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Pancreatic cancer (PC) mobilizes myeloid cells from the bone marrow to the tumor where they promote tumor growth and proliferation. Cancer stem cells (CSCs) are a population of tumor cells that are responsible for tumor initiation. Aldehyde dehydrogenase-1 activity in PC identifies CSCs, and its activity has been correlated with poor overall prognosis in human PC. Myeloid cells have been shown to impact tumor stemness, but the impact of immunosuppressive tumor-infiltrating granulocytic and monocytic myeloid-derived suppressor cells (Mo-MDSC) on ALDH1 Bright CSCs and epithelial to mesenchymal transition is not well understood. In this study, we demonstrate that Mo-MDSC (CD11b + /Gr1 + /Ly6G − /Ly6C hi ) significantly increase the frequency of ALDH1 Bright CSCs in a mouse model of PC. Additionally, there was significant upregulation of genes associated with epithelial to mesenchymal transition. We also found that human PC converts CD14 + peripheral blood monocytes into Mo-MDSC (CD14 + /HLA-DR low/− ) in vitro, and this transformation is dependent on the activation of the STAT3 pathway. In turn, these Mo-MDSC increase the frequency of ALDH1 Bright CSCs and promote mesenchymal features of tumor cells. Finally, blockade of STAT3 activation reversed the increase in ALDH1 Bright CSCs. These data suggest that the PC tumor microenvironment transforms monocytes to Mo-MDSC by STAT3 activation, and these cells increase the frequency of ALDH1 Bright CSCs. Therefore, targeting STAT3 activation may be an effective therapeutic strategy in targeting CSCs in PC.

To reveal the clonal architecture of melanoma and associated driver mutations, whole genome sequencing (WGS) and targeted extension sequencing were used to characterize 124 melanoma cases. Significantly mutated gene analysis using 13 WGS cases and 15 additional paired extension cases identified known melanoma genes such as BRAF, NRAS, and CDKN2A, as well as a novel gene EPHA3, previously implicated in other cancer types. Extension studies using tumors from another 96 patients discovered a large number of truncation mutations in tumor suppressors (TP53 and RB1), protein phosphatases (e.g., PTEN, PTPRB, PTPRD, and PTPRT), as well as chromatin remodeling genes (e.g., ASXL3, MLL2, and ARID2). Deep sequencing of mutations revealed subclones in the majority of metastatic tumors from 13 WGS cases. Validated mutations from 12 out of 13 WGS patients exhibited a predominant UV signature characterized by a high frequency of C->T transitions occurring at the 3' base of dipyrimidine sequences while one patient (MEL9) with a hypermutator phenotype lacked this signature. Strikingly, a subclonal mutation signature analysis revealed that the founding clone in MEL9 exhibited UV signature but the secondary clone did not, suggesting different mutational mechanisms for two clonal populations from the same tumor. Further analysis of four metastases from different geographic locations in 2 melanoma cases revealed phylogenetic relationships and highlighted the genetic alterations responsible for differential drug resistance among metastatic tumors. Our study suggests that clonal evaluation is crucial for understanding tumor etiology and drug resistance in melanoma.

We examine the cellular and soluble determinants of coronavirus disease 2019 (COVID-19) relative to aging by performing mass cytometry in parallel with clinical blood testing and plasma proteomic profiling of ~4,700 proteins from 71 individuals with pulmonary disease and 148 healthy donors (25-80 years old). Distinct cell populations were associated with age (GZMK CD8 T cells and CD25 CD4 T cells) and with COVID-19 (TBET EOMES CD4 T cells, HLA-DR CD38 CD8 T cells and CD27 CD38 B cells). A unique population of TBET EOMES CD4 T cells was associated with individuals with COVID-19 who experienced moderate, rather than severe or lethal, disease. Disease severity correlated with blood creatinine and urea nitrogen levels. Proteomics revealed a major impact of age on the disease-associated plasma signatures and highlighted the divergent contribution of hepatocyte and muscle secretomes to COVID-19 plasma proteins. Aging plasma was enriched in matrisome proteins and heart/aorta smooth muscle cell-specific proteins. These findings reveal age-specific and disease-specific changes associated with COVID-19, and potential soluble mediators of the physiological impact of COVID-19.

The summer of 2016 was one of the driest on record in the Seacoast of New Hampshire. Southeastern New Hampshire, along with much of New England, experienced an extreme drought in 2016 which required water suppliers to monitor and manage their resources in ways that have not been necessary in many years. The City of Portsmouth responded to the drought conditions in a variety of ways, including withdrawal rate adjustments between surface and groundwater sources, increased aeration of surface water, preparation for an emergency well connection, and controlling demands through the implementation of water use restrictions. The following information provides a summary of the weather that lead to this deficit and the Portsmouth Water Division's efforts to track and respond to the drought.

The more complex a public sector project becomes, the more Important cooperation, negotiation, and collaboration are in creating a path toward a viable long-term solution. These efforts are even more critical when the project involves public health along with stakeholders from federal, state, and local agencies, as well as citizens' advocates. This need for collaboration was very apparent in the cooperative response to the discovery of per- and poly-fluorinated alkyl substances (PFAS) in several drinking water wells near the Pease International Tradeport (Tradeport) in Portsmouth, New Hampshire, the former home of Pease Air Force Base. This system, operated by city of Portsmouth staff, is located west of the city and the city's own water system. From the initial discovery of PFAS in the Haven Well in 2014 that caused its shutdown, to the formal dedication of a new state-of-the-art treatment facility during the summer of 2021 that brought the well back online, there were numerous instances of collaborative and innovative efforts that addressed and overcame project challenges. This article discusses the many unique approaches used over the last seven years to ensure the supply of safe, reliable drinking water to the Tradeport during the well shutdown.

Using multiparadigm programming (MPP) has costs as well as benefits. Over email, guest editors Dean Wampler and Tony Clark discussed with Neal Ford and Brian Goetz the practical issues for MPP in industrial software development teams. What follows is a transcript.

Water demands of community water systems in New Hampshire vary widely and are dependant on the demographics of the customers and population served. Weather patterns have the greatest impact to monthly changes in water use. Findings from this analysis show that dryer summers increase demands; however, they vary from system to system. Normal summer demands increase by 14 to 90 percent over baseline winter demands. Warm and dry summer demands show increases of 29 to 157%. Systems with demand management/conservation programs have been successful in reducing these peak demands.

When you obtain a reference to a remote object through a directory service, you don't receive an actual reference to that object, but rather a reference to a stub object that implements the same interface as the remote object. When you invoke a method on the stub object, the stub has to marshal the method parameters -- convert them into a byte-stream representation, a process similar to serialization. The stub sends the marshaled parameters over the network to a skeleton object, which unmarshals them and invokes the actual remote method you wanted to invoke. Then the method returns a value to the skeleton, the skeleton marshals the return value and ships it to the stub, and the stub unmarshals it and returns the value to the caller. Phew! That's a lot of work for a single method call. Clearly, despite an outward similarity, a remote method invocation is a more expensive operation than a local method invocation. The above description glosses over some important details that are significant for program performance. What happens when a remote method returns not a primitive type, but an object? That depends. If the returned object is a type that supports remote method invocation, then it creates a stub and skeleton object, as is the case when looking up a remote object in the registry. That is clearly an expensive operation. (Remote objects support a form of distributed garbage collection, which involves each of the participating JVMs maintaining a thread for talking to the remote garbage collection thread of other JVMs, and sending reference status information back and forth.) If the returned object doesn't support remote invocation, then all of the object's fields and any objects referenced by the returned object have to be marshaled, which could also be an expensive operation. A third technique for further lightening the load on the RMI layer would be to not make the DirectoryEntry a remote object, but instead define it as an ordinary object with fields or accessors for name, address, email address, and so forth. (In a CORBA system, we would use the analogous object-by-value mechanism.) Then, when the email application calls getEntryByName(), it will retrieve an entry object by value -- which doesn't require the creation of a stub or skeleton, and the invocation of getEmailAddress() will be a local invocation instead of a remote one.

Programs that heavily use BadRegExpMatcher will run slower than those using BetterRegExpMatcher. First, callers have to create a String object to pass into match(), which then has to create another String object to return the matched text to the caller. That results in at least two object creations per invocation, which may not sound like much, but if you call match() frequently, the performance overhead of those object creations can really add up. The problem with BadRegExpMatcher's performance is not in its implementation but in its interface; with the interface defined as it is, there is no way to avoid creating several temporary objects. In the RegExpMatcher example, you saw that when a method had a return type of String, it usually necessitated the creation of a new String object. One of the problems with BadRegExpMatcher was that match() returned an object rather than a primitive type -- but just because a method returns an object, doesn't mean that a new object must be created. Consider the geometry classes in java.awt such as Point and Rectangle. A Rectangle is just a container of four integers (x, y, width, and height). The AWT Component class stores the component location and returns it as a Rectangle through the getBounds() accessor method: In the case of String, the object creations were required because String is immutable. But in this case, an object creation seems to be required because Rectangle is mutable. We avoided the problem with String by not using any objects in our interfaces. While that worked in the case of RegExpMatcher, that solution is not always possible or desirable. Fortunately, you can employ several techniques when designing classes that allow you to rid yourself of the too-many- small-objects problem without avoiding small objects altogether.

The semantics of synchronized do indeed include mutual exclusion of execution based on the status of a semaphore, but they also include rules about the synchronizing thread's interaction with main memory. In particular, the acquisition or release of a lock triggers a memory barrier -- a forced synchronization between the thread's local memory and main memory. (Some processors -- like the Alpha -- have explicit machine instructions for performing memory barriers.) When a thread exits a synchronized block, it performs a write barrier -- it must flush out any variables modified in that block to main memory before releasing the lock. Similarly, when entering a synchronized block, it performs a read barrier -- it is as if the local memory has been invalidated, and it must fetch any variables that will be referenced in the block from main memory. DCL relies on an unsynchronized use of the resource field. That appears to be harmless, but it is not. To see why, imagine that thread A is inside the synchronized block, executing the statement resource = new Resource(); while thread B is just entering getResource(). Consider the effect on memory of this initialization. Memory for the new Resource object will be allocated; the constructor for Resource will be called, initializing the member fields of the new object; and the field resource of SomeClass will be assigned a reference to the newly created object. Other concurrency hazards are embedded in DCL -- and in any unsynchronized reference to memory written by another thread, even harmless-looking reads. Suppose thread A has completed initializing the Resource and exits the synchronized block as thread B enters getResource(). Now the Resource is fully initialized, and thread A flushes its local memory out to main memory. The resource's fields may reference other objects stored in memory through its member fields, which will also be flushed out. While thread B may see a valid reference to the newly created Resource, because it didn't perform a read barrier, it could still see stale values of resource's member fields.