Modeling Complex Ligands for High Oxidation State Catalysis: Titanium Hydroamination with Unsymmetrical Ligands.

A method for modeling high oxidation state catalysts is used on precatalysts with unsymmetrical and symmetrical bidentate ligands to get a more detailed understanding of how changes to ancillary ligands affect the hydroamination of alkynes catalyzed by titanium. To model the electronic donor ability, the ligand donor parameter (LDP) was used, and to model the steric effects, percent buried volume (% Vbur) was employed. For the modeling study, 7 previously unpublished unsymmetrical Ti(XX')(NMe2)2 precatalysts were prepared, where XX' is a chelating ligand with pyrrolyl/indolyl linkages. The rates of these unsymmetrical and 10 previously reported symmetrical precatalysts were used with the model kobs = a + b(LDP)1 + c(LDP)2 + d(% Vbur)1 + e(% Vbur)2, where a-e were found through least-squares refinement. The model suggests that (1) the two attachment points of the bidentate ligand XX' are in different environments on the metal (e.g., axial and equatorial in a trigonal bipyramidal or square pyramidal structure), (2) the position of the unsymmetrical ligand on the metal is determined by the electronics of the ligand rather than the sterics, and (3) that one side of the chelating ligand's electronics strongly influences the rate, while the other side's sterics more strongly influences the rate. From these studies, we were able to generate catalysts fitting to this model with rate constants larger than the fastest symmetrical catalyst tested.

Acetylenic tricyclic bis-(cyano enone) interacts with Cys 374 of actin, a residue necessary for stress fiber formation and cell migration.

The migratory and invasive potential of tumour cells relies on the actin cytoskeleton. We previously demonstrated that the tricyclic compound, TBE-31, inhibits actin polymerization and here we further examine the precise interaction between TBE-31 and actin. We demonstrate that iodoacetamide, a cysteine (Cys) alkylating agent, interferes with the ability of TBE-31 to interact with actin. In addition, in silico analysis identified Cys 217, Cys 272, Cys 285 and Cys 374 as potential binding sites for TBE-31. Using mass spectrometry analysis, we determined that TBE-31 associates with actin with a stoichiometric ratio of 1:1. We mutated the identified cysteines of actin to alanine and performed a pull-down analysis with a biotin labeled TBE-31 and demonstrated that by mutating Cys 374 to alanine the association between TBE-31 and actin was significantly reduced, suggesting that TBE-31 binds to Cys 374. A characterization of the NIH3T3 cells overexpressing eGFP-actin-C374A showed reduced stress fiber formation, suggesting Cys 374 is necessary for efficient incorporation into filamentous actin. Furthermore, migration of eGFP-Actin-WT expressing cells were observed to be inhibited by TBE-31, however fewer eGFP-Actin-C374A expressing cells were observed to migrate compared to the cells expressing eGFP-Actin-WT in the presence or absence of TBE-31. Taken together, our results suggest that TBE-31 binds to Cys 374 of actin to inhibit actin stress fiber formation and may potentially be a mechanism through which TBE-31 inhibits cell migration.

Reactivity of [(PNP)Mn(CO)2] with Organophosphates.

Organophosphorus nerve agents (OPAs) are a toxic class of synthetic compounds that cause adverse effects with many biological systems. Development of methods for environmental remediation and passivation has been ongoing for years. However, little progress has been made in therapeutic development for exposure victims. Given the postexposure behavior of OPA materials in enzymes such as acetylcholinesterase (AChE), development of electrophilic compounds as therapeutics may be more beneficial than the currently employed nucleophilic countermeasures. In this report, we present our studies with an electrophilic, 16-electron manganese complex (iPrPNP)Mn(CO)2 (1) and the nucleophilic hydroxide derivative (iPrPNHP)Mn(CO)2(OH) (2). The reactivity of 1 with phosphorus acids and the reactivity of 2 with the P-F bond of diisopropylfluorophosphate (DIPF) were studied. The role of water in both nucleophilic and electrophilic reactivity was investigated with the use of 17O-labeled water. Promising results arising from reactions of both 1 and 2 with organophosphorus substrates are reported.

Hindbrain modules differentially transform activity of single collicular neurons to coordinate movements.

Seemingly simple behaviors such as swatting a mosquito or glancing at a signpost involve the precise coordination of multiple body parts. Neural control of coordinated movements is widely thought to entail transforming a desired overall displacement into displacements for each body part. Here we reveal a different logic implemented in the mouse gaze system. Stimulating superior colliculus (SC) elicits head movements with stereotyped displacements but eye movements with stereotyped endpoints. This is achieved by individual SC neurons whose branched axons innervate modules in medulla and pons that drive head movements with stereotyped displacements and eye movements with stereotyped endpoints, respectively. Thus, single neurons specify a mixture of endpoints and displacements for different body parts, not overall displacement, with displacements for different body parts computed at distinct anatomical stages. Our study establishes an approach for unraveling motor hierarchies and identifies a logic for coordinating movements and the resulting pose.

Spinal Cord Delineation Based on Computed Tomography Myelogram Versus T2 Magnetic Resonance Imaging in Spinal Stereotactic Body Radiation Therapy.

Purpose: Spinal cord delineation is critical to the delivery of stereotactic body radiation therapy (SBRT). Although underestimating the spinal cord can lead to irreversible myelopathy, overestimating the spinal cord may compromise the planning target volume coverage. We compare spinal cord contours based on computed tomography (CT) simulation with a myelogram to spinal cord contours based on fused axial T2 magnetic resonance imaging (MRI). Methods and Materials: Eight patients with 9 spinal metastases treated with spinal SBRT were contoured by 8 radiation oncologists, neurosurgeons, and physicists, with spinal cord definition based on (1) fused axial T2 MRI and (2) CT-myelogram simulation images, yielding 72 sets of spinal cord contours. The spinal cord volume was contoured at the target vertebral body volume based on both images. The mixed-effect model assessed comparisons of T2 MRI- to myelogram-defined spinal cord in centroid deviations (deviations in the center point of the cord) through the vertebral body target volume, spinal cord volumes, and maximum doses (0.035 cc point) to the spinal cord applying the patient's SBRT treatment plan, in addition to in-between and within-subject variabilities. Results: The estimate for the fixed effect from the mixed model showed that the mean difference between 72 CT volumes and 72 MRI volumes was 0.06 cc and was not statistically significant (95% confidence interval, -0.034, 0.153; P = .1832). The mixed model showed that the mean dose at 0.035 cc for CT-defined spinal cord contours was 1.24 Gy lower than that of MRI-defined spinal cord contours and was statistically significant (95% confidence interval, -2.292, -0.180; P = .0271). Also, the mixed model indicated no statistical significance for deviations in any of the axes between MRI-defined spinal cord contours and CT-defined spinal cord contours. Conclusions: CT myelogram may not be required when MRI imaging is feasible, although uncertainty at the cord-to-treatment volume interface may result in overcontouring and hence higher estimated cord dose-maximums with axial T2 MRI-based cord definition.

Provision of smoking cessation support for patients following a diagnosis of cancer in Ireland.

There is growing evidence that smoking cessation (SC) improves outcomes following diagnosis of cancer. Notwithstanding adverse outcomes, a significant number of those diagnosed with cancer continue to smoke. Our objective was to document the SC services provided for patients with cancer by specialist adult cancer hospitals across Ireland, a country with a stated tobacco endgame goal. A cross-sectional survey based on recent national clinical guidelines was used to determine SC care delivery across eight adult cancer specialist hospitals, and one specialist radiotherapy centre. Qualtrics was used. The response rate was 88.9% with data reported from seven cancer hospitals and one specialist radiotherapy centre, all indicating they had some SC related provision (100%). Stop smoking medications were provided to cancer inpatients in two hospitals, at outpatients and attending day ward services in one hospital. Smokers with cancer were referred automatically to the SC service in two hospitals at diagnosis. While stop smoking medications were available 24 h a day in five hospitals, most did not stock all three (Nicotine Replacement Therapy, Bupropion, Varenicline). One hospital advised they had data on uptake of SC services for smokers with cancer but were unable to provide detail. There is considerable variation in SC information and services provided to cancer patients across adult cancer specialist centres in Ireland, reflecting the suboptimal practice of smoking cessation for patients with cancer found in the limited international audits. Such audits are essential to demonstrate service gaps and provide a baseline for service improvement.

Factors influencing nodal yield in neck dissections for head and neck malignancies.

OBJECTIVE: A standard lateral neck dissection should yield at least 18 lymph nodes. The goal of the present study was to examine what factors might influence the number of lymph nodes retrieved during a neck dissection. METHODS: This was a retrospective cohort study in a tertiary academic referral centre for head and neck oncology. Two hundred and nineteen consecutive neck dissections were examined. Age of the patient and primary site were recorded, along with tumour histology, previous radiotherapy and final nodal count. RESULTS: The mean age was 62.2 ± 13.0 years. The most common primary site was the oral cavity (38.8 per cent). The mean number of lymph nodes was 30.63 ± 13.9. In total, 17.8 per cent had undergone previous radiotherapy. The mean number of lymph nodes was 33.26 ± 13.27 in patients with no previous radiation exposure and 18.47 ± 9.46 in those with previous radiation treatment. CONCLUSION: Lymph node yield from a neck dissection is likely multi-factorial in nature. Previous radiotherapy, the only significant contributor, led to a mean reduction of lymph node yield from 33.3 to 18.5.

Homoleptic Uranium-Bis(acyl)phosphide Complexes.

The first uranium bis(acyl)phosphide (BAP) complexes were synthesized from the reaction between sodium bis(mesitoyl)phosphide (Na(mesBAP)) or sodium bis(2,4,6-triisopropylbenzoyl)phosphide (Na(trippBAP)) and UI3(1,4-dioxane)1.5. Thermally stable, homoleptic BAP complexes were characterized by single-crystal X-ray diffraction and electron paramagnetic resonance (EPR) spectroscopy, when appropriate, for the elucidation of the electronic structure and bonding of these complexes. EPR spectroscopy revealed that the BAP ligands on the uranium center retain a significant amount of electron density. The EPR spectrum of the trivalent U(trippBAP)3 has a rhombic signal near g = 2 (g1 = 2.03; g2 = 2.01; and g3 = 1.98) that is consistent with the EPR-observed unpaired electron being located in a molecular orbital that appears ligand-derived. However, upon warming the complex to room temperature, no resonance was observed, indicating the presence of uranium character.

Oro-Naso-Sino-Orbital-Cutaneous Fistula From Prolonged Cocaine Use.

Presentation We present the case of a 48-year-old man with nasal cellulitis and subsequent oro-naso-sino-orbital-cutaneous fistula from prolonged cocaine use. Diagnosis Initial laboratory investigations reported a raised white cell count (WBC) and C-Reactive Protein (CRP) and subsequently a positive atypical anti-neutrophil cytoplasm antibodies (ANCA) and positive anti-proteinase (PR3). Perihilar lung nodularity on chest imaging raised the possibility of a systemic autoimmune response. His urinalysis was positive for cocaine. Treatment He was commenced on Augmentin, Amphotericin B and Prednisolone. An obturator was created to manage the oro-nasal fistula. A subsequent naso-cutaneous defect was re-approximated. Daily nasal saline douche and abstinence of cocaine were recommended. Discussion Cocaine use in the community is rising and poses a challenge to multiple facets of our health care system.

What makes interventions aimed at improving dietary behaviours successful in the secondary school environment? A systematic review of systematic reviews.

OBJECTIVE: To systematically review evidence from systematic reviews of interventions to improve dietary behaviours and reduce food wastage in secondary school pupils. DESIGN: CINAHL, Cochrane Reviews, EMBASE, MEDLINE, PsychINFO and Web of Science were searched for systematic reviews of school-based dietary interventions from 2000 to 2020 published in a peer-reviewed journal in English. Articles were reviewed independently by two authors. AMSTAR-2 was used for quality assessment. SETTING: Secondary school dietary interventions. PARTICIPANTS: Adolescents (aged 11-18). RESULTS: In total, thirteen systematic reviews of dietary interventions in secondary schools met the inclusion criteria. A number of key characteristics of interventions that contributed to improvements in food choices in secondary school pupils were identified. These included the combination of education and environmental restructuring, incorporation of computer-based feedback, media or messaging, peer and/or parent involvement, an increase in the availability of healthy foods and the use of behavioural theory as a basis to the intervention. Intervention components that contributed specifically to a reduction in sugar-sweetened beverage intake or an increase in fruit and vegetable consumption, which are particularly relevant to adolescents, could not be determined. Similarly, evidence for interventions that improve nutritional knowledge and attitudes was limited. CONCLUSIONS: This systematic review of systematic reviews has identified a number of components of dietary interventions that can be explored to improve dietary behaviours in secondary school environments and, if demonstrated to be effective, be considered for inclusion in policies and strategies to improve the school food environment and promote dietary change.

An Allyl Uranium(IV) Sandwich Complex: Are ϕ Bonding Interactions Possible?

A method to explore head-to-head ϕ back-bonding from uranium f-orbitals into allyl π* orbitals has been pursued. Anionic allyl groups were coordinated to uranium with tethered anilide ligands, then the products were investigated by using NMR spectroscopy, single-crystal XRD, and theoretical methods. The (allyl)silylanilide ligand, N-((dimethyl)prop-2-enylsilyl)-2,6-diisopropylaniline (LH), was used as either the fully protonated, singly deprotonated, or doubly deprotonated form, thereby highlighting the stability and versatility of the silylanilide motif. A free, neutral allyl group was observed in UI2 (L1)2 (1), which was synthesized by using the mono-deprotonated ligand [K][N-((dimethyl)prop-2-enyl)silyl)-2,6-diisopropylanilide] (L1). The desired homoleptic sandwich complex U[L2]2 (2) was prepared from all three ligand precursors, but the most consistent results came from using the dipotassium salt of the doubly deprotonated ligand [K]2 [N-((dimethyl)propenidesilyl)-2,6-diisopropylanilide] (L2). This allyl-based sandwich complex was studied by using theoretical techniques with supporting experimental spectroscopy to investigate the potential for phi (ϕ) back-bonding. The bonding between UIV and the allyl fragments is best described as ligand-to-metal electron donation from a two carbon fragment-localized electron density into empty f-orbitals.

Expanding the Nonaqueous Chemistry of Neptunium: Synthesis and Structural Characterization of [Np(NR2)3Cl], [Np(NR2)3Cl]-, and [Np{N(R)(SiMe2CH2)}2(NR2)]- (R = SiMe3).

Reaction of 3 equiv of NaNR2 (R = SiMe3) with NpCl4(DME)2 in THF afforded the Np(IV) silylamide complex, [Np(NR2)3Cl] (1), in good yield. Reaction of 1 with 1.5 equiv of KC8 in THF, in the presence of 1 equiv of dibenzo-18-crown-6, resulted in formation of [{K(DB-18-C-6)(THF)}3(µ3-Cl)][Np(NR2)3Cl]2 (4), also in good yield. Complex 4 represents the first structurally characterized Np(III) amide. Finally, reaction of NpCl4(DME)2 with 5 equiv of NaNR2 and 1 equiv of dibenzo-18-crown-6 afforded the Np(IV) bis(metallacycle), [{Na(DB-18-C-6)(Et2O)0.62(κ1-DME)0.38}2(µ-DME)][Np{N(R)(SiMe2CH2)}2(NR2)]2 (8), in moderate yield. Complex 8 was characterized by 1H NMR spectroscopy and X-ray crystallography and represents a rare example of a structurally characterized neptunium-hydrocarbyl complex. To support these studies, we also synthesized the uranium analogues of 4 and 8, namely, [K(2,2,2-cryptand)][U(NR2)3Cl] (2), [K(DB-18-C-6)(THF)2][U(NR2)3Cl] (3), [Na(DME)3][U{N(R)(SiMe2CH2)}2(NR2)] (6), and [{Na(DB-18-C-6)(Et2O)0.5(κ1-DME)0.5}2(µ-DME)][U{N(R)(SiMe2CH2)}2(NR2)]2 (7). Complexes 2, 3, 6, and 7 were characterized by a number of techniques, including NMR spectroscopy and X-ray crystallography.

Combination of a T cell activating therapy and anti-phosphatidylserine enhances anti-tumour immune responses in a HPV16 E7-expressing C3 tumour model.

DPX is a novel delivery platform that generates targeted CD8 + T cells and drives antigen-specific cytotoxic T cells into tumours. Cancer cells upregulate phosphatidylserine (PS) on the cell surface as a mechanism to induce an immunosuppressive microenvironment. Development of anti-PS targeting antibodies have highlighted the ability of a PS-blockade to enhance tumour control by T cells by releasing immunosuppression. Here, C57BL/6 mice were implanted with HPV16 E7 target-expressing C3 tumours and subjected to low dose intermittent cyclophosphamide (CPA) in combination with DPX-R9F treatment targeting an E7 antigen with and without anti-PS and/or anti-PD-1 targeting antibodies. Immune responses were assessed via IFN-γ ELISPOT assay and the tumour microenvironment was further analyzed using RT-qPCR. We show that the combination of DPX-R9F and PS-targeting antibodies with and without anti-PD-1 demonstrated increased efficacy compared to untreated controls. All treatments containing DPX-R9F led to T cell activation as assessed by IFN-γ ELISPOT. Furthermore, DPX-R9F/anti-PS treatment significantly elevated cytotoxic T cells, macrophages and dendritic cells based on RT-qPCR analysis. Overall, our data indicates that anti-tumour responses are driven through a variety of immune cells within this model and highlights the need to investigate combination therapies which increase tumour immune infiltration, such as anti-phosphotidylserine.

Tracheostomy stomal seeding following oral cavity resection.

BACKGROUND: Tracheal stoma recurrence following oral cavity surgery is exceedingly rare. Although several different mechanisms for this have been described, the pathogenesis still remains uncertain. METHODS: We present the case of a gentleman who presented 6-months following oral cavity SCC resection with a large fungating mass at his previous tracheostomy site, and also review the reported literature on this rare phenomenon. RESULTS: Four weeks after diagnosis of his recurrence he underwent a total laryngectomy, wide-local skin excision and reconstruction with a pectoralis major pedicled flap. He recovered well initially following his operation, however unfortunately contracted nosocomial SARS-Cov2 and succumbed from respiratory complications during his post-operative recovery. CONCLUSION: Stomal recurrence after temporary tracheostomy for oral cavity malignancies are very rare. Previously reported management of these can vary from surgical to palliative treatment. Methods to prevent these include delaying tracheostomy until after surgical resection, packing the pharynx during resection and adjuvant radiotherapy.

Referral communication for pediatric intensive care unit admission and the diagnosis of critically ill children: A pilot ethnography.

PURPOSE: The effect of communication between referring and accepting clinicians during patient transitions to the pediatric intensive care unit (PICU) on diagnostic quality is largely unknown. This pilot study aims to determine the feasibility of using focused ethnography to understand the relationship between referral communication and the diagnostic process for critically ill children. MATERIALS AND METHODS: We conducted focused ethnography in an academic tertiary referral PICU by directly observing the referral and admission of 3 non-electively admitted children 0-17 years old. We also conducted 21 semi-structured interviews of their parents and admitting PICU staff (intensivists, fellows/residents, medical students, nurses, and respiratory therapists) and reviewed their medical records post-discharge. RESULTS: Performing focused ethnography in a busy PICU is feasible. We identified three areas for additional exploration: (1) how information transfer affects the PICU diagnostic process; (2) how uncertainty in patient assessment affects the decision to transfer to the PICU; and (3) how the PICU team's expectations are influenced by referral communication. CONCLUSIONS: Focused ethnography in the PICU is feasible to investigate relationships between clinician referral communication and the diagnostic process for critically ill children.

Employing Lewis Acidity to Generate Bimetallic Lanthanide Complexes.

With the advent of lanthanide-based technologies, there is a clear need to advance the fundamental understanding of 4f-element chelation chemistry. Herein, we contribute to a growing body of lanthanide chelation chemistry and report the synthesis of bimetallic 4f-element complexes within an imine/hemiacetalate framework, Ln2TPTOMe [Ln = lanthanide; TPTOMe = tris(pyridineimine)(Tren)tris(methoxyhemiacetalate); Tren = tris(2-aminoethylamine)]. These products are generated from hydrolysis and methanolysis of the cage ligand tris(pyridinediimine)bis(Tren) (TPT; Tadanobu et al. Chem. Lett. 1993, 22 (5), 859-862) likely facilitated by inductive effects stemming from the Lewis acidic lanthanide cations. These complexes are interesting because they result from imine cleavage to generate two metal binding sites: one pocketed site within the macrocycle and the other terminal site capping a hemiacetalate moiety. A clear demarcation in reactivity is observed between samarium and europium, where the lighter and larger lanthanides generate a mixture of products, Ln2TPTOMe and LnTPT. Meanwhile, the heavier and smaller lanthanides generate exclusively bimetallic Ln2TPTOMe. The cleavage reactivity to form Ln2TPTOMe was extended beyond methanol to include other primary alcohols.

Targeting Lifestyle Behavior to Improve Brain Health: User-Experiences of an Online Program for Individuals with Subjective Cognitive Decline.

BACKGROUND: Online programs targeting lifestyle have the potential to benefit brain health. We aimed to develop such a program for individuals with subjective cognitive decline (SCD). These individuals were reported to be at increased risk for dementia, and report both an intrinsic need for brain health information and motivation to participate in prevention strategies. Co-creation and user-evaluation benefits the adherence to and acceptance of online programs. Previously, we developed a prototype of the online program in co-creation with the users . OBJECTIVES: We now aimed to evaluate the user-experiences of our online lifestyle program for brain health. DESIGN: 30-day user test; multi-method. SETTING: Participants were recruited in a memory clinic and (online) research registries in the Netherlands (Alzheimer Center Amsterdam) and Germany (Center for memory disorders, Cologne). PARTICIPANTS: Individuals with SCD (N=137, 65±9y, 57% female). MEASUREMENTS: We assessed user-experiences quantitatively with rating daily advices and usefulness, satisfaction and ease of use questionnaires as well as qualitatively using telephone interviews. RESULTS: Quantitative data showed that daily advices were rated moderately useful (3.5 ±1.5, range 1-5 points). Participants (n=101, 78%) gave moderate ratings on the programs' usability (3.7±1.3, max 7), ease of learning (3.6±1.9) and satisfaction (4.0±1.5), and marginal ratings on the overall usability (63.7±19.0, max 100). Qualitative data collected during telephone interviews showed that participants highly appreciated the content of the program. They elaborated that lower ratings of the program were mainly due to technical issues that hindered a smooth walk through. Participants reported that the program increased awareness of lifestyle factors related to brain health. CONCLUSIONS: Overall user-experience of the online lifestyle program was moderate to positive. Qualitative data showed that content was appreciated and that flawless, easy access technique is essential. The heterogeneity in ratings of program content and in program use highlights the need for personalization. These findings support the use of online self-applied lifestyle programs when aiming to reach large groups of motivated at-risk individuals for brain health promotion.

Upregulation of BST-2 by Type I Interferons Reduces the Capacity of Vpu To Protect HIV-1-Infected Cells from NK Cell Responses.

The HIV-1 accessory protein Vpu enhances viral release by counteracting the restriction factor BST-2. Furthermore, Vpu promotes NK cell evasion by downmodulating cell surface NTB-A and PVR, known ligands of the NK cell receptors NTB-A and DNAM-1, respectively. While it has been established that Vpu's transmembrane domain (TMD) is required for the interaction and intracellular sequestration of BST-2, NTB-A, and PVR, it remains unclear how Vpu manages to target these proteins simultaneously. In this study, we show that upon upregulation, BST-2 is preferentially downregulated by Vpu over its other TMD substrates. We found that type I interferon (IFN)-mediated BST-2 upregulation greatly impairs the ability of Vpu to downregulate NTB-A and PVR. Our results suggest that occupation of Vpu by BST-2 affects its ability to downregulate other TMD substrates. Accordingly, knockdown of BST-2 increases Vpu's potency to downmodulate NTB-A and PVR in the presence of type I IFN treatment. Moreover, we show that expression of human BST-2, but not that of the macaque orthologue, decreases Vpu's capacity to downregulate NTB-A. Importantly, we show that type I IFNs efficiently sensitize HIV-1-infected cells to NTB-A- and DNAM-1-mediated direct and antibody-dependent NK cell responses. Altogether, our results reveal that type I IFNs decrease Vpu's polyfunctionality, thus reducing its capacity to protect HIV-1-infected cells from NK cell responses.IMPORTANCE The restriction factor BST-2 and the NK cell ligands NTB-A and PVR are among a growing list of membrane proteins found to be downregulated by HIV-1 Vpu. BST-2 antagonism enhances viral release, while NTB-A and PVR downmodulation contributes to NK cell evasion. However, it remains unclear how Vpu can target multiple cellular factors simultaneously. Here we provide evidence that under physiological conditions, BST-2 is preferentially targeted by Vpu over NTB-A and PVR. Specifically, we show that type I IFNs decrease Vpu's polyfunctionality by upregulating BST-2, thus reducing its capacity to protect HIV-1-infected cells from NK cell responses. This indicates that there is a hierarchy of Vpu substrates upon IFN treatment, revealing that for the virus, targeting BST-2 as part of its resistance to IFN takes precedence over evading NK cell responses. This reveals a potential weakness in HIV-1's immunoevasion mechanisms that may be exploited therapeutically to harness NK cell responses against HIV-1.