Contemporary HIV-1 consensus Env with AI-assisted redesigned hypervariable loops promote antibody binding.

An effective HIV-1 vaccine must elicit broadly neutralizing antibodies (bnAbs) against highly diverse Envelope glycoproteins (Env). Since Env with the longest hypervariable (HV) loops is more resistant to the cognate bnAbs than Env with shorter HV loops, we redesigned hypervariable loops for updated Env consensus sequences of subtypes B and C and CRF01_AE. Using modeling with AlphaFold2, we reduced the length of V1, V2, and V5 HV loops while maintaining the integrity of the Env structure and glycan shield, and modified the V4 HV loop. Spacers are designed to limit strain-specific targeting. All updated Env are infectious as pseudoviruses. Preliminary structural characterization suggests that the modified HV loops have a limited impact on Env's conformation. Binding assays show improved binding to modified subtype B and CRF01_AE Env but not to subtype C Env. Neutralization assays show increases in sensitivity to bnAbs, although not always consistently across clades. Strikingly, the HV loop modification renders the resistant CRF01_AE Env sensitive to 10-1074 despite the absence of a glycan at N332.

Evolution of HIV-1 envelope towards reduced neutralization sensitivity, as demonstrated by contemporary HIV-1 subtype B from the United States.

Subtype B HIV-1 has been the primary driver of the HIV-1 epidemic in the United States (U.S.) for over forty years and is also a prominent subtype in the Americas, Europe, Australia, the Middle East and North Africa. In this study, the neutralization profiles of contemporary subtype B Envs from the U.S. were assessed to characterize changes in neutralization sensitivities over time. We generated a panel of 30 contemporary pseudoviruses (PSVs) and demonstrated continued diversification of subtype B Env from the 1980s up to 2018. Neutralization sensitivities of the contemporary subtype B PSVs were characterized using 31 neutralizing antibodies (NAbs) and were compared with strains from earlier in the HIV-1 pandemic. A significant reduction in Env neutralization sensitivity was observed for 27 out of 31 NAbs for the contemporary as compared to earlier-decade subtype B PSVs. A decline in neutralization sensitivity was observed across all Env domains; the NAbs that were most potent early in the pandemic suffered the greatest decline in potency over time. A meta-analysis demonstrated this trend across multiple subtypes. As HIV-1 Env diversification continues, changes in Env antigenicity and neutralization sensitivity should continue to be evaluated to inform the development of improved vaccine and antibody products to prevent and treat HIV-1.

Electronic specific heat capacities and entropies from density matrix quantum Monte Carlo using Gaussian process regression to find gradients of noisy data.

We present a machine learning approach to calculating electronic specific heat capacities for a variety of benchmark molecular systems. Our models are based on data from density matrix quantum Monte Carlo, which is a stochastic method that can calculate the electronic energy at finite temperature. As these energies typically have noise, numerical derivatives of the energy can be challenging to find reliably. In order to circumvent this problem, we use Gaussian process regression to model the energy and use analytical derivatives to produce the specific heat capacity. From there, we also calculate the entropy by numerical integration. We compare our results to cubic splines and finite differences in a variety of molecules in which Hamiltonians can be diagonalized exactly with full configuration interaction. We finally apply this method to look at larger molecules where exact diagonalization is not possible and make comparisons with more approximate ways to calculate the specific heat capacity and entropy.

Dispersal changes soil bacterial interactions with fungal wood decomposition.

Although microbes are the major agent of wood decomposition - a key component of the carbon cycle - the degree to which microbial community dynamics affect this process is unclear. One key knowledge gap is the extent to which stochastic variation in community assembly, e.g. due to historical contingency, can substantively affect decomposition rates. To close this knowledge gap, we manipulated the pool of microbes dispersing into laboratory microcosms using rainwater sampled across a transition zone between two vegetation types with distinct microbial communities. Because the laboratory microcosms were initially identical this allowed us to isolate the effect of changing microbial dispersal directly on community structure, biogeochemical cycles and wood decomposition. Dispersal significantly affected soil fungal and bacterial community composition and diversity, resulting in distinct patterns of soil nitrogen reduction and wood mass loss. Correlation analysis showed that the relationship among soil fungal and bacterial community, soil nitrogen reduction and wood mass loss were tightly connected. These results give empirical support to the notion that dispersal can structure the soil microbial community and through it ecosystem functions. Future biogeochemical models including the links between soil microbial community and wood decomposition may improve their precision in predicting wood decomposition.

The Relationship Between Alcohol and Drug Use, Compulsive Sexual Behavior, and Condomless Anal Sex in Men Who have Sex with Men: Analysis of Retrospectively-Reported Sexual Behavior.

Men who have sex with men (MSM) are disproportionately impacted by HIV in the United States, and substance use and compulsive sexual behavior (CSB) are contributors to HIV risk behavior. This study sought to examine the direct and interactive effects of concurrent substance use and CSB on condomless anal sex (CAS) in a community sample of MSM (N = 200) utilizing a 90-day timeline follow-back assessment. Results indicated CSB did not directly increase risk for CAS when controlling for substance use and age. There was limited evidence for a direct effect of concurrent alcohol use on CAS, and no evidence for an interaction effect with CSB. The relationship between concurrent drug use and CAS was moderated by CSB, such that concurrent drug use was positively associated with CAS for those who screened positive for CSB, while the association was non-significant for those who screened negative. Implications and limitations of these findings are discussed.

RESUMEN: En los Estados Unidos, los hombres que tienen sexo con hombres (HSH) se ven afectados de manera desproporcionada, por el VIH, el uso de sustancias y el comportamiento sexual compulsivo (CSB), lo que contribuye al comportamiento de riesgo del VIH. Este estudio buscó examinar los efectos directos e interactivos del uso simultáneo de sustancias y el CSB sobre el sexo anal sin condón (CAS) en una muestra comunitaria de HSH (N = 200) utilizando una evaluación de retrospectiva de 90 días. Los resultados indicaron que CSB no aumentó directamente el riesgo de CAS al controlar el uso de sustancias y la edad. Se encontró evidencia limitada de un efecto directo del consumo concurrente de alcohol sobre CAS y no se encontró evidencia de efecto de interacción con la CSB. La relación entre el uso concurrente de drogas y CAS fue moderada por CSB, de modo que el uso concurrente de drogas se asoció positivamente con CAS para aquellos que dieron positivo para CSB, mientras que la asociación no fue significativa para aquellos que dieron negativo. Se discuten las implicaciones y limitaciones de estos hallazgos.

Identification of Degenerative Cervical Myelopathy in the Chiropractic Office: Case Report and a Review of the Literature.

Degenerative cervical myelopathy (DCM) is a common cause of spinal cord dysfunction, yet it may be challenging to identify as it presents with variable symptoms. A 62-year-old woman presented to a chiropractor with a three-month exacerbation of neck pain, hand/finger numbness, and torso dysesthesia. She had previously seen primary care, physical therapy, rheumatology, and pain management. Previous cervical magnetic resonance imaging showed moderate cervical canal stenosis; however, previous providers had diagnosed her with radiculopathy and possible carpal tunnel syndrome yet had not requested neurosurgical consultation. On examination, the chiropractor identified sensorimotor deficits, hyperreflexia, and bilateral Hoffman reflexes, and referred the patient to a neurosurgeon for suspected DCM. The neurosurgeon performed an anterior cervical discectomy and fusion from C4-7. The patient's symptoms and disability level improved within two months of follow-up. We identified 11 previous cases in which a chiropractor suspected DCM which was then confirmed by a surgeon. Including the current case (i.e., 12 total), patients were older and mostly male; 50% had neck pain, 92% had hyperreflexia. Chiropractors referred each patient to a surgeon; 83% underwent cervical spine surgery. This case highlights the identification of DCM by a chiropractor and referral for neurosurgical evaluation with a positive outcome. Patients with previously undiagnosed DCM may present to chiropractors with varied symptoms and examination findings. DCM may contraindicate spinal manipulation and instead warrant surgery. Accordingly, chiropractors play a key role in the detection and referral of patients with misdiagnosed or overlooked DCM.

Defending Earth's terrestrial microbiome.

Microbial life represents the majority of Earth's biodiversity. Across disparate disciplines from medicine to forestry, scientists continue to discover how the microbiome drives essential, macro-scale processes in plants, animals and entire ecosystems. Yet, there is an emerging realization that Earth's microbial biodiversity is under threat. Here we advocate for the conservation and restoration of soil microbial life, as well as active incorporation of microbial biodiversity into managed food and forest landscapes, with an emphasis on soil fungi. We analyse 80 experiments to show that native soil microbiome restoration can accelerate plant biomass production by 64% on average, across ecosystems. Enormous potential also exists within managed landscapes, as agriculture and forestry are the dominant uses of land on Earth. Along with improving and stabilizing yields, enhancing microbial biodiversity in managed landscapes is a critical and underappreciated opportunity to build reservoirs, rather than deserts, of microbial life across our planet. As markets emerge to engineer the ecosystem microbiome, we can avert the mistakes of aboveground ecosystem management and avoid microbial monocultures of single high-performing microbial strains, which can exacerbate ecosystem vulnerability to pathogens and extreme events. Harnessing the planet's breadth of microbial life has the potential to transform ecosystem management, but it requires that we understand how to monitor and conserve the Earth's microbiome.

Clinical Utility of Routine Postoperative Imaging in Spinal Fusion Surgery: A Systematic Review.

OBJECTIVE: Following spinal fusion surgery, routine imaging is often obtained in all patients regardless of clinical presentation. Such routine imaging may include x-ray, computed tomography, or magnetic resonance imaging studies in both the immediate postoperative period and after discharge. The clinical utility of this practice is questionable. Our goal is to assess the existing literature for evidence of impact on clinical care from routine radiographic surveillance following spinal fusion. METHODS: A systematic search of Embase, Scopus, PubMed, Cochrane, and Ovid databases was performed for studies investigating postoperative imaging following spinal fusion surgery. Studies were analyzed for imaging findings and rates of change in management due to imaging. RESULTS: In total, the review identified 9 studies that separated data by unique patient or by unique clinic visits. The 4 studies reporting per-patient data totaled 475 patients with 328 (69%) receiving routine imaging. Among these, 28 (8.5%) patients had abnormal routine findings with no patients having a change to their clinical course. Of the 5 studies that reported clinic visit data, 3119 patient visits were included with 2365 (76%) clinic visits accompanied by imaging. Across these 5 studies, 146 (6.2%) visits noted abnormal imaging with only 12 (0.5%) subsequent management changes. CONCLUSIONS: Our analysis found that routine imaging after spinal fusion surgery had no direct benefit on clinical management. The utility of baseline imaging for long-term comparison and medicolegal concerns were not studied and remain up to the provider's judgment. Further research is necessary to identify optimal imaging criteria following spinal fusion surgery.

Pudendal tumor mimicking cauda equina syndrome and acute radiculopathy: case report.

INTRODUCTION: Cauda equina syndrome (CES) is most caused by lumbar disc herniation, and the associated treatment involves prompt surgical decompression. Rarer causes of CES include perineural (Tarlov) cysts. CLINICAL PRESENTATION: A 62-year-old female with history of rheumatoid arthritis, hip and knee replacements, and chronic low back pain presented with worsening back pain, left leg weakness and pain for 6 weeks, and bowel/bladder incontinence with diminished sensation in the perianal region for 24 h prior to presentation. MRI demonstrated severe spinal stenosis at L4-S1, central disc herniation at L5-S1, and compression of the cauda equina, consistent with CES. A lumbar decompression was performed. Patient did well at 2-week follow up, but presented 5 weeks post-discharge with increased left leg pain/weakness and genitalia anesthesia. Imaging was unremarkable. Two months later, the patient presented with diminished sensation in the buttocks and bilateral lower extremities and bowel/bladder incontinence. Imaging demonstrated a large cystic presacral mass with involvement of the left sciatic foramen and S3 neural foramen. A team of plastic, orthopedic, and neurological surgeons performed an S3 sacral laminectomy, foraminotomy, partial sacrectomy, and S3 rhizotomy, and excision of the large left hemorrhagic pudendal mass. Final pathology demonstrated a perineural cyst with organizing hemorrhage. On follow-up, the patient's pain and weakness improved. CONCLUSION: CES-like symptoms were initially attributed to a herniated disk. However, lumbar decompression did not resolve symptoms, prompting further radiographic evaluation at two separate presentations. This represents the first reported case of a pudendal tumor causing symptoms initially attributed to a herniated disc.

Global relationships in tree functional traits.

Due to massive energetic investments in woody support structures, trees are subject to unique physiological, mechanical, and ecological pressures not experienced by herbaceous plants. Despite a wealth of studies exploring trait relationships across the entire plant kingdom, the dominant traits underpinning these unique aspects of tree form and function remain unclear. Here, by considering 18 functional traits, encompassing leaf, seed, bark, wood, crown, and root characteristics, we quantify the multidimensional relationships in tree trait expression. We find that nearly half of trait variation is captured by two axes: one reflecting leaf economics, the other reflecting tree size and competition for light. Yet these orthogonal axes reveal strong environmental convergence, exhibiting correlated responses to temperature, moisture, and elevation. By subsequently exploring multidimensional trait relationships, we show that the full dimensionality of trait space is captured by eight distinct clusters, each reflecting a unique aspect of tree form and function. Collectively, this work identifies a core set of traits needed to quantify global patterns in functional biodiversity, and it contributes to our fundamental understanding of the functioning of forests worldwide.

Spine centers of excellence: a systematic review and single-institution description of a spine center of excellence.

Background: Centers of excellence (COEs) are interdisciplinary healthcare organizations created with the goal of improving health/economic outcomes in medical treatment for both individuals and health systems, compared to traditionally structured counterparts. Multiple studies have highlighted both societal/individual burdens associated with back pain, underscoring the importance of identifying new avenues for improving both cost/clinical outcomes for this patient population. Here, we utilize available literature to better characterize the features of a spine COE at a tertiary care center and determine the impact of COEs on patient satisfaction and outcomes. Methods: A systematic review describing spine COEs was performed. PubMed, OVID, Cochrane, Web of Science, and Scopus were utilized for electronic literature search. Data including institution, department, pathologies treated, patient satisfaction scores, patient outcomes, and descriptions of the COE, were extracted and analyzed by two reviewers per full-text article. Inclusion criteria consisted of literature describing the organization, purpose, or outcomes of a spine COE, all publication types (except technical/operative report), adult or pediatric patients, publication from inception through September 2021. Exclusion criteria consisted of articles that do not discuss spinal COEs, technical/operative reports, studies unavailable in English language, unavailable full text, or non-human subjects. The Newcastle-Ottawa Quality Assessment Scale was used to assess the quality of the included studies. Results: Five hundred and sixty-seven unique publications were obtained from the literature search. Of these articles, 20 were included and 547 were excluded based on inclusion and exclusion criteria. Following full-text review of the 20 publications, 6 contained pertinent data. Quantitative data comparing COE versus non-COE was contradictory in comparing complication rates and episodic costs. Qualitative data included descriptions of spine COE features and cited improved patient care, technical advancements, and individualized care paths as positive aspects of the COE model. Mean risk of bias assessment was 3.67. Discussion: There is little evidence regarding if spine COEs provide an advantage over traditionally organized facilities. The current number and heterogeneity of publications, and lack of standardized metrics used to define a spinal COE are limiting factors. Spinal COE may offer higher value care, reduced complication rates and advancements in knowledge and technical skill.

Optimizing the Local Chemical Environment on a Bifunctional Helical Peptide Scaffold Enables Enhanced Enantioselectivity and Cooperative Catalysis.

We describe a proof-of-concept study in which peptide-bound enamine and thiourea catalysts are used to facilitate the conjugate addition of cyclohexanone to nitroolefins. Our bifunctional peptide scaffold is modified to optimize the local environment around both catalysts to enhance both reactivity and enantioselectivity, affording selectivities of ≤95% ee. Circular dichroism, nuclear magnetic resonance nuclear Overhauser effect studies, and molecular dynamics simulations verify the helical structure of our catalyst in solution and the importance of the secondary structure in catalysis.

Treatments for objective and subjective cognitive functioning in young people with depression: Systematic review of current evidence.

AIM: Cognitive deficits are recognized features of depressive disorders in youth aged 12-25. These deficits are distressing, predict functional impairment and limit the effectiveness of psychological therapies. Cognitive enhancement using behavioural, biochemical or physical treatments may be useful in young people with depression, but studies have not been synthesized. The aim was to systematically review the evidence for treatments for objective and subjective cognitive functioning, and their acceptability and functional outcomes in people aged 12-25 with depression. METHOD: Three electronic databases were searched for articles using pre-specified criteria. Pharmacological treatments were not eligible. Risk of bias was rated using the Cochrane Collaboration's revised risk-of-bias tool. Dual full-text article screening, data extraction and quality ratings were completed. RESULTS: Twelve studies were included for review (median participant age: 20.39 years), five of which were randomized-controlled trials (RCTs). Sample sizes were generally small (median = 23; range: 9-46). Eight studies investigated behavioural treatments including aerobic exercise, cognitive training and education or strategy-based methods. Four studies examined repetitive transcranial magnetic brain stimulation (rTMS). Most behavioural treatments revealed preliminary evidence of improved cognitive function in youth depression. Consent rates were greatest for exercise- and education-based approaches, which may indicate higher acceptability levels. Findings from rTMS trials were mixed, with only half showing cognitive improvement. Functional outcomes were reported by three behavioural treatment trials and one rTMS trial, with functional improvement reported only in the former. Some concern of risk of bias was found in each RCT. CONCLUSION: Behavioural treatments, such as exercise, cognitive training and education/strategy-focused techniques, show encouraging results and appear to be acceptable methods of addressing cognitive deficits in youth depression based on participation rates. Brain stimulation and biochemical treatments (e.g., nutrient-based treatment) require further investigation.

Multiple distinct, scale-dependent links between fungi and decomposition.

Decomposition has historically been considered a function of climate and substrate but new research highlights the significant role of specific micro-organisms and their interactions. In particular, wood decay is better predicted by variation in fungal communities than in climate. Multiple links exist: interspecific competition slows decomposition in more diverse fungal communities, whereas trait variation between different communities also affects process rates. Here, we paired field and laboratory experiments using a dispersal gradient at a forest-shrubland ecotone to examine how fungi affect wood decomposition across scales. We observed that while fungal communities closer to forests were capable of faster decomposition, wood containing diverse fungal communities decomposed more slowly, independent of location. Dispersal-driven stochasticity in small-scale community assembly was nested within large-scale turnover in the regional species pool, decoupling the two patterns. We thus find multiple distinct links between microbes and ecosystem function that manifest across different spatial scales.

Decadal changes in fire frequencies shift tree communities and functional traits.

Global change has resulted in chronic shifts in fire regimes. Variability in the sensitivity of tree communities to multi-decadal changes in fire regimes is critical to anticipating shifts in ecosystem structure and function, yet remains poorly understood. Here, we address the overall effects of fire on tree communities and the factors controlling their sensitivity in 29 sites that experienced multi-decadal alterations in fire frequencies in savanna and forest ecosystems across tropical and temperate regions. Fire had a strong overall effect on tree communities, with an average fire frequency (one fire every three years) reducing stem density by 48% and basal area by 53% after 50 years, relative to unburned plots. The largest changes occurred in savanna ecosystems and in sites with strong wet seasons or strong dry seasons, pointing to fire characteristics and species composition as important. Analyses of functional traits highlighted the impact of fire-driven changes in soil nutrients because frequent burning favoured trees with low biomass nitrogen and phosphorus content, and with more efficient nitrogen acquisition through ectomycorrhizal symbioses. Taken together, the response of trees to altered fire frequencies depends both on climatic and vegetation determinants of fire behaviour and tree growth, and the coupling between fire-driven nutrient losses and plant traits.

Immediate Postoperative Imaging Following Elective Lumbar Fusion Provides Little Clinical Utility.

STUDY DESIGN: Retrospective review at a single institution of all adult patients who underwent elective lumbar fusion surgery for degenerative spinal disease from 2013 to 2018. Reoperation rates and change in clinical management due to routine imaging findings were the primary outcomes. OBJECTIVE: To investigate what effects immediate routine postoperative imaging has on the clinical management of patients following lumbar fusion surgery. SUMMARY OF BACKGROUND DATA: The clinical utility of routine postoperative imaging following lumbar fusion surgery remains uncertain. Existing studies on the clinical utility of postoperative imaging in lumbar fusion patients have largely focused on imaging obtained post-discharge. We present a retrospective analysis that to our knowledge is the first study reporting on the clinical utility of routine imaging in lumbar fusion patients during the immediate postoperative period. METHODS: The medical records of patients who had undergone elective lumbar instrumented fusion for degenerative disease from 2013 to 2018 by neurosurgeons across one regional healthcare system were retrospectively analyzed. Inpatient records and imaging orders for patients were reviewed. Routine immediate postoperative imaging was defined by any lumbar spine imaging prior to discharge in the absence of specific indications. RESULTS: Analysis identified 115 patients who underwent elective lumbar instrumented fusion for degenerative disease. One-hundred-twelve patients received routine postoperative imaging. Routine imaging was abnormal in four patients (4%). There was one instance (<1%) where routine immediate postoperative imaging led to change in clinical management. Abnormal routine imaging was not associated with either reoperation or development of neurological symptoms postoperatively (P = 0.10), however, new or worsening neurologic deficits did predict reoperation (P < 0.01). CONCLUSION: New neurologic deficit was the only significant predictor of reoperation. Routine imaging, whether normal or abnormal, was not found to be associated with reoperation. The practice of routine imaging prior to discharge following elective lumbar fusion surgery appears to provide little utility to clinical management.Level of Evidence: 3.