CRISPR screening in human trophoblast stem cells reveals both shared and distinct aspects of human and mouse placental development.

The placenta serves as the interface between the mother and fetus, facilitating the exchange of gases and nutrients between their separate blood circulation systems. Trophoblasts in the placenta play a central role in this process. Our current understanding of mammalian trophoblast development relies largely on mouse models. However, given the diversification of mammalian placentas, findings from the mouse placenta cannot be readily extrapolated to other mammalian species, including humans. To fill this knowledge gap, we performed CRISPR knockout screening in human trophoblast stem cells (hTSCs). We targeted genes essential for mouse placental development and identified more than 100 genes as critical regulators in both human hTSCs and mouse placentas. Among them, we further characterized in detail two transcription factors, DLX3 and GCM1, and revealed their essential roles in hTSC differentiation. Moreover, a gene function-based comparison between human and mouse trophoblast subtypes suggests that their relationship may differ significantly from previous assumptions based on tissue localization or cellular function. Notably, our data reveal that hTSCs may not be analogous to mouse TSCs or the extraembryonic ectoderm (ExE) in which in vivo TSCs reside. Instead, hTSCs may be analogous to progenitor cells in the mouse ectoplacental cone and chorion. This finding is consistent with the absence of ExE-like structures during human placental development. Our data not only deepen our understanding of human trophoblast development but also facilitate cross-species comparison of mammalian placentas.

A Retrospective Analysis of Clinical Biomarkers for Olaparib Maintenance Therapy in Patients with Recurrent Ovarian Cancer.

Poly(ADP-ribose) polymerase (PARP) inhibitors theoretically promote synthetic lethality in cancer cells with homologous recombination deficiency (HRD). However, clinical evidence indicates that PARP inhibitors are also effective for treating HRD-negative ovarian cancer. The PARP inhibitor olaparib became available in Japan as a maintenance therapy for platinum-sensitive recurrent ovarian cancer regardless of homologous recombination status in April 2018. The purpose of this study was to identify potential clinical biomarkers for olaparib sensitivity in patients with recurrent ovarian cancer. Clinical information about the patients with recurrent ovarian cancer treated with olaparib maintenance therapy (OMT) was retrospectively collected. OMT duration was used as an indicator for olaparib sensitivity. The relationship between OMT duration and clinical parameters was statistically analyzed. We found a positive correlation between OMT duration and progression-free survival (PFS) or treatment free interval (TFI). In some cases, OMT duration exceeded PFS before olaparib introduction. We also found that more than half of the patients with measurable target lesions at the time of OMT introduction showed partial or complete response to OMT. These results validated the effectiveness of OMT and identified PFS and TFI as potential clinical markers for olaparib sensitivity in the patients with recurrent ovarian cancer.

Characteristics of proteinaceous additives in stabilizing enzymes during freeze-thawing and -drying.

Protein-stabilizing characteristics of sixteen proteins during freeze-thawing and freeze-drying were investigated. Five enzymes, each with different instabilities against freezing and dehydration, were employed as the protein to be stabilized. Proteinaceous additives generally resulted in greater enzyme stabilization during freeze-thawing than sugars while the degree of stabilization for basic lysozyme and protamine were inferior to that of neutral and acidic proteins. Freeze-drying-induced inactivation of enzyme was also reduced by the presence of a proteinaceous additive, the extent of which was lower than that for a sugar. In both freeze thawing and freeze drying, the enzymes stabilization by the proteinaceous additive increased with increasing additive concentration. The enhancement of enzyme inactivation caused by pH change was also reduced in the presence of proteinaceous additives. The combined use of a sugar such as sucrose and dextran tended to increase the stabilizing effect of the proteinaceous additive.

[Dynamic characteristics of flow trainer for dpi and its clinical relevance].

BACKGROUND: Trainer devices are widely employed for flow instruction in the use of dry powder inhalers (DPI). However, their aerodynamic characteristics in actual use have yet to be investigated. METHODS: We recorded inhalation flow signals and sounds produced from trainers for Diskus®, Symbicort®, Pulmicort® and Twisthaler® while five volunteers inhaled from the trainers with various inhalation patterns. RESULTS: Inhalation flow was classified into four patterns; the best, trapezoid, delayed peak and others. All the trainers exhibited flow-thresholds with appropriate precision for instruction. Sound intensity from the Diskus® trainer was almost proportional to inhaled flow rate, and it may be useful for flow pattern estimation. In other trainers, when flow exceeded some thresholds, sounds abruptly developed and continued with high intensity. Thus, they may be convenient for recognizing appropriate flow rates. In all trainers, when the subjects inhaled rapidly and forcefully, sound developed at 0.19-0.24 s after the onset of inhalation. Thus, with this flow pattern, trainers may indicate a flow rate approaching the peak of drug dispersion from the DPI. When the subject inhaled less rapidly, the threshold for sound development decreased by 10%. CONCLUSION: The instructor in DPI use should be aware of the aerodynamic characteristics of each individual trainer. Rapid inhalation should also be encouraged.

Two cases of CRPC with BRCA mutation treated by olaparib after favorable response to cisplatin.

Introduction: Several prostate cancers carry homologous recombination repair mutations that respond to olaparib. Because of the mechanism, the efficacy of platinum-based therapy can be used to predict the efficacy of poly(adenosine diphosphate-ribose) polymerase inhibitors such as olaparib. Case presentation: We experienced two neuroendocrine prostate cancer patients who achieved a response duration of more than 1 year with platinum-based therapy. Case 1 had a BRCA2 mutation in the germline and case 2 had a BRCA2 mutation in a somatic chromosome only. Both patients responded well to olaparib. Conclusion: Cisplatin and olaparib may overlap in response due to their medicinal action. It may be useful to consider genetic testing in some CRPC patients who have responded to cisplatin.

Controlling primary chain dispersity in network polymers: elucidating the effect of dispersity on degradation.

Although dispersity has been demonstrated to be instrumental in determining many polymer properties, current synthetic strategies predominantly focus on tailoring the dispersity of linear polymers. In contrast, controlling the primary chain dispersity in network polymers is much more challenging, in part due to the complex nature of the reactions, which has limited the exploration of properties and applications. Here, a one-step method to prepare networks with precisely tuned primary chain dispersity is presented. By using an acid-switchable chain transfer agent and a degradable crosslinker in PET-RAFT polymerization, the in situ crosslinking of the propagating polymer chains was achieved in a quantitative manner. The incorporation of a degradable crosslinker, not only enables the accurate quantification of the various primary chain dispersities, post-synthesis, but also allows the investigation and comparison of their respective degradation profiles. Notably, the highest dispersity networks resulted in a 40% increase in degradation time when compared to their lower dispersity analogues, demonstrating that primary chain dispersity has a substantial impact on the network degradation rate. Our experimental findings were further supported by simulations, which emphasized the importance of higher molecular weight polymer chains, found within the high dispersity materials, in extending the lifetime of the network. This methodology presents a new and promising avenue to precisely tune primary chain dispersity within networks and demonstrates that polymer dispersity is an important parameter to consider when designing degradable materials.

Precautions during Direct Oral Anticoagulant Introduction in Gynecologic Malignancies: A Single-Center Retrospective Cohort Study.

The risk factors for venous thromboembolism (VTE) recurrence/exacerbation or a change from a direct oral anticoagulant (DOAC) to another anticoagulant in patients with gynecologic cancer using DOACs have not been thoroughly elucidated. Here, we aimed to investigate the risk factors for a composite primary outcome, including VTE recurrence/exacerbation, or a change from a DOAC to another anticoagulant, in this population. A total of 63 patients were analyzed. Risk factors for a primary outcome within 2 years after DOAC initiation were investigated using multiple logistic regression analysis. Among the 63 patients, 10 developed a primary outcome. Clear cell carcinoma of the ovary (adjusted odds ratio (aOR), 18.9; 95% confidence interval (CI), 2.25-350.74), pulmonary embolism (PE) or proximal deep vein thrombosis without PE (aOR, 55.6; 95% CI, 3.29-11,774.66), and D-dimer levels in the third tertile (≥7.6 µg/dL) when VTE was first diagnosed (aOR, 6.37; 95% CI, 1.17-66.61) were associated with increased odds of a primary outcome in patients with gynecologic cancer using DOACs. Patients with one or more risk factors for a primary outcome require careful follow-up after DOAC initiation for the early recognition of treatment failure.

Demonstration of 12.5-Gbps optical interconnects integrated with lasers, optical splitters, optical modulators and photodetectors on a single silicon substrate.

One of the most serious issues in information industries is the bandwidth bottleneck in inter-chip interconnects. We propose a photonics-electronics convergence system to solve this issue. We fabricated a high density optical interposer to demonstrate the feasibility of the system by using silicon photonics integrated with an arrayed laser diode, an optical splitter, silicon optical modulators, germanium photodetectors, and silicon optical waveguides on a single silicon substrate. Error-free data transmission at 12.5 Gbps and a transmission density of 6.6 Tbps/cm2 were achieved with the optical interposer. We believe this technology will solve the bandwidth bottleneck problem in the future.

Tourism infrastructure and the environment: how does environmental regulation affect welfare, tourism industry, and domestic wage inequality?

This study presents a general equilibrium model of a small open developing economy with pollution generated by the tourism industry. The national government issues emission permits and constructs tourism infrastructure for the tourism sector. We examine the effects of a stricter environmental regulation on welfare, production, and income distribution. If the elasticity of substitution in the tourism sector is sufficiently low, a stricter environmental regulation paradoxically expands the tourism sector and narrows domestic wage inequality, even under constant tourism terms of trade. In this model, in addition to the two traditional channels, there is a new channel through which a stricter environmental regulation affects the tourism terms of trade and domestic welfare. The new channel, which arises from the difference between the marginal value product of tourism infrastructure and its price, improves the tourism terms of trade and domestic welfare if (1) the marginal value product of tourism infrastructure is greater than its price, (2) the output of tourism infrastructure is increased by a stricter environmental regulation, and (3) the excess supply of a tourism service decreases with a stricter environmental regulation.

Snapping Knee Syndrome of the Sartorius Accompanying Osteoarthritis Cured by Osteophyte Removal During Total Knee Arthroplasty.

Snapping knee syndrome on the medial side is rare. Here, we report the case of a patient with snapping knee syndrome of the sartorius with knee osteoarthritis. A large osteophyte at the posteromedial femoral condyle impinged on the sartorius myotendinous junction, causing painless snapping. The patient was successfully treated with osteophyte removal and total knee arthroplasty while preserving the tendon. Hence, tendon release or resection to treat snapping syndrome is not always necessary if the underlying cause can be eliminated. Furthermore, we found that while tendon tension is important for the occurrence of snapping syndrome, the impingement site determines the occurrence of snapping pain.

First demonstration of high density optical interconnects integrated with lasers, optical modulators, and photodetectors on single silicon substrate.

Engineers are currently facing some technical issues in support of the exponential performance growths in information industries. One of the most serious issues is a bottleneck of inter-chip interconnects. We propose a new "Photonics-Electronics Convergence System" concept. High density optical interconnects integrated with a 13-channel arrayed laser diode, silicon optical modulators, germanium photodetectors, and silicon optical waveguides on single silicon substrate were demonstrated for the first time using this system. A 5-Gbps error free data transmission and a 3.5-Tbps/cm(2) transmission density were achieved. We believe that this technology will solve the bandwidth bottleneck problem among LSI chips in the future.

Tuning Ligand Concentration in Cu(0)-RDRP: A Simple Approach to Control Polymer Dispersity.

Cu(0)-reversible deactivation radical polymerization (RDRP) is a versatile polymerization tool, providing rapid access to well-defined polymers while utilizing mild reaction conditions and low catalyst loadings. However, thus far, this method has not been applied to tailor dispersity, a key parameter that determines the physical properties and applications of polymeric materials. Here, we report a simple to perform method, whereby Cu(0)-RDRP can systematically control polymer dispersity (D = 1.07-1.72), while maintaining monomodal molecular weight distributions. By varying the ligand concentration, we could effectively regulate the rates of initiation and deactivation, resulting in polymers of various dispersities. Importantly, both low and high dispersity PMA possess high end-group fidelity, as evidenced by MALDI-ToF-MS, allowing for a range of block copolymers to be prepared with different dispersity configurations. The scope of our method can also be extended to include inexpensive ligands (i.e., PMDETA), which also facilitated the polymerization of lower propagation rate constant monomers (i.e., styrene) and the in situ synthesis of block copolymers. This work significantly expands the toolbox of RDRP methods for tailoring dispersity in polymeric materials.

Standing stock and mass balance of marine litter in the Seto Inland Sea, Japan.

The basin of Seto Inland Sea has a population of 31 million people. The standing stock and mass balance of marine litter in this area was estimated using rapid assessment for beach litter, questionnaire surveys on removed amounts of marine litter, and existing data. The mass balance of marine litter was explained by using a single box model, assuming complete mixing and uniform density. If the standing stock of drifting and beach litter combined was 3400 tons, the inflow of litter from rivers was 3000 tons/year, generation of litter at sea was 1200 tons/year, and inflow from the open sea was 300 tons/year. The amount of marine litter removed from the beach and sea surface was 1400 tons/year, outflow to the open sea was 2400 tons/year, and deposition on the sea bottom was 700 tons/year.

Estimating spatial variation in the effects of climate change on the net primary production of Japanese cedar plantations based on modeled carbon dynamics.

Spatiotemporal prediction of the response of planted forests to a changing climate is increasingly important for the sustainable management of forest ecosystems. In this study, we present a methodology for estimating spatially varying productivity in a planted forest and changes in productivity with a changing climate in Japan, with a focus on Japanese cedar (Cryptomeria japonica D. Don) as a representative tree species of this region. The process-based model Biome-BGC was parameterized using a plant trait database for Japanese cedar and a Bayesian optimization scheme. To compare productivity under historical (1996-2000) and future (2096-2100) climatic conditions, the climate scenarios of two representative concentration pathways (i.e., RCP2.6 and RCP8.5) were used in five global climate models (GCMs) with approximately 1-km resolution. The seasonality of modeled fluxes, namely gross primary production, ecosystem respiration, net ecosystem exchange, and soil respiration, improved after two steps of parameterization. The estimated net primary production (NPP) of stands aged 36-40 years under the historical climatic conditions of the five GCMs was 0.77 ± 0.10 kgC m-2 year-1 (mean ± standard deviation), in accordance with the geographical distribution of forest NPP estimated in previous studies. Under the RCP2.6 and RCP8.5 scenarios, the mean NPP of the five GCMs increased by 0.04 ± 0.07 and 0.14 ± 0.11 kgC m-2 year-1, respectively. The increases in annual NPP were small in the southwestern region because of the decreases in summer NPP and the small increases in winter NPP under the RCP2.6 and RCP8.5 scenarios, respectively. Under the RCP2.6 scenario, Japanese cedar was at risk in the southwestern region, in accordance with previous studies, and monitoring and silvicultural practices should be modified accordingly.

Viral shedding after p53 adenoviral gene therapy in 10 cases of esophageal cancer.

We detected adenoviral DNA fragments in excretions of 10 esophageal cancer patients by DNA-PCR after tumor injection of Ad-CMV-vector. A total of 220 samples consisting of feces, gargling saliva, urine, and blood plasma were assessed. A total of 29.7% of feces samples and 13.2% of gargling saliva samples were positive for adenoviral DNA fragments, but 89.7% of the positive feces samples and all of the positive gargling saliva samples turned negative on day 12 after tumor injection. Although adenoviral DNA fragments may be pathogen-free, patients' feces and gargling saliva contain adenoviral DNA fragments for 12 days after injection.

Seasonal variations in coastal debris on Awaji Island, Japan.

The subject of our study was Awaji Island, an island located in the west of Japan that is surrounded by sea and that has serious problems relating to coastal debris. We conducted a long-term investigation focusing on three beaches and evaluated the results. The study was designed to develop an understanding of the actual situation, to inform local citizens, and raise their concerns about the problem of debris with a view to taking action against it. We obtained the following results: the amount, type, and ratio of debris changed according to weather and ocean conditions; debris also differs according to geographical conditions; social and economic activities of the surrounding area influence the type of debris encountered. Following this study, we have continued our investigation, and are continuing to gather data. At the same time, it is important to spread our ideas and enlighten people so as to encourage them not to dump debris. We hope that these actions manage to raise the level of consciousness among local citizens and to expand their anti-debris activities.