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TrIP2 is an advanced version of the transformer interatomic potential (TrIP) trained on the expanded ANI-2x data set, including more diverse molecular configurations with sulfur, fluorine, and chlorine. It leverages the equivariant SE(3)-transformer architecture, incorporating physical biases and continuous atomic representations. TrIP was introduced as a highly promising transferable interatomic potential, which we show here to generalize to new atom types with no alterations to the underlying model design. Benchmarking on COMP6 energy and force calculations, structure minimization tasks, torsion drives, and applications to molecules with unexpected conformational energy minima demonstrates TrIP2’s high accuracy and transferability. Direct architectural comparisons demonstrate superior performance against ANI-2x, while holistic model evaluations─including training data and level-of-theory considerations─show comparative performance with state-of-the-art models like AIMNet2 and MACE-OFF23. Notably, TrIP2 achieves state-of-the-art force prediction performance on the COMP6 benchmarks and closely approaches DFT-optimized structures in torsion drives and geometry optimization tasks. Without requiring any architectural modifications, TrIP2 successfully capitalizes on additional training data to deliver enhanced generalizability and precision, establishing itself as a robust and scalable framework capable of accommodating future expansions or applications to new domains with minimal reengineering.

Objective

To investigate the dose-response relationship between dietary sugar and T2D risk.

Methods

MEDLINE, Embase, CINAHL, Web of Science and Cochrane databases were searched through July 9, 2024 for prospective cohorts reporting relative measures of incident T2D risk by categories of dietary sugar (total, free, added, fructose, sucrose) or two beverage sources (non-diet SSB, fruit juice) in healthy adults (Prospero ID: CRD42023401800). Linear and restricted cubic spline dose-response models were fitted for each exposure and study-specific slopes and confidence intervals (CIs) were calculated. Heterogeneity was evaluated using Q-statistics. Risk of bias was evaluated using ROBINS-E tool GRADE approach was applied to assess the certainty of evidence.

Results

Of 10,384 studies, 29 cohorts were included: SSB:18 (n = 541,288); fruit juice:14 (n = 490,413); sucrose: 7 (n = 223,238); total sugar: 4 (n = 109,858); fructose: 5 (n = 158,136); and added sugar: 2 (n = 31,004). Studies were conducted in Europe (13), USA (11), Asia (6), Australia (4), and Latin America (3). Each additional serving of SSB and fruit juice was associated with a higher risk of T2D (RR: 1.25; 95% CI: 1.17–1.35 and RR: 1.05; 95% CI: >1.00–1.11, respectively; moderate certainty). In contrast, 20 g/d intakes of total sugar and sucrose were inversely associated with T2D (RR: 0.96; 95% CI: 0.94–0.98; low certainty; and RR: 0.95; 95% CI: 0.91– <1.00; moderate certainty, respectively). No associations for added sugar (RR: 0.99; 95% CI: 0.96–1.01; low certainty) or fructose (RR: 0.98; 95% CI: 0.83–1.15; very low certainty).

Conclusion

These findings suggest that dietary sugar consumed as a beverage (SSB and fruit juice) is associated with incident T2D risk. The results do not support the common assumption that dietary sugar (i.e., total sugar and sucrose), irrespective of type and amount, is consistently associated with increased T2D risk.

A general method for designing proteins with high conformational specificity is desirable for a variety of applications, including enzyme design and drug target redesign. To assess the ability of algorithms to design for conformational specificity, we introduce MotifDiv, a benchmark dataset of 200 conformational specificity design challenges. We also introduce CSDesign, an algorithm for designing proteins with high preference for a target conformation over an alternate conformation. On the MotifDiv benchmark, CSDesign designs protein sequences that are predicted to prefer the target conformation. We apply this method in vitro to redesign human MAP kinase ERK2, an enzyme with active and inactive conformations. Out of two designs for the active conformation, one increased activity sufficiently to retain activity in the absence of activating phosphorylations, a property not present in the wild type protein.