nils-herrmann/clean_scirepeval huggingface dataset:
Noncanonical TGF-β signaling leads to FBXO3-mediated degradation of ΔNp63α promoting breast cancer metastasis and poor clinical prognosis
Venue: PLoS biology

Transforming growth factor-β (TGF-β) signaling plays a critical role in promoting epithelial-to-mesenchymal transition (EMT), cell migration, invasion, and tumor metastasis. ΔNp63α, the major isoform of p63 protein expressed in epithelial cells, is a key transcriptional regulator of cell adhesion program and functions as a critical metastasis suppressor. It has been documented that the expression of ΔNp63α is tightly controlled by oncogenic signaling and is frequently reduced in advanced cancers. However, whether TGF-β signaling regulates ΔNp63α expression in promoting metastasis is largely unclear. In this study, we demonstrate that activation of TGF-β signaling leads to stabilization of E3 ubiquitin ligase FBXO3, which, in turn, targets ΔNp63α for proteasomal degradation in a Smad-independent but Erk-dependent manner. Knockdown of FBXO3 or restoration of ΔNp63α expression effectively rescues TGF-β-induced EMT, cell motility, and tumor metastasis in vitro and in vivo. Furthermore, clinical analyses reveal a significant correlation among TGF-β receptor I (TβRI), FBXO3, and p63 protein expression and that high expression of TβRI/FBXO3 and low expression of p63 are associated with poor recurrence-free survival (RFS). Together, these results demonstrate that FBXO3 facilitates ΔNp63α degradation to empower TGF-β signaling in promoting tumor metastasis and that the TβRI-FBXO3-ΔNp63α axis is critically important in breast cancer development and clinical prognosis. This study suggests that FBXO3 may be a potential therapeutic target for advanced breast cancer treatment.
Silencing of SRRM4 suppresses microexon inclusion and promotes tumor growth across cancers
Venue: PLoS biology

RNA splicing is widely dysregulated in cancer, frequently due to altered expression or activity of splicing factors (SFs). Microexons are extremely small exons (3–27 nucleotides long) that are highly evolutionarily conserved and play critical roles in promoting neuronal differentiation and development. Inclusion of microexons in mRNA transcripts is mediated by the SF Serine/Arginine Repetitive Matrix 4 (SRRM4), whose expression is largely restricted to neural tissues. However, microexons have been largely overlooked in prior analyses of splicing in cancer, as their small size necessitates specialized computational approaches for their detection. Here, we demonstrate that despite having low expression in normal nonneural tissues, SRRM4 is further silenced in tumors, resulting in the suppression of normal microexon inclusion. Remarkably, SRRM4 is the most consistently silenced SF across all tumor types analyzed, implying a general advantage of microexon down-regulation in cancer independent of its tissue of origin. We show that this silencing is favorable for tumor growth, as decreased SRRM4 expression in tumors is correlated with an increase in mitotic gene expression, and up-regulation of SRRM4 in cancer cell lines dose-dependently inhibits proliferation in vitro and in a mouse xenograft model. Further, this proliferation inhibition is accompanied by induction of neural-like expression and splicing patterns in cancer cells, suggesting that SRRM4 expression shifts the cell state away from proliferation and toward differentiation. We therefore conclude that SRRM4 acts as a proliferation brake, and tumors gain a selective advantage by cutting off this brake.
Ecological rules for the assembly of microbiome communities
Venue: PLoS biology

Humans and many other hosts establish a diverse community of beneficial microbes anew each generation. The order and identity of incoming symbionts is critical for health, but what determines the success of the assembly process remains poorly understood. Here we develop ecological theory to identify factors important for microbial community assembly. Our method maps out all feasible pathways for the assembly of a given microbiome—with analogies to the mutational maps underlying fitness landscapes in evolutionary biology. Building these “assembly maps” reveals a tradeoff at the heart of the assembly process. Ecological dependencies between members of the microbiota make assembly predictable—and can provide metabolic benefits to the host—but these dependencies may also create barriers to assembly. This effect occurs because interdependent species can fail to establish when each relies on the other to colonize first. We support our predictions with published data from the assembly of the preterm infant microbiota, where we find that ecological dependence is associated with a predictable order of arrival. Our models also suggest that hosts can overcome barriers to assembly via mechanisms that either promote the uptake of multiple symbiont species in one step or feed early colonizers. This predicted importance of host feeding is supported by published data on the impacts of breast milk in the assembly of the human microbiome. We conclude that both microbe to microbe and host to microbe interactions are important for the trajectory of microbiome assembly.
The plant metabolome guides fitness-relevant foraging decisions of a specialist herbivore
Venue: PLoS biology

Plants produce complex mixtures of primary and secondary metabolites. Herbivores use these metabolites as behavioral cues to increase their fitness. However, how herbivores combine and integrate different metabolite classes into fitness-relevant foraging decisions in planta is poorly understood. We developed a molecular manipulative approach to modulate the availability of sugars and benzoxazinoid secondary metabolites as foraging cues for a specialist maize herbivore, the western corn rootworm. By disrupting sugar perception in the western corn rootworm and benzoxazinoid production in maize, we show that sugars and benzoxazinoids act as distinct and dynamically combined mediators of short-distance host finding and acceptance. While sugars improve the capacity of rootworm larvae to find a host plant and to distinguish postembryonic from less nutritious embryonic roots, benzoxazinoids are specifically required for the latter. Host acceptance in the form of root damage is increased by benzoxazinoids and sugars in an additive manner. This pattern is driven by increasing damage to postembryonic roots in the presence of benzoxazinoids and sugars. Benzoxazinoid- and sugar-mediated foraging directly improves western corn rootworm growth and survival. Interestingly, western corn rootworm larvae retain a substantial fraction of their capacity to feed and survive on maize plants even when both classes of chemical cues are almost completely absent. This study unravels fine-grained differentiation and combination of primary and secondary metabolites into herbivore foraging and documents how the capacity to compensate for the lack of important chemical cues enables a specialist herbivore to survive within unpredictable metabolic landscapes.
COVID-19 induces a hyperactive phenotype in circulating platelets
Venue: PLoS biology

Coronavirus Disease 2019 (COVID-19), caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has affected over 30 million globally to date. Although high rates of venous thromboembolism and evidence of COVID-19-induced endothelial dysfunction have been reported, the precise aetiology of the increased thrombotic risk associated with COVID-19 infection remains to be fully elucidated. Therefore, we assessed clinical platelet parameters and circulating platelet activity in patients with severe and nonsevere COVID-19. An assessment of clinical blood parameters in patients with severe COVID-19 disease (requiring intensive care), patients with nonsevere disease (not requiring intensive care), general medical in-patients without COVID-19, and healthy donors was undertaken. Platelet function and activity were also assessed by secretion and specific marker analysis. We demonstrated that routine clinical blood parameters including increased mean platelet volume (MPV) and decreased platelet:neutrophil ratio are associated with disease severity in COVID-19 upon hospitalisation and intensive care unit (ICU) admission. Strikingly, agonist-induced ADP release was 30- to 90-fold higher in COVID-19 patients compared with hospitalised controls and circulating levels of platelet factor 4 (PF4), soluble P-selectin (sP-selectin), and thrombopoietin (TPO) were also significantly elevated in COVID-19. This study shows that distinct differences exist in routine full blood count and other clinical laboratory parameters between patients with severe and nonsevere COVID-19. Moreover, we have determined all COVID-19 patients possess hyperactive circulating platelets. These data suggest abnormal platelet reactivity may contribute to hypercoagulability in COVID-19 and confirms the role that platelets/clotting has in determining the severity of the disease and the complexity of the recovery path.
Nonsense-mediated decay controls the reactivation of the oncogenic herpesviruses EBV and KSHV
Venue: PLoS biology

The oncogenic human herpesviruses Epstein–Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) are the causative agents of multiple malignancies. A hallmark of herpesviruses is their biphasic life cycle consisting of latent and lytic infection. In this study, we identified that cellular nonsense-mediated decay (NMD), an evolutionarily conserved RNA degradation pathway, critically regulates the latent-to-lytic switch of EBV and KSHV infection. The NMD machinery suppresses EBV and KSHV Rta transactivator expression and promotes maintenance of viral latency by targeting the viral polycistronic transactivator transcripts for degradation through the recognition of features in their 3′ UTRs. Treatment with a small-molecule NMD inhibitor potently induced reactivation in a variety of EBV- and KSHV-infected cell types. In conclusion, our results identify NMD as an important host process that controls oncogenic herpesvirus reactivation, which may be targeted for the therapeutic induction of lytic reactivation and the eradication of tumor cells.
The protease corin regulates electrolyte homeostasis in eccrine sweat glands.
Venue: PLoS biology

Sweating is a basic skin function in body temperature control. In sweat glands, salt excretion and reabsorption are regulated to avoid electrolyte imbalance. To date, the mechanism underlying such regulation is not fully understood. Corin is a transmembrane protease that activates atrial natriuretic peptide (ANP), a cardiac hormone essential for normal blood volume and pressure. Here, we report an unexpected role of corin in sweat glands to promote sweat and salt excretion in regulating electrolyte homeostasis. In human and mouse eccrine sweat glands, corin and ANP are expressed in the luminal epithelial cells. In corin-deficient mice on normal- and high-salt diets, sweat and salt excretion is reduced. This phenotype is associated with enhanced epithelial sodium channel (ENaC) activity that mediates Na+ and water reabsorption. Treatment of amiloride, an ENaC inhibitor, normalizes sweat and salt excretion in corin-deficient mice. Moreover, treatment of aldosterone decreases sweat and salt excretion in wild-type (WT), but not corin-deficient, mice. These results reveal an important regulatory function of corin in eccrine sweat glands to promote sweat and salt excretion.
Redundant and specific roles of individual MIR172 genes in plant development
Venue: PLoS biology

Evolutionarily conserved microRNAs (miRNAs) usually have high copy numbers in the genome. The redundant and specific roles of each member of a multimember miRNA gene family are poorly understood. Previous studies have shown that the miR156-SPL-miR172 axis constitutes a signaling cascade in regulating plant developmental transitions. Here, we report the feasibility and utility of CRISPR-Cas9 technology to investigate the functions of all 5 MIR172 family members in Arabidopsis. We show that an Arabidopsis plant devoid of miR172 is viable, although it displays pleiotropic morphological defects. MIR172 family members exhibit distinct expression pattern and exert functional specificity in regulating meristem size, trichome initiation, stem elongation, shoot branching, and floral competence. In particular, we find that the miR156-SPL-miR172 cascade is bifurcated into specific flowering responses by matching pairs of coexpressed SPL and MIR172 genes in different tissues. Our results thus highlight the spatiotemporal changes in gene expression that underlie evolutionary novelties of a miRNA gene family in nature. The expansion of MIR172 genes in the Arabidopsis genome provides molecular substrates for the integration of diverse floral inductive cues, which ensures that plants flower at the optimal time to maximize seed yields.
Systematic analyses of the MIR172 family members of Arabidopsis define their distinct roles in regulation of APETALA2 during floral transition
Venue: PLoS biology

MicroRNAs (miRNAs) play important roles in regulating flowering and reproduction of angiosperms. Mature miRNAs are encoded by multiple MIRNA genes that can differ in their spatiotemporal activities and their contributions to gene regulatory networks, but the functions of individual MIRNA genes are poorly defined. We functionally analyzed the activity of all 5 Arabidopsis thaliana MIR172 genes, which encode miR172 and promote the floral transition by inhibiting the accumulation of APETALA2 (AP2) and APETALA2-LIKE (AP2-LIKE) transcription factors (TFs). Through genome editing and detailed confocal microscopy, we show that the activity of miR172 at the shoot apex is encoded by 3 MIR172 genes, is critical for floral transition of the shoot meristem under noninductive photoperiods, and reduces accumulation of AP2 and TARGET OF EAT2 (TOE2), an AP2-LIKE TF, at the shoot meristem. Utilizing the genetic resources generated here, we show that the promotion of flowering by miR172 is enhanced by the MADS-domain TF FRUITFULL, which may facilitate long-term silencing of AP2-LIKE transcription, and that their activities are partially coordinated by the TF SQUAMOSA PROMOTER-BINDING-LIKE PROTEIN 15. Thus, we present a genetic framework for the depletion of AP2 and AP2-LIKE TFs at the shoot apex during floral transition and demonstrate that this plays a central role in floral induction.
The E3 ubiquitin ligase Cul4b promotes CD4+ T cell expansion by aiding the repair of damaged DNA.
Venue: PLoS biology

The capacity for T cells to become activated and clonally expand during pathogen invasion is pivotal for protective immunity. Our understanding of how T cell receptor (TCR) signaling prepares cells for this rapid expansion remains limited. Here we provide evidence that the E3 ubiquitin ligase Cullin-4b (Cul4b) regulates this process. The abundance of total and neddylated Cul4b increased following TCR stimulation. Disruption of Cul4b resulted in impaired proliferation and survival of activated T cells. Additionally, Cul4b-deficient CD4+ T cells accumulated DNA damage. In T cells, Cul4b preferentially associated with the substrate receptor DCAF1, and Cul4b and DCAF1 were found to interact with proteins that promote the sensing or repair of damaged DNA. While Cul4b-deficient CD4+ T cells showed evidence of DNA damage sensing, downstream phosphorylation of SMC1A did not occur. These findings reveal an essential role for Cul4b in promoting the repair of damaged DNA to allow survival and expansion of activated T cells.
Anti-science kills: From Soviet embrace of pseudoscience to accelerated attacks on US biomedicine
Venue: PLoS biology

The United States witnessed an unprecedented politicization of biomedical science starting in 2015 that has exploded into a complex, multimodal anti-science empire operating through mass media, political elections, legislation, and even health systems. Anti-science activities now pervade the daily lives of many Americans, and threaten to infect other parts of the world. We can attribute the deaths of tens of thousands of Americans from COVID-19, measles, and other vaccine-preventable diseases to anti-science. The acceleration of anti-science activities demands not only new responses and approaches but also international coordination. Vaccines and other biomedical advances will not be sufficient to halt COVID-19 or future potentially catastrophic illnesses, unless we simultaneously counter anti-science aggression.
Why Lyme disease is common in the northern US, but rare in the south: The roles of host choice, host-seeking behavior, and tick density
Venue: PLoS biology

Lyme disease is common in the northeastern United States, but rare in the southeast, even though the tick vector is found in both regions. Infection prevalence of Lyme spirochetes in host-seeking ticks, an important component to the risk of Lyme disease, is also high in the northeast and northern midwest, but declines sharply in the south. As ticks must acquire Lyme spirochetes from infected vertebrate hosts, the role of wildlife species composition on Lyme disease risk has been a topic of lively academic discussion. We compared tick–vertebrate host interactions using standardized sampling methods among 8 sites scattered throughout the eastern US. Geographical trends in diversity of tick hosts are gradual and do not match the sharp decline in prevalence at southern sites, but tick–host associations show a clear shift from mammals in the north to reptiles in the south. Tick infection prevalence declines north to south largely because of high tick infestation of efficient spirochete reservoir hosts (rodents and shrews) in the north but not in the south. Minimal infestation of small mammals in the south results from strong selective attachment to lizards such as skinks (which are inefficient reservoirs for Lyme spirochetes) in the southern states. Selective host choice, along with latitudinal differences in tick host-seeking behavior and variations in tick densities, explains the geographic pattern of Lyme disease in the eastern US.
Neural signatures of syntactic variation in speech planning
Venue: PLoS biology

Planning to speak is a challenge for the brain, and the challenge varies between and within languages. Yet, little is known about how neural processes react to these variable challenges beyond the planning of individual words. Here, we examine how fundamental differences in syntax shape the time course of sentence planning. Most languages treat alike (i.e., align with each other) the 2 uses of a word like “gardener” in “the gardener crouched” and in “the gardener planted trees.” A minority keeps these formally distinct by adding special marking in 1 case, and some languages display both aligned and nonaligned expressions. Exploiting such a contrast in Hindi, we used electroencephalography (EEG) and eye tracking to suggest that this difference is associated with distinct patterns of neural processing and gaze behavior during early planning stages, preceding phonological word form preparation. Planning sentences with aligned expressions induces larger synchronization in the theta frequency band, suggesting higher working memory engagement, and more visual attention to agents than planning nonaligned sentences, suggesting delayed commitment to the relational details of the event. Furthermore, plain, unmarked expressions are associated with larger desynchronization in the alpha band than expressions with special markers, suggesting more engagement in information processing to keep overlapping structures distinct during planning. Our findings contrast with the observation that the form of aligned expressions is simpler, and they suggest that the global preference for alignment is driven not by its neurophysiological effect on sentence planning but by other sources, possibly by aspects of production flexibility and fluency or by sentence comprehension. This challenges current theories on how production and comprehension may affect the evolution and distribution of syntactic variants in the world’s languages.
Repurposing the orphan drug nitisinone to control the transmission of African trypanosomiasis
Venue: PLoS biology

Tsetse transmit African trypanosomiasis, which is a disease fatal to both humans and animals. A vaccine to protect against this disease does not exist so transmission control relies on eliminating tsetse populations. Although neurotoxic insecticides are the gold standard for insect control, they negatively impact the environment and reduce populations of insect pollinator species. Here we present a promising, environment-friendly alternative to current insecticides that targets the insect tyrosine metabolism pathway. A bloodmeal contains high levels of tyrosine, which is toxic to haematophagous insects if it is not degraded and eliminated. RNA interference (RNAi) of either the first two enzymes in the tyrosine degradation pathway (tyrosine aminotransferase (TAT) and 4-hydroxyphenylpyruvate dioxygenase (HPPD)) was lethal to tsetse. Furthermore, nitisinone (NTBC), an FDA-approved tyrosine catabolism inhibitor, killed tsetse regardless if the drug was orally or topically applied. However, oral administration of NTBC to bumblebees did not affect their survival. Using a novel mathematical model, we show that NTBC could reduce the transmission of African trypanosomiasis in sub-Saharan Africa, thus accelerating current disease elimination programmes.
The evolution of group differences in changing environments
Venue: PLoS biology

The selection pressures that have shaped the evolution of complex traits in humans remain largely unknown, and in some contexts highly contentious, perhaps above all where they concern mean trait differences among groups. To date, the discussion has focused on whether such group differences have any genetic basis, and if so, whether they are without fitness consequences and arose via random genetic drift, or whether they were driven by selection for different trait optima in different environments. Here, we highlight a plausible alternative: that many complex traits evolve under stabilizing selection in the face of shifting environmental effects. Under this scenario, there will be rapid evolution at the loci that contribute to trait variation, even when the trait optimum remains the same. These considerations underscore the strong assumptions about environmental effects that are required in ascribing trait differences among groups to genetic differences.
Seipin traps triacylglycerols to facilitate their nanoscale clustering in the endoplasmic reticulum membrane.
Venue: PLoS biology

Seipin is a disk-like oligomeric endoplasmic reticulum (ER) protein important for lipid droplet (LD) biogenesis and triacylglycerol (TAG) delivery to growing LDs. Here we show through biomolecular simulations bridged to experiments that seipin can trap TAGs in the ER bilayer via the luminal hydrophobic helices of the protomers delineating the inner opening of the seipin disk. This promotes the nanoscale sequestration of TAGs at a concentration that by itself is insufficient to induce TAG clustering in a lipid membrane. We identify Ser166 in the α3 helix as a favored TAG occupancy site and show that mutating it compromises the ability of seipin complexes to sequester TAG in silico and to promote TAG transfer to LDs in cells. While the S166D-seipin mutant colocalizes poorly with promethin, the association of nascent wild-type seipin complexes with promethin is promoted by TAGs. Together, these results suggest that seipin traps TAGs via its luminal hydrophobic helices, serving as a catalyst for seeding the TAG cluster from dissolved monomers inside the seipin ring, thereby generating a favorable promethin binding interface.