The Damietta Server: a comprehensive protein design toolkit.

The growing importance of protein design to various research disciplines motivates the development of integrative computational platforms that enhance the accessibility and interoperability of different design tools. To this end, we describe a web-based toolkit that builds on the Damietta protein design engine, which deploys a tensorized energy calculation framework. The Damietta Server seamlessly integrates different design tools, in addition to other tools such as message-passing neural networks and molecular dynamics routines, allowing the user to perform multiple operations on structural models and forward them across tools. The toolkit can be used for tasks such as core or interface design, symmetric design, mutagenic scanning, or conformational sampling, through an intuitive user interface. With the envisioned integration of more tools, the Damietta Server will provide a central resource for protein design and analysis, benefiting basic and applied biomedical research communities. The toolkit is available with no login requirement through https://damietta.de/.

The design of functional proteins using tensorized energy calculations.

In protein design, the energy associated with a huge number of sequence-conformer perturbations has to be routinely estimated. Hence, enhancing the throughput and accuracy of these energy calculations can profoundly improve design success rates and enable tackling more complex design problems. In this work, we explore the possibility of tensorizing the energy calculations and apply them in a protein design framework. We use this framework to design enhanced proteins with anti-cancer and radio-tracing functions. Particularly, we designed multispecific binders against ligands of the epidermal growth factor receptor (EGFR), where the tested design could inhibit EGFR activity in vitro and in vivo. We also used this method to design high-affinity Cu2+ binders that were stable in serum and could be readily loaded with copper-64 radionuclide. The resulting molecules show superior functional properties for their respective applications and demonstrate the generalizable potential of the described protein design approach.

Equations of Disturbed Motion of the Moving Part of the Gyroscope Suspension.

The response of the float two-stage angular velocity sensor to the simultaneous perturbation from the rocket body-kinematic perturbation-and the penetrating acoustic radiation from the propulsion engines of the launch vehicle were determined. The solution of two equations was successively analyzed: the first and second approximations, and the synchronous and asynchronous fuselage pitch. The reaction of the float gyroscope to harmonic oscillations of the base was analyzed. The effect of the zero shift of the device due only to the angular oscillations of the launch vehicle body and the penetrating acoustic radiation was considered. The presented results reveal the nature of the appearance of inertia forces acting on the impedance surface of the gyroscope float suspension. Acoustic radiation that passes into a device generates many vibration modes on the surface and can have a considerable effect on the precision of float two-stage angular velocity sensor and gyro-stabilized platforms.

A topological refactoring design strategy yields highly stable granulopoietic proteins.

Protein therapeutics frequently face major challenges, including complicated production, instability, poor solubility, and aggregation. De novo protein design can readily address these challenges. Here, we demonstrate the utility of a topological refactoring strategy to design novel granulopoietic proteins starting from the granulocyte-colony stimulating factor (G-CSF) structure. We change a protein fold by rearranging the sequence and optimising it towards the new fold. Testing four designs, we obtain two that possess nanomolar activity, the most active of which is highly thermostable and protease-resistant, and matches its designed structure to atomic accuracy. While the designs possess starkly different sequence and structure from the native G-CSF, they show specific activity in differentiating primary human haematopoietic stem cells into mature neutrophils. The designs also show significant and specific activity in vivo. Our topological refactoring approach is largely independent of sequence or structural context, and is therefore applicable to a wide range of protein targets.

Design of novel granulopoietic proteins by topological rescaffolding.

Computational protein design is rapidly becoming more powerful, and improving the accuracy of computational methods would greatly streamline protein engineering by eliminating the need for empirical optimization in the laboratory. In this work, we set out to design novel granulopoietic agents using a rescaffolding strategy with the goal of achieving simpler and more stable proteins. All of the 4 experimentally tested designs were folded, monomeric, and stable, while the 2 determined structures agreed with the design models within less than 2.5 Å. Despite the lack of significant topological or sequence similarity to their natural granulopoietic counterpart, 2 designs bound to the granulocyte colony-stimulating factor (G-CSF) receptor and exhibited potent, but delayed, in vitro proliferative activity in a G-CSF-dependent cell line. Interestingly, the designs also induced proliferation and differentiation of primary human hematopoietic stem cells into mature granulocytes, highlighting the utility of our approach to develop highly active therapeutic leads purely based on computational design.

'If she is a good woman ' and 'to be a real man ': gender, risk and access to HIV services among key populations in Tajikistan.

The HIV epidemic continues to grow in Tajikistan, especially among people who inject drugs, sex workers, men who have sex with men and incarcerated populations. Despite their susceptibility to HIV, members of these groups do not always have access to HIV prevention, testing and treatment. The purpose of this study was to identify and understand the gender constraints in accessing HIV services for key populations in Tajikistan. Using focus-group discussions and key-informant interviews the assessment team collected information from members of key populations and those who work with them. Several themes emerged from the data, including: low levels of HIV knowledge, gender constraints to condom use and safer drug use, gender constraints limit HIV testing opportunities, gender-based violence, stigma and discrimination, and the lack of female spaces in the HIV response. The results of this study show that there are well-defined gender norms in Tajikistan, and these gender norms influence key populations' access to HIV services. Addressing these gender constraints may offer opportunities for more equitable access to HIV services in Tajikistan.