DNAJC9 prevents CENP-A mislocalization and chromosomal instability by maintaining the fidelity of histone supply chains.

The centromeric histone H3 variant CENP-A is overexpressed in many cancers. The mislocalization of CENP-A to noncentromeric regions contributes to chromosomal instability (CIN), a hallmark of cancer. However, pathways that promote or prevent CENP-A mislocalization remain poorly defined. Here, we performed a genome-wide RNAi screen for regulators of CENP-A localization which identified DNAJC9, a J-domain protein implicated in histone H3-H4 protein folding, as a factor restricting CENP-A mislocalization. Cells lacking DNAJC9 exhibit mislocalization of CENP-A throughout the genome, and CIN phenotypes. Global interactome analysis showed that DNAJC9 depletion promotes the interaction of CENP-A with the DNA-replication-associated histone chaperone MCM2. CENP-A mislocalization upon DNAJC9 depletion was dependent on MCM2, defining MCM2 as a driver of CENP-A deposition at ectopic sites when H3-H4 supply chains are disrupted. Cells depleted for histone H3.3, also exhibit CENP-A mislocalization. In summary, we have defined novel factors that prevent mislocalization of CENP-A, and demonstrated that the integrity of H3-H4 supply chains regulated by histone chaperones such as DNAJC9 restrict CENP-A mislocalization and CIN.

Single-cell RNA sequencing reveals cellular and molecular landscape of fetal cystic hygroma.

BACKGROUND: The molecular mechanism of fetal cystic hygroma (CH) is still unclear, and no study has previously reported the transcriptome changes of single cells in CH. In this study, single-cell transcriptome sequencing (scRNA-seq) was used to investigate the characteristics of cell subsets in the lesion tissues of CH patients. METHODS: Lymphoid tissue collected from CH patients and control donors for scRNA-seq analysis. Differentially expressed gene enrichment in major cell subpopulations as well as cell-cell communication were analyzed. At the same time, the expression and interactions of important VEGF signaling pathway molecules were analyzed, and potential transcription factors that could bind to KDR (VEGFR2) were predicted. RESULTS: The results of scRNA-seq showed that fibroblasts accounted for the largest proportion in the lymphatic lesions of CH patients. There was a significant increase in the proportion of lymphatic endothelial cell subsets between the cases and controls. The VEGF signaling pathway is enriched in lymphatic endothelial cells and participates in the regulation of cell-cell communication between lymphatic endothelial cells and other cells. The key regulatory gene KDR in the VEGF signaling pathway is highly expressed in CH patients and interacts with other differentially expressed EDN1, TAGLN, and CLDN5 Finally, we found that STAT1 could bind to the KDR promoter region, which may play an important role in promoting KDR up-regulation. CONCLUSION: Our comprehensive delineation of the cellular composition in tumor tissues of CH patients using single-cell RNA-sequencing identified the enrichment of lymphatic endothelial cells in CH and highlighted the activation of the VEGF signaling pathway in lymphoid endothelial cells as a potential modulator. The molecular and cellular pathogenesis of fetal cystic hygroma (CH) remains largely unknown. This study examined the distribution and gene expression signature of each cell subpopulation and the possible role of VEGF signaling in lymphatic endothelial cells in regulating the progression of CH by single-cell transcriptome sequencing. The enrichment of lymphatic endothelial cells in CH and the activation of the VEGF signaling pathway in lymphatic endothelial cells provide some clues to the pathogenesis of CH from the perspective of cell subpopulations.

The Villain Who Saved the Day: The Paradoxical Value of Amiodarone in Managing Recurrent Ventricular Tachycardia Secondary to Amiodarone-Induced Thyroiditis.

Thyroiditis is a rare and serious complication for patients taking amiodarone. It can manifest with symptoms of hyperthyroidism and serious life-threatening arrhythmias. We present a case of a patient with amiodarone-induced thyrotoxicosis presenting with an electrical storm in which rhythm control was achieved with the utilization of amiodarone.

Spilled gallstone mimicking intra-abdominal seeding of gallbladder adenocarcinoma: A case report.

BACKGROUND: Gallbladder rupture is common in laparoscopic cholecystectomy because the gallbladder is usually in acute or chronic inflammation status. The gallstones may sometime be spilled into the peritoneal cavity, resulting in intra-abdominal abscess if the gallstones were not retrieved. The diagnosis of intra-abdominal abscess caused by unretrieved gallstone can usually be correctly identified in the routine imaging studies, such as abdominal ultrasonography or computed tomography (CT). Here we present a case of abscess formation from unretrieved gallstone following laparoscopic cholecystectomy, which mimics the imaging findings of metastatic gallbladder adenocarcinoma. CASE SUMMARY: This case described a 78-year-old man who received laparoscopic cholecystectomy and gallbladder adenocarcinoma was diagnosed after surgery. After adjuvant chemotherapy, the following up abdominal CT showed several small nodules at right upper abdomen and peritoneal carcinomatosis is considered. Repeated laparoscopic surgery for the excision of seeding tumor was conducted and the pathological diagnosis of the nodules and mass was inflammatory tissues and gallbladder stone. CONCLUSION: Spilled gallstones are a common complication during laparoscopic cholecystectomy and some gallstones fail to be retrieved due to the size or the restricted view of laparoscopic surgery. For spilled gall bladder stones, surgeons may consider regular computerized tomography follow-up, and if necessary, laparoscopic examination can be used as a means of confirming the diagnostic and treatment.

Facilitating effects of the synergy with zero-valent iron and peroxysulfate on the sludge anaerobic fermentation system: Combined biological enzyme, microbial community and fermentation mechanism assessment.

This study evaluated a synergetic waste activated sludge treatment strategy with environmentally friendly zero-valent iron nanoparticles (Fe0) and peroxysulfate. To verify the feasibility of the synergistic treatment, Fe0, peroxysulfate, and the mixture of peroxysulfate and Fe0 (synergy treatment) were added to different sludge fermentation systems. The study demonstrated that the synergy treatment fermentation system displayed remarkable hydrolysis performance with 435.50 mg COD/L of protein and 197.67 mg COD/L of polysaccharide, which increased 1.13-2.85 times (protein) and 1.12-1.49 times (polysaccharide) for other three fermentation system. Additionally, the synergy treatment fermentation system (754.52 mg COD/L) exhibited a well acidification performance which was 1.35-41.73 times for other systems (18.08-557.27 mg COD/L). The synergy treatment fermentation system had a facilitating effect on the activity of protease, dehydrogenase, and alkaline phosphatase, which guaranteed the transformation of organic matter. Results also indicated that Comamonas, Soehngenia, Pseudomonas, and Fusibacter were enriched in synergy treatment, which was beneficial to produce SCFAs. The activation of Fe0 on peroxysulfate promoting electron transfer, improving the active groups, and increasing the enrichment of functional microorganisms showed the advanced nature of synergy treatment. These results proved the feasibility of synergy treatment with Fe0 and peroxysulfate to enhance waste activated sludge anaerobic fermentation.

Unpacking the navigation toolbox: insights from comparative cognition.

The study of navigation is informed by ethological data from many species, laboratory investigation at behavioural and neurobiological levels, and computational modelling. However, the data are often species-specific, making it challenging to develop general models of how biology supports behaviour. Wiener et al. outlined a framework for organizing the results across taxa, called the 'navigation toolbox' (Wiener et al. In Animal thinking: contemporary issues in comparative cognition (eds R Menzel, J Fischer), pp. 51-76). This framework proposes that spatial cognition is a hierarchical process in which sensory inputs at the lowest level are successively combined into ever-more complex representations, culminating in a metric or quasi-metric internal model of the world (cognitive map). Some animals, notably humans, also use symbolic representations to produce an external representation, such as a verbal description, signpost or map that allows communication of spatial information or instructions between individuals. Recently, new discoveries have extended our understanding of how spatial representations are constructed, highlighting that the hierarchical relationships are bidirectional, with higher levels feeding back to influence lower levels. In the light of these new developments, we revisit the navigation toolbox, elaborate it and incorporate new findings. The toolbox provides a common framework within which the results from different taxa can be described and compared, yielding a more detailed, mechanistic and generalized understanding of navigation.

Landmarks, beacons, or panoramic views: What do pigeons attend to for guidance in familiar environments?

Birds and social insects represent excellent systems for understanding visually guided navigation. Both animal groups use surrounding visual cues for homing and foraging. Ants extract sufficient spatial information from panoramic views, which naturally embed all near and far spatial information, for successful homing. Although egocentric panoramic views allow for parsimonious explanations of navigational behaviors, this potential source of spatial information has been mostly neglected during studies of vertebrates. Here we investigate how distinct landmarks, a beacon, and panoramic views influence the reorientation behavior in pigeons (Columba livia). Pigeons were trained to search for a location characterized by a beacon and several distinct landmarks. Transformation tests manipulated aspects of the landmark configuration, allowing for a dissociation among navigational strategies. Quantitative image and path analyses provided support that the panoramic view was used by the pigeons. Although the results from some individuals support the use of beaconing, overall the pigeons relied predominantly on the panoramic view when spatial cues provided conflicting information regarding the goal location. Reorientation based on vector and bearing information derived from distinct landmarks as well as environmental geometry failed to account fully for the results. Thus, the results of our study support that pigeons can use panoramic views for reorientation in familiar environments. Given that the current model for landmark use by pigeons posits the use of different vectors from an object, a global panorama-matching strategy suggests a fundamental change in the theory of how pigeons use surrounding visual cues for localization.

AKT1 interacts with DHX9 to Mitigate R Loop-Induced Replication Stress in Ovarian Cancer.

PARP inhibitor (PARPi)-resistant BRCA-mutant (BRCAm) high-grade serous ovarian cancer (HGSOC) represents a new clinical challenge with unmet therapeutic needs. Here, we performed a quantitative high-throughput drug combination screen that identified the combination of an ATR inhibitor (ATRi) and an AKT inhibitor (AKTi) as an effective treatment strategy for both PARPi-sensitive and PARPi-resistant BRCAm HGSOC. The ATRi and AKTi combination induced DNA damage and R loop-mediated replication stress (RS). Mechanistically, the kinase domain of AKT1 directly interacted with DHX9 and facilitated recruitment of DHX9 to R loops. AKTi increased ATRi-induced R loop-mediated RS by mitigating recruitment of DHX9 to R loops. Moreover, DHX9 was upregulated in tumors from patients with PARPi-resistant BRCAm HGSOC, and high coexpression of DHX9 and AKT1 correlated with worse survival. Together, this study reveals an interaction between AKT1 and DHX9 that facilitates R loop resolution and identifies combining ATRi and AKTi as a rational treatment strategy for BRCAm HGSOC irrespective of PARPi resistance status. SIGNIFICANCE: Inhibition of the AKT and ATR pathways cooperatively induces R loop-associated replication stress in high-grade serous ovarian cancer, providing rationale to support the clinical development of AKT and ATR inhibitor combinations. See related commentary by Ramanarayanan and Oberdoerffer, p. 793.

Oscillators and servomechanisms in navigation and orientation.

I summarize my recent theorizing on orientation and navigation across life. Organisms use navigational servomechanisms working with oscillators to get to goals. Navigational servomechanisms track errors from the best direction of travel and initiate action to correct the error. They work with endogenously generated action patterns, oscillations produced by oscillators, to adjust the course of travel. The theme applies to all scales of life from micrometers to thousands of kilometers. Servomechanisms and oscillators also characterize some other domains of cognition.

Effect of repetition of vertical and horizontal routes on navigation performance in Australian bull ants.

Solitarily foraging ant species differ in their reliance on their two primary navigational systems- path integration and visual learning. Despite many species of Australian bull ants spending most of their foraging time on their foraging tree, little is known about the use of these systems while climbing. "Rewinding" displacements are commonly used to understand navigational system usage, and work by introducing a mismatch between these navigational systems, by displacing foragers after they have run-down their path integration vector. We used rewinding to test the role of path integration on the arboreal and terrestrial navigation of M. midas. We rewound foragers along either the vertical portion, the ground surface portion, or across both portions of their homing trip. Since rewinding involves repeatedly capturing and releasing foragers, we included a nondisplacement, capture-and-release control, in which the path integration vector is unchanged. We found that rewound foragers do not seem to accumulate path integration vector, although a limited effect of vertical rewinding was found, suggesting a potential higher sensitivity while descending the foraging tree. However, the decrease in navigational efficiency due to capture was larger than the vertical rewinding effect, which along with the negative impact of the vertical surface, and an interaction between capture and rewinding, may suggest aversion rather than path integration caused the vertical rewinding response. Together these results add to the evidence that M. midas makes minimal use of path integration while foraging, and the growing evidence that they are capable of quickly learning from aversive stimulus.

Prenatal diagnosis and perinatal outcomes of twin pregnancies disharmonious for one fetus with nuchal translucency above the 95th percentile.

OBJECTIVE: To assess prenatal diagnosis and pregnancy outcomes in twin pregnancies where one fetus has nuchal translucency (NT) above the 95th percentile. METHOD: In this retrospective analysis, 130 twin pregnancies (260 fetuses) in which one twin had an NT measurement above the 95th percentile while that of the other twin was normal were analyzed. Prenatal diagnostic results such as G bands, chromosomal microarray analysis, ultrasound findings, and pregnancy outcomes were reviewed. RESULTS: Karyotype analysis and CMA results revealed that 15 (15.6 percent, 15/96) fetuses exhibited chromosomal abnormalities and that 13 fetuses were Variant of Uncertain Significance. Chromosome abnormalities were detected at a rate of 8.9% (5/56) in the DCT group and 25.0% (10/40) in the MCT group (p = 0.033, X2 = 4.571). 2 fetuses in DCT (3.9 percent, 2/51) and 4 fetuses in MCT (13.3 percent, 4/30) (p = 0.187) revealed structural abnormalities among the cases with normal prenatal diagnosis. Fetuses in the DCT group had an overall survival rate of 75.4 percent (95/126), whereas those in the MCT group had a survival rate of 60.4 percent (81/134) (p = 0.01, X2 = 6.636). According to the findings of Logistics regression analysis, NT thickening, maternal age and method of conception were all significant risk factors for chromosome abnormalities. CONCLUSION: In twin pregnancies with one fetus with NT above the 95th percentile, the prevalence of fetal structural abnormalities of the MCT group and the DCT group were comparable. Pregnant women's age and mode of pregnancy are risk factors for chromosomal abnormalities.

Past-expiration-date liquid disinfectants to deactivate biological and chemical toxins on building material surfaces.

In this study, we evaluated the deactivating efficacy of strong basicity-based (T4-102) and hydrogen peroxide-based (DF-200) disinfectants that were past their expiration date when used to deactivate biological and chemical toxins on building material surfaces. The decontamination efficacies of DF-200 and T4-102 disinfectants against dimethyl methylphosphonate (DMMP) and 2-chloroethyl ethylsulfide (2-CEES) were studied using GC-MS analysis. The bactericidal efficacies of disinfectants against Gram-negative E. coli and P. aeruginosa, and Gram-positive B. subtilis and S. aureus, were assessed in terms of the zone of inhibition, minimum inhibitory concentration (MIC), and minimum bactericidal concentration (MBC). The results indicated that the deactivation efficacy varied significantly according to the disinfectant amount, contact time, and building material. Higher efficacy of up to 99-100% was observed for biological toxins, despite passing their expiration dates. Approximately 70-78% of deactivation efficacies were observed for disinfectants against DMMP on the tile coupon at 100 µL and 24 h contact time. Moreover, the deactivation efficacy of DF-200 was better than that of T4-102. The data presented here demonstrate that the responders may use past-expiration-date disinfectants for efficacious disinfectaion in large-scale contamination incidents.

Associative learning: Box jellyfish learns to avoid bumps.

Operant conditioning - learning to do something for a desired outcome - has never been convincingly demonstrated in Cnidaria. A study now shows that box jellyfish, Tripedalia cystophora, can learn to avoid bumping into an obstacle based on visual cues.

Porphyria cutanea tarda: an under-recognised manifestation of haemochromatosis.

We present a case of a woman who presented with a photosensitive skin rash and blisters on her extremities which did not improve with steroids. These were associated with polyarthralgia and a deranged liver function test on her admission. Further workup revealed that the patient has an undiagnosed porphyria cutanea tarda (PCT) and hereditary haemochromatosis. The patient later underwent regular venesections which improved her condition. This case report not only illustrates the challenge in diagnosing PCT but also aims to highlight the association between PCT and hereditary haemochromatosis.

Resolving conflict between aversive and appetitive learning of views: how ants shift to a new route during navigation.

Ants store and recall views associated with foraging success, facilitating future foraging journeys. Negative views are also learned, but instead prompt avoidance behaviors such as turning away. However, little is known about the aversive view's role in navigation, the effect of cue conflict, or the contextual relationship between learning and recalling. In this study, we tested Myrmecia midas' capacity for aversive learning of views either independently of or in conflict with appetitive events. We either captured and released foragers when reaching a location or let them pass unhindered. After a few journeys, captured foragers exhibited aversive learning by circumventing the capture location and increasing both meandering and scanning. Ants that experienced foraging-appetitive and homing-aversive events on their journeys exhibited lower rates of avoidance behavior and scans than those experiencing aversive events in both outbound and homebound journeys. The foraging-aversive and homing-aversive ants exhibited similar levels of avoidance and scanning as those that experienced the foraging-aversive and homing-appetitive. We found that foragers showed evidence of context specificity in their scanning behavior, but not in other measures of aversive learning. The foragers did not increase their meandering and scans while approaching the views associated with aversive events. In addition to shedding light on the role of aversive views in navigation, our finding has important implications for understanding the learning mechanisms triggered by handling animals.

Learning in Cnidaria: a summary.

Based on a systematic literature search, I recently reviewed learning in the phylum Cnidaria, animals possessing a nerve net as a nervous system but no centralized brain. I found abundant evidence of non-associative learning, both habituation and sensitization, but only sparse evidence of associative learning. Only one well-controlled study on classical conditioning in sea anemones provided firm evidence, and no studies firmly supported operant conditioning in Cnidaria, although several provided suggestive evidence. More research on associative learning in this phylum is needed.

Ants on featureless saltpans build tall nest mounds.

North African desert ants Cataglyphis fortis living on a featureless saltpan far from the shoreline build a mound at their nest entrance. Experimental manipulations show that they do this purposefully to make it easier for returning foragers to find their nest.