AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Interferon alpha-2b in the treatment of chronic hepatitis C: early experience.

The antiviral and immunomodulatory effects of interferon were assessed in the treatment of chronic Hepatitis C in multi-ethnic patients to prevent viral replication and chronic liver damage. Three million units of recombinant interferon alpha-2b were administered three times a week for 48 weeks to a group of 9 active Hepatitis C patients. A clinical response was defined as normalization of serum ALT values. Serum was frozen and stored for Hepatitis C viral assays. Four patients normalized their liver functions. When viral levels were measured only two patients had unmeasurable levels of HCV RNA after treatment. Therapeutic results were observed and much work needs to be done to improve therapy because a serious epidemic is predicted for the future

Long-term low dose interferon alpha-2b in the treatment of chronic hepatitis B in multi-ethnic patients in Hawaii.

The antiviral and immunomodulatory effects of interferon were assessed in the treatment of chronic hepatitis B in multi-ethnic patients to prevent viral replication and chronic liver damage. Five million units of recombinant interferon alpha-2b were administered three times a week for 48 weeks to a group of 18 chronic active hepatitis B patients. A complete response was defined as seroconversion to anti-HBe and/or loss of HBe antigen. Seroconversion to anti-HBe in 5 of 12 (42%) chronic active hepatitis B patients occurred after 48 weeks of therapy. HBV-DNA decreased to undetectable levels in 8 of 12 (67%) patients. This chronic low-dose interferon administration regimen demonstrated responses comparable to other studies

Enteric Fever in a 6-Year-Old Traveler Caused by Salmonella enterica Serotypes Typhi and Paratyphi A: Laboratory Detection Strategies and Treatment Options ▿

We report the first pediatric case of enteric fever caused by Salmonella enterica serotypes Typhi and Paratyphi A. Mixed infections are infrequently reported, potentially because detection of two different Salmonella serotypes in blood cultures is technically challenging. We suggest laboratory strategies to aid in the recognition of mixed infections

Autologous Neutralizing Antibody to Human Immunodeficiency Virus-1 and Replication-Competent Virus Recovered from CD4+ T-Cell Reservoirs in Pediatric HIV-1–Infected Patients on HAART

A patient's ability to produce autologous neutralizing antibody (ANAB) to current and past HIV isolates correlates with reduced disease progression and protects against maternal–fetal transmission. Little is known about the effects of prolonged viral suppression on the ANAB response in pediatric HIV-infected patients receiving HAART because the virus is hard to isolate, except by special methods. We therefore assessed ANAB to pre-HAART PBMC virus isolates and post-HAART replication-competent virus (RCV) isolates recovered from latent CD4+ T-cell reservoirs in perinatally HIV-infected children by using a PBMC-based assay and 90% neutralization titers. We studied two infants and three children before and after HAART. At the time of RCV isolation (n = 4), plasma HIV RNA was <50 copies/ml. At baseline, four of five children had detectable ANAB titers to concurrent pre-HAART virus isolates. Although ANAB was detected in all subjects at several time points despite prolonged HAART and undetectable viremia, the response was variable. ANAB titers to concurrent post-HAART RCV and earlier pre-HAART plasma were present in 3 children suggesting prior exposure to this virus. Post-HAART RCV isolates had reduced replication kinetics in vitro compared to pre-HAART viruses. The presence of ANAB over time suggests that low levels of viral replication may still be ongoing despite HAART. The observation of baseline ANAB activity with earlier plasma against a later RCV suggests that the “latent” reservoir may be established early in life before HAART

Building a coupled data assimilation system for the atmosphere, land-surface and subsurface on the catchment scale

We present a data assimilation (DA) system for the atmosphere-land-surface-subsurface system on the catchment scale. The Neckar catchment in SW-Germany served as the specific case where the DA in combination with the coupled atmosphere-land surface-subsurface model TSMP was used. TSMP couples the atmospheric model COSMO, the land-surface model CLM and the hydrological model ParFlow to the DA framework PDAF. We will discuss how the ensemble system is set up in order to work properly and what issues we faced during our initial testing. For the atmosphere we found that it is important to have a good ensemble of lateral forcings as changing internal parameters for various parametrizations does not introduce sufficient variability on its own due to the rather small size of our domain. For the sub-surface the choice of parameters becomes most important and as such parameter estimation will be a valuable tool for improving DA results significantly. Finally, we are showing some first DA results with our system concerning soil moisture with two different assimilation methods with a fully coupled model setup. In the first assimilation scenario in-situ soil moisture data measured by cosmic ray probes are assimilated, while in the second assimilation scenario remotely sensed near surface soil moisture is assimilated. The first results are encouraging and we discuss additional planned simulation scenarios with the fully coupled atmosphere-land surface-subsurface modelling system as well as plans to test strongly coupled DA, where measurements are used to update states across compartments, possibly resulting in additional accuracy gain compared to traditional uncoupled DA.&#160;</p

Increased lipid deposition observed in two of the three pellet-fed groups compared to controls with the exception of Group C.

<p>Panel (A-D): cross sections of posterior liver stained with H/E of Groups (A-D) respectively; Green arrows = hepatocytes containing lipid droplet. Panel (a-d); 40x magnification, scale bar = 50μm. Panel E: Quantitative analysis of mean hepatocyte diameter detected within Groups (A-D); Post ANOVA Dunnett’s multiple comparisons test was performed between the mean of each group with the mean of the control group. Means significantly different from Group A are noted with (*—P_adj < 0.05; **—P_adj < 0.01; ***—P_adj < 0.001; ****—P_adj < 0.0001).</p

Wide-ranging differences among the relative body weight gains in Asian seabass fed pelleted feeds compared to control.

<p>Total percentage of body weight gain after the consumption of three different pelleted feeds (Feeds B-D) relative to frozen baitfish (Feed A) during a two-month period (107–168 days post-hatch). Post-ANOVA Tukey's multiple comparison test was performed to compare the mean values of every group. Error bars are plotted with 95% confidence intervals from the mean. Significantly different means are noted with *—P_adj < 0.05; **—P_adj < 0.01; ***—P_adj < 0.001; and ****—P_adj < 0.0001.</p