Direct probing of low-energy intra d-band transitions in gas-phase cobalt clusters.

The interplay between constituent localized and itinerant electrons of metal clusters defines their physical and chemical properties. In turn, the electronic and geometrical structures are strongly entwined and exhibit strong size-dependent variations. Current understanding of low-energy excited states of metal clusters relies on stand-alone theoretical investigations and few comparisons with measured properties, since direct identification of low-lying states is lacking hitherto. Here, we report on the measurement of low-lying electronic transitions in cationic cobalt clusters using infrared photofragmentation spectroscopy. Broad and size-dependent absorption features were observed within 0.056 - 0.446 eV, well above the energies of the sharp absorption bands caused by cluster vibrations. Complementary time-dependent density functional theory calculations reproduce the main observed absorption features, providing direct evidence that they correspond to transitions between electronic states of mainly d-character, arising from the open d-shells of the Co atoms and the high spin multiplicity of the clusters.

Early versus delayed cranioplasty after decompressive craniectomy in traumatic brain injury: a multicenter observational study within CENTER-TBI and Net-QuRe.

OBJECTIVE: The aim of this study was to compare the outcomes of early (≤ 90 days) and delayed (> 90 days) cranioplasty following decompressive craniectomy (DC) in patients with traumatic brain injury (TBI). METHODS: The authors analyzed participants enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) and the Neurotraumatology Quality Registry (Net-QuRe) studies who were diagnosed with TBI and underwent DC and subsequent cranioplasty. These prospective, multicenter, observational cohort studies included 5091 patients enrolled from 2014 to 2020. The effect of cranioplasty timing on functional outcome was evaluated with multivariable ordinal regression and with propensity score matching (PSM) in a sensitivity analysis of functional outcome (Glasgow Outcome Scale-Extended [GOSE] score) and quality of life (Quality of Life After Brain Injury [QOLIBRI] instrument) at 12 months following DC. RESULTS: Among 173 eligible patients, 73 (42%) underwent early cranioplasty and 100 (58%) underwent delayed cranioplasty. In the ordinal logistic regression and PSM, similar 12-month GOSE scores were found between the two groups (adjusted odds ratio [aOR] 0.87, 95% CI 0.61-1.21 and 0.88, 95% CI 0.48-1.65, respectively). In the ordinal logistic regression, early cranioplasty was associated with a higher risk for hydrocephalus than that with delayed cranioplasty (aOR 4.0, 95% CI 1.2-16). Postdischarge seizure rates (early cranioplasty: aOR 1.73, 95% CI 0.7-4.7) and QOLIBRI scores (ß -1.9, 95% CI -9.1 to 9.6) were similar between the two groups. CONCLUSIONS: Functional outcome and quality of life were similar between early and delayed cranioplasty in patients who had undergone DC for TBI. Neurosurgeons may consider performing cranioplasty during the index admission (early) to simplify the patient's chain of care and prevent readmission for cranioplasty but should be vigilant for an increased possibility of hydrocephalus. Clinical trial registration nos.: CENTER-TBI, NCT02210221 (clinicaltrials.gov); Net-QuRe, NTR6003 (trialsearch.who.int) and NL5761 (onderzoekmetmensen.nl).

Extensor tendon transfer for fracture-related extensor pollicis longus rupture: Long-term outcome case series.

BACKGROUND: Spontaneous rupture of the extensor pollicis longus (EPL) tendon following both nonoperative and operative treatment of distal radius fractures has been well described. PURPOSE: The purpose of this study was to assess long-term outcomes of extensor indicis proprius to EPL tendon transfers for patients following distal radius fracture and EPL tendon repair. STUDY DESIGN: Retrospective case series focusing on long-term clinical outcomes. METHODS: A retrospective review was conducted for patients who sustained a distal radius fracture and subsequently underwent extensor tendon transfer from 2005-2015 at a private practice center. Outcome measures including index finger (IF) metacarpophalangeal (MCP) and thumb interphalangeal (IP) active range of motion (ROM), digital extension against resistance, subjective complaints, and QuickDASH scores were recorded at final follow-up. RESULTS: Seven patients were included in the study. There were six females and one male subject, mean age of 54 ± 13 years at injury of EPL, and 5/7 involved the left upper extremity. For isolated function, 7/7 (100%) patients had isolated, active IF MCP extension, 6/7 (86%) could extend IF MCP and thumb IP against resistance. Mean IF MCP extension was 1° ± 2°, mean IF MCP flexion was 89° ± 2°, mean thumb IP extension was -5° ± 4°, and mean thumb IP flexion was 67° ± 15°. Mean QuickDASH score was 16 ± 14. CONCLUSIONS: This series shows good long-term functional and patient reported outcomes in patients following extensor indicis proprius to EPL tendon transfers at a single center.

Polycyclic Aromatic Hydrocarbons and Pancreatic Cancer: An Analysis of the Blood Biomarker, r-1,t-2,3,c-4-Tetrahydroxy-1,2,3,4-tetrahydrophenanthrene and Selected Metabolism Gene SNPs.

Exposure to polycyclic aromatic hydrocarbons (PAHs), byproducts of incomplete combustion, and their effects on the development of cancer are still being evaluated. Recent studies have analyzed the relationship between PAHs and tobacco or dietary intake in the form of processed foods and smoked/well-done meats. This study aims to assess the association of a blood biomarker and metabolite of PAHs, r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT), dietary intake, selected metabolism SNPs, and pancreatic cancer. Demographics, food-frequency data, SNPs, treatment history, and levels of PheT in plasma were determined from 400 participants (202 cases and 198 controls) and evaluated based on pancreatic adenocarcinoma diagnosis. Demographic and dietary variables were selected based on previously published literature indicating association with pancreatic cancer. A multiple regression model combined the significant demographic and food items with SNPs. Final multivariate logistic regression significant factors (p-value < 0.05) associated with pancreatic cancer included: Type 2 Diabetes [OR = 6.26 (95% CI = 2.83, 14.46)], PheT [1.03 (1.02, 1.05)], very well-done red meat [0.90 (0.83, 0.96)], fruit/vegetable servings [1.35 (1.06, 1.73)], recessive (rs12203582) [4.11 (1.77, 9.91)], recessive (rs56679) [0.2 (0.06, 0.85)], overdominant (rs3784605) [3.14 (1.69, 6.01)], and overdominant (rs721430) [0.39 (0.19, 0.76)]. Of note, by design, the level of smoking did not differ between our cases and controls. This study does not provide strong evidence that PheT is a biomarker of pancreatic cancer susceptibility independent of dietary intake and select metabolism SNPs among a nonsmoking population.

External Quality Assessment on Molecular Tumor Profiling with Circulating Tumor DNA-Based Methodologies Routinely Used in Clinical Pathology within the COIN Consortium.

BACKGROUND: Identification of tumor-derived variants in circulating tumor DNA (ctDNA) has potential as a sensitive and reliable surrogate for tumor tissue-based routine diagnostic testing. However, variations in pre(analytical) procedures affect the efficiency of ctDNA recovery. Here, an external quality assessment (EQA) was performed to determine the performance of ctDNA mutation detection work flows that are used in current diagnostic settings across laboratories within the Dutch COIN consortium (ctDNA on the road to implementation in The Netherlands). METHODS: Aliquots of 3 high-volume diagnostic leukapheresis (DLA) plasma samples and 3 artificial reference plasma samples with predetermined mutations were distributed among 16 Dutch laboratories. Participating laboratories were requested to perform ctDNA analysis for BRAF exon 15, EGFR exon 18-21, and KRAS exon 2-3 using their regular circulating cell-free DNA (ccfDNA) analysis work flow. Laboratories were assessed based on adherence to the study protocol, overall detection rate, and overall genotyping performance. RESULTS: A broad range of preanalytical conditions (e.g., plasma volume, elution volume, and extraction methods) and analytical methodologies (e.g., droplet digital PCR [ddPCR], small-panel PCR assays, and next-generation sequencing [NGS]) were used. Six laboratories (38%) had a performance score of >0.90; all other laboratories scored between 0.26 and 0.80. Although 13 laboratories (81%) reached a 100% overall detection rate, the therapeutically relevant EGFR p.(S752_I759del) (69%), EGFR p.(N771_H773dup) (50%), and KRAS p.(G12C) (48%) mutations were frequently not genotyped accurately. CONCLUSIONS: Divergent (pre)analytical protocols could lead to discrepant clinical outcomes when using the same plasma samples. Standardization of (pre)analytical work flows can facilitate the implementation of reproducible liquid biopsy testing in the clinical routine.

Water footprints and crop water use of 175 individual crops for 1990-2019 simulated with a global crop model.

The water footprint of a crop (WF) is a common metric for assessing agricultural water consumption and productivity. To provide an update and methodological enhancement of existing WF datasets, we apply a global process-based crop model to quantify consumptive WFs of 175 individual crops at a 5 arcminute resolution over the 1990-2019 period. This model simulates the daily crop growth and vertical water balance considering local environmental conditions, crop characteristics, and farm management. We partition WFs into green (water from precipitation) and blue (from irrigation or capillary rise), and differentiate between rainfed and irrigated production systems. The outputs include gridded datasets and national averages for unit water footprints (expressed in m3 t-1 yr-1), water footprints of production (m3 yr-1), and crop water use (mm yr-1). We compare our estimates to other global studies covering different historical periods and methodological approaches. Provided outputs can offer insights into spatial and temporal patterns of agricultural water consumption and serve as inputs for further virtual water trade studies, life cycle and water footprint assessments.

United States Experience With a Femoral Neck Retaining Total Hip Arthroplasty Stem: A Retrospective Study With Control Comparison From the Literature.

BACKGROUND: Femoral neck retaining prostheses have gained popularity in Europe, but the United States has not seen the same trends occurring. Previous reports demonstrate high survivorship for these implants, but to our knowledge, there are no reports examining US data. METHODS: After institutional review board approval, 824 primary total hip arthroplasties utilizing a femoral neck-retaining prosthesis were examined for femoral component survivorship rates. European studies were systematically reviewed to determine survivorship rates. The data were used to formulate a Kaplan-Meier survivorship curve and compare US data to that of the European studies. RESULTS: European studies demonstrated survivorship rates for all causes of 97.7 and 99.0% for aseptic loosening at an average of 6 years (range, 4.5 to 10). The current study demonstrated an all-cause 94% Kaplan-Meier survivorship estimate at 5 years and when aseptic loosening only was considered, survivorship increased to 99.4% at 5 years and 98.4% at 11 years. CONCLUSION: This femoral neck-retaining prosthesis demonstrated excellent survivorship that is comparable to the rates seen in European studies as well as the rates of standard and mid-stem prostheses in the United States.

Monitoring for the adaptive management of rivers.

Monitoring for adaptive management (AM) involves collection of data with the aim of reducing uncertainty about links between human pressures (e.g. water abstraction from rivers), consequent stressors (e.g. low river flows) and environmental state (e.g. biodiversity). 'Surveillance monitoring' involves documenting trends in state, without the aim of understanding relationships between state, stressors, and pressures. Critics have highlighted that surveillance monitoring dominates monitoring investments but is not supporting AM. Decision-makers continue to be disappointed by monitoring data that are unsuitable for AM, yet designers of monitoring programs tend to make decisions that reinforce rather than reimagine the status quo. We argue that a structured, collaborative approach to objective-setting is required to break the status quo. We collaborated with regional management authorities to develop monitoring objectives and implementation strategies to support AM of New Zealand's rivers. Our collaborative approach discouraged 'failure fearing' and encouraged reimagining 'what could be' as opposed to 'what is.' Seventeen monitoring objectives were identified based on the AM requirements of national policy and regional authorities. Several objectives-particularly those arising from national policy-stretch the limits of what environmental science can currently provide. There were also strong trade-offs among objectives. We offer practical implementation strategies for overcoming the technical challenges of, and reducing trade-offs among, monitoring objectives. These strategies point to a monitoring program that contrasts strongly with one aimed at surveillance. Monitoring for AM is more complex than monitoring for surveillance, so strong leadership is required for successful implementation.

Hemodynamic Parameters in the Parent Arteries of Unruptured Intracranial Aneurysms Depend on Aneurysm Size and Are Different Compared to Contralateral Arteries: A 7 Tesla 4D Flow MRI Study.

BACKGROUND: Different Circle of Willis (CoW) variants have variable prevalences of aneurysm development, but the hemodynamic variation along the CoW and its relation to presence and size of unruptured intracranial aneurysms (UIAs) are not well known. PURPOSE: Gain insight into hemodynamic imaging markers of the CoW for UIA development by comparing these outcomes to the corresponding contralateral artery without an UIA using 4D flow magnetic resonance imaging (MRI). STUDY TYPE: Retrospective, cross-sectional study. SUBJECTS: Thirty-eight patients with an UIA, whereby 27 were women and a mean age of 62 years old. FIELD STRENGTH/SEQUENCE: Four-dimensional phase-contrast (PC) MRI with a 3D time-resolved velocity encoded gradient echo sequence at 7 T. ASSESSMENT: Hemodynamic parameters (blood flow, velocity pulsatility index [vPI], mean velocity, distensibility, and wall shear stress [peak systolic (WSSMAX ), and time-averaged (WSSMEAN )]) in the parent artery of the UIA were compared to the corresponding contralateral artery without an UIA and were related to UIA size. STATISTICAL TESTS: Paired t-tests and Pearson Correlation tests. The threshold for statistical significance was P < 0.05 (two-tailed). RESULTS: Blood flow, mean velocity, WSSMAX , and WSSMEAN were significantly higher, while vPI was lower, in the parent artery relative to contralateral artery. The WSSMAX of the parent artery significantly increased linearly while the WSSMEAN decreased linearly with increasing UIA size. CONCLUSIONS: Hemodynamic parameters and WSS differ between parent vessels of UIAs and corresponding contralateral vessels. WSS correlates with UIA size, supporting a potential hemodynamic role in aneurysm pathology. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Observations of COVID-19 vaccine coverage and vaccine hesitancy on COVID-19 outbreak: An American ecological study.

In this ecological study, we aim to establish the role vaccines play in bringing the pandemic under control, as well as the impact of pathogen variants, vaccine hesitancy, and medical resource availability during the process by utilizing publicly available data. The study spans a three-year data collection period for daily hospital admissions due to COVID-19 and the daily reported cases of COVID-19 across all 50 states in the USA. In doing so, we aim to demonstrate the difference in severity of the SARS-CoV-2 pathogen among vaccinated and unvaccinated populations in the USA. The study assesses the correlation of COVID-19 vaccines (e.g., Pfizer, Moderna, and Janssen) and disease outcomes (transmissibility, severity, and deaths) caused by different strains of SARS-CoV-2 and establishes a negative correlation between COVID-19 vaccine and disease outcomes. By considering potential confounders in vaccine hesitancy, medical resource availability and vaccine dosage, we demonstrate the aforementioned to be insubstantial in predicting disease outcomes while the latter displays a contrasting significance in terms of disease outcomes. Between all the major variants of concern, the Delta and Omicron variants in particular have been associated with higher virulence and transmissibility factors respectively. Hence, the CDC continues to encourage the US population to get vaccinated since vaccines are one of the most effective ways to protect the community from potential outbreaks and prevent severe disease manifestations.

Large-scale violence in Late Neolithic Western Europe based on expanded skeletal evidence from San Juan ante Portam Latinam.

This paper explores the nature and extent of conflict in Late Neolithic Europe based on expanded skeletal evidence for violence from the San Juan ante Portam Latinam rockshelter in present-day Spain (ca. 3380-3000 cal. BC). The systematic osteological re-examination has identified 65 unhealed and 89 healed traumas-of which 77 were previously undocumented-consistent with aggression. They affect 23.1% of the 338 individuals represented. Adolescent and adult males are particularly affected (44.9% of the 107 identified), comprising 97.6% of unhealed trauma and 81.7% of healed trauma recorded in individuals whose sex could be estimated and showing higher frequencies of injuries per individual than other demographic subgroups. Results suggest that many individuals, essentially men, were exposed to violence and eventually killed in battle and raids, since warriorship is mainly restricted to this demographic in many societies. The proportion of casualties is likely to have been far greater than indicated by the 10.1% individuals exhibiting unhealed trauma, given the presence of isolated cases of unhealed postcranial trauma and of arrowheads potentially having impacted into soft tissues. This, together with skeletal indicators of poor health and the possible socioeconomic outcomes evidenced in the region, suggest wider social impacts, which may relate to a more sophisticated and formalized way of warfare than previously appreciated in the European Neolithic record.

Screening for intracranial aneurysms in persons ⩾35 years with hypertension and atherosclerotic disease who smoke(d).

INTRODUCTION: Lifetime risk of aneurysmal subarachnoid haemorrhage (aSAH) is high (7%) in persons ⩾35 years with hypertension who smoke(d). Whether screening for intracranial aneurysms (IAs) to prevent aSAH is effective in these patients is unknown. PATIENTS AND METHODS: Participants were retrieved from a cohort of patients with clinically manifest atherosclerotic vascular disease included between 2012 and 2019 at the University Medical Centre Utrecht (SMART-ORACLE, NCT01932671) in whom CT-angiography (CTA) of intracranial arteries was performed. We selected patients ⩾35 years with hypertension who smoke(d). CTAs were reviewed for the presence of IAs by experienced neuroradiologists. Patients with IAs were offered follow-up imaging to detect aneurysmal growth. We determined aneurysm prevalence and developed a diagnostic model for IA risk at screening using multivariable logistic regression. RESULTS: IA were found in 25 of 500 patients (5.0% prevalence, 95%CI: 3.3%-7.3%). Median 5 year risk of rupture assessed with the PHASES score was 0.9% (IQR: 0.7%-1.3%). During a median follow-up of 57 months (IQR: 39-83 months) no patients suffered from aSAH. Aneurysmal growth was detected in one patient for whom preventive treatment was advised. IA risk at screening ranged between 1.6% and 13.4% with predictors being age, female sex and current smoking. DISCUSSION AND CONCLUSION: IA prevalence in persons ⩾35 years with hypertension and atherosclerotic vascular disease who smoke(d) was 5%. Given the very small proportion of IA that needed preventive treatment, we currently do not advise screening for Caucasian persons older than 35 years of age who smoke and have hypertension in general. Whether screening may be effective for certain subgroups (e.g. women older than 50 years of age) or other ethnic populations should be the subject of future studies.

Aneurysm Prevalence and Quality of Life During Screening in Relatives of Patients With Unruptured Intracranial Aneurysms: A Prospective Study.

BACKGROUND AND OBJECTIVES: Screening for unruptured intracranial aneurysms (UIAs) is effective for first-degree relatives (FDRs) of patients with aneurysmal subarachnoid hemorrhage (aSAH). Whether screening is also effective for FDRs of patients with UIA is unknown. We determined the yield of screening in such FDRs, assessed rupture risk and treatment decisions of aneurysms that were found, identified potential high-risk subgroups, and studied the effects of screening on quality of life (QoL). METHODS: In this prospective cohort study, we included FDRs, aged 20-70 years, of patients with UIA without a family history of aSAH who visited the Neurology outpatient clinic in 1 of 3 participating tertiary referral centers in the Netherlands. FDRs were screened for UIA with magnetic resonance angiography between 2017 and 2021. We determined UIA prevalence and developed a prediction model for UIA risk at screening using multivariable logistic regression. QoL was evaluated with questionnaires 6 times during the first year after screening and assessed with a linear mixed-effects model. RESULTS: We detected 24 UIAs in 23 of 461 screened FDRs, resulting in a 5.0% prevalence (95% CI 3.2-7.4). The median aneurysm size was 3 mm (interquartile range [IQR] 2-4 mm), and the median 5-year rupture risk assessed with the PHASES score was 0.7% (IQR 0.4%-0.9%). All UIAs received follow-up imaging, and none were treated preventively. After a median follow-up of 24 months (IQR 13-38 months), no UIA had changed. Predicted UIA risk at screening ranged between 2.3% and 14.7% with the highest risk in FDRs who smoke and have excessive alcohol consumption (c-statistic: 0.76; 95% CI 0.65-0.88). At all survey moments, health-related QoL and emotional functioning were comparable with those in a reference group from the general population. One FDR with a positive screening result expressed regret about screening. DISCUSSION: Based on the current data, we do not advise screening FDRs of patients with UIA because all identified UIAs had a low rupture risk. We observed no negative effect of screening on QoL. A longer follow-up should determine the risk of aneurysm growth requiring preventive treatment.

Extraoral anterior approach for the treatment of os odontoideum: illustrative case.

BACKGROUND: Os odontoideum is typically treated with instrumented fusion through a posterior cervical approach. When this approach fails, limited options for revision are available. Occipitocervical fusion and transoral anterior fusions have been utilized in the past but are associated with high morbidity and complications. OBSERVATIONS: Here the authors report a case of os odontoideum that was treated with an anterior cervical extraoral approach after failed posterior instrumented fusion. They discuss the challenges that can be encountered with the failure of fusion and the limited options when it comes to approach and fixation of os odontoideum. LESSONS: To the authors' knowledge and based on a review of the literature, this case represents the first use of an anterior extraoral prevascular approach to the high cervical spine to address os odontoideum. They demonstrate that this approach can be utilized as a reasonable alternative to transoral surgery and should be considered in cases where additional or alternative fixation is desired without the morbidity and complications associated with occipitocervical fusion or a transoral approach, especially in a younger patient population.

Carriers of the p.P522R variant in PLCγ2 have a slightly more responsive immune system.

BACKGROUND: The rs72824905 single-nucleotide polymorphism in the PLCG2 gene, encoding the p.P522R residue change in Phospholipase C gamma 2 (PLCγ2), associates with protection against several dementia subtypes and with increased likelihood of longevity. Cell lines and animal models indicated that p.P522R is a functional hypermorph. We aimed to confirm this in human circulating peripheral immune cells. METHODS: We compared effects of p.P522R on immune system function between carriers and non-carriers (aged 59-103y), using in-depth immunophenotyping, functional B-cell and myeloid cell assays, and in vivo SARS-CoV-2 vaccination. RESULTS: In line with expectations, p.P522R impacts immune cell function only slightly, but it does so across a wide array of immune cell types. Upon B-cell stimulation, we observed increased PLCγ2 phosphorylation and calcium release, suggesting increased B-cell sensitivity upon antigen recognition. Further, p.P522R-carriers had higher numbers of CD20++CD21-CD24+ naive B cells and IgG1+ memory B cells. In myeloid cells, normalized ROS production was higher upon PLCγ2-dependent stimulation. On classical monocytes, CD33 levels were elevated. Furthermore, carriers expressed lower levels of allergy-related FcεRI on several immune cell subsets. Nevertheless, carriers and non-carriers had similar serological responses to SARS-CoV-2 vaccination. CONCLUSION: The immune system from p.P522R-carriers is slightly more responsive to stimulation than in non-carriers.

Exploring familial factors in the migrant mortality advantage among domestic migrants in later life: Zeeland, the Netherlands, 1812-1962.

Many historical and contemporary studies have shown that migrants enjoy survival advantages over non-migrants, even if they originate from higher mortality regimes and have a lower socio-economic and educational status compared to non-migrants in the destination area. This so-called migrant mortality advantage or healthy migrant effect is explained in various ways. One of the main explanations refers to selection effects in the area of origin in the sense that healthier individuals are more likely to move compared to less healthy individuals. So far life-course analysis on the healthy migrant effect were focused on the survival chances of individual migrants compared to non-migrants. However, kin members of migrants might also enjoy survival advantages, given that health and mortality are often clustered in families due to shared environments, behaviors, resources, and household dynamics. We study whether kin members of migrants within the Dutch province of Zeeland also enjoy survival advantages. Although we find a mortality advantage for the migrating men and women in our sample, we find no mortality advantage for their siblings or offspring. However, there was a gendered effect of familial migration in the sense that women, contrary to men, had higher mortality risks if their siblings and parents migrated.

Reversible Dual-Covalent Molecular Locking of the 14-3-3/ERRγ Protein-Protein Interaction as a Molecular Glue Drug Discovery Approach.

Molecules that stabilize protein-protein interactions (PPIs) are invaluable as tool compounds for biophysics and (structural) biology, and as starting points for molecular glue drug discovery. However, identifying initial starting points for PPI stabilizing matter is highly challenging, and chemical optimization is labor-intensive. Inspired by chemical crosslinking and reversible covalent fragment-based drug discovery, we developed an approach that we term "molecular locks" to rapidly access molecular glue-like tool compounds. These dual-covalent small molecules reversibly react with a nucleophilic amino acid on each of the partner proteins to dynamically crosslink the protein complex. The PPI between the hub protein 14-3-3 and estrogen-related receptor γ (ERRγ) was used as a pharmacologically relevant case study. Based on a focused library of dual-reactive small molecules, a molecular glue tool compound was rapidly developed. Biochemical assays and X-ray crystallographic studies validated the ternary covalent complex formation and overall PPI stabilization via dynamic covalent crosslinking. The molecular lock approach is highly selective for the specific 14-3-3/ERRγ complex, over other 14-3-3 complexes. This selectivity is driven by the interplay of molecular reactivity and molecular recognition of the composite PPI binding interface. The long lifetime of the dual-covalent locks enabled the selective stabilization of the 14-3-3/ERRγ complex even in the presence of several other competing 14-3-3 clients with higher intrinsic binding affinities. The molecular lock approach enables systematic, selective, and potent stabilization of protein complexes to support molecular glue drug discovery.

Assigning trend-based conservation status despite high uncertainty.

Estimates of temporal trends in species' occupancy are essential for conservation policy and planning, but limitations to the data and models often result in very high trend uncertainty. A critical source of uncertainty that degrades scientific credibility is that caused by disagreement among studies or models. Modelers are aware of this uncertainty but usually only partially estimate it and communicate it to decision makers. At the same time, there is growing awareness that full disclosure of uncertainty is critical for effective translation of science into policies and plans. But what are the most effective approaches to estimating uncertainty and communicating uncertainty to decision makers? We explored how alternative approaches to estimating and communicating uncertainty of species trends could affect decisions concerning conservation status of freshwater fishes. We used ensemble models to propagate trend uncertainty within and among models and communicated this uncertainty with categorical distributions of trend direction and magnitude. All approaches were designed to fit an established decision-making system used to assign species conservation status by the New Zealand government. Our results showed how approaches that failed to fully disclose uncertainty, while simplifying the information presented, could hamper species conservation or lead to ineffective decisions. We recommend an approach that was recently used effectively to communicate trend uncertainty to a panel responsible for setting the conservation status of New Zealand's freshwater fishes.

Designación del estado de conservación basada en tendencias a pesar de gran incertidumbre Resumen Las estimaciones de las tendencias temporales de la presencia de especies son esenciales para la planeación de la conservación y sus políticas, pero las limitaciones de los datos y los modelos suelen derivar en una incertidumbre muy elevada en cuanto a las tendencias. Los desacuerdos entre los estudios y los modelos son una fuente importante de incertidumbre que contribuye a la degradación de la credibilidad científica. Los modeladores están conscientes de esta incertidumbre, pero casi nunca la estiman o comunican por completo a los responsables de las decisiones. Al mismo tiempo, cada vez hay mayor conciencia de que divulgar esta incertidumbre es importante para que la ciencia se traduzca efectivamente en políticas y planes. ¿Pero cuáles son las estrategias más efectivas para estimar la incertidumbre y comunicarla a los responsables de las decisiones? Exploramos cómo las estrategias alternativas para estimar y comunicar la incertidumbre que rodea a las tendencias de las especies podría afectar las decisiones con respecto al estado de conservación de los peces de agua dulce. Usamos modelos de conjuntos para propagar la incertidumbre dentro y entre modelos y comunicamos esta incertidumbre con distribuciones categóricas de la dirección y magnitud de la tendencia. Diseñamos todas las estrategias para que se ajustaran a un sistema establecido de toma de decisiones que usa el gobierno de Nueva Zelanda para designar el estado de conservación de las especies. Nuestros resultados mostraron cómo las estrategias que no divulgaron por completo la incertidumbre, mientras simplificaban la información presentada, podrían dificultar la conservación de las especies o llevar a decisiones poco efectivas. Recomendamos una estrategia que se usó recientemente para comunicar eficientemente la incertidumbre de las tendencias a un panel responsable de establecer el estado de conservación de los peces de agua dulce de Nueva Zelanda.