosine phosphatase RPTPζ, altered the appearance of nets from a reticulated structure to puncta on the surface of cortical neuron bodies in adult mice. The structural alterations mirror those found in Tnr-/- mice, and TNR is absent from the net structures that form in dissociated cultures of Ptprz1-/- cortical neurons. These findings raised the possibility that TNR and RPTPζ cooperate to promote the assembly of PNNs. Here, we show that TNR associates with the RPTPζ ectodomain and provide a structural basis for these interactions. Furthermore, we show that RPTPζ forms an identical complex with tenascin-C, a homolog of TNR that also regulates neural plasticity. Finally, we demonstrate that mutating residues at the RPTPζ-TNR interface impairs the formation of PNNs in dissociated neuronal cultures. Overall, this work sets the stage for analyzing the roles of protein-protein interactions that underpin the formation of nets.

Hierarchical Materials from High Information Content Macromolecular Building Blocks: Construction, Dynamic Interventions, and Prediction.

Hierarchical materials that exhibit order over multiple length scales are ubiquitous in nature. Because hierarchy gives rise to unique properties and functions, many have sought inspiration from nature when designing and fabricating hierarchical matter. More and more, however, nature's own high-information content building blocks, proteins, peptides, and peptidomimetics, are being coopted to build hierarchy because the information that determines structure, function, and interfacial interactions can be readily encoded in these versatile macromolecules. Here, we take stock of recent progress in the rational design and characterization of hierarchical materials produced from high-information content blocks with a focus on stimuli-responsive and "smart" architectures. We also review advances in the use of computational simulations and data-driven predictions to shed light on how the side chain chemistry and conformational flexibility of macromolecular blocks drive the emergence of order and the acquisition of hierarchy and also on how ionic, solvent, and surface effects influence the outcomes of assembly. Continued progress in the above areas will ultimately usher in an era where an understanding of designed interactions, surface effects, and solution conditions can be harnessed to achieve predictive materials synthesis across scale and drive emergent phenomena in the self-assembly and reconfiguration of high-information content building blocks.

Parents' anti-Black messages, empathic reactions toward racism, fear of Black individuals, and perceived ability to engage in anti-racism advocacy among Asian American emerging adults.

Asian Americans, historically oppressed and influenced by White supremacist norms, may internalize anti-Blackness (beliefs of behaviors that minimize, marginalize, or devalue Black individuals) as they navigate White-dominated environments to survive and seek acceptance. However, there is limited research addressing the intergenerational socialization of anti-Blackness within Asian American communities and its impact as a barrier to cross-racial solidarity and involvement in anti-racism efforts. Thus, we tested whether parents' anti-Black messages were associated with fear of Black individuals and lack of empathic reactions to anti-Black racism, and in turn, related to hindrance in the perceived ability to engage in anti-racism advocacy among Asian American emerging adults. With data from 205 participants (Mage = 19.92, SD = 2.64, online convenience sample), we conducted a path analysis of parents' anti-Black messages indirectly associated with perceived ability in advocacy against anti-Black racism through fear of Black individuals and empathic reactions to anti-Black racism. Parents' anti-Black messages were associated with greater fear of Black individuals, which was associated with lower empathic reactions to racism, and in turn, ultimately associated with a lower perceived ability to engage in advocacy against anti-Black racism. This pathway was the best-fitting model compared with an alternative parallel model (fear and empathy as separate mediators) and a model with empathy as the first mediator. Our study suggests that clinicians, educators, and researchers should target parents' anti-Black messages and Asian American emerging adults' emotional responses (fear, empathy) to anti-Black racism in disrupting anti-Blackness at parental/family and individual levels.

Amphiphilic Peptoid-Directed Assembly of Oligoanilines into Highly Crystalline Conducting Nanotubes.

It is reported herein the synthesis of a novel amphiphilic diblock peptoid bearing a terminal conjugated oligoaniline and its self-assembly into small-diameter (D ≈ 35 nm) crystalline nanotubes with high aspect ratios (>30). It is shown that both tetraaniline (TANI)-peptoid and bianiline (BANI)-peptoid triblock molecules self-assemble in solution to form rugged highly crystalline nanotubes that are very stable to protonic acid doping and de-doping processes. The similarity of the crystalline tubular structure of the nanotube assemblies revealed by electron microscopy imaging, and X-ray diffraction analysis of the nanotube assemblies of TANI-functionalized peptoids and nonfunctionalized peptoids showed that the peptoid is an efficient ordered structure directing motif for conjugated oligomers. Films of doped TANI-peptoid nanotubes has a dc conductivity of ca. 95 mS cm-1 , while the thin films of doped un-assembled TANI-peptoids show a factor of 5.6 lower conductivity, demonstrating impact of the favorable crystalline ordering of the assemblies on electrical transport. These results demonstrate that peptoid-directed supramolecular assembly of tethered π-conjugated oligo(aniline) exemplify a novel general strategy for creating rugged ordered and complex nanostructures that have useful electronic and optoelectronic properties.

Multispecies facial detection for individual identification of wildlife: a case study across ursids.

To address biodiversity decline in the era of big data, replicable methods of data processing are needed. Automated methods of individual identification (ID) via computer vision are valuable in conservation research and wildlife management. Rapid and systematic methods of image processing and analysis are fundamental to an ever-growing need for effective conservation research and practice. Bears (ursids) are an interesting test system for examining computer vision techniques for wildlife, as they have variable facial morphology, variable presence of individual markings, and are challenging to research and monitor. We leveraged existing imagery of bears living under human care to develop a multispecies bear face detector, a critical part of individual ID pipelines. We compared its performance across species and on a pre-existing wild brown bear Ursus arctos dataset (BearID), to examine the robustness of convolutional neural networks trained on animals under human care. Using the multispecies bear face detector and retrained sub-applications of BearID, we prototyped an end-to-end individual ID pipeline for the declining Andean bear Tremarctos ornatus. Our multispecies face detector had an average precision of 0.91-1.00 across all eight bear species, was transferable to images of wild brown bears (AP = 0.93), and correctly identified individual Andean bears in 86% of test images. These preliminary results indicate that a multispecies-trained network can detect faces of a single species sufficiently to achieve high-performance individual classification, which could speed-up the transferability and application of automated individual ID to a wider range of taxa. Supplementary Information: The online version contains supplementary material available at 10.1007/s42991-021-00168-5.

Characterization of a novel roseophage and the morphological and transcriptional response of the sponge symbiont Ruegeria AU67 to infection.

Sponges have recently been recognized to contain complex communities of bacteriophages; however, little is known about how they interact with their bacterial hosts. Here, we isolated a novel phage, called Ruegeria phage Tedan, and characterized its impact on the bacterial sponge symbiont Ruegeria AU67 on a morphological and molecular level. Phage Tedan was structurally, genomically and phylogenetically characterized to be affiliated with the genus Xiamenvirus of the family Siphoviridae. Through microscopic observations and transcriptomic analysis, we show that phage Tedan upon infection induces a process leading to metabolic and morphological changes in its host. These changes would render Ruegeria AU67 better adapted to inhabit the sponge holobiont due to an improved utilization of ecologically relevant energy and carbon sources as well as a potential impediment of phagocytosis by the sponge through cellular enlargement. An increased survival or better growth of the bacterium in the sponge environment will likely benefit the phage reproduction. Our results point towards the possibility that phages from host-associated environments require, and have thus evolved, different strategies to interact with their host when compared to those phages from free-living or planktonic environments.

Comparison of management options for specific antibody deficiency.

Background: Specific antibody deficiency is a primary immunodeficiency characterized by normal immunoglobulins with an inadequate response to polysaccharide antigen vaccination. This disease can result in recurrent infections, the most common being sinopulmonary infections. Treatment options include clinical observation, prophylactic antibiotic therapy, and immunoglobulin supplementation therapy, each with limited clinical data about their efficacy. Objective: This study aimed to identify whether there was a statistically significant difference in the rate of infections for patients who were managed with clinical observation, prophylactic antibiotics, or immunoglobulin supplementation therapy. Methods: A retrospective chart review was conducted. Patients were eligible for the study if they had normal immunoglobulin levels, an inadequate antibody response to polysaccharide antigen-based vaccination, and no other known causes of immunodeficiency. Results: A total of 26 patients with specific antibody deficiency were identified. Eleven patients were managed with immunoglobulin supplementation, ten with clinical observation, and five with prophylactic antibiotic therapy. The frequency of antibiotic prescriptions was assessed for the first year after intervention. A statistically significant rate of decreased antibiotic prescriptions after intervention was found for patients treated with immunoglobulin supplementation (n = 11; p = 0.0004) and for patients on prophylactic antibiotics (n = 5; p = 0.01). There was no statistical difference in antibiotic prescriptions for those patients treated with immunoglobulin supplementation versus prophylactic antibiotics (p = 0.21). Conclusion: Prophylactic antibiotics seemed to be equally effective as immunoglobin supplementation therapy for the treatment of specific antibody deficiency. Further studies are needed in this area.

A Review of Patient and Provider Satisfaction with Telemedicine.

PURPOSE OF REVIEW: The purpose of this review is to describe the determinants of satisfaction with telemedicine (TM) and how they compare with in-person visits from both the perspective of patients and of providers. RECENT FINDINGS: The use of TM will expand only if patients and providers are at least as satisfied with it as they are with in-person visits. Since deviations from expected care can result in reduced satisfaction regardless of the quality of the visit or objective medical outcomes, it is important to understand and to help form those expectations when possible. Patients consistently report 95-100% satisfaction rate with TM when compared with in-person appointments. They tend to cite the convenience of decreased travel times and costs as the main drivers for satisfaction with TM. Providers tend to be satisfied with TM if they have input into its development, there is administrative support, the technology is reliable and easy to use, and if there is adequate reimbursement for its use. Satisfaction with TM is necessary for adoption of this new technology. To improve satisfaction it is important to consider factors that drive it both for patients and for providers.

The influence of polarizability and charge transfer on specific ion effects in the dynamics of aqueous salt solutions.

The diffusion rates for water molecules in salt solutions depend on the identity of the ions, as well as their concentration. Among the alkali metal ions, cesium and potassium increase and sodium strongly decreases the diffusion constant of water. The origin of the difference can be understood by examining the simulation results using different potential models. In this work, aqueous solutions of salts are simulated with a variety of models. Commonly used non-polarizable models, which otherwise reproduce many experimental properties, do not capture the trend in the diffusion constant, while models which include polarization and/or charge transfer interactions do. For the non-polarizable models, the diffusion constant decreases too strongly with salt concentration. The changes in the water diffusion constant with increasing salt concentration match the diffusion constant of the ion. The ion diffusion constant is dependent on the residence time for water in the ion solvation shell. The non-polarizable models over-estimate the residence time, relative to the translational diffusion constant and so tend to under-estimate the ion and water diffusion constants.

Catalytic Hydroalkylation of Allenes.

We have developed a catalytic method for the hydroalkylation of allenes using alkyl triflates as electrophiles and silane as a hydride source. The reaction has an excellent substrate scope and is compatible with a wide range of functional groups, including esters, aryl halides, aryl boronic esters, sulfonamides, alkyl tosylates, and alkyl bromides. We found evidence for a reaction mechanism that involves unusual dinuclear copper ally complexes as catalytic intermediates. The unusual structure of these complexes provides a rationale for their unexpected reactivity.

AKT2 confers protection against aortic aneurysms and dissections.

RATIONALE: Aortic aneurysm and dissection (AAD) are major diseases of the adult aorta caused by progressive medial degeneration of the aortic wall. Although the overproduction of destructive factors promotes tissue damage and disease progression, the role of protective pathways is unknown. OBJECTIVE: In this study, we examined the role of AKT2 in protecting the aorta from developing AAD. METHODS AND RESULTS: AKT2 and phospho-AKT levels were significantly downregulated in human thoracic AAD tissues, especially within the degenerative medial layer. Akt2-deficient mice showed abnormal elastic fibers and reduced medial thickness in the aortic wall. When challenged with angiotensin II, these mice developed aortic aneurysm, dissection, and rupture with features similar to those in humans, in both thoracic and abdominal segments. Aortas from Akt2-deficient mice displayed profound tissue destruction, apoptotic cell death, and inflammatory cell infiltration that were not observed in aortas from wild-type mice. In addition, angiotensin II-infused Akt2-deficient mice showed significantly elevated expression of matrix metalloproteinase-9 (MMP-9) and reduced expression of tissue inhibitor of metalloproteinase-1 (TIMP-1). In cultured human aortic vascular smooth muscle cells, AKT2 inhibited the expression of MMP-9 and stimulated the expression of TIMP-1 by preventing the binding of transcription factor forkhead box protein O1 to the MMP-9 and TIMP-1 promoters. CONCLUSIONS: Impaired AKT2 signaling may contribute to increased susceptibility to the development of AAD. Our findings provide evidence of a mechanism that underlies the protective effects of AKT2 on the aortic wall and that may serve as a therapeutic target in the prevention of AAD.

Synthesis of Small 3-Fluoro- and 3,3-Difluoropyrrolidines Using Azomethine Ylide Chemistry.

Here, we report accessing small 3-fluoropyrrolidines and 3,3-difluoropyrrolidines through a 1,3-dipolar cycloaddition with a simple azomethine ylide and a variety of vinyl fluorides and vinyl difluorides. We demonstrate that vinyl fluorides within α,ß-unsaturated, styrenyl and even enol ether systems can participate in the cycloaddition reaction. The vinyl fluorides are relatively easy to synthesize through a variety of methods, making the 3-fluoropyrrolidines very accessible.

Ankyrin-repeat proteins from sponge symbionts modulate amoebal phagocytosis.

Bacteria-eukaryote symbiosis occurs in all stages of evolution, from simple amoebae to mammals, and from facultative to obligate associations. Sponges are ancient metazoans that form intimate symbiotic interactions with complex communities of bacteria. The basic nutritional requirements of the sponge are in part satisfied by the phagocytosis of bacterial food particles from the surrounding water. How bacterial symbionts, which are permanently associated with the sponge, survive in the presence of phagocytic cells is largely unknown. Here, we present the discovery of a genomic fragment from an uncultured gamma-proteobacterial sponge symbiont that encodes for four proteins, whose closest known relatives are found in a sponge genome. Through recombinant approaches, we show that these four eukaryotic-like, ankyrin-repeat proteins (ARP) when expressed in Eschericha coli can modulate phagocytosis of amoebal cells and lead to accumulation of bacteria in the phagosome. Mechanistically, two ARPs appear to interfere with phagosome development in a similar way to reduced vacuole acidification, by blocking the fusion of the early phagosome with the lysosome and its digestive enzymes. Our results show that ARP from sponge symbionts can function to interfere with phagocytosis, and we postulate that this might be one mechanism by which symbionts can escape digestion in a sponge host.

Charge and sequence effects on the self-assembly and subsequent hydrogelation of Fmoc-depsipeptides.

Herein we report on the self-assembly of a family of Fmoc-depsipeptides into nanofibers and hydrogels. We show that fiber formation occurs in depsipeptide structures in which the fluorenyl group is closely associated and that side-chain charge and sequence affect the extent of self-assembly and subsequent gelation. Using fluorescence emission spectroscopy and circular dichroism, we show that self-assembly can be monitored and is observed in these slow-gelling systems prior to hydrogel formation. We also demonstrate that the ionic strength of salt-containing solutions affects the time at which self-assembly results in gelation of the bulk solution. From transmission electron microscopy, we report that morphological changes progress over time and are observed as micelles transitioning to fibers prior to the onset of gelation. Gelled depsipeptides degraded at a slower rate than non-gelled samples in the presence of salt, while hydrolysis in water of both gels and solution samples was minimal even after 14 days. Our work shows that while incorporating ester functionality within a peptide backbone reduces the number of hydrogen bonding sites available for forming and stabilizing supramolecular assemblies, the substitution does not prohibit self-assembly and subsequent gelation.

Gendered Racial Microaggressions and Depressive Symptoms Among Emerging Adult Asian American Women: Racial/Ethnic Differences Among Asian and White Romantic Partners.

Discrimination can contribute to adverse mental health outcomes among individuals in romantic partnerships. However, research has yet to examine how differences in partner race/ethnicity can shape the link between gendered racial microaggressions, an intersectional form of discrimination, and depressive symptoms among Asian American women. Accordingly, we assessed the link between gendered racial microaggressions and depressive symptoms, and whether partner race/ethnicity (White vs. Asian) moderated the link. Using a sample of 156 Asian American women (Mage = 26.5, SD = 5.33), we conducted multiple regressions to assess the main effects between four gendered racial microaggression stress subscale factors and depressive symptoms. We then examined partner race/ethnicity as a moderator in these associations. All four gendered racial microaggression stress subscale factors of ascribed submissiveness, assumptions of universal appearance, Asian fetishism, and media invalidation significantly predicted greater depressive symptoms. However, only Asian fetishism experiences maintained a significant and positive association with depressive symptoms for Asian American women with White male partners. The association between Asian fetishism and depressive symptoms was no longer significant for Asian American women with Asian male partners. Results indicate that Asian fetishization may be a uniquely oppressive experience for Asian American women with White partners that can contribute to greater depressive symptoms. These findings demonstrate an increased need for the development of critical consciousness in individual and couples counseling sessions to help Asian American women and their romantic partners identify and mitigate the negative effects of gendered racial microaggressions.

Treatment Effects in Randomized and Nonrandomized Studies of Pharmacological Interventions: A Meta-Analysis.

Importance: Randomized clinical trials (RCTs) are widely regarded as the methodological benchmark for assessing clinical efficacy and safety of health interventions. There is growing interest in using nonrandomized studies to assess efficacy and safety of new drugs. Objective: To determine how treatment effects for the same drug compare when evaluated in nonrandomized vs randomized studies. Data Sources: Meta-analyses published between 2009 and 2018 were identified in MEDLINE via PubMed and the Cochrane Database of Systematic Reviews. Data analysis was conducted from October 2019 to July 2024. Study Selection: Meta-analyses of pharmacological interventions were eligible for inclusion if both randomized and nonrandomized studies contributed to a single meta-analytic estimate. Data Extraction and Synthesis: For this meta-analysis using a meta-epidemiological framework, separate summary effect size estimates were calculated for nonrandomized and randomized studies within each meta-analysis using a random-effects model and then these estimates were compared. The reporting of this study followed the Guidelines for Reporting Meta-Epidemiological Methodology Research and relevant portions of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline. Main Outcome and Measures: The primary outcome was discrepancies in treatment effects obtained from nonrandomized and randomized studies, as measured by the proportion of meta-analyses where the 2 study types disagreed about the direction or magnitude of effect, disagreed beyond chance about the effect size estimate, and the summary ratio of odds ratios (ROR) obtained from nonrandomized vs randomized studies combined across all meta-analyses. Results: A total of 346 meta-analyses with 2746 studies were included. Statistical conclusions about drug benefits and harms were different for 130 of 346 meta-analyses (37.6%) when focusing solely on either nonrandomized or randomized studies. Disagreements were beyond chance for 54 meta-analyses (15.6%). Across all meta-analyses, there was no strong evidence of consistent differences in treatment effects obtained from nonrandomized vs randomized studies (summary ROR, 0.95; 95% credible interval [CrI], 0.89-1.02). Compared with experimental nonrandomized studies, randomized studies produced on average a 19% smaller treatment effect (ROR, 0.81; 95% CrI, 0.68-0.97). There was increased heterogeneity in effect size estimates obtained from nonrandomized compared with randomized studies. Conclusions and Relevance: In this meta-analysis of treatment effects of pharmacological interventions obtained from randomized and nonrandomized studies, there was no overall difference in effect size estimates between study types on average, but nonrandomized studies both overestimated and underestimated treatment effects observed in randomized studies and introduced additional uncertainty. These findings suggest that relying on nonrandomized studies as substitutes for RCTs may introduce additional uncertainty about the therapeutic effects of new drugs.

TOPORS E3 ligase mediates resistance to hypomethylating agent cytotoxicity in acute myeloid leukemia cells.

Hypomethylating agents (HMAs) are frontline therapies for Myelodysplastic Neoplasms (MDS) and Acute Myeloid Leukemia (AML). However, acquired resistance and treatment failure are commonplace. To address this, we perform a genome-wide CRISPR-Cas9 screen in a human MDS-derived cell line, MDS-L, and identify TOPORS as a loss-of-function target that synergizes with HMAs, reducing leukemic burden and improving survival in xenograft models. We demonstrate that depletion of TOPORS mediates sensitivity to HMAs by predisposing leukemic blasts to an impaired DNA damage response (DDR) accompanied by an accumulation of SUMOylated DNMT1 in HMA-treated TOPORS-depleted cells. The combination of HMAs with targeting of TOPORS does not impair healthy hematopoiesis. While inhibitors of TOPORS are unavailable, we show that inhibition of protein SUMOylation with TAK-981 partially phenocopies HMA-sensitivity and DDR impairment. Overall, our data suggest that the combination of HMAs with inhibition of SUMOylation or TOPORS is a rational treatment option for High-Risk MDS (HR-MDS) or AML.