A Talented Duo: IFIT1 and IFIT3 Patrol Viral RNA Caps.

Hosts respond to viral infection by expressing interferon-stimulated genes, of which IFITs are potent inhibitors of viral RNA translation. Johnson et al. (2018) solved the structure of the IFIT1-IFIT3 complex bound cap 0 RNA and explored their concerted antiviral activity.

NASC 2023: Showcasing Diversity in North American Supramolecular Chemistry.

Diversity in supramolecular chemistry can showcase itself in many ways. This includes the diversity of thought and topics covered in research (from fundamental science to applications in biology and materials), as well as the diversity of people (e.g., diversity in race, gender, sexual orientation, country of origin, type of higher education institute, career stage,…). At the North American Supramolecular Chemistry (NASC) meetings, we aim to bring together the best that supramolecular chemistry has to offer in North America, create a sense of community and provide a platform for researchers at any stage of their career to present their work. NASC 2023 was the successful second edition of the NASC meeting series, and this proceedings article highlights the research and impressions of some of the speakers at NASC 2023.

Structural Insight on Supramolecular Polyion Salts: Inositol Hexaphosphate Enclosed in Cationic Macrocyclic Clusters.

Supramolecular macrocyclic forces have been used to trap phytate, myo-inositol-1,2,3,4,5,6-hexakisphosphate, a key bioanion with multiple roles in metabolic processes. Due to the complex chemistry of six multivalent phosphates surrounding the small, cyclic inositol framework, crystallographic information of simple phytate salts has been elusive. This report represents a combined crystallographic, theoretical, and solution binding investigation of a supramolecular macrocyclic complex of phytate. Together, the results provide significant insight to phytate's intramolecular and intermolecular interactions at the microenvironment level. The macrocycle-phytate aggregates consist of phytate anionic pairs, each partly sandwiched by two 24-membered, amide/amine-based cationic macrocycles. The phytate ion pairs hold the tetrameric macrocyclic array together by six strong intermolecular hydrogen bonds. Both phytates crystallize in 1a5e phosphate conformations (one axial (P2) and five equatorial phosphates). Solution NMR binding studies in 1 : 1 DMSO-d6 : D2 O indicate 2 : 1 macrocycle:phytate associations, suggesting that the sandwich-like nature of the complex holds together in solution. DFT studies indicate the likely occurrence of dynamic intramolecular interchange of phosphate protons, as well as important roles for the axial (P2) phosphate in both intramolecular and intermolecular hydrogen bonding interactions.

Inflammatory Bowel Disease: A Concise Review.

Inflammatory bowel disease is a term describing a group of diseases, Crohn's disease and ulcerative colitis, that cause chronic inflammation in the gastrointestinal tract. Both conditions tend to have episodic flares of diarrhea, abdominal pain, fatigue, and unintentional weight loss. This analysis will discuss the etiology, pathophysiology, epidemiology, clinical and histologic features, treatment, and complications of Crohn's disease and ulcerative colitis. Though there are many similarities between these two conditions it is important to recognize their differences for accurate diagnosis, treatment, and surveillance for potential long-term complications.

Updated U.S. Public Health Service Guideline for Testing of Transplant Candidates Aged <12 Years for Infection with HIV, Hepatitis B Virus, and Hepatitis C Virus - United States, 2022.

The U.S. Public Health Service (PHS) has periodically published recommendations about reducing the risk for transmission of HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) through solid organ transplantation (1-4). Updated guidance published in 2020 included the recommendation that all transplant candidates receive HIV, HBV, and HCV testing during hospital admission for transplant surgery to more accurately assess their pretransplant infection status and to better identify donor transmitted infection (4). In 2021, CDC was notified that this recommendation might be unnecessary for pediatric organ transplant candidates because of the low likelihood of infection after the perinatal period and out of concern that the volume of blood drawn for testing could negatively affect critically ill children.* CDC and other partners reviewed surveillance data from CDC on estimates of HIV, HBV, and HCV infection rates in the United States and data from the Organ Procurement & Transplantation Network (OPTN)† on age and weight distributions among U.S. transplant recipients. Feedback from the transplant community was also solicited to understand the impact of changes to the existing policy on organ transplantation. The 2020 PHS guideline was accordingly updated to specify that solid organ transplant candidates aged <12 years at the time of transplantation who have received postnatal infectious disease testing are exempt from the recommendation for HIV, HBV, and HCV testing during hospital admission for transplantation.

Assessing Solid Organ Donors and Monitoring Transplant Recipients for Human Immunodeficiency Virus, Hepatitis B Virus, and Hepatitis C Virus Infection - U.S. Public Health Service Guideline, 2020.

The recommendations in this report supersede the U.S Public Health Service (PHS) guideline recommendations for reducing transmission of human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) through organ transplantation (Seem DL, Lee I, Umscheid CA, Kuehnert MJ. PHS guideline for reducing human immunodeficiency virus, hepatitis B virus, and hepatitis C virus transmission through organ transplantation. Public Health Rep 2013;128:247-343), hereafter referred to as the 2013 PHS guideline. PHS evaluated and revised the 2013 PHS guideline because of several advances in solid organ transplantation, including universal implementation of nucleic acid testing of solid organ donors for HIV, HBV, and HCV; improved understanding of risk factors for undetected organ donor infection with these viruses; and the availability of highly effective treatments for infection with these viruses. PHS solicited feedback from its relevant agencies, subject-matter experts, additional stakeholders, and the public to develop revised guideline recommendations for identification of risk factors for these infections among solid organ donors, implementation of laboratory screening of solid organ donors, and monitoring of solid organ transplant recipients. Recommendations that have changed since the 2013 PHS guideline include updated criteria for identifying donors at risk for undetected donor HIV, HBV, or HCV infection; the removal of any specific term to characterize donors with HIV, HBV, or HCV infection risk factors; universal organ donor HIV, HBV, and HCV nucleic acid testing; and universal posttransplant monitoring of transplant recipients for HIV, HBV, and HCV infections. The recommendations are to be used by organ procurement organization and transplant programs and are intended to apply only to solid organ donors and recipients and not to donors or recipients of other medical products of human origin (e.g., blood products, tissues, corneas, and breast milk). The recommendations pertain to transplantation of solid organs procured from donors without laboratory evidence of HIV, HBV, or HCV infection. Additional considerations when transplanting solid organs procured from donors with laboratory evidence of HCV infection are included but are not required to be incorporated into Organ Procurement and Transplantation Network policy. Transplant centers that transplant organs from HCV-positive donors should develop protocols for obtaining informed consent, testing and treating recipients for HCV, ensuring reimbursement, and reporting new infections to public health authorities.

Hydrophilic and hydrophobic carboxamide pincers as anion hosts.

Hydrophobic and hydrophilic, monotopic and ditopic carboxamide pincer hosts containing ethyl, hexyl, 2-hydroxyethyl and 2-hydroxyethyl ethyl ether pendant arms were synthesized. Solubility trends indicated that solubilities in water or hydrocarbon solvents varied depending on the nature of the pendant arms. Binding constants for hydrophilic pincers were larger in general than their hydrophobic analogs. Significant synergistic binding effects for the ditopic hosts were not observed.

Impact of US Public Health Service increased risk deceased donor designation on organ utilization.

Under US Public Health Service guidelines, organ donors with risk factors for human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) are categorized as increased risk donors (IRD). Previous studies have suggested that IRD organs are utilized at lower rates than organs from standard risk donors (SRD), but these studies were conducted prior to universal donor nucleic acid test screening. We conducted risk-adjusted analyses to determine the effect of IRD designation on organ utilization using 2010-2017 data (21 626 heart, 101 160 kidney, 52 714 liver, and 16 219 lung recipients in the United States) from the Organ Procurement and Transplantation Network. There was no significant difference (P < .05) between risk-adjusted utilization rates for IRD vs SRD organs for adult hearts and livers and pediatric kidneys, livers, and lungs. Significantly lower utilization was found among IRD adult kidneys, lungs, and pediatric hearts. Analysis of the proportion of transplanted organs recovered from IRD by facility suggests that a subset of facilities contribute to the underutilization of adult IRD kidneys. Along with revised criteria and nomenclature to identify donors with HIV, HBV, or HCV risk factors, educational efforts to standardize informed consent discussions might improve organ utilization.

Characteristics of Deceased Solid Organ Donors and Screening Results for Hepatitis B, C, and Human Immunodeficiency Viruses - United States, 2010-2017.

The ongoing U.S. opioid crisis has resulted in an increase in drug overdose deaths and acute hepatitis C virus (HCV) infections, with young persons (who might be eligible organ donors) most affected.*,† In 2013, the Public Health Service released a revised guideline to reduce the risk for unintended organ transplantation-associated hepatitis B virus (HBV), HCV, and human immunodeficiency virus (HIV) transmission (1). The guideline describes criteria to categorize donors at increased risk (increased risk donors [IRDs]) for transmitting these viruses to recipients (1). It also recommends universal donor testing for HBV, HCV, and HIV.§ CDC analyzed deceased donor data for the period 2010-2017 reported to the Organ Procurement and Transplantation Network for IRDs and standard risk donors (SRDs) (i.e., donors who do not meet any of the criteria for increased risk designation). During this period, the proportion of IRDs increased approximately 200%, from 8.9% to 26.3%; the percentage with drug intoxication reported as the mechanism of death also increased approximately 200%, from 4.3% to 13.4%; and the proportion of these donors with reported injection drug use (IDU) increased approximately 500%, from 1.3% to 8.0%. Compared with SRDs, IRDs were significantly more likely to have positive HBV and HCV screening results. These findings demonstrate the continuing need for identifying viral bloodborne pathogen infection risk factors among deceased donors to reduce the risk for transmission, monitor posttransplant infection in recipients, and offer treatment if infection occurs.

Characterizing Hydrogen-Bond Interactions in Pyrazinetetracarboxamide Complexes: Insights from Experimental and Quantum Topological Analyses.

Experimental and topological analyses of dipalladium(II) complexes with pyrazinetetracarboxamide ligands containing tetraethyl (1), tetrahexyl (2), and tetrakis(2-hydroxyethyl) ethyl ether (3) are described. The presence of two very short O---O distances between adjacent amide carbonyl groups in the pincer complexes revealed two protons, which necessitated two additional anions to satisfy charge requirements. The results of the crystal structures indicate carbonyl O---O separations approaching that of low barrier hydrogen bonds, ranging from 2.413(5) to 2.430(3) Å. Solution studies and quantum topological analyses, the latter including electron localization function, noncovalent interaction, and Bader's quantum theory of atoms in molecules, were carried out to probe the nature of the short hydrogen bonds and the influence of the ligand environment on their strength. Findings indicated that the ligand field, and, in particular, the counterion at the fourth coordination site, may play a subtle role in determining the degree of covalent association of the bridging protons with one or the other carbonyl groups.

Pyrazinetetracarboxamide: A Duplex Ligand for Palladium(II).

Tetraethylpyrazine-2,3,5,6-tetracarboxamide forms a dipalladium(II) complex with acetates occupying the fourth coordination sites of the two bound metal ions. Crystallographic results indicate that the "duplex" dipincer has captured two protons that serve as the counterions. The protons lie between adjacent amide carbonyl groups with very short O···O distances of 2.435(5) Å. In the free base, the adjacent carbonyl groups are farther apart, averaging 3.196(3) Å. While the dipalladium(II) complexes stack in an ordered stepwise fashion along the a axis, the free base molecules stack on top of each other, with each pincer rotated by about 60° from the one below.

Chelate effects in sulfate binding by amide/urea-based ligands.

The influence of chelate and mini-chelate effects on sulfate binding was explored for six amide-, amide/amine-, urea-, and urea/amine-based ligands. Two of the urea-based hosts were selective for SO4(2-) in water-mixed DMSO-d6 systems. Results indicated that the mini-chelate effect provided by a single urea group with two NH binding sites appears to provide enhanced binding over two amide groups. Furthermore, additional urea binding sites incorporated into the host framework appeared to overcome to some extent competing hydration effects with increasing water content.

Clinical outcomes in perineural spread of cutaneous squamous cell carcinoma via the ophthalmic nerve.

BACKGROUND: There are no large studies reporting oncological or survival outcomes for patients diagnosed with perineural spread (PNS) of cutaneous squamous cell carcinoma (cSCC) via the ophthalmic nerve (V1). Where orbital exenteration may be necessary for curative treatment, it is critical to have survival data with which the morbidity associated with surgical treatment can be justified. Furthermore, with the emerging treatment option of immunotherapy, current standard of care outcomes are needed to help guide future trial design and eventually changed management guidelines. OBJECTIVE: To determine the oncological and survival outcomes observed in patients with PNS of cSCC via V1. MATERIALS AND METHODS: Retrospective analysis of prospectively maintained cohort of patients with PNS of cSCC via V1 treated in a tertiary Australian head and neck oncology/skull base referral center. Consecutive sample of 53 patients managed between March 1, 1999 and April 30, 2020. Follow-up closure date was September 1, 2021. Curative-intent surgery, curative-intent radiotherapy, or palliative care was undertaken. Endpoints included five-year overall, disease-specific, and disease-free survival from the date of treatment. RESULTS: Five-year Kaplan-Meier overall survival was 61.9% (95% CI 46.2%-74.3%), with disease-specific survival of 74.6% (95% CI 58.8%-85.3%), and disease-free survival 62.1% (95% CI 46.5%-74.3%). Survival was superior in patients treated via surgery and adjuvant radiotherapy than in those receiving surgery alone or definitive radiotherapy. Survival was superior among patients with less advanced disease as assessed by the Williams zonal staging system; patients with Zone 1 disease had disease-specific survival of 94.1% at 5 years with 82.5% disease-free survival. DISCUSSION: Five-year oncological and survival outcomes in this cohort were favorable. Superior survival was observed in patients treated with curative-intent surgery and adjuvant radiotherapy. Less extensive disease as delineated by the Williams zonal staging system was associated with improved survival. CONCLUSION: Surgical resection with adjuvant radiotherapy confers favourable oncological and survival outcome in patients with V1 PNS, particularly with early disease limited to Zone 1.

Complete combinatorial mutational enumeration of a protein functional site enables sequence-landscape mapping and identifies highly-mutated variants that retain activity.

Understanding how proteins evolve under selective pressure is a longstanding challenge. The immensity of the search space has limited efforts to systematically evaluate the impact of multiple simultaneous mutations, so mutations have typically been assessed individually. However, epistasis, or the way in which mutations interact, prevents accurate prediction of combinatorial mutations based on measurements of individual mutations. Here, we use artificial intelligence to define the entire functional sequence landscape of a protein binding site in silico, and we call this approach Complete Combinatorial Mutational Enumeration (CCME). By leveraging CCME, we are able to construct a comprehensive map of the evolutionary connectivity within this functional sequence landscape. As a proof of concept, we applied CCME to the ACE2 binding site of the SARS-CoV-2 spike protein receptor binding domain. We selected representative variants from across the functional sequence landscape for testing in the laboratory. We identified variants that retained functionality to bind ACE2 despite changing over 40% of evaluated residue positions, and the variants now escape binding and neutralization by monoclonal antibodies. This work represents a crucial initial stride toward achieving precise predictions of pathogen evolution, opening avenues for proactive mitigation.

Long-term outcomes in advanced anterior skull base malignancy: a single quaternary institution experience.

BACKGROUND: Advanced skull base malignancies are a heterogenous subset of head and neck cancers, and management is often complex. In recent times, there has been a paradigm shift in surgical technique and the advent of novel systemic options. Our goal was to analyse the long-term outcomes of a single quaternary head and neck and skull base service. METHODS: A retrospective review of 127 patients with advanced anterior skull base malignancies that were treated at our institution between 1999 and 2015 was performed. Multiple variables were investigated to assess their significance on 5 and 10-year outcomes. RESULTS: The mean age was 60.9 (± 12.6 SD). Sixty-four percent were males and 36% were females. Ninety percent of patients had T4 disease. Median survival time was 133 months. The 5-year overall survival (OS) was 66.2%, disease-specific survival (DSS) was 74.7%, and recurrence-free survival (RFS) was 65.0%. The 10-year OS was 55.1%, DSS was 72.1%, and RFS was 53.4%. Histological type and margin status significantly affected OS & DSS. CONCLUSION: Surgical management of advanced skull base tumours has evolved over the last few decades at our institution with acceptable survival outcomes and complication rates. Histological diagnosis and margin status are the main predictors of survival. The addition of neoadjuvant systemic agents in current trials may improve outcomes.

TXNIP-mediated crosstalk between oxidative stress and glucose metabolism.

Thioredoxin-interacting protein (TXNIP) has emerged as a key player in cancer and diabetes since it targets thioredoxin (TRX)-mediated redox regulation and glucose transporter (GLUT)-mediated metabolism. TXNIP consists of two arrestin (ARR, N-ARR and C-ARR) domains at its amino-terminus and two PPxY (PY) motifs and a di-leucine (LL) motif for endocytosis at its carboxyl-terminus. Here, we report that TXNIP shuffles between TRX and GLUTs to regulate homeostasis of intracellular oxidative stress and glucose metabolism. While TXNIP functions as a gatekeeper of TRX by default, it robustly interacted with class I GLUTs through its C-ARR domain upon increase of intracellular reactive oxygen species. This interaction prompted the surface expression downregulation and lysosomal degradation of GLUTs by its carboxyl-terminal LL endocytic signaling motif to attenuate glucose uptake. Consequently, TXNIP expression significantly limited glucose uptake, leading to the suppression of glycolysis, hexosamine biosynthesis, and the pentose phosphate pathway. Our findings establish a fundamental link between ROS and glucose metabolism through TXNIP and provide a promising target for the drug development against GLUT-related metabolic disorders.

Skull base surgery for malignant tumors: The 2nd international collaborative study (1995-2015).

BACKGROUND: The current study presents the effort of a global collaborative group to review the management and outcomes of malignant tumors of the skull base worldwide. PATIENTS AND METHODS: A total of 28 institutions contributed data on 3061 patients. Analysis evaluated clinical variables, survival outcomes, and multivariable factors associated with outcomes. RESULTS: The median age was 56 years (IQR 44-67). The open surgical approach was used in 55% (n = 1680) of cases, endoscopic resection was performed in 36% (n = 1087), and the combined approach in 9.6% (n = 294). With a median follow-up of 7.1 years, the 5-year OS DSS and RFS were 65%, 71.7% and 53%, respectively. On multivariable analysis, older age, comorbidities, histology, dural/intracranial involvement, positive margins, advanced stage, and primary site were independent prognostic factors for OS, DSS, and RFS. Adjuvant RT was a protective prognostic factor. CONCLUSION: The progress across various disciplines may have contributed to improved OS and DSS in this study compared to previous reports.

Chemistry and structure of a host-guest relationship: the power of NMR and X-ray diffraction in tandem.

An amine/amide mixed covalent organic tetrahedral cage 1 (H(12)) was synthesized and characterized. The H(12) cage contains 12 amide NH groups plus four tertiary amine N groups, the latter of which are positioned in a pseudo-tetrahedral array. Crystallographic findings indicate that the tetrahedral host can adopt either a pseudo-C(3) symmetric "compressed tetrahedron" structure, or one in which there are two sets of three stacked pyridine units related by a pseudo-S(4) axis. The latter conformation is ideal for encapsulating small pentameric clusters, either a water molecule or a fluoride ion surrounded by a tetrahedral array of water molecules, i.e., H(2)O·4H(2)O or F(-)·4H(2)O, as observed crystallographically. In solution, however, (19)F NMR spectroscopy indicates that H(12) encapsulates fluoride ion through direct amide hydrogen bonding. By collectively combining one-dimensional (1)H, (13)C, and (19)F with two-dimensional (1)H-(1)H COSY, (1)H-(13)C HSQC, and (1)H-(19)F HETCOR NMR techniques, the solution binding mode of fluoride can be ascertained as consisting of four sets of independent structural subunits with C(3) symmetry. A complex deuterium exchange process for the fluoride complex can also be unraveled by multiple NMR techniques.