Clarifying status of DNNs as models of human vision.

On several key issues we agree with the commentators. Perhaps most importantly, everyone seems to agree that psychology has an important role to play in building better models of human vision, and (most) everyone agrees (including us) that deep neural networks (DNNs) will play an important role in modelling human vision going forward. But there are also disagreements about what models are for, how DNN-human correspondences should be evaluated, the value of alternative modelling approaches, and impact of marketing hype in the literature. In our view, these latter issues are contributing to many unjustified claims regarding DNN-human correspondences in vision and other domains of cognition. We explore all these issues in this response.

Deep problems with neural network models of human vision.

Deep neural networks (DNNs) have had extraordinary successes in classifying photographic images of objects and are often described as the best models of biological vision. This conclusion is largely based on three sets of findings: (1) DNNs are more accurate than any other model in classifying images taken from various datasets, (2) DNNs do the best job in predicting the pattern of human errors in classifying objects taken from various behavioral datasets, and (3) DNNs do the best job in predicting brain signals in response to images taken from various brain datasets (e.g., single cell responses or fMRI data). However, these behavioral and brain datasets do not test hypotheses regarding what features are contributing to good predictions and we show that the predictions may be mediated by DNNs that share little overlap with biological vision. More problematically, we show that DNNs account for almost no results from psychological research. This contradicts the common claim that DNNs are good, let alone the best, models of human object recognition. We argue that theorists interested in developing biologically plausible models of human vision need to direct their attention to explaining psychological findings. More generally, theorists need to build models that explain the results of experiments that manipulate independent variables designed to test hypotheses rather than compete on making the best predictions. We conclude by briefly summarizing various promising modeling approaches that focus on psychological data.

Insights Into Drug Repurposing, as Well as Specificity and Compound Properties of Piperidine-Based SARS-CoV-2 PLpro Inhibitors.

The COVID-19 pandemic continues unabated, emphasizing the need for additional antiviral treatment options to prevent hospitalization and death of patients infected with SARS-CoV-2. The papain-like protease (PLpro) domain is part of the SARS-CoV-2 non-structural protein (nsp)-3, and represents an essential protease and validated drug target for preventing viral replication. PLpro moonlights as a deubiquitinating (DUB) and deISGylating enzyme, enabling adaptation of a DUB high throughput (HTS) screen to identify PLpro inhibitors. Drug repurposing has been a major focus through the COVID-19 pandemic as it may provide a fast and efficient route for identifying clinic-ready, safe-in-human antivirals. We here report our effort to identify PLpro inhibitors by screening the ReFRAME library of 11,804 compounds, showing that none inhibit PLpro with any reasonable activity or specificity to justify further progression towards the clinic. We also report our latest efforts to improve piperidine-scaffold inhibitors, 5c and 3k, originally developed for SARS-CoV PLpro. We report molecular details of binding and selectivity, as well as in vitro absorption, distribution, metabolism and excretion (ADME) studies of this scaffold. A co-crystal structure of SARS-CoV-2 PLpro bound to inhibitor 3k guides medicinal chemistry efforts to improve binding and ADME characteristics. We arrive at compounds with improved and favorable solubility and stability characteristics that are tested for inhibiting viral replication. Whilst still requiring significant improvement, our optimized small molecule inhibitors of PLpro display decent antiviral activity in an in vitro SARS-CoV-2 infection model, justifying further optimization.

Tract level associations between historical residential redlining and contemporary fatal encounters with police.

How does structural racism influence where people are killed during encounters with police? We analyzed geo-located incidents of fatal encounters with police that occurred between 2000 and 2020 in Census tracts that received a classification by the Home Owners Loan Corporation (HOLC) during the 1930's. Statistical models show that incidents of fatal encounters with police in formerly redlined areas are 66% more likely than in zones that received the most favorable "A" rating. These differences remain even when tract historical and contemporary racial compositions, along with contemporary economic conditions, are taken into account. The effects of contemporary racial composition and economic conditions overshadow the effect of zone classifications only in areas with high proportions of Black residents or residents in poverty (>60% or >30% respectively). These findings provide evidence of structural biases in policing rooted in historical segregation policies.

Ethylene vinyl alcohol copolymer to treat an intracranial arteriovenous malformation in a dog.

A 6-year-old neutered male German shepherd dog was evaluated for obtundation, blindness, and bilateral exophthalmos. A magnetic resonance imaging scan of the brain was performed and identified an arteriovenous malformation (AVM) with several feeding arterial branches, and venous drainage through the cavernous sinus. Venous vessels rostral to the AVM were severely distended and extended into the retrobulbar spaces. Liquid embolization by injection of ethylene vinyl alcohol copolymer was performed from access points in the maxillary arteries and internal carotid arteries. No intraprocedural complications were encountered, and the dog was discharged the next day. Bilateral enucleation eventually was performed because of exposure keratopathy. At 31 months post-embolization, owners reported that the dog was doing very well clinically with high activity level and normal appetite, and the dog also appeared to be pain free. Although intracranial AVMs are very rare in companion animals, successful treatment using liquid embolization is possible and should be considered.

Social Trust and Anti-immigrant Attitudes in Europe: A Longitudinal Multi-Level Analysis.

Research investigating how social conditions influence attitudes about immigrants has focused primarily on demographic and economic factors as potential threat inducing contexts that lead to anti-immigrant sentiment. However, the empirical evidence supporting this link is mixed, while social cohesion indicators such as the influence of social trust, have largely been left unexamined. This article uses the European Social Survey (2002-2016) to test how differences in social trust, both within and between countries influence attitudes about immigrants. Results from longitudinal analyses show that countries with higher levels of social trust have more favorable attitudes toward immigrants, and while changes in social trust over time are small, they result in comparably large changes in anti-immigrant attitudes, even when controlling for other social factors. These results are robust across different model specifications and data sources.

Analytical Model of Two-Directional Cracking Shear-Friction Membrane for Finite Element Analysis of Reinforced Concrete.

There are a multitude of existing material models for the finite element analysis of cracked reinforced concrete that provide reduced shear stiffness but do not limit shear strength. In addition, typical models are not based on the actual physical behavior of shear transfer across cracks by shear friction recognized in the ACI 318 Building Code. A shear-friction model was recently proposed that was able to capture the recognized cracked concrete behavior by limiting shear strength as a yielding function in the reinforcement across the crack. However, the proposed model was formulated only for the specific case of one-directional cracking parallel to the applied shear force. This study proposed and generalized an orthogonal-cracking shear-friction model for finite element use. This was necessary for handling the analysis of complex structures and nonproportional loading cases present in real design and testing situations. This generalized model was formulated as a total strain-based model using the approximation that crack strains are equal to total strains, using the proportional load vector, constant vertical load, and modified Newton-Raphson method to improve the model's overall accuracy.

Continuum of care for disasters and catastrophes.

Disasters and their more extensive and more serious variant, catastrophes, are different than most human experiences. They are inherently quite complex. Extensive and diverse resources are required to assist disaster survivors as well as disaster response personnel, and hospital medical staffs. Except for warfare, there are few other human predicaments that require such a massive and highly coordinated response. Traditional psycho-therapeutic interventions have little chance of being helpful in the acute stages of a disaster. Research demonstrates that selected crisis intervention processes provided by crisis-trained psychological support personnel have been quite successful in assisting both the survivors and responders in coping with disasters and catastrophes. Assistance to military personnel, emergency operations personnel, and survivors must be carefully crafted to assure that the right type of help is provided at the right time by the most appropriate, well-trained, and experienced personnel. This paper employed a scoping review methodology synthesizing the lessons gleaned from wars and past disasters beginning in the late 1800's up to the present. It sets a course for the appropriate management of the psychological impacts of future disasters and catastrophes. Evidence suggests effective psychiatric and psychological services provided during and in the aftermath of a disaster must be simple, brief, immediate, practical, and innovative. Most importantly, disaster mental health support services must consist of an integrated and comprehensive continuum of mental health services spanning all levels of intensity of support and care.

Agricultural Soil Management Practices Differentially Shape the Bacterial and Fungal Microbiome of Sorghum bicolor.

Soils play important roles in biological productivity. While past work suggests that microbes affect soil health and respond to agricultural practices, it is not well known how soil management shapes crop host microbiomes. To elucidate the impact of management on microbial composition and function in the sorghum microbiome, we performed 16S rRNA gene and ITS2 amplicon sequencing and metatranscriptomics on soil and root samples collected from a site in California's San Joaquin Valley that is under long-term cultivation with 1) standard (ST) or no tilling (NT) and 2) cover-cropping (CC) or leaving the field fallow (NO). Our results revealed that microbial diversity, composition, and function change across tillage and cover type, with a heightened response in fungal communities, versus bacterial. Surprisingly, ST harbored greater microbial alpha diversity than NT, indicating that tillage may open niche spaces for broad colonization. Across management regimes, we observed class-level taxonomic level shifts. Additionally, we found significant functional restructuring across treatments, including enrichment for microbial lipid and carbohydrate transport and metabolism and cell motility with NT. Differences in carbon cycling were also observed, with increased prevalence of glycosyltransferase and glycoside hydrolase carbohydrate active enzyme families with CC. Lastly, treatment significantly influenced arbuscular mycorrhizal fungi, which had the greatest prevalence and activity under ST, suggesting that soil practices mediate known beneficial plant-microbe relationships. Collectively, our results demonstrate how agronomic practices impact critical interactions within the plant microbiome and inform future efforts to configure trait-associated microbiomes in crops.Importance While numerous studies show that farming practices can influence the soil microbiome, there are often conflicting results on how microbial diversity and activity respond to treatment. In addition, there is very little work published on how the corresponding crop plant microbiome is impacted. With bacteria and fungi known to critically affect soil health and plant growth, we concurrently compared how the practices of no and standard tillage, in combination with either cover-cropping or fallow fields, shape soil and plant-associated microbiomes between the two classifications. In determining not only the response to treatment in microbial diversity and composition, but for activity as well, this work demonstrates the significance of agronomic practice in modulating plant-microbe interactions, as well as encourages future work on the mechanisms involved in community assemblages supporting similar crop outcomes.

Mechanism and inhibition of the papain-like protease, PLpro, of SARS-CoV-2.

The SARS-CoV-2 coronavirus encodes an essential papain-like protease domain as part of its non-structural protein (nsp)-3, namely SARS2 PLpro, that cleaves the viral polyprotein, but also removes ubiquitin-like ISG15 protein modifications as well as, with lower activity, Lys48-linked polyubiquitin. Structures of PLpro bound to ubiquitin and ISG15 reveal that the S1 ubiquitin-binding site is responsible for high ISG15 activity, while the S2 binding site provides Lys48 chain specificity and cleavage efficiency. To identify PLpro inhibitors in a repurposing approach, screening of 3,727 unique approved drugs and clinical compounds against SARS2 PLpro identified no compounds that inhibited PLpro consistently or that could be validated in counterscreens. More promisingly, non-covalent small molecule SARS PLpro inhibitors also target SARS2 PLpro, prevent self-processing of nsp3 in cells and display high potency and excellent antiviral activity in a SARS-CoV-2 infection model.

Transforming Performance of Clinical Trials in Pediatric Type 2 Diabetes: A Consortium Model.

Background: Completing phase 3 trials of new drugs for youth with type 2 diabetes is challenging. The Pediatric Diabetes Consortium (PDC) of U.S. pediatric treatment centers developed a Consortium model to improve the efficiency of successfully completing these trials. Aims and Innovations: An aim of the PDC model is to utilize the resources of the PDC Coordinating Center and Executive Committee to improve study protocols, centralize interactions with sponsors, and oversee the performance of PDC Clinical Centers. Key features include a Consulting Group to improve protocol design; Master Service Agreements between the Coordinating Center and Clinical Centers covering confidentiality agreements and contract language; negotiation of a standard Site Budget with Contract Research Organizations (CROs)/Sponsors that reflect actual Clinical Center costs; Weekly Conference Calls with CROs/sponsors to track progress of Clinical Center launches, Monthly Oversight Calls with investigators and study Coordinators to track Clinical Center performance, discuss enrollment strategies, and identify emerging problems. Successes and Challenges: The Consortium model played a key role in the completion of the pivotal trial of liraglutide for treatment of youth with type 2 diabetes. PDC centers also played a pivotal role in exceeding the projected number of randomized subjects needed by two ongoing studies that are nearing completion. Conclusions: While the Consortium model is still a work in progress, PDC has assisted in the successful launch of new type 2 diabetes studies, and negotiations are in underway for PDC participation in pediatric type 1 diabetes and other diabetes-related studies.

Metabolic engineering of Chinese hamster ovary cells towards reduced biosynthesis and accumulation of novel growth inhibitors in fed-batch cultures.

Chinese hamster ovary (CHO) cells in fed-batch cultures are known to consume large amounts of nutrients and divert significant portion of them towards the formation of byproducts, some of which, including lactate and ammonia, are known to be growth inhibitory in nature. A major fraction of these inhibitory metabolites are byproducts or intermediates of amino acid catabolism. Limiting the supply of amino acids has been shown to curtail the production of corresponding inhibitory byproducts resulting in enhanced growth and productivities in CHO cell fed-batch cultures (Mulukutla et al., 2017). In the current study, metabolic engineering of CHO cells was undertaken in order to reduce the biosynthesis of these novel growth inhibitors. Phenylalanine-tyrosine (Phe-Tyr) and branched chain amino acid (BCAA) catabolic pathways were engineered as part of this effort. Four genes that encode enzymes in the Phe-Tyr pathway, which were observed to be minimally expressed in CHO cells, were in turn overexpressed. Metabolically engineered cells were prototrophic to tyrosine and had reduced production of the inhibitory byproducts from Phe-Tyr pathway including 3-phenyllactate and 4-hydroxyphenyllactate. In case of BCAA catabolic pathway, branched chain aminotransferase 1 (BCAT1) gene, which encodes the enzyme that catalyzes the first step in the catabolism of BCAAs, was knocked out in CHO cells. Knockout (KO) of BCAT1 function completely eliminated production of inhibitory byproducts from BCAA catabolic pathway, including isovalerate, isobutyrate and 2-methylbutyrate, resulting in significantly enhanced cell growth and productivities in fed-batch cultures. This study is first of its kind to demonstrate that metabolic engineering of essential amino acid metabolism of CHO cells can significantly improve cell culture process performance.

Cardiorespiratory effects of variable pressure thoracic insufflation in cats undergoing video-assisted thoracic surgery.

OBJECTIVE: To evaluate the effects of intrathoracic insufflation on cardiorespiratory variables and working space in cats undergoing video-assisted thoracic surgery. STUDY DESIGN: Prospective randomized study. ANIMALS: Six healthy cats. METHODS: Cats were anesthetized using a standardized protocol. A Swan-Ganz catheter was positioned in the pulmonary artery under fluoroscopic guidance for measurement of cardiac output. Intrathoracic pressures (ITP) of 0 (baseline), 3, and 5 mm Hg were induced with CO2 and maintained for 30 minutes. Statistical comparison of cardiorespiratory variables was performed. After the procedures, all cats were recovered from anesthesia. Videos of thoracic working space at each ITP level were scored in a blinded fashion by 3 board-certified surgeons using a numerical scale from 0-10. RESULTS: All cats tolerated insufflation with 3 and 5 mm Hg for 30 minutes without oxygen desaturation, although ventilatory levels had to be increased substantially to maintain eucapnia and oxygenation. Cardiac index was not significantly different from baseline after 30 minutes at 3 mm Hg but was significantly lower after 30 minutes at 5 mm Hg compared with 3 mm Hg. Oxygen delivery was unaffected by 3 or 5 mm Hg compared with baseline. Scores for working space increased between baseline and 3 and 5 mm Hg but were not different between 3 and 5 mm Hg. CONCLUSION: CO2 insufflation to 5 mm Hg seems well tolerated in healthy cats, provided ventilatory settings are substantially increased as ITP increases. CLINICAL SIGNIFICANCE: Thoracic CO2 insufflation of 3 mm Hg in cats during video-assisted thoracic surgery is associated with less hemodynamic perturbation than 5 mm Hg insufflation and may provide the benefit of improved working space compared with baseline.

Rational optimization of a monoclonal antibody for simultaneous improvements in its solution properties and biological activity.

Developability considerations should be integrated with lead engineering of antibody drug candidates in interest of their cost effective translations into medicines. To explore feasibility of this imperative, we have performed rational mutagenesis studies on a monoclonal antibody (MAB1) whose development was discontinued owing to manufacturability hurdles. Seven computationally designed variants of MAB1 containing single point (V44K, E59S, E59T and E59Y) and double (V44KE59S, V44KE59T and V44KE59Y) mutations in its light chain were produced in Chinese Hamster Ovary (CHO) cells and purified by using platform processes employed during commercial scale production of monoclonal antibodies. MAB1 and its variants were formulated in the same platform buffer and subjected to a battery of experiments to assess their solution behaviors, and biological activities. Five of the seven (71%) variants of MAB1 demonstrated improved biophysical attributes in multiple experimental testings. Contrary to the commonly expressed reservations about potential biological activity loss upon developability optimizations, the improvements in solution behavior of MAB1 also increased its biological activity up to ~180%. In particular, concentrate-ability and apparent solubility of V44KE59S improved to ~150% and ~160%, respectively. Its diffusion interaction parameter (kD) reduced to 28% and viscosity at ~100 mg/ml decreased to less than half of the corresponding values for MAB1. V44KE59S is also slightly more active and its transfections in CHO cells were more productive. It also degraded slower than MAB1 in three month long 25°C and 40°C formulation stability studies. These results open doors to an exciting realm of structure-based biologic drug design where developability and biological activity can be simultaneously optimized at the molecular engineering stages.

Video-assisted thoracoscopic thoracic duct sealing is inconsistent when performed with a bipolar vessel-sealing device in healthy cats.

OBJECTIVE: To describe a technique for video-assisted thoracoscopic (VATS) thoracic duct ligation (TDL) in normal cats with a bipolar vessel-sealing device and to assess durability of the seal. STUDY DESIGN: Prospective case series. ANIMALS: Six healthy research cats. METHODS: Cats were placed under anesthesia for computed tomography lymphangiography (CTLA) to identify thoracic duct anatomy. On the basis of CTLA findings, cats were positioned in either right or left lateral recumbency for a 3-port VATS TDL. Thoracic duct branches were dissected from the aorta after subcutaneous indirect near-infrared fluorescence (NIRF) lymphography with indocyanine green was performed to optimize detection. A vessel-sealing device was used to seal each thoracic duct in 1 or more locations. Postattenuation, indirect NIRF lymphography was repeated to confirm complete occlusion of thoracic duct flow. CTLA was repeated in all cats 3 months postoperatively. RESULTS: The thoracic duct was surgically approached from the right in 3 cats and from the left in 3 cats. A median of 2.5 (range 1-6) TDL seal sites were applied. In 2 cats, leakage of chyle was detected during dissection. At 3 months postoperatively, CTLA confirmed reestablished chylous flow in 5 of 6 cats, appearing to occur through recanalization of previously sealed sites rather than through development of de novo lymphatic vessels. CONCLUSION: VATS TDL is feasible in cats, although the variable and delicate nature of feline thoracic duct anatomy should be considered preoperatively. CLINICAL SIGNIFICANCE: Bipolar vessel-sealing devices are not a durable modality for thoracic duct sealing in healthy cats in a seal only fashion.

Long-term use of cover crops and no-till shift soil microbial community life strategies in agricultural soil.

Reducing tillage and growing cover crops, widely recommended practices for boosting soil health, have major impacts on soil communities. Surprisingly little is known about their impacts on soil microbial functional diversity, and especially so in irrigated Mediterranean ecosystems. In long-term experimental plots at the West Side Research and Extension Center in California's Central Valley, we characterized soil microbial communities in the presence or absence of physical disturbance due to tillage, in the presence or absence of cover crops, and at three depths: 0-5, 5-15 and 15-30 cm. This characterization included qPCR for bacterial and archaeal abundances, DNA sequencing of the 16S rRNA gene, and phylogenetic estimation of two ecologically important microbial traits (rRNA gene copy number and genome size). Total (bacterial + archaeal) diversity was higher in no-till than standard till; diversity increased with depth in no-till but decreased with depth in standard till. Total bacterial numbers were higher in cover cropped plots at all depths, while no-till treatments showed higher numbers in 0-5 cm but lower numbers at lower depths compared to standard tillage. Trait estimates suggested that different farming practices and depths favored distinctly different microbial life strategies. Tillage in the absence of cover crops shifted microbial communities towards fast growing competitors, while no-till shifted them toward slow growing stress tolerators. Across all treatment combinations, increasing depth resulted in a shift towards stress tolerators. Cover crops shifted the communities towards ruderals-organisms with wider metabolic capacities and moderate rates of growth. Overall, our results are consistent with decreasing nutrient availability with soil depth and under no-till treatments, bursts of nutrient availability and niche homogenization under standard tillage, and increases in C supply and variety provided by cover crops. Understanding how agricultural practices shift microbial abundance, diversity and life strategies, such as presented here, can assist with designing farming systems that can support high yields, while enhancing C sequestration and increasing resilience to climate change.

Nonsurgical correction of straight back syndrome (thoracic hypokyphosis), increased lung capacity and resolution of exertional dyspnea by thoracic hyperkyphosis mirror image® traction: a CBP® case report.

[Purpose] To present the increase in thoracic kyphosis in a patient suffering from exertional dyspnea, reduced lung capacity, and spinal pains related to straight back syndrome (SBS). [Subject and Methods] A 33-year-old male patient was put on a CBP® corrective care program involving mirror image® traction procedures designed to increase the thoracic kyphosis. [Results] This patient had a 10° improvement in thoracic kyphosis in 16-weeks that was maintained 7-months later. There was a simultaneous reduction of pain, resolved exertional dyspnea, and a greater than 2 liter increase in lung capacity. [Conclusion] This case illustrates that nonsurgical improvement in thoracic kyphosis in a patient with SBS is possible and that this may positively influence lung capacity, health and function.

Recruiting a representative sample in adherence research-The MALT multisite prospective cohort study experience.

Medication adherence is an important determinant of transplant outcomes. Attempts to investigate adherence are frequently undermined by selection bias: It is very hard to recruit and retain non-adherent patients in research efforts. This manuscript presents recruitment strategies and results from the MALT (Medication Adherence in children who had a Liver Transplant) multisite prospective cohort study. MALT sites recruited 400 pediatric liver transplant patients who agreed to be followed for 2 years. The primary purpose was to determine whether a marker of adherence, the Medication Level Variability Index (MLVI), predicts rejection outcomes. The present manuscript describes methods used in MALT to ensure that a representative sample was recruited, and presents detailed recruitment results. MALT sites were able to recruit a nationally representative sample, as determined by a comparison between the MALT cohort and a national sample of transplant recipients. Strategies that helped ensure that the sample was representative included monitoring of the outcome measure in comparison with a national sample, drastically limiting patient burden, and specific recruitment methods. We discuss the importance of a representative sample in adherence research and recommend that future efforts to study adherence pay special attention to sample characteristics.

Outcome of laparoscopic adrenalectomy for resection of unilateral noninvasive adrenocortical tumors in 11 cats.

OBJECTIVE: To describe the technique and outcomes of laparoscopic adrenalectomy (LA) in cats with adrenocortical neoplasia. STUDY DESIGN: Retrospective case series. ANIMALS: Eleven client-owned cats with unilateral adrenal tumors. METHODS: Medical records of cats that underwent LA for unilateral functional adrenal tumors at 3 veterinary teaching hospitals were reviewed. Data collected included signalment, clinical signs, physical examination findings, diagnostic imaging results, preoperative laboratory tests, laparoscopic port placement and techniques, duration of anesthesia and surgery, complications, concomitant procedures, need for conversion to an open celiotomy, histopathological diagnosis, and postoperative survival. RESULTS: Eleven cats were included, 5 with right-sided and 6 with left-sided tumors. Tumors were aldosterone-secreting (n = 8), progesterone-secreting (n = 2), or testosterone-secreting (n = 1). Adrenalectomy was successfully performed in all 11 cats although 4 cases required conversion to an open celiotomy, due to poor visualization (n = 2), close adherence of the tumor to the caudal vena cava (n = 1), and inability to maintain adequate pneumoperitoneum (n = 1). Ten of the 11 cats were discharged from the hospital, with a median survival time of 803 days (range 467-1123 days). One cat died from severe pancreatitis and cardiogenic pulmonary edema. CONCLUSION: Adrenalectomy can be performed in cats via laparoscopy but is technically challenging, and associated with a relatively high conversion rate (36%).