We introduce a deep learning-based ligand pose scoring model called zPoseScore for predicting protein-ligand complexes in the 15th Critical Assessment of Protein Structure Prediction (CASP15). Our contributions are three-fold: firstly, we generate six training and evaluation datasets by employing advanced data augmentation and sampling methods. Secondly, we redesign the “zFormer” module, inspired by AlphaFold2’s Evoformer, to efficiently describe protein-ligand interactions. This module enables the extraction of protein-ligand paired features that lead to accurate predictions. Lastly, we develop the zPoseScore framework with zFormer for scoring and ranking ligand poses, allowing for atomic-level protein-ligand feature encoding and fusion to output refined ligand poses and ligand per-atom deviations. Our results demonstrate excellent performance on various testing datasets, achieving Pearson’s correlation R = 0.783 and 0.659 for ranking docking decoys generated based on experimental and predicted protein structures of CASF-2016 protein-ligand complexes. Additionally, we obtain an averaged lDDT = 0.558 of AIchemy_LIG2 in CASP15 for de novo protein-ligand complex structure predictions. Detailed analysis shows that accurate ligand binding site prediction and side-chain orientation are crucial for achieving better prediction performance. Our proposed model is one of the most accurate protein-ligand pose prediction models and could serve as a valuable tool in small molecule drug discovery.

AlphaFold has transformed structure prediction by enabling highly accurate predictions on par with experimentally determined structures. Still, for difficult cases, in particular, multimers, there is still room for improvement. Important for the success of AlphaFold is its ability to assess its own predictions. The basic idea for the Wallner group in CASP15 was to exploit the excellent ranking score in AlphaFold by massive sampling. To this end, we ran AlphaFold using six different settings, with and without templates, and with an increased number of recycles using both multimer v1 and v2 weights. In all cases, the dropout layers were enabled at inference to sample the uncertainty and increase the diversity of the generated models. A median of 4,810 models per target was generated and almost all (35/38) received a ranking_confidence >0.7. Compared to other groups in CASP15, Wallner obtained the highest sum of Z-scores based on the DockQ score, 40.8 compared to 26.3 for the second highest, much higher than -0.2 achieved by the AlphaFold baseline method, NBIS-AF2-multimer. The improvement over the baseline is substantial with the mean DockQ increasing from 0.43 to 0.56, with several targets showing a DockQ score increase by +0.6 units. Remarkable, considering Wallner and NBIS-AF2-multimer were using identical input data. The reason for the success can be attributed to the diversified sampling using dropout with different settings and, in particular, the use of multimer v1, which seems to be much more susceptible to sampling compared to v2. The method is available here: http://wallnerlab.org/AFsample/.

Rare Presentation of Papillary Thyroid CancerMahfujul Z. Haque, BS1Michael Burcescu, MD2Zirak Sajjad, BS11Michigan State University College of Human Medicine, Grand Rapids, MI, USA2Detroit Medical Center, Detroit, MI, USAWord Count: 444Table/Figure Count: 4Reference Count: 4Acknowledgements: N/AFunding Sources: NoneConflicts of Interest: NoneConsent Statement: N/ACorresponding author:Mahfujul Haque15 Michigan St NE,Grand Rapids, MI 49503Email: [email protected] informed consent was obtained from the patient to publish this report in accordance with the journal’s patient consent policy.Key Words: papillary thyroid cancer, thyroid nodule, neoplasm, endocrine cancerArticle Type: Case ImageThe patient is a 51-year-old African American female with incidental thyroid nodules identified on MRI of the cervical spine. Patient describes a tender palpable right thyroid nodule but is otherwise asymptomatic. There is no history of tobacco use or toxic occupational exposure. There is no palpable neck mass. Thyroid panel was within normal limits. The majority of parathyroid adenomas are located adjacent and posterior or just inferior to the thyroid gland. Rarely, an intrathyroidal ectopic parathyroid gland may become adenomatous and mimic thyroid nodule. When it does, it is usually homogenously hypoechoic to thyroid tissue and may demonstrate a peripheral rim of hyper-vascularity. Here we describe the case of an incidental nodule with irregular margins and punctate echogenic foci consistent with a TI-RADS 5 nodule and suggestive of malignancy.Fine needle aspiration biopsy of right upper thyroid nodule showed moderately cellular with cohesive groups as sheets and singly scattered cells exhibiting nuclear grooves, powdery chromatin, irregular nuclear outlines. A few intranuclear pseudo-inclusions are seen with some colloids in the background. True papillae, psammoma bodies, and necrosis were not detectable despite sampling with 3 adequate passes.Figure 1A is an axial T1 that demonstrates an unexpected nodule of the right thyroid lobe after gadolinium administration.Figure 1B demonstrates the same nodule with a traditional T1 view. Figure 1C demonstrates a T2 hyper intensive nodularity of the right thyroid lobe. Figure 2A demonstrates a long-axis ultrasound image of the right thyroid lobe revealed a 1.5 x 1.0 x 1.3 cm hypoechoic solid nodule with irregular margins, punctate echogenic foci, and mildly increased vascularity on color Doppler investigation.Figure 2B demonstrates a transverse ultrasound image of the right thyroid lobe showed a 1.5 x 1.0 x 1.3 cm hypoechoic solid nodule with irregular margins and punctate echogenic foci. Figure 3Ademonstrates a longitudinal-axis ultrasound image of the right thyroid lobe with a slight enlargement of the nodule, measuring 1.5 x 1.2 x 1.3 cm, with hypoechoic wider than tall features, irregular margins, and punctate echogenic foci, which are consistent with the previous sonographic evaluation. Figure 3B demonstrates a longitudinal-axis color Doppler image of the right thyroid lobe reveals increased vascularity within the thyroid nodule, indicating heightened blood flow to the nodule. Figure 4A demonstrates a Longitudinal-axis ultrasound image of the right thyroid lobe with further nodule enlargement to 1.9 x 1.3 x 0.9 cm.Studies report that 5-15% of all detected thyroid nodules and up to 11% of incidental thyroid nodules, represent malignancy [2]. The SEER database reports the USA incidence of thyroid carcinoma to be 14.9 per 100,000 with a 1:2.8 male to female predilection [3]. Papillary thyroid cancer (PTC), a common endocrine tumor originating from thyroid follicular cells, represents 85% of thyroid malignancy [1]. PTC is invasive and known to metastasize to adjacent structures including: lungs, mediastinal lymph nodes, and bone. Well-established risk factors for thyroid cancer include radiation exposure, family history of thyroid cancer, occupational exposure, and obesity [1].PTC is associated with favorable mortality of 11-17% and a low recurrence rate of 5-15% [1][4]. Extra-thyroidal growth, larger tumor size, and older age at diagnosis detrimentally impact outcome [1]. The primary treatment for PTC is surgical. Preprocedural considerations include tumor size, metastases, extra-thyroidal extension, and airway compromise. Patients with unifocal PTC, measuring > 4 cm, are candidates for thyroid lobectomy [1][5]. For larger lesions, total or near-total thyroidectomy is often required [1][5]. Ablation with radioactive iodine (RAI) is recommended for patients with residual tumor or metastasis. Additional considerations include patient age, microvascular invasion, and histologic subtyping [1]. RAI is performed 4 - 6 weeks following excision and repeated until residual radiotracer uptake is eliminated [1]. Successful intervention results in decreased serum thyroglobulin within 4 - 6 weeks. Thyroid hormone supplementation reduces tumor stimulation by suppressing TSH production [1]. Sonographic and biochemical recurrence monitoring are typically performed at 6-12 month intervals for at least 5 years.

Comment on: Viral infections in pediatric brain tumor patients treated with targeted therapiesAimen Waqar KhanDepartment of Medicine, Jinnah Sindh Medical University, Karachi, PakistanDear Dr. Newburger,We have read with great enthusiasm the article titled Viral infections in pediatric brain tumor patients treated with targeted therapies by Lisa Mayr et al [1]. We commend the authors’ efforts in collating epidemiologic data and investigating infectious outcomes between pediatric patients being treated with targeted therapy versus conventional therapies. It was a pleasure to read such a well-written paper. We concur with the conclusion that patients receiving targeted therapies are made more susceptible to developing viral infections than those receiving conventional treatment. However, we would like to draw attention to some key points regarding the study following a thorough appraisal.To begin with, the retrospective nature of the study adds several unavoidable biases such as recollection bias and incorrect data retrieval, which may have been mitigated had the investigators included current cases at the time. The study is also limited in its single-centered scope making it difficult to generalize the findings to this particular pediatric demographic. Moreover, the comparison between the two subsets of brain tumor patients is also subject to several partialities. For instance, it is noted that those receiving targeted therapies were managed in an outpatient setting and by extension, exposed to greater environmental stressors than those being managed on conventional chemotherapy. As a result, a greater proportion of virological infections were reported in children receiving targeted therapy than those being managed conventionally. Further, due to the lack of available data correlating disease severity with treatment option, the possibility that patients receiving conventional chemotherapy simply had a lower disease grade than those on targeted therapies and vice versa exists. Knowing this is pertinent as the body’s ability to fight off infections is greatly influenced by the grade of cancer and hence degree of inflammation [2]. Next, it remains to be seen what the baseline nutritional status of the participants was as nutrition and metabolism are known to have a bearing on immune status and hence infectious susceptibility [3]. Finally, the deduction that patients treated with bevacizumab or mTOR (mechanistic target of rapamycin) inhibitors suffered more infections than those treated with other targeted therapeutic drugs cannot be made with certainty as not enough patients were treated with drugs other than bevacizumab or mTOR inhibitors for a fair and accurate comparison.In conclusion, multi-centered prospective studies are required to better lay claims regarding infectious outcomes and attention to potential influencers of immunity must be given to minimize bias in future studies.

IntroductionVasculitis is an inflammatory disease with variable end-organ damage that is classified based on involvement of small, medium or large vessels.1 Leukocytoclastic vasculitis is a small-vessel vasculitis predominantly affecting dermal capillaries and venules, and often secondary to underlying systemic vasculitis, infection or drug exposure.1 Commonly implicated drugs include beta-lactam antibiotics and non-steroidal anti-inflammatory drugs,1 while calcium channel blockers and hydroxymethylglutaryl-coA reductase inhibitors (statins) have been rarely associated2-6 – with no previous formal case report for verapamil. We present a case of cutaneous leukocytoclastic vasculitis associated with recently initiated verapamil and atorvastatin.

Title: Outcome of PML-RARα Short Isoform and FLT3-ITD in a Patient with Several Adverse Prognostic Markers: a Case ReportMohammed A Bafail1, Rahaf AlTahan1Manar A Samman1, Suha A Tashkandi1, Ibraheem H Motabi2 , Abdul Ali Peer-Zada1*

Leukemic retinopathy is a severe complication of severe leukocytosis that results from untreated chronic myelogenous leukemia (CML). Immediate cytoreduction via leukapheresis may reverse ocular manifestations and prevent permanent vision damage. We present a case of a patient with acute unilateral vision loss found to have leukemic retinopathy in the setting of

Objective: To investigate the optimal range of quantitative ablation index (AI) value during superior vena cava (SVC) electrical isolation by radiofrequency catheter ablation (RFCA). Methods: First, in a development cohort of patients with atrial fibrillation (AF), the RFCA with 40W was performed to complete SVC isolation guided by the conduction breakthrough point from the right atrium to SVC. Then, the range of AI value was calculated by offline analysis on different segments of SVC. Lastly, for the validation of AF patients, the safety and effectiveness of SVC isolation with the optimized target range of AI value were evaluated with an additional adenosine test. Results: A total of 101 patients with AF were included in the study (44 patients in the development cohort / 57 in the validation cohort). The segmental ablation strategy was applied in 70% of the patients. According to the offline analysis of the AI values in the development cohort, the target AI value range was set as 350-400. The success rate of SVC isolation in the validation cohort was significantly higher than that in the exploration cohort (100% vs 90.9%, P = 0.02), and no complications occurred in the exploration cohort. During the adenosine test, the recovery rate of electrical conduction in SVC was significantly lower than that in the pulmonary vein (3.5% vs 17.5%). Conclusion: The target AI value with a range from 350 to 400 is safe and effective for high-power RFCA to complete SVC isolation.

We herein report a simple ether-directed iridium-catalyzed site- and enantioselective C(sp2)-H borylation of benzhydryl ethers for the first time. Various chiral benzhydryl ethers were obtained with high enantioselectivities in the presence of a tailor-made chiral bi-dentate boryl ligand. We found that the kinetic resolution relay significantly amplified the enantioselectivity. The synthetic utility of the current method was demonstrated by gram-scale C-H borylation and C-B bond transformations.

A document by Reynaldo Jr. Balintona. Click on the document to view its contents.

In May 2022, several countries reported mpox cases from patients without history of traveling to endemic areas. France was one of the most affected European countries. In this study, we described the clinical characteristics of mpox cases in France, and studied the genetic diversity of the virus. Patients diagnosed with mpox infection (qPCR ct<28) between 21 th May and 4 th July 2022 and between 16 th August and 10 th September 2022 were included to this study. Twelve amplicons corresponding to the most polymorphic regions of the mpox genome and covering ~30,000 nucleotides were generated and sequenced using the S5 XL Ion Torrent technology to evaluate the genetic diversity of mpox sequences. One hundred and fourty-eight patients were diagnosed with mpox-infection. 95% were men, 5% transgender (M-to-F), 50% were taking HIV pre-exposure prophylaxis, and 25% were HIV seropositive. One hundred and sixty-two samples were sequenced and compared to GenBank sequences. Thirty-two distinct mutational patterns were identified. Overall, low genetic diversity of mpox sequences was found compared with pre-epidemic Western-African sequences, with 32 distinct mutational patterns. Our results provide a first glance at the mutational landscape of early mpox 2022 circulating strains in Paris (France).

Since 1999, Vaccinia virus (VACV) has been described as a causative agent of bovine vaccinia (BV), a zoonotic disease that occurs mainly in rural areas of Brazil. However, the circulation of VACV in urban environments and its associated burden has been poorly explored. Moreover, the current Mpox outbreak has raised questions regarding the immune status of the worldwide population previous vaccinated against smallpox. Hence, we conducted a cross-sectional study to better understand the prevalence of anti-OPV neutralizing antibodies (NA) in a susceptible urban population of Brazil. A total of 372 individuals were sampled, yielding an overall seroprevalence of 16.9% (CI95%=13.4–21.1), and antibodies titers ranging from 100 to 800 NU/ml. The prevalence of NA among vaccinated individuals (≥36yo) was 24.9% (IC 95%=19.5–31.2), and among those unvaccinated (<36yo) was 6.7% (IC 95%=3.7–11.8). Multivariate logistic regression analysis indicated that age ≥36yo and the presence of vaccine take were independently associated with the presence of anti-OPV NA. Our findings suggest that vulnerable populations could be subclinically exposed to VACV in urban areas, drawing attention to alternative routes of zoonotic VACV exposure. Our data is also important for better strategies in order to mitigate zoonotic OPV infections mainly among vulnerable populations.

Next-generation sequencing of pooled samples (Pool-seq) is a popular method to assess genome-wide diversity patterns in natural and experimental populations. However, Pool-seq is associated with specific sources of noise, such as unequal individual contributions. Consequently, using Pool-seq for the reconstruction of evolutionary history has remained underexplored. Here we describe a novel Approximate Bayesian Computation (ABC) method to infer demographic history, explicitly modeling Pool-seq sources of error. By jointly modeling Pool-seq data, demographic history and the effects of selection due to barrier loci, we obtain estimates of demographic history parameters accounting for technical errors associated with Pool-seq. Our ABC approach is computationally efficient as it relies on simulating subsets of loci (rather than the whole-genome), and on using relative summary statistics and relative model parameters. Our simulation study results indicate Pool-seq data allows distinction between general scenarios of ecotype formation (single versus parallel origin), and to infer relevant demographic parameters (e.g., effective sizes, split times). We exemplify the application of our method to Pool-seq data from the rocky-shore gastropod Littorina saxatilis, sampled on a narrow geographical scale at two Swedish locations where two ecotypes (Wave and Crab) are found. Our model choice and parameter estimates show that ecotypes formed before colonization of the two locations (i.e., single origin) and are maintained despite gene flow. These results indicate that demographic modeling and inference can be successful based on pool-sequencing using ABC, contributing to the development of suitable null models that allow for a better understanding of the genetic basis of divergent adaptation.

1. Metabarcoding of environmental DNA (eDNA) has recently improved our understanding of biodiversity patterns in marine and terrestrial ecosystems. However, the complexity of these data prevents current methods to extract and analyze all the relevant ecological information they contain. Therefore, ecological modeling could greatly benefit from new methods providing better dimensionality reduction and clustering. 2. Here we present two new deep learning-based methods that combine different types of neural networks to ordinate eDNA samples and visualize ecosystem properties in a two-dimensional space: the first is based on variational autoencoders (VAEs) and the second on deep metric learning (DML). The strength of our new methods lies in the combination of several inputs: the number of sequences found for each molecular operational taxonomic unit (MOTU), together with the genetic sequence information of each detected MOTU within an eDNA sample. 3. Using three different datasets, we show that our methods represent well three different ecological indicators in a two-dimensional latent space: MOTU richness per sample, sequence α-diversity per sample, and sequence ꞵ-diversity between samples. We show that our nonlinear methods are better at extracting features from eDNA datasets while avoiding the major biases associated with eDNA. Our methods outperform traditional dimension reduction methods such as Principal Component Analysis, t-distributed Stochastic Neighbour Embedding, and Uniform Manifold Approximation and Projection for dimension reduction. 4. Our results suggest that neural networks provide a more efficient way of extracting structure from eDNA metabarcoding data, thereby improving their ecological interpretation and thus biodiversity monitoring.

Eucalyptus snout beetles (Curculionidae: Gonipterus scutellatus complex), native to mainland Australia and Tasmania, defoliate Eucalyptus trees and are considered important pests. Since the 19th century, species of the G. scutellatus complex have been introduced to other continents. Here, we document the presence of Eucalyptus snout beetles in Ecuador and use ecological niche models to analyze their potential distribution in South America. Phylogenetic analyses of DNA sequences unambiguously demonstrated that the Ecuadorian specimens belong to the species G. platensis, which has low genetic diversity compared with other species in the complex. Ecological niche models revealed several areas of high to intermediate climatic suitability for the pest in South America, even in countries where it has not been registered, like Peru and Bolivia. Accurate identification of species in the Gonipterus scutellatus complex and understanding of their potential distribution are essential tools for improved management and prevention tactics.

Aiming at the problem of crosstalk between microstrip lines, a method of reducing crosstalk by using Cross-Shape Resonators (CSR) structures is proposed. On the premise of not changing the spacing of microstrip lines, this method adds CSR structures between the coupled microstrip lines to increase the capacitive coupling and thus to suppress the far-end crosstalk. Based on the analysis of the equivalent circuit of CSR structure, the parameters simulation and verification are carried out by ADS and HFSS software. Through HFSS simulation and physical test of the designed CSR structure, the results show that: the CSR structure can significantly reduce the far-end crosstalk by about 15 dB in the frequency of 0~10GHz, and the maximum can reach 43 dB. Compared with 3W crosstalk reduction method and RectangularShape Resonators (RSR) crosstalk reduction method, the crosstalk reduction effect is improved.

Urbanization and the expansion of human activities foster radical ecosystem changes with cascading effects also involving host-pathogen interactions. Urban pollinator insects face several stressors related to landscape and local scale features such as green habitat loss, fragmentation, and availability reduction of floral resources with unpredictable effects on parasite transmission. Furthermore, beekeeping may contribute to the spread of parasites to wild pollinators by increasing the number of parasite hosts. Here we used DNA-based diagnostics tools to evaluate how the occurrence of parasites, namely microsporidians (Nosema spp.), trypanosomatids (Crithidia spp.) and neogregarines (Apicystis bombi), is shaped by the above-mentioned stressors in two bumblebee species (i.e, Bombus terrestris and B. pascuorum). Infection rates of the two species were different and generally higher in B. terrestris. Moreover, they showed different responses towards the same ecological variables, possibly due to differences in body size and foraging habits supposed to affect their susceptibility to parasite infection. The probability of infection was found to be reduced in B. pascuorum by green habitat fragmentation, while increased along with floral resource availability. Unexpectedly, B. terrestris had a lower parasite richness nearby apiaries probably because parasites are prone to be transmitted among the most abundant species. Our finding supports the need to design proper conservation measures based on species-specific knowledge, as suggested by the variation in the parasite occurrence of the two species. Moreover, conservation policies aiming at safeguarding pollinators through flower planting should consider the indirect effects of these measures for parasite transmission together with pollinator biodiversity issues.

The paper devises a H ∞ -norm theory for the CSVIU (control and state variations increase uncertainty) class of stochastic systems. This system model appeals to stochastic control problems to express the state evolution of a possibly nonlinear dynamic system restraint to poor modeling. Contrary to other H ∞ stochastic formulations that mimic deterministic models dealing with finite energy disturbances, the focus is on the H ∞ control with infinity energy disturbance signals. Thus, the approach portrays the persistent perturbations due to the environment more naturally. In this regard, it requires a refined connection between a suitable notion of stability and the systems’ energy or power finiteness. It delves into the control solution employing the relations between H ∞ optimization and differential games, connecting the worst-case stability analysis of CSVIU systems with a perturbed Lyapunov type of equation. The norm characterization relies on the optimal cost induced by the Min-Max control strategy. The rise of a pure saddle point is linked to the solvability of a modified Riccati-type equation in a form known as a generalized game-type Riccati equation, which yields the solution of the CSVIU dynamic game. The emerging optimal disturbance compensator produces inaction regions in the sense that, for sufficiently minor deviations from the model, the optimal action is constant or null in the face of the uncertainty involved. A numerical example illustrates the synthesis.