Genetically guided precision medicine clinical decision support tools: a systematic review.

OBJECTIVES: Patient care using genetics presents complex challenges. Clinical decision support (CDS) tools are a potential solution because they provide patient-specific risk assessments and/or recommendations at the point of care. This systematic review evaluated the literature on CDS systems which have been implemented to support genetically guided precision medicine (GPM). MATERIALS AND METHODS: A comprehensive search was conducted in MEDLINE and Embase, encompassing January 1, 2011-March 14, 2023. The review included primary English peer-reviewed research articles studying humans, focused on the use of computers to guide clinical decision-making and delivering genetically guided, patient-specific assessments, and/or recommendations to healthcare providers and/or patients. RESULTS: The search yielded 3832 unique articles. After screening, 41 articles were identified that met the inclusion criteria. Alerts and reminders were the most common form of CDS used. About 27 systems were integrated with the electronic health record; 2 of those used standards-based approaches for genomic data transfer. Three studies used a framework to analyze the implementation strategy. DISCUSSION: Findings include limited use of standards-based approaches for genomic data transfer, system evaluations that do not employ formal frameworks, and inconsistencies in the methodologies used to assess genetic CDS systems and their impact on patient outcomes. CONCLUSION: We recommend that future research on CDS system implementation for genetically GPM should focus on implementing more CDS systems, utilization of standards-based approaches, user-centered design, exploration of alternative forms of CDS interventions, and use of formal frameworks to systematically evaluate genetic CDS systems and their effects on patient care.

Disrupting the Hofmeister bias in salt liquid-liquid extraction with an arylethynyl bisurea anion receptor.

Host-mediated liquid-liquid extraction is a convenient method for the separation of inorganic salts. However, selective extraction of an anion, regardless of its hydrophilicity or lipophilicity as qualitatively described by its place in the Hofmeister series, remains challenging. Herein we report the complete disruption of the Hofmeister-based ordering of anions in host-mediated extraction by a rigidified tweezer-type receptor possessing remarkably strong anion-binding affinity under the conditions examined. Experiments introduce a convenient new method for determination of anion binding using phosphorus inductively coupled plasma mass spectrometry (ICP-MS) to measure extraction of tetra-n-butylphosphonium (TBP+) salts from water into nitrobenzene, specifically examining the disrupting effect of the added arylethynyl bisurea anion receptor. In the absence of the receptor, the salt partitioning follows the expected Hofmeister-type ordering favoring the larger, less hydrated anions; the analysis yields the value -24 kJ mol-1 for the standard Gibbs energy of partitioning of TBP+ cation from water into nitrobenzene at 25 °C. Selectivity is markedly changed by the addition of receptor to the nitrobenzene and is concentration dependent, giving rise to three selectivity regimes. We then used SXLSQI liquid-liquid equilibrium analysis software developed at Oak Ridge National Laboratory to fit host-mediated extraction equilibria for TBP+ salts of Cl-, Br-, I-, and NO3- to the distribution data. While the reverse-Hofmeister 1 : 1 binding of the anions by the receptor effectively cancels the Hofmeister selectivity of the TBPX partitioning into nitrobenzene, formation of unexpected 2 : 1 receptor : anion complexes favoring Cl- and Br- dominates the selectivity at elevated receptor concentrations, producing the unusual order Br- > Cl- > NO3- > I- in anion distribution wherein a middle member of the series is selected and the most lipophilic anion is disfavored. Density functional theory calculations confirmed the likelihood of forming 2 : 1 complexes, where Cl- and Br- are encapsulated by two receptors adopting energetically competitive single or double helix structures. The calculations explain the rare non-Hofmeister preference for Br-. This example shows that anion receptors can be used to control the selectivity and efficiency of salt extraction regardless of the position of the anion in the Hofmeister series.

Indirect costs of reproduction and the tradeoff between offspring size and number: A framework illustrated by fitness costs and benefits of ovarian fluid.

Theory describing evolution of offspring size often assumes that the production cost per unit volume is the same for small and large offspring. However, this may not be true if indirect costs of reproduction (e.g., material and energetic costs of supporting offspring development) scale disproportionately with offspring size. Here we show how direct and indirect costs of reproduction can be explicitly modeled within the Smith-Fretwell framework and how observations of size-number relationships can thus be used to evaluate indirect costs. We applied this analysis to measures of egg volume and fecundity for over 300 individuals of a coastal fish species and found that the tradeoff was much stronger than the expected inverse (fecundity scaled with volume-1.843). Larger offspring were thus more expensive to produce. For our study species, an important indirect cost was that larger eggs were accompanied by disproportionately more ovarian fluid. Calorimetry and removal experiments were used to further measure both the energetic costs and fitness benefits of ovarian fluid. In addition, we show that indirect costs of reproduction can intensify size-number tradeoffs in a variety of fishes. Indirect costs of reproduction can be large and may therefore play an important role in the evolution of offspring size.

Genomics in nephrology: identifying informatics opportunities to improve diagnosis of genetic kidney disorders using a human-centered design approach.

BACKGROUND: Genomic kidney conditions often have a long lag between onset of symptoms and diagnosis. To design a real time genetic diagnosis process that meets the needs of nephrologists, we need to understand the current state, barriers, and facilitators nephrologists and other clinicians who treat kidney conditions experience, and identify areas of opportunity for improvement and innovation. METHODS: Qualitative in-depth interviews were conducted with nephrologists and internists from 7 health systems. Rapid analysis identified themes in the interviews. These were used to develop service blueprints and process maps depicting the current state of genetic diagnosis of kidney disease. RESULTS: Themes from the interviews included the importance of trustworthy resources, guidance on how to order tests, and clarity on what to do with results. Barriers included lack of knowledge, lack of access, and complexity surrounding the case and disease. Facilitators included good user experience, straightforward diagnoses, and support from colleagues. DISCUSSION: The current state of diagnosis of kidney diseases with genetic etiology is suboptimal, with information gaps, complexity of genetic testing processes, and heterogeneity of disease impeding efficiency and leading to poor outcomes. This study highlights opportunities for improvement and innovation to address these barriers and empower nephrologists and other clinicians who treat kidney conditions to access and use real time genetic information.

Incidence of Osteoarthritis Diagnosis Within 5 Years of Surgery Was Greater Following Partial Meniscectomy Than Meniscus Repair and/or Anterior Cruciate Ligament Reconstruction.

Purpose: To compare knee osteoarthritis (OA) incidence within 5 years of surgery between 5 common sports medicine procedures: isolated anterior cruciate ligament (ACL) reconstruction, isolated meniscus repair (MR), isolated arthroscopic partial meniscectomy (APM), ACL reconstruction with MR (ACL + MR), and ACL reconstruction with APM (ACL + APM). Methods: The PearlDiver Mariner M157Ortho database was searched. Five cohorts were identified using Current Procedural Terminology (CPT) codes and included those 16 to 60 years old who underwent isolated ACL reconstruction, isolated MR, ACL + MR, isolated APM, or ACL + APM repair. Groups were matched by age, sex, and presence of diagnosis codes for obesity. The incidence of knee OA diagnosis within 5 years of the index procedure was determined for each group, and odds ratios (ORs) were calculated and compared against isolated ACL reconstruction. Results: Each group consisted of 7,672 patients (3,450 females, 4,222 males). A significantly greater proportion of the APM group was diagnosed with knee OA within 5 years of surgery compared to isolated ACL reconstruction (APM = 1,032/7,672 [13.5%] vs ACL = 745/7,672 [9.7%]; P ≤ .001; OR, 1.45; 95% confidence interval [CI], 1.31-1.60). Similarly, a greater proportion of the MR group was diagnosed with OA compared to isolated ACL reconstruction (MR = 826/7,672 [10.7%]; P = .030; OR, 1.12; 95% CI, 1.01-1.25). No differences in OA incidence were noted between the ACL + APM group when compared to isolated ACL reconstruction (P = .81). Patients undergoing ACL + MR demonstrated the lowest OA incidence with reduced odds when compared to isolated ACL reconstruction (ACL + MR = 575/7,672 [7.5%]; P < .001; OR, 0.75; 95% CI, 0.67-0.84). Conclusions: In this analysis using CPT codes, APM was associated with the highest knee OA incidence, and ACL + MR was associated with the lowest OA incidence within 5 years of surgery. Level of Evidence: Level III, retrospective cohort study.

Sex Differences in Quadriceps Atrophy After Anterior Cruciate Ligament Tear.

BACKGROUND: Female athletes lag behind their male counterparts in recovery from anterior cruciate ligament (ACL) injury. Quadriceps muscle size and strength are crucial factors for regaining function after ACL injury, but little is known about how these metrics vary due to biological sex. HYPOTHESIS: Female patients have reduced vastus lateralis fiber cross-sectional area (CSA) and lower quadriceps strength after ACL injury than male patients. STUDY DESIGN: Cross-sectional study. LEVEL OF EVIDENCE: Level 4. METHODS: A total of 60 participants with recent ACL tear were evaluated for vastus lateralis muscle fiber CSA, isometric quadriceps peak torque, and quadriceps rate of torque development. Linear mixed models were fit to determine differences across sex and limb for each variable of interest. RESULTS: The female group averaged almost 20% atrophy between limbs (P < 0.01), while the male group averaged just under 4% (P = 0.05). Strength deficits between limbs were comparable between female and male groups. CONCLUSION: Immediately after ACL injury, female patients have greater between-limb differences in muscle fiber CSA but between-limb strength deficits comparable with those of male patients. CLINICAL RELEVANCE: These results indicate that the underpinnings of strength loss differ based on biological sex, and thus individual patients could benefit from a sex-specific treatment approach to ACL injury.

Editorial Commentary: Routine Use of Suture Tape Augmentation for Primary Anterior Cruciate Ligament Reconstruction Surgery Is Not Justified.

High rates of graft failure after primary anterior cruciate ligament reconstruction (ACLR) and the need for revision ACLR continue to be a challenge. Multiple studies demonstrate graft failure rates and the need for revision ACLR in 10% to 15% of young patients participating in pivot sporting activities. Currently, a wide range of strategies to mitigate this is problem being investigated, including extra-articular augmentation (with modified lateral extra-articular tenodesis or anterolateral ligament reconstruction) and intra-articular fixation (that aim for primary anterior cruciate ligament healing or augmentation of an ACLR with suture tape). While the early data on suture tape augmentation of primary ACLR seem optimistic, it does not justify its routine use.

Evaluating impacts of bambusuril pocket size and sterics on anion binding trends using ChemFET sensors.

Chemically-sensitive Field Effect Transistors (ChemFETs) are a useful tool to evaluate aqueous anion affinity of hydrophobic supramolecular scaffolds. More specifically, ChemFETs can be used to probe impacts of receptor modification to aqueous anion affinity. In this study, ChemFETs are used to evaluate the anion affinity of both dodeca-n-butyl bambus[6]uril and dodecabenzyl bambus[6]uril to assess steric effects in the chemical selectivity of the sensor membrane. The ChemFETs were evaluated through a series of common anions in the Hofmeister series in order to ascertain the difference in detection limit imparted by the specific functionalization of the bambus[6]uril macrocycles, which are quite sensitive to modest steric effects. Significant improvements to perchlorate and nitrate detection limits were observed via n-butyl bambusuril-containing sensor membranes over detection limits recorded with benzyl bambusuril sensors.

The Seated Trunk Control Test: Investigation of Reliability and Known-Groups Validity Using Individuals Post-Anterior Cruciate Ligament Reconstruction.

CONTEXT: Decreased trunk neuromuscular control is a risk factor for both upper- and lower-extremity injuries, yet there are few reliable and valid clinical tests to identify deficits. OBJECTIVE: The purpose of this study was to determine the reliability and known-groups validity of a novel clinical test, the seated trunk control test (STCT). DESIGN: Cross-sectional reliability and known-groups validity study. SETTING: Laboratory. PARTICIPANTS: 89 unique participants: 34 were 3 months postoperative anterior cruciate ligament reconstruction (ACLR) and 55 healthy controls. METHODS: For the STCT, participants sat on a balance board with their eyes closed for three 30-second trials while investigators counted balance errors. Intraclass correlations (ICCs) were used to assess interrater reliability (N = 20) and test-retest reliability (N = 40). To assess known-groups validity, independent t tests were used to compare STCT errors at 3 months post-ACLR with healthy matched controls (N = 34/group). Area under a receiver operating characteristic curve identified an optimal cutoff for distinguishing between groups. RESULTS: The STCT had perfect interrater reliability (ICC2,3 = 1.00) and good test-retest reliability (ICC3,3 = .79; 95% confidence interval = .61-.89). The ACLR group made significantly more errors on the STCT (mean [SD] = 15.5 [5.4]) than controls (mean [SD] = 8.2 [4.1]; P < .001, Cohen d = 1.52). The STCT's ability to distinguish between groups was excellent (area under a ROC curve = 0.86). A cutoff of 12 errors maximized sensitivity (76%) and specificity (85%). CONCLUSIONS: The STCT is reliable between raters and across days. It also has excellent ability to distinguish between individuals with a recent ACLR and healthy matched controls, which provides initial evidence to suggest that the STCT may be clinically useful for identifying deficits in trunk neuromuscular control.

Overexpression of manganese superoxide dismutase mitigates ACL injury-induced muscle atrophy, weakness and oxidative damage.

Oxidative stress has been implicated in the etiology of skeletal muscle weakness following joint injury. We investigated longitudinal patient muscle samples following knee injury (anterior cruciate ligament tear). Following injury, transcriptomic analysis revealed downregulation of mitochondrial metabolism-related gene networks, which were supported by reduced mitochondrial respiratory flux rates. Additionally, enrichment of reactive oxygen species (ROS)-related pathways were upregulated in muscle following knee injury, and further investigation unveiled marked oxidative damage in a progressive manner following injury and surgical reconstruction. We then investigated whether antioxidant protection is effective in preventing muscle atrophy and weakness after knee injury in mice that overexpress Mn-superoxide dismutase (MnSOD+/-). MnSOD+/- mice showed attenuated oxidative damage, atrophy, and muscle weakness compared to wild type littermate controls following ACL transection surgery. Taken together, our results indicate that ROS-related damage is a causative mechanism of muscle dysfunction after knee injury, and that mitochondrial antioxidant protection may hold promise as a therapeutic target to prevent weakness and development of disability.

Guanine-containing ssDNA and RNA induce dimeric and tetrameric structural forms of SAMHD1.

The dNTPase activity of tetrameric SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) plays a critical role in cellular dNTP regulation. SAMHD1 also associates with stalled DNA replication forks, DNA repair foci, ssRNA and telomeres. The above functions require nucleic acid binding by SAMHD1, which may be modulated by its oligomeric state. Here we establish in cryo-EM and biochemical studies that the guanine-specific A1 activator site of each SAMHD1 monomer is used to target the enzyme to guanine nucleotides within single-stranded (ss) DNA and RNA. Remarkably, nucleic acid strands containing a single guanine base induce dimeric SAMHD1, while two or more guanines with ∼20 nucleotide spacing induce a tetrameric form. A cryo-EM structure of ssRNA-bound tetrameric SAMHD1 shows how ssRNA strands bridge two SAMHD1 dimers and stabilize the structure. This ssRNA-bound tetramer is inactive with respect to dNTPase and RNase activity.

Azaphosphinines and their derivatives.

Six-membered heterocycles containing one phosphorus and one nitrogen atom, known as azaphosphinines, have existed in the shadows of their single heteroatom-containing analogues for almost 150 years. Despite this, recent chemistry has seen a rapid increase in publications concerning this uncommon scaffold. Azaphosphinines exist in one of six isomers-there are three possible orientations of the pnictogen atoms and in each of these, the phosphorus is in one of two valences (PIIIvs. PV). This review aims to outline and inform on the synthesis and applications of all six isomers. PV-oxo azaphosphinines are of particular interest to this review as many of the discussed heterocycles either form as the pentavalent species directly or oxidize to this over time. In very recent years the published applications of azaphosphinines have blossomed into subjects spanning several fields of chemistry such as asymmetric catalysis, supramolecular association, cellular imaging, and medicinal chemistry.

GDF8 inhibition enhances musculoskeletal recovery and mitigates posttraumatic osteoarthritis following joint injury.

Musculoskeletal disorders contribute substantially to worldwide disability. Anterior cruciate ligament (ACL) tears result in unresolved muscle weakness and posttraumatic osteoarthritis (PTOA). Growth differentiation factor 8 (GDF8) has been implicated in the pathogenesis of musculoskeletal degeneration following ACL injury. We investigated GDF8 levels in ACL-injured human skeletal muscle and serum and tested a humanized monoclonal GDF8 antibody against a placebo in a mouse model of PTOA (surgically induced ACL tear). In patients, muscle GDF8 was predictive of atrophy, weakness, and periarticular bone loss 6 months following surgical ACL reconstruction. In mice, GDF8 antibody administration substantially mitigated muscle atrophy, weakness, and fibrosis. GDF8 antibody treatment rescued the skeletal muscle and articular cartilage transcriptomic response to ACL injury and attenuated PTOA severity and deficits in periarticular bone microarchitecture. Furthermore, GDF8 genetic deletion neutralized musculoskeletal deficits in response to ACL injury. Our findings support an opportunity for rapid targeting of GDF8 to enhance functional musculoskeletal recovery and mitigate the severity of PTOA after injury.

Prevalence and Predictors of Postoperative Depression and Anxiety After Anterior Cruciate Ligament Reconstruction.

PURPOSE: Preoperative mood disorders influence postoperative outcomes after anterior cruciate ligament (ACL) reconstruction (ACLR), but the prevalence and risk factors associated with postoperative depression/anxiety development remain unknown. The purposes of this study were to quantify the prevalence of postoperative diagnoses of depression or anxiety following ACLR in patients under the age of 25 and assess the interplay between patient sex and ACL reoperation on the prevalence of a depression or anxiety diagnosis following ACLR. METHODS: ACLR patients under the age of 25 years old were identified in the Truven Healthcare Marketscan database. Patients with incomplete coverage +/- one year of the index surgical procedure were excluded. Patients were categorized by the presence of preoperative, postoperative, or no depression/anxiety using the International Classification of Diseases, Ninth Revision (ICD-9) codes. We compared patient demographics and reoperation rates following the index ACLR between the depression and anxiety categories. Additionally, logistic regression was fit to assess the interaction between sex and either ipsilateral or contralateral ACL surgery on postoperative depression/anxiety diagnosis. RESULTS: Of the 42,174 patients, 10.7% had a new depression/anxiety diagnosis after ACLR. Postoperative depression/anxiety was nearly twice as prevalent for females (F: 14.4%, M: 7.6%) despite having similar rates of secondary ACLR (F: 15.5%, M: 13.0%). Those with postoperative depression/anxiety had a considerably greater prevalence of reoperation (18.8%) than those without depression/anxiety (13.7%) and those with pre-existing preoperative depression/anxiety (12.9%). Sex and reoperation were independently associated with postoperative depression/anxiety diagnosis. CONCLUSION: Female sex and secondary ACL surgery are independently associated with an increased prevalence of postoperative depression/anxiety. Nearly one in seven young females are diagnosed with depression/anxiety after ACLR. Similarly, a greater proportion of patients who suffer a secondary ACL surgery are subsequently diagnosed with depression/anxiety. The orthopedic community must be cognizant of the increased risk of postoperative depression/anxiety for females and those who suffer a secondary ACL surgery, and screening for depression/anxiety in these at-risk populations with referrals to mental health professionals may be warranted.

Repurposing Normal Chromosomal Microarray Data to Harbor Genetic Insights into Congenital Heart Disease.

About 15% of congenital heart disease (CHD) patients have a known pathogenic copy number variant. The majority of their chromosomal microarray (CMA) tests are deemed normal. Diagnostic interpretation typically ignores microdeletions smaller than 100 kb. We hypothesized that unreported microdeletions are enriched for CHD genes. We analyzed "normal" CMAs of 1762 patients who were evaluated at a pediatric referral center, of which 319 (18%) had CHD. Using CMAs from monozygotic twins or replicates from the same individual, we established a size threshold based on probe count for the reproducible detection of small microdeletions. Genes in the microdeletions were sequentially filtered by their nominal association with a CHD diagnosis, the expression level in the fetal heart, and the deleteriousness of a loss-of-function mutation. The subsequent enrichment for CHD genes was assessed using the presence of known or potentially novel genes implicated by a large whole-exome sequencing study of CHD. The unreported microdeletions were modestly enriched for both known CHD genes and those of unknown significance identified using their de novo mutation in CHD patients. Our results show that readily available "normal" CMA data can be a fruitful resource for genetic discovery and that smaller deletions should receive more attention in clinical evaluation.

Vitamin D status associates with skeletal muscle loss after anterior cruciate ligament reconstruction.

BACKGROUNDAlthough 25-hydroxyvitamin D [25(OH)D] concentrations of 30 ng/mL or higher are known to reduce injury risk and boost strength, the influence on anterior cruciate ligament reconstruction (ACLR) outcomes remains unexamined. This study aimed to define the vitamin D signaling response to ACLR, assess the relationship between vitamin D status and muscle fiber cross-sectional area (CSA) and bone density outcomes, and discover vitamin D receptor (VDR) targets after ACLR.METHODSTwenty-one young, healthy, physically active participants with recent ACL tears were enrolled (17.8 ± 3.2 years, BMI 26.0 ± 3.5 kg/m2). Data were collected through blood samples, vastus lateralis biopsies, dual energy x-ray bone density measurements, and isokinetic dynamometer measures at baseline, 1 week, 4 months, and 6 months after ACLR. The biopsies facilitated CSA, Western blotting, RNA-seq, and VDR ChIP-seq analyses.RESULTSACLR surgery led to decreased circulating bioactive vitamin D and increased VDR and activating enzyme expression in skeletal muscle 1 week after ACLR. Participants with less than 30 ng/mL 25(OH)D levels (n = 13) displayed more significant quadriceps fiber CSA loss 1 week and 4 months after ACLR than those with 30 ng/mL or higher (n = 8; P < 0.01 for post hoc comparisons; P = 0.041 for time × vitamin D status interaction). RNA-seq and ChIP-seq data integration revealed genes associated with energy metabolism and skeletal muscle recovery, potentially mediating the impact of vitamin D status on ACLR recovery. No difference in bone mineral density losses between groups was observed.CONCLUSIONCorrecting vitamin D status prior to ACLR may aid in preserving skeletal muscle during recovery.FUNDINGNIH grants R01AR072061, R01AR071398-04S1, and K99AR081367.

Observation of alumina nanoparticles generated from aqueous solutions of a "flat" aluminum-13 cluster.

Amorphous alumina nanoparticles were synthesized via dynamic processes during the dissolution of aluminum hydroxide by nitric acid, a method commonly used to produce aqueous solutions of aluminum oxide molecular clusters. These particles were characterized by DLS measurements, and corroborated by other solution and solid state analyses. The methods used represent a highly tuneable, facile synthetic pathway that allows for size targeting and scalability for industrial purposes, and provides insight into pH- and temperature-dependent alumina speciation and aggregation.

2-λ5-Phosphaquinolin-2-ones as Non-cytotoxic, Targetable, and pH-Stable Fluorophores.

Several phosphaquinolinone derivatives have been synthesized and characterized to explore their usefulness in the realm of cell imaging. Solution-state photophysical properties in both aqueous and organic solutions were collected for these derivatives. Additionally, CCK-8 cell viability assays and fluorescent imaging in HeLa cells incubated with the new heterocyclic derivatives show evidence of favorable cell permeability, cell viability, and moderate intracellular localization when appended with the well-known morpholine targeting motif.

Benchmarking the placement of hydrosulfide in the Hofmeister series using a bambus[6]uril-based ChemFET sensor.

Hydrosulfide (HS-) is the conjugate base of gasotransmitter hydrogen sulfide (H2S) and is a physiologically-relevant small molecule of great interest in the anion sensing community. However, selective sensing and molecular recognition of HS- in water remains difficult because, in addition to the diffuse charge and high solvation energy of anions, HS- is highly nucleophilic and readily oxidizes into other reactive sulfur species. Moreover, the direct placement of HS- in the Hofmeister series remains unclear. Supramolecular host-guest interactions provide a promising platform on which to recognize and bind hydrosulfide, and characterizing the placement of HS- in the Hofmeister series would facilitate the future design of selective receptors for this challenging anion. Few examples of supramolecular HS- binding have been reported, but the Sindelar group reported HS- binding in water using bambus[6]uril macrocycles in 2018. We used this HS- binding platform as a starting point to develop a chemically-sensitive field effect transistor (ChemFET) to facilitate assigning HS- to a specific place in the Hofmeister series. Specifically, we prepared dodeca-n-butyl bambus[6]uril and incorporated it into a ChemFET as the HS- receptor motif. The resultant device provided an amperometric response to HS-, and we used this device to measure the response of other anions, including SO42-, F-, Cl-, Br-, NO3-, ClO4-, and I-. Using this response data, we were able to experimentally determine that HS- lies between Cl- and Br- in the Hofmeister series, which matches recent theoretical computational work that predicted a similar placement. Taken together, these results highlight the potential of using molecular recognition coupled with ChemFET architectures to develop new approaches for direct and reversible HS- detection and measurement in water and further advance our understanding of different recognition approaches for this challenging anion.

Guanine-containing ssDNA and RNA induce dimeric and tetrameric SAMHD1 in cryo-EM and binding studies.

The dNTPase activity of tetrameric SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) plays a critical role in cellular dNTP regulation. SAMHD1 also associates with stalled DNA replication forks, DNA repair foci, ssRNA, and telomeres. The above functions require nucleic acid binding by SAMHD1, which may be modulated by its oligomeric state. Here we establish that the guanine-specific A1 activator site of each SAMHD1 monomer is used to target the enzyme to guanine nucleotides within single-stranded (ss) DNA and RNA. Remarkably, nucleic acid strands containing a single guanine base induce dimeric SAMHD1, while two or more guanines with ~20 nucleotide spacing induce a tetrameric form. A cryo-EM structure of ssRNA-bound tetrameric SAMHD1 shows how ssRNA strands bridge two SAMHD1 dimers and stabilize the structure. This ssRNA-bound tetramer is inactive with respect to dNTPase and RNase activity.