Minimal pairs approach

ConspectusIn 1960, Weber prophesied that "There are many ways in which the properties of the excited state can be utilized to study points of ignorance of the structure and function of proteins". This has been realized, illustrating that an intrinsic and highly responsive fluorophore such as tryptophan can alter the course of an entire scientific discipline. But what about RNA and DNA? Adapting Weber's protein photophysics prophecy to nucleic acids requires the development of intrinsically emissive nucleoside surrogates as, unlike Trp, the canonical nucleobases display unusually low emission quantum yields, which render nucleosides, nucleotides, and oligonucleotides practically dark for most fluorescence-based applications...

Inducing apoptosis in cancer cells is a primary goal in anti-cancer therapy, but curing cancer with a single drug is unattainable due to drug resistance. The complex molecular network in cancer cells causes heterogeneous responses to single-target drugs, thereby inducing an adaptive drug response. Here, we showed that targeted drug perturbations can trigger state conflicts between multi-stable motifs within a molecular regulatory network, resulting in heterogeneous drug responses. However, we revealed that properly regulating an interconnecting molecule between these motifs can synergistically minimize the heterogeneous responses and overcome drug resistance...

Limited-angle computed tomography (CT) presents a challenge due to its ill-posed nature. In such scenarios, analytical reconstruction methods often exhibit severe artifacts. To tackle this inverse problem, several supervised deep learning-based approaches have been proposed. However, they are constrained by limitations such as generalization issue and the difficulty of acquiring a large amount of paired CT images.
Approach. In this work, we propose an iterative neural reconstruction framework designed for limited-angle CT...

Managing diabetes during pregnancy is challenging, given the significant risk it poses for both maternal and foetal health outcomes. While traditional methods involve capillary self-monitoring of blood glucose level monitoring and periodic HbA1c tests, the advent of continuous glucose monitoring (CGM) systems has revolutionized the approach. These devices offer a safe and reliable means of tracking glucose levels in real-time, benefiting both women with diabetes during pregnancy and the healthcare providers...

Antimicrobial resistance (AMR) has become a global health crisis in need of novel solutions. To this end, antibiotic combination therapies, which combine multiple antibiotics for treatment, have attracted significant attention as a potential approach for combating AMR. To facilitate advances in antibiotic combination therapies, most notably in investigating antibiotic interactions and identifying synergistic antibiotic combinations however, there remains a need for automated high-throughput platforms that can create and examine antibiotic combinations on-demand, at scale, and with minimal reagent consumption...

Human papillomavirus (HPV) vaccines, primarily relying on neutralizing antibodies, have proven highly effective. Recently, HPV-specific antibodies have been detected in the female genital tract secretions captured by first-void urine (FVU), offering a minimally invasive diagnostic approach. In this study, we investigated whether HPV16-specific antibodies present in FVU samples retain their neutralizing capacity by using pseudovirion-based neutralization assays. Paired FVU and serum samples (vaccinated n  = 25, unvaccinated n  = 25, aged 18-25) were analyzed using two orthogonal pseudovirion-based neutralization assays, one using fluorescence microscopy and the other using luminescence-based spectrophotometry...

INTRODUCTION: The standard approach to treatment in psychiatry is known as "treatment as usual" (TAU), in which the same types of treatment are administered to a group of patients. TAU often requires numerous dose adjustments and medication changes due to ineffectiveness and/or the occurrence of adverse drug reactions (ADRs). This process is not only time-consuming but also costly. Antipsychotic medications are commonly used to treat various psychiatric disorders such as schizophrenia and mood disorders...

OBJECTIVE: Simulation training for minimally invasive colorectal procedures is in developing stages. This study aims to assess the impact of simulation on procedural knowledge and simulated performance in laparoscopic low anterior resection (LLAR) and robotic right colectomy (RRC). DESIGN: LLAR and RRC simulation procedures were designed using human cadaveric models. Resident case experience and simulation selfassessments scores for operative ability and knowledge were collected before and after the simulation...

BACKGROUND AND OBJECTIVE: A notable paradigm shift has emerged in the choice of prostate biopsy approach, with a transition from transrectal biopsy (TRBx) to transperineal biopsy (TPBx) driven by the lower risk of severe urinary tract infections. The impact of this change on detection of clinically significant prostate cancer (csPCa) remains a subject of debate. Our aim was to compare the csPCa detection rate of TRBx and TPBx. METHODS: Patients who underwent magnetic resonance imaging (MRI)-targeted and systematic biopsies for clinically localized PCa at 15 European referral centers from 2016 to 2023 were included...

INTRODUCTION: Minimally invasive Pancreatoduodenectomy (MIPD), or the Whipple procedure, is increasingly utilized. No study has compared laparoscopic (LPD) and robotic (RPD) approaches, and the impact of the learning curve on oncologic, technical, and post-operative outcomes remains relatively understudied. METHODS: The National Cancer Database was queried for patients undergoing LPD or RPD from 2010 to 2020 with a diagnosis of pancreatic cancer. Outcomes were compared between approaches using propensity-score matching (PSM); the impact of annual center-level volume of MIPD was also assessed by dividing volume into quartiles...

Recent developments in synthetic biology, next-generation sequencing, and machine learning provide an unprecedented opportunity to rationally design new disease treatments based on measured responses to gene perturbations and drugs to reprogram cells. The main challenges to seizing this opportunity are the incomplete knowledge of the cellular network and the combinatorial explosion of possible interventions, both of which are insurmountable by experiments. To address these challenges, we develop a transfer learning approach to control cell behavior that is pre-trained on transcriptomic data associated with human cell fates, thereby generating a model of the network dynamics that can be transferred to specific reprogramming goals...

Bispecific antibodies (BsAbs) represent an emerging class of biologics that can recognize two different antigens or epitopes. T-cell engagers (TcEs) bind two targets in trans on the cell surface of the effector and target cell to induce proximal immune effects, opening exciting windows for immunotherapies. To date, the engineering of BsAbs has been mainly focused on tuning the molecular weight and valency. However, the effects of spatial factors on the biological functions of BsAbs have been less explored due to the lack of biochemical methods to precisely manipulate protein geometry...

BACKGROUND: Anatomical sectionectomy based on Takasaki's segmentation has shown advantages in hepatocellular carcinoma. However, whether this approach improves the survival of intrahepatic cholangiocarcinoma (ICC) remains unknown. METHODS: A series of 248 consecutive patients with solitary ICCs who underwent hepatectomy were studied retrospectively. The patients were classified into the groups of anatomical sectionectomy based on Takasaki's segmentation (TS group) and non-Takasaki's hepatectomy (NTH group)...

Objective
Performing PET denoising within the image space proves effective in reducing the variance in PET images. In recent years, deep learning has demonstrated superior denoising performance, but models trained on a specific noise level typically fail to generalize well on different noise levels, due to inherent distribution shifts between inputs. The distribution shift usually results in bias in the denoised images. Our goal is to tackle such a problem using a domain generalization technique.
Approach
We propose to utilize the domain generalization technique with a novel feature space continuous discriminator (CD) for adversarial training, using the fraction of events as a continuous domain label...

Histopathologic diagnosis and classification of cancer plays a critical role in guiding treatment. Advances in next-generation sequencing have ushered in new complementary molecular frameworks. However, existing approaches do not independently assess both site-of-origin (e.g. prostate) and lineage (e.g. adenocarcinoma) and have minimal validation in metastatic disease, where classification is more difficult. Utilizing gradient-boosted machine learning, we developed ATLAS, a pair of separate AI Tumor Lineage and Site-of-origin models from RNA expression data on 8249 tumor samples...

MOF-808, a metal-organic framework containing Zr6 O8 clusters, can serve as a secure anchoring point for stabilizing copper single-sites with redox activity, thus making it a promising candidate for catalytic applications. In this study, we target the incorporation of Cu-MOF-808 into a mixed-matrix membrane for the degradation of tyrosol, an emerging endocrine-disrupting compound commonly found in water sources, through Fenton reactions, developing innovative technologies for water treatment. We successfully demonstrate the effectiveness of this approach by preparing catalytic membranes with minimal metal leaching, which is one of the primary challenges in developing copper-based Fenton heterogeneous catalysts...

A polygenic risk score (PRS) combines the associations of multiple genetic variants that could be due to direct causal effects, indirect genetic effects, or other sources of familial confounding. We have developed new approaches to assess evidence for and against causation by using family data for pairs of relatives (Inference about Causation from Examination of FAmiliaL CONfounding [ICE FALCON]) or measures of family history (Inference about Causation from Examining Changes in Regression coefficients and Innovative STatistical AnaLyses [ICE CRISTAL])...

A unique assembly of a two-electron superatom, [Ag10 {S2 P(O i Pr)2 }8 ], as a primary building unit in the construction of a supramolecule [Ag10 {S2 P(O i Pr)2 }8 ]2 (μ-4,4'-bpy) through a 4,4'-bipyridine (4,4'-bpy) linker is reported. This approach is facilitated by an open site in the structure that allows for effective pairing. The assembled structure demonstrates a minimal solvatochromic shift across organic solvents with variable polarities, highlighting the influence of self-assembly on the photophysical properties of silver nanoclusters...

Undesired on- and off-target effects of CRISPR-Cas nucleases remain a challenge in genome editing. While the use of Cas9 nickases has been shown to minimize off-target mutagenesis, their use in therapeutic genome editing has been hampered by a lack of efficacy. To overcome this limitation, we and others have developed double nickase-based strategies to generate staggered DNA double-strand breaks to mediate gene disruption or gene correction with high efficiency. However, the impact of paired single-strand nicks on genome integrity has remained largely unexplored...

Recent developments in synthetic biology, next-generation sequencing, and machine learning provide an unprecedented opportunity to rationally design new disease treatments based on measured responses to gene perturbations and drugs to reprogram cells. The main challenges to seizing this opportunity are the incomplete knowledge of the cellular network and the combinatorial explosion of possible interventions, both of which are insurmountable by experiments. To address these challenges, we develop a transfer learning approach to control cell behavior that is pre-trained on transcriptomic data associated with human cell fates, thereby generating a model of the network dynamics that can be transferred to specific reprogramming goals...