Protein tyrosine phosphatase 1B (PTP1B) plays important roles in cellular homeostasis and is a highly validated therapeutic target for multiple human ailments, including diabetes, obesity and breast cancer. However, much remains to be learned about how conformational changes may convey information through the structure of PTP1B to enable allosteric regulation by ligands or functional responses to mutations. High-resolution X-ray crystallography can offer unique windows into protein conformational ensembles, but comparison of even high-resolution structures is often complicated by differences between data sets, including non-isomorphism. Here, the highest resolution crystal structure of apo wild-type (WT) PTP1B to date is presented out of a total of ∼350 PTP1B structures in the PDB. This structure is in a crystal form that is rare for PTP1B, with two unique copies of the protein that exhibit distinct patterns of conformational heterogeneity, allowing a controlled comparison of local disorder across the two chains within the same asymmetric unit. The conformational differences between these chains are interrogated in the apo structure and between several recently reported high-resolution ligand-bound structures. Electron-density maps in a high-resolution structure of a recently reported activating double mutant are also examined, and unmodeled alternate conformations in the mutant structure are discovered that coincide with regions of enhanced conformational heterogeneity in the new WT structure. These results validate the notion that these mutations operate by enhancing local dynamics, and suggest a latent susceptibility to such changes in the WT enzyme. Together, these new data and analysis provide a detailed view of the conformational ensemble of PTP1B and highlight the utility of high-resolution crystallography for elucidating conformational heterogeneity with potential relevance for function.

RAS genes are the most commonly mutated in human cancers and play critical roles in tumor initiation, progression, and drug resistance. Identification of targets that block RAS signaling is pivotal to develop therapies for RAS-related cancer. As RAS translocation to the plasma membrane (PM) is essential for its effective signal transduction, we devised a high-content screening assay to search for genes regulating KRAS membrane association. We found that the tyrosine phosphatase PTPN2 regulates the plasma membrane localization of KRAS. Knockdown of PTPN2 reduced the proliferation and promoted apoptosis in KRAS-dependent cancer cells, but not in KRAS-independent cells. Mechanistically, PTPN2 negatively regulates tyrosine phosphorylation of KRAS, which, in turn, affects the activation KRAS and its downstream signaling. Consistently, analysis of the TCGA database demonstrates that high expression of PTPN2 is significantly associated with poor prognosis of patients with KRAS-mutant pancreatic adenocarcinoma. These results indicate that PTPN2 is a key regulator of KRAS and may serve as a new target for therapy of KRAS-driven cancer.

In a network containing multiple nodes, the need for synchronization between the various nodes is not just instrumental but also a complicated and highly complex process. This process becomes even more tricky if we synchronize the clocks between the Manager and the Peripheral. As we know, in a real-time network, some of the nodes would behave like Managers while some would be a Peripheral. If we must make the communication process smooth, then the local clocks of these nodes must be synchronized. 

The problem with this synchronization is that we have the clock running in the Manager as well. If we send the value of the Manager clock to the Peripheral, the synchronization doesn’t happen as we have a propagation delay of the messages, along with the propagation delay of the electronic circuits of Manager and the Peripheral.  

The cherry on the cake is that these electronic circuit propagation delays are not random and remain constant, so we can add a time offset to it to match the clock. To tackle this challenge, IEEE has come up with a protocol named “Precision Timing Protocol.” 

Operation of PTP: 

To synchronize the clocks, a Sync message is sent by the Manager to the Peripheral, which then timestamps the receiving time of the same. Following this, a ‘Follow up’ message is issued by the Manager stating the timestamp at which the Sync message was sent. 

The Peripheral then finds the difference between the two values and adds this to its current time. After this, the time difference between the Manager and the Peripheral narrows down to only the propagation delay of the messages.  

To overcome this, the Peripheral issues a ‘Delay Request’ to the Manager, and the Manager, in turn, issues a ‘Delay Response.’ Both these messages have the timestamp of when they were issued. The time at which they are received is then noted. Since two messages are sent, one from the Peripheral and the other from the Manager, there are two propagation delays. Then half of this value is our propagation delay. 

The Peripheral then adds this propagation delay to its clock, and hence the clock gets synchronized. 

Advantages of PTP: 

1. It provides accurate time stamping. 
2. It is a well-known clock synchronization protocol. 
3. It provides intensified security inside the premises. 
4. It provides the possibility of setting coordinated actions and synchronized communication. 

There are various versions of PTP that have been developed over time, namely PTPv1, PTPv2, PTPv2_1, and the latest PTP-AS. 

Cadence Verification IP for Ethernet is available to support the newer version of PTP, allowing simulation of the device for efficient IP, SoC, and system-level design verification. Semiconductor companies can start using it to fully verify their controller design and achieve functional verification closure on it within no time. 

Actor Elliot Page and musician Rufus Wainwright were among the stars who honoured 2SLGBTQ+ charities at the inaugural PTP Pink Awards in Toronto Thursday, in the shadow of a U.S. election that has many worried about queer and trans rights.

The WGA and the AMPTP have delayed the start of their contract negotiations by a week because of scheduling issues. The talks for a new film and TV deal, which had been set to start next week, will now begin on May 18. The AMPTP is also in the midst of negotiating a new contract […]

Provided herein are methods, compounds, and compositions for reducing expression of PTP1B mRNA and protein in an animal. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate metabolic disease, for example, diabetes, or a symptom thereof.

PTP-RAT is a proof of concept that allows data theft via screen-share protocols. Each screen flash starts with a header. This contains a magic string, "PTP-RAT-CHUNK" followed by a sequence number. When the receiver is activated, it starts taking screenshots at twice the transmission frequency (the Nyquist rate). When it detects a valid header, it decodes the pixel colour information and waits on the next flash. As soon as a valid header is not detected, it reconstructs all the flashes and saves the result to a file. To transfer a file, you run an instance of the Rat locally on your hacktop, and set that up as a receiver. Another instance is run on the remote server and this acts as a sender. You simply click on send file, and select a file to send. The mouse pointer disappears and the screen begins to flash as the file is transmitted via the pixel colour values. At the end of the transfer, a file-save dialog appears on the receiver, and the file is saved.

Halle : C.E.M. Pfeffer, 1875-1877.