Cell-to-cell variability in inducible Caspase9-mediated cell death

AbstractiCasp9 suicide gene has been widely used as a promising killing strategy in various cell therapies. However, different cells show significant heterogeneity in response to apoptosis inducer, posing challenges in clinical applications of killing strategy. The cause of the heterogeneity remains elusive so far. Here, by simultaneously monitoring the dynamics of iCasp9 dimerization, Caspase3 activation, and cell fate in single cells, we found that the heterogeneity was mainly due to cell-to-cell variability in initial iCasp9 expression and XIAP/Caspase3 ratio. Moreover, multiple-round drugging cannot increase the killing efficiency. Instead, it will place selective pressure on protein levels, especially on the level of initial iCasp9, leading to drug resistance. We further show this resistance can be largely eliminated by combinatorial drugging with XIAP inhibitor at the end, but not at the beginning, of the multiple-round treatments. Our results unveil the source of cell fate heterogeneity and drug resistance in iCasp9-mediated cell death, which may enlighten better therapeutic strategies for optimized killing.

Cryptococcal Prostatitis Forming Caseous and Suppurative Granulomas Diagnosed by Needle Biopsy: A Case Report

Cryptococcal granulomatous prostatitis is extremely rare, and there have been few reports of its diagnosis by prostate needle biopsy. The patient, an 81–year–old man, was receiving immunosuppressive treatment for rheumatoid arthritis. He had an oropharyngeal ulcer, and it was diagnosed alongside a methotrexate-related diffuse large B-cell lymphoma. A systemic imaging examination revealed a prostatic tumor-like mass clinically suspected to be prostatic cancer, and a needle biopsy was performed. The biopsy specimen showed various types of inflammatory cell infiltration, and suppurative granuloma and caseous granuloma were observed. Both granulomas showed multiple round and oval organisms that were revealed with Grocott methenamine silver staining. Acid–fast bacilli were not detected by Ziehl–Neelsen staining. We histologically diagnosed granulomatous prostatitis caused by Cryptococcus infection. Caseous granulomas often develop in the prostate after bacillus Calmette–Guerin immunotherapy for bladder cancer, although the possibility of cryptococcal granulomatous prostatitis should also be considered.

Design of Combined Auction Model for Emission Rights of International Forestry Carbon Sequestration and Other Pollutants Based on SMRA

In this paper, the combined transactions for emission rights of international carbon sequestration and other pollutants in forestry have been taken as the research object, and the Simultaneous Multiple Round Auction (SMRA) theory has been used to design a new model for the current auction transactions. In this paper, the feasibility and application of the SMRA model of reach object are studied by the methods of simulation experiment, model analysis, and analogical analysis, and the promotion of this model is discussed. The results show that the new auction model designed in this paper fills in the blank of the combined auction of international forestry carbon sequestration and other pollutant emission rights. It successfully eliminates the winners’ curse and the losses of the sellers. Meanwhile, it provides a new way of resolving ecological deficits problems, achieving the ultimate goal of an overall reduction in carbon and pollution emission. Moreover, it’s beneficial in resolving the structural contradictions between ecological purification and pollutants discharge, hence maximizing the benefits for all the stakeholders. Finally, it is suggested that the SMRA should be adopted in the international trading of emission rights of international carbon sequestration and other pollutants to promote the emission reduction of greenhouse gases and pollutants.

XStore : Fast RDMA-Based Ordered Key-Value Store Using Remote Learned Cache

RDMA ( Remote Direct Memory Access ) has gained considerable interests in network-attached in-memory key-value stores. However, traversing the remote tree-based index in ordered key-value stores with RDMA becomes a critical obstacle, causing an order-of-magnitude slowdown and limited scalability due to multiple round trips. Using index cache with conventional wisdom—caching partial data and traversing them locally—usually leads to limited effect because of unavoidable capacity misses, massive random accesses, and costly cache invalidations. We argue that the machine learning (ML) model is a perfect cache structure for the tree-based index, termed learned cache . Based on it, we design and implement XStore , an RDMA-based ordered key-value store with a new hybrid architecture that retains a tree-based index at the server to perform dynamic workloads (e.g., inserts) and leverages a learned cache at the client to perform static workloads (e.g., gets and scans). The key idea is to decouple ML model retraining from index updating by maintaining a layer of indirection from logical to actual positions of key-value pairs. It allows a stale learned cache to continue predicting a correct position for a lookup key. XStore ensures correctness using a validation mechanism with a fallback path and further uses speculative execution to minimize the cost of cache misses. Evaluations with YCSB benchmarks and production workloads show that a single XStore server can achieve over 80 million read-only requests per second. This number outperforms state-of-the-art RDMA-based ordered key-value stores (namely, DrTM-Tree, Cell, and eRPC+Masstree) by up to 5.9× (from 3.7×). For workloads with inserts, XStore still provides up to 3.5× (from 2.7×) throughput speedup, achieving 53M reqs/s. The learned cache can also reduce client-side memory usage and further provides an efficient memory-performance tradeoff, e.g., saving 99% memory at the cost of 20% peak throughput.

Impacts of the invasive round goby (Neogobius melanostomus) on benthic invertebrate fauna: a case study from the Baltic Sea

The round goby (Neogobius melanostomus) was first observed in the Baltic Sea in 1990 and has since displayed substantial secondary dispersal, establishing numerous dense populations where they may outcompete native fish and negatively impact prey species. There have been multiple round goby diet studies from both the Baltic Sea and the North American Great Lakes where they are similarly invasive. However, studies that quantify their effects on recipient ecosystems and, specifically, their impacts on the benthic invertebrate macrofauna are rare, particularly from European waters. In this study, we conducted the first before-after study of the potential effects of round goby on benthic invertebrate macrofauna taxa in marine-brackish habitats in Europe, focusing of two sites in the Western Baltic Sea, Denmark. Results were in line with those from the Great Lakes, indicating negative impacts on specific molluscan taxa (e.g. Cardiidae bivalves and Neritidae gastropods, which both showed a fall in detected densities of approximately 98% within the Guldborgsund Strait). In contrast, many other groups appeared to be largely unaffected or even show positive trends following invasion. Round goby gut content data were available at one of our study sites from the period immediately after the invasion. These data confirmed that round goby had in fact been preying on the subset of taxa displaying negative trends.

Varicella gangrenosa: A rare chickenpox complication

Varicella gangrenosa is a rare but life-threatening dermatological complication of infection with varicella-zoster virus. A healthy 37-year-old male who had been diagnosed with varicella 20 days back was admitted to our hospital with complaints of fever and painful necrotic skin lesions. Physical examination revealed multiple round to oval ulcers covered with eschar predominantly over arms, lower limbs, back of trunk and flanks. Streptococcus pyogenes and Staphylococcus aureus grew in wound culture. Biopsy revealed ulceration and necrosis of epidermis, and edema, hemorrhage and granulation tissue formation involving the dermis and subcutaneous tissue. The patient was treated with acyclovir - parenteral followed by oral, antibiotics and supportive measures. The lesions healed and he was discharged after 20 days. We report this case to draw attention to the fact that varicella gangrenosum, even though a rare complication, may occur in the lesions of chicken pox and that the survival of patient depends on early diagnosis and aggressive treatment.

Impacts of the invasive round goby (Neogobius melanostomus) on benthic invertebrate fauna: a case study from the Baltic Sea

Non-indigenous animals can impact native fauna via predation and competition for food and habitat. The round goby (Neogobius melanostomus) was first observed in the Baltic Sea in 1990 and has since displayed substantial secondary dispersal, establishing numerous dense populations where they may outcompete native fish and negatively impact prey species. There have been multiple round goby diet studies from both the Baltic Sea and the North American Great Lakes where they are similarly invasive. However, studies that quantify their effects on recipient ecosystems and, specifically, their impacts on the benthic invertebrate macrofauna are rare, particularly from European waters. In this study, we conducted the first before-after study of the potential effects of round goby on benthic invertebrate macrofauna taxa in marine-brackish habitats in Europe, focusing of two sites in the Western Baltic Sea, Denmark. Results were in line with those from the Great Lakes, indicating negative impacts to be focused on specific molluscan taxa, particularly gastropods, while other groups appeared to be largely unaffected or even show positive trends following invasion. Round goby gut content data was available at one of our study sites from the period immediately after the invasion. This data confirmed that round goby had in fact been preying on the subset of taxa displaying negative trends.

Cell-to-cell variability in inducible Caspase9-mediated cell death

iCasp9 suicide gene has been widely used as a promising killing strategy in various cell therapies. However, different cells show significant heterogeneity in response to apoptosis inducer, posing challenges in clinical applications of killing strategy. The cause of the heterogeneity remains elusive so far. Here, by simultaneously monitoring the dynamics of iCasp9 dimerization, Caspase3 activation and cell fate in single cells, we found that the heterogeneity was mainly due to cell-to-cell variability in initial iCasp9 expression and XIAP/Caspase3 ratio. Moreover, multiple-round drugging cannot increase the killing efficiency. Instead, it will place selective pressure on protein levels, especially on the level of initial iCasp9, leading to drug resistance. We further show this resistance can be largely eliminated by combinatorial drugging with XIAP inhibitor at the end, but not at the beginning, of the multiple-round treatments. Our results unveil the source of cell fate heterogeneity and drug resistance in iCasp9-mediated cell death, which may enlighten better therapeutic strategies for optimized killing.