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This study aimed to study the public's sentiments on the current monkeypox outbreaks via an unsupervised machine learning analysis of social media posts.This was an exploratory analysis of tweets sentiments.We extracted original tweets containing the terms 'monkeypox', 'monkey pox' or 'monkey_pox' and posted them in the English language from 6 May 2022 (first case detected in the United Kingdom) to 23 July 2022 (when World Health Organization declared Monkeypox to be a global health emergency). Retweets and duplicate tweets were excluded from study. Bidirectional Encoder Representations from Transformers (BERT) Named Entity Recognition. This was followed by topic modelling (specifically BERTopic) and manual thematic analysis by the study team, with independent reviews of the topic labels and themes.Based on topic modelling and thematic analysis of a total of 352,182 Twitter posts, we derived five topics clustered into three major themes related to the public discourse on the ongoing outbreaks. These include concerns of safety, stigmatisation of minority communities, and a general lack of faith in public institutions. The public sentiments underscore growing (and existing) partisanship, personal health worries in relation to the evolving situation, as well as concerns of the media's portrayal of lesbian, gay, bisexual, transgender and queer and minority communities, which might further stigmatise these groups.Monkeypox is an emerging infectious disease of public concern. Our study has highlighted important societal issues, including misinformation, political mistrust and anti-gay stigma that should be sensitively considered when designing public health policies to contain the ongoing outbreaks.

Understanding the unique functions of different subregions of primate prefrontal cortex has been a longstanding goal in cognitive neuroscience. Yet, the anatomy and function of one of its largest subregions (the frontopolar cortex) remain enigmatic and underspecified. Our Society for Neuroscience minisymposiumPrimate Frontopolar Cortex: From Circuits to Complex Behaviorswill comprise a range of new anatomic and functional approaches that have helped to clarify the basic circuit anatomy of the frontal pole, its functional involvement during performance of cognitively demanding behavioral paradigms in monkeys and humans, and its clinical potential as a target for noninvasive brain stimulation in patients with brain disorders. This review consolidates knowledge about the anatomy and connectivity of frontopolar cortex and provides an integrative summary of its function in primates. We aim to answer the question: what, if anything, does frontopolar cortex contribute to goal-directed cognition and action?

Peripheral nerve injury due to animal bite is a rare phenomenon. Most animal bites are from dogs. Monkey bites constitute a common risk, second only to dog bites, among travelers. Peripheral nerve injuries may occur due to a combination of monkey's strong jaws and sharp long teeth penetrating deep into the soft tissues. Such injuries are associated with increased perineural fibrosis. Human amniotic membrane (HAM) wrap around the nerve repair site reduces fibrotic response, prevents adhesions and scar formation thereby improving outcome. We report a case of "High Radial nerve palsy due to monkey bite, treated by neurorrhaphy with HAM wrap".A 3-year old boy presented with wrist drop, and inability to extend the fingers and thumb of his right dominant hand, following a monkey bite over the distal arm. The diagnosis of high radial nerve injury was corroborated by high frequency ultrasound and electrodiagnostic studies. On exploration the radial nerve was found to be transected. An end to end repair was performed, with HAM wrap around the neurorrhaphy.Wrist dorsiflexion recovered at 2.5 months followed by active finger and thumb extension at 4 months with no infection or immune rejection.Nerve regeneration in our patient occurred at a faster rate as compared to the conventional 1 mm/day. This could be attributed to decreased perineural fibrosis, improved neurotropism due to the HAM wrap and neuronal plasticity in young brain in addition, the patient being a small child having better regenerative ability in comparison to an adult.

Inhibition of tissue-nonspecific alkaline phosphatase (TNAP) may prevent ectopic soft tissue calcification by increasing endogenous pyrophosphate (PPi). DS-1211 is a potent and selective novel small molecule TNAP inhibitor with well-characterized pharmacokinetics (PKs) in rodent and monkey. Herein, we report a comprehensive summary of studies establishing the pharmaceutical profile of DS-1211. In vitro studies characterized the mode of inhibition and inhibitory effects of DS-1211 on three human alkaline phosphatase (ALP) isozymes-TNAP, human intestinal ALP, human placental ALP-and on ALP activity across species in mouse, monkey, and human plasma. In vivo PK and pharmacodynamic (PD) effects of a single oral dose of DS-1211 in mice and monkeys were evaluated, including biomarker changes in PPi and pyridoxal 5'-phosphate (PLP). Oral bioavailability (BA) was determined through administration of DS-1211 at a 0.3-mg/kg dose in monkeys. In vitro experiments demonstrated DS-1211 inhibited ALP activity through an uncompetitive mode of action. DS-1211 exhibited TNAP selectivity and potent inhibition of TNAP across species. In vivo studies in mice and monkeys after single oral administration of DS-1211 showed linear PKs, with dose-dependent inhibition of ALP activity and increases in plasma PPi and PLP. Inhibitory effects of DS-1211 were consistent in both mouse and monkey. Mean absolute oral BA was 73.9%. Overall, in vitro and in vivo studies showed DS-1211 is a potent and selective TNAP inhibitor across species. Further in vivo pharmacology studies in ectopic calcification animal models and clinical investigations of DS-1211 in patient populations are warranted. © 2022 Daiichi Sankyo, Inc. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Within the last decade, a large number of viruses genetically related to human hepatitis viruses have been identified in different animal species, including monkeys. Numerous viruses related to human hepatitis A virus (HAV, Picornaviridae: Hepatovirus: Hepatovirus A) were detected in various mammalian species in 20152018, predominantly in bats and rodents, but also in shrews, seals and marsupials. Zoonotic hepatitis E virus (HEV, Hepeviridae: Orthohepevirus: Orthohepevirus A) genotypes have been found in wild boars, deer, camels, and rabbits, as well as in non human primates. In addition, viruses that are genetically close to HEV have been described in bats, ferrets, rodents, birds, and fish. Nevertheless, monkeys remain important laboratory animals in HAV and HEV research. The study of spontaneous and experimental infection in these animals is an invaluable source of information about the biology and pathogenesis of these viruses and continues to be an indispensable tool for vaccine and drug testing. The purpose of this literature review was to summarize and analyze published data on the circulation of HAV and HEV among wild and captive primates, as well as the results of experimental studies of HAV and HEV infections in monkeys.

Small sensory spinal injuries induce plasticity across the neuraxis, but little is understood about their effect on segmental connections or motor neuron (MN) function. Here, we begin to address this at two levels. First, we compared afferent input distributions from the skin and muscles of the digits with corresponding MN pools to determine their spatial relationship, in both the normal state and 4-6 months after a unilateral dorsal root/dorsal column lesion (DRL/DCL), affecting digits 1-3. Second, we looked at specific changes to MN inputs and membrane properties that likely impact functional recovery. Monkeys received a targeted unilateral DRL/DCL, and 4-6 months later, cholera toxin subunit B (CT-B) was injected bilaterally into either the distal pads of digits 1-3, or related intrinsic hand muscles, to label inputs to the cord, and corresponding MNs. In controls (unlesioned side), cutaneous and proprioceptive afferents from digits 1-3 showed different distribution patterns but similar rostrocaudal spread within the dorsal horn from C1 to T2. In contrast, MNs were distributed across just two segments (C7-8). Following the lesion, sensory inputs were significantly diminished across all 10 segments, though this did not alter MN distributions. Afferent and monoamine inputs, as well as KCC2 cotransporters, were also significantly altered on the cell membrane of CT-B labeled MNs postlesion. In contrast, inhibitory neurotransmission and perineuronal net integrity were not altered at this prechronic timepoint. Our findings indicate that even a small sensory injury can significantly impact sensory and motor spinal neurons and provide new insight into the complex process of recovery.

Prediction of rat, dog, monkey, and human volume of distribution (VD

Predicting human pharmacokinetics (PK) during the drug discovery phase is valuable to assess doses required to reach therapeutic exposures. For orally administered compounds, however, this can be especially difficult, since the absorption process is complex. Vismodegib is a compound with unique nonlinear oral PK characteristics in humans. Oral physiologically based pharmacokinetic (PBPK) models were built using preclinical in vitro and in vivo data and successfully predicted the oral PK profiles in rats, dogs, and monkeys. Simulated drug exposures (area under the concentration-time curve from time 0 to infinity and C

We studied changes in the expression of growth-associated protein 43 (GAP43), glial fibrillary acidic protein (GFAP), and calcium-binding proteins (calbindin [Cb] and parvalbumin [Pv]) in the dorsal lateral geniculate nucleus (dLGN) of four capuchin monkeys with laser-induced retinal lesions. The lesions were generated with the aid of a neodymium-YAG dual-frequency laser with shots of different intensity and at different survival time in each animal. The expression of these proteins in the layers of the dLGN was evaluated by performing histodensitometry of coronal sections throughout the nucleus. High-power laser shots administered at the border of the optic disc (OD)-injured fibers resulted in large scotomas. These lesions produced a devastating effect on fibers in this passage, resulting in large deafferentation of the dLGN. The time course of plasticity expressed in this nucleus varied with the degree of the retinal lesion. Topographically, corresponding portions of the dLGN were inferred by the extent of the ocular dominance column revealed by cytochrome oxidase histochemistry in flattened preparations of V1. In the region representing the retinal lesion, the expression of GFAP, GAP43, Pv, and Cb increased and decreased in the corresponding dLGN layers shortly after lesion induction and returned to their original values with different time courses. Synaptogenesis (indicated by GAP43 expression) appeared to be increased in all layers, while "cleansing" of the glial-damaged region (indicated by GFAP expression) was markedly greater in the parvocellular layers, followed by the magnocellular layers. Schematic drawings of optic discs laser lesions and of series of coronal sections of the dLGN, in three monkeys, depicting the areas of the nucleus deafferented by the lesions.

In the present investigation, we examined the role of different cortical fields in the fronto-parietal reaching and grasping network in awake, behaving macaque monkeys. This network is greatly expanded in primates compared to other mammals and coevolved with glabrous hands with opposable thumbs and the extraordinary dexterous behaviors employed by a number of primates, including humans. To examine this, we reversibly deactivated the primary motor area (M1), anterior parietal area 2, and posterior parietal areas 5L and 7b individually while monkeys were performing two types of reaching and grasping tasks. Reversible deactivation was accomplished with small microfluidic thermal regulators abutting specifically targeted cortical areas. Placement of these devices in the different cortical fields was confirmed post hoc in histologically processed tissue. Our results indicate that the different areas examined form a complex network of motor control that is overlapping. However, several consistent themes emerged that suggest the independent roles that motor cortex, area 2, area 7b, and area 5L play in the motor planning and execution of reaching and grasping movements. Area 5L is involved in the early stages and area 7b the later stages of a reaching and grasping movement, motor cortex is involved in all aspects of the execution of the movement, and area 2 provides proprioceptive feedback throughout the movement. We discuss our results in the context of previous studies that explored the fronto-parietal network, the overlapping (but also independent) functions of different nodes of this network, and the rapid compensatory plasticity of this network. NEW & NOTEWORTHY This is the first study to directly compare the results of cooling different portions of the fronto-parietal reaching and grasping network (motor cortex, anterior and posterior parietal cortex) in the same animals and the first to employ a complex, bimanual reaching and grasping task that is ethologically relevant. Whereas cooling area 7b or area 5L evoked deficits at distinct task phases, cooling M1 evoked a general set of deficits and cooling area 2 evoked proprioceptive deficits.

An enduring question in the study of human evolution is why tool use evolved. A new study has found that stone tools improve diet quality in wild capuchin monkeys. Tools may have similarly increased the nutritional security in ancestral hominins.

The use of anaesthesia is a fundamental tool in the investigation of consciousness. Anesthesia procedures allow to investigate different states of consciousness from sedation to deep anesthesia within controlled scenarios. In this study we use information quantifiers to measure the complexity of electrocorticogram recordings in monkeys. We apply these metrics to compare different stages of general anesthesia for evaluating consciousness in several anesthesia protocols. We find that the complexity of brain activity can be used as a correlate of consciousness. For two of the anaesthetics used, propofol and medetomidine, we find that the anaesthetised state is accompanied by a reduction in the complexity of brain activity. On the other hand we observe that use of ketamine produces an increase in complexity measurements. We relate this observation with increase activity within certain brain regions associated with the ketamine used doses. Our measurements indicate that complexity of brain activity is a good indicator for a general evaluation of different levels of consciousness awareness, both in anesthetized and non anesthetizes states.

A hallmark of human evolution resides in the ability to adapt our actions to those of others. This aptitude optimizes collective behavior, allowing to achieve goals unattainable by acting alone. We have previously shown that macaque monkeys are able to coordinate their actions when engaged in dyadic contexts, therefore they offer a good model to study the roots of joint action. Here, we analyze the behavior of five macaques required to perform visuomotor isometric tasks, either individually or together with a partner. By pre-cueing or not the future action condition (SOLO or TOGETHER) we investigated the existence of a 'We-representation' in monkeys. We found that pre-instructing the action context improves the dyadic performance, thanks to the emergence of an optimal kinematic setting, that facilitates inter-individual motor coordination. Our results offer empirical evidence of a 'We-representation' in macaques, that when evoked provides an overall beneficial effect on joint performance.

Neuronal spiking was sampled from the frontal eye field (FEF) and from the rostral part of area 6 that reaches to the superior limb of the arcuate sulcus, dorsal to the arcuate spur when present (F2vr) in macaque monkeys performing memory-guided saccades and visually guided saccades for visual search. Neuronal spiking modulation in F2vr resembled that in FEF in many but not all respects. A new consensus clustering algorithm of neuronal modulation patterns revealed that F2vr and FEF contain a greater variety of modulation patterns than previously reported. The areas differ in the proportions of visuomotor neuron types, the proportions of neurons discriminating a target from distractors during visual search, and the consistency of modulation patterns across tasks. However, between F2vr and FEF we found no difference in the magnitude of delay period activity, the timing of the peak discharge rate relative to saccades, or the time of search target selection. The observed similarities and differences between the 2 cortical regions contribute to other work establishing the organization of eye fields in the frontal lobe and may help explain why FEF in monkeys is identified within granular prefrontal area 8 but in humans is identified within agranular premotor area 6.

Motivation boosts motor performance. Activity of the ventral midbrain (VM), consisting of the ventral tegmental area (VTA), the substantia nigra pars compacta (SNc) and the retrorubral field (RRF), plays an important role in processing motivation. However, little is known about the neural substrate bridging the VM and the spinal motor output. We hypothesized that the VM might exert a modulatory influence over the descending motor pathways. By retrograde transneuronal labelling with rabies virus, we demonstrated the existence of multisynaptic projections from the VM to the cervical enlargement in monkeys. The distribution pattern of spinal projection neurons in the VM exhibited a caudorostral gradient, in that the RRF and the caudal part of the SNc contained more retrogradely labelled neurons than the VTA and the rostral part of the SNc. Electrical stimulation of the VM induced muscle responses in the contralateral forelimb with a delay of a few milliseconds following the responses of the ipsilateral primary motor cortex (M1). The magnitude and number of evoked muscle responses were associated with the stimulus intensity and number of pulses. The muscle responses were diminished during M1 inactivation. Thus, the present study has identified a multisynaptic VM-spinal pathway that is mediated, at least in part, by the M1 and might play a pivotal role in modulatory control of the spinal motor output. KEY POINTS: Motivation to obtain reward is thought to boost motor performance, and activity in the ventral midbrain is important to the motivational process. Little is known about a neural substrate bridging the ventral midbrain and the spinal motor output. Retrograde trans-synaptic experiments revealed that the ventral midbrain projects multisynaptically to the spinal cord in macaque monkeys. Ventral midbrain activation by electrical stimulation generated cortical activity in the motor cortex and forelimb muscle activity. A multisynaptic ventral midbrain-spinal pathway most probably plays a pivotal role in modulatory control of the spinal motor output.

The temporomandibular joint is the direct interface between the mandible and the cranium and is critical for transmitting joint reaction forces and determining mandibular range of motion. As a consequence, understanding variation in the morphology of this joint and how it relates to other aspects of craniofacial form is important for better understanding masticatory function. Here, we present a detailed three-dimensional (3D) geometric morphometric analysis of the cranial component of this joint, the glenoid fossa, across a sample of 17 anthropoid primates, and we evaluate covariation between the glenoid and the cranium and mandible. We find high levels of intraspecific variation in glenoid shape that is likely linked to sexual dimorphism and joint remodeling, and we identify differences in mean glenoid shape across taxonomic groups and in relation to size. Analyses of covariation reveal strong relationships between glenoid shape and a variety of aspects of cranial and mandibular form. Our findings suggest that intraspecific variation in glenoid shape in primates could further be reflective of high levels of functional flexibility in the masticatory apparatus, as has also been suggested for primate jaw kinematics and muscle activation patterns. Conversely, interspecific differences likely reflect larger scale differences between species in body size and/or masticatory function. Results of the covariation analyses dovetail with those examining covariation in the cranium of canids and may be indicative of larger patterns across mammals.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3C-like protease inhibitor PF-07321332 (nirmatrelvir), in combination with ritonavir (Paxlovid), was recently granted emergency use authorization by multiple regulatory agencies for the treatment of coronavirus disease 2019 (COVID-19) in adults and pediatric patients. Disposition studies on nirmatrelvir in animals and in human reagents, which were used to support clinical studies, are described herein. Plasma clearance was moderate in rats (27.2 ml/min per kg) and monkeys (17.1 ml/min per kg), resulting in half-lives of 5.1 and 0.8 hours, respectively. The corresponding oral bioavailability was moderate in rats (34%-50%) and low in monkeys (8.5%), primarily due to oxidative metabolism along the gastrointestinal tract in this species. Nirmatrelvir demonstrated moderate plasma protein binding in rats, monkeys, and humans with mean unbound fractions ranging from 0.310 to 0.478. The metabolism of nirmatrelvir was qualitatively similar in liver microsomes and hepatocytes from rats, monkeys, and humans; prominent metabolites arose via cytochrome P450 (CYP450)-mediated oxidations on the P1 pyrrolidinone ring, P2 6,6-dimethyl-3-azabicyclo[3.1.0]hexane, and the tertiary-butyl group at the P3 position. Reaction phenotyping studies in human liver microsomes revealed that CYP3A4 was primarily responsible (fraction metabolized = 0.99) for the oxidative metabolism of nirmatrelvir. Minor clearance mechanisms involving renal and biliary excretion of unchanged nirmatrelvir were also noted in animals and in sandwich-cultured human hepatocytes. Nirmatrelvir was a reversible and time-dependent inhibitor as well as inducer of CYP3A activity in vitro. First-in-human pharmacokinetic studies have demonstrated a considerable boost in the oral systemic exposure of nirmatrelvir upon coadministration with the CYP3A4 inhibitor ritonavir, consistent with the predominant role of CYP3A4 in nirmatrelvir metabolism. SIGNIFICANCE STATEMENT: The manuscript describes the preclinical disposition, metabolism, and drug-drug interaction potential of PF-07321332 (nirmatrelvir), an orally active peptidomimetic-based inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3CL protease, which has been granted emergency use authorization by multiple regulatory agencies around the globe for the treatment of coronavirus disease 2019 (COVID-19) in COVID-19-positive adults and pediatric patients who are at high risk for progression to severe COVID-19, including hospitalization or death.

The nonclinical safety profile of GS-8873, a hepatitis B virus RNA transcript inhibitor was evaluated in rat and monkey 13-week toxicity studies with 8-week recovery phases. Vehicle or GS-8873 was dosed orally for 13 weeks at 2, 6, 20, and 60 mg/kg/day to Wistar Han rats and at 0.5, 1.5, 3, and 6 mg/kg/day to cynomolgus monkeys. In vitro and in vivo screening results from an analog discovered prior to GS-8873 informed the 13-week toxicology study designs. Neuroelectrophysiology and neurobehavioral evaluations were included at weeks 4 and 13 of the dosing and recovery phases for GS-8873. No adverse neurobehavioral effects were observed. Significant nerve conduction velocity (NCV) decreases and latency increases occurred at the high doses after 4 weeks of dosing. By week 13, dose-responsive NCV reductions and latency increases worsened across all dose groups compared with controls. Some reversal occurred 8 weeks after the last dose administered, but not to vehicle control levels. A minimal, axonal degeneration was observed in rat spinal and peripheral nerves across dose groups compared with controls. No monkey nervous system microscopic findings were observed. No-observed-adverse-effect-levels could not be determined for either species due to the neuroelectrophysiology findings and development was halted in the interest of safety. A retrospective risk assessment approach utilizing benchmark dose (BMD) modeling contributed 13-week NCV BMDL estimates (lower limits of the 95% confidence interval) in lieu of no-observed-adverse-effect-levels. The best-fitted models extrapolated NCV BMDLs for the rat caudal and monkey sural nerve at 0.3 and 0.1 mg/kg/day, respectively.

In this manuscript, we present a translational physiologically-based pharmacokinetic (PBPK) model to characterize receptor-mediated transcytosis (RMT) of anti-transferrin receptor (TfR) monoclonal antibodies (mAbs) in the central nervous system (CNS). The model accounts for the state-of-the-art knowledge of the brain's anatomy and physiology, and physiological parameters were fixed according to different species. By estimating a few parameters associated with the TfR concentration, the TfR turnover, and the internalization rate, the model simultaneously characterizes plasma, whole brain, interstitial fluid (ISF), and cerebrospinal fluid (CSF) PK of unbound and bound anti-TfR mAbs with different binding affinities in mice, rats, and monkeys obtained from various literature sources within a threefold prediction error. The final PBPK model was validated using external anti-TfR mAb PK data in mice and monkeys with different affinities and doses. The simulation reasonably predicted plasma and brain PK of monovalent/bivalent anti-TfR mAbs within a threefold prediction error and characterized a bell-shaped relationship between the brain ISF/plasma AUC ratio and the K

In Japan, hepatitis E virus (HEV) causes hepatitis in humans through the consumption of raw or undercooked meat, including game meat. In the present study, nationwide surveillance of HEV infection among a total of 5,557 wild animals, including 15 species, was conducted in Japan. The prevalence of anti-HEV antibodies in wild boar was 12.4%, with higher positive rates in big boars (over 50 kg, 18.4%) than in small individuals (less than 30 kg, 5.3%). Furthermore, HEV RNA was more frequently detected in piglets than in older boars. Interestingly, the detection of HEV among wildlife by ELISA and RT-PCR suggested that HEV infection in Sika deer was a very rare event, and that there was no HEV infection among wild animals except for wild boar, Sika deer and Japanese monkeys. In conclusion, wild boar, especially piglets, are at high risk of HEV infection, while other wild animals showed less risk or no risk of HEV transmission.

Blood feeding and host-seeking behaviors of a mosquito play an imperative role in determining its vectorial capacity in transmitting pathogens. Unfortunately, limited information is available regarding blood feeding behavior of Anopheles species in Malaysia. Collection of resting Anopheles mosquitoes for blood meal analysis poses a great challenge especially for forest dwelling mosquitoes. Therefore, a laboratory-based study was conducted to evaluate the potential use of mosquitoes caught using human landing catch (HLC) for blood meal analysis, and subsequently to document blood feeding behavior of local Anopheles mosquitoes in Peninsular Malaysia. The laboratory-based experiment from this study revealed that mosquitoes caught using HLC had the potential to be used for blood meal analysis. Besides HLC, mosquitoes were also collected using manual aspirator and Mosquito Magnet. Overall, 47.4% of 321 field-caught Anopheles mosquitoes belonging to six species were positive for vertebrate host DNA in their blood meal. The most frequent blood meal source was human (45.9%) followed by wild boar (27.4%), dog (15.3%) and monkey (7.5%). Interestingly, only Anopheles cracens and Anopheles introlatus (Leucosphyrus Group) fed on monkey. This study further confirmed that members of the Leucosphyrus Group are the predominant vectors for knowlesi malaria transmission in Peninsular Malaysia mainly due to their simio-anthropophagic feeding behavior.

The basis for rotavirus (RV) host range restriction (HRR) is not fully understood but is likely multigenic. RV genes encoding VP3, VP4, NSP1, NSP2, NSP3, and NSP4 have been associated with HRR in various studies. With the exception of NSP1, little is known about the relative contribution of the other RV genes to HRR. VP4 has been linked to HRR because it functions as the RV cell attachment protein, but its actual role in HRR has not been fully assessed. We generated a collection of recombinant RVs (rRVs) in an isogenic murine-like RV genetic background, harboring either heterologous or homologous VP4 genes from simian, bovine, porcine, human, and murine RV strains, and characterized these rRVs in vitro and in vivo. We found that a murine-like rRV encoding a simian VP4 was shed, spread to uninoculated littermates, and induced diarrhea comparably to rRV harboring a murine VP4. However, rRVs carrying VP4s from both bovine and porcine RVs had reduced diarrhea, but no change in fecal shedding was observed. Both diarrhea and shedding were reduced when VP4 originated from a human RV strain. rRVs harboring VP4s from human or bovine RVs did not transmit to uninoculated littermates. We also generated two rRVs harboring reciprocal chimeric murine or bovine VP4. Both chimeras replicated and caused disease as efficiently as the parental strain with a fully murine VP4. These data suggest that the genetic origin of VP4 partially modulates HRR in the suckling mouse and that both the VP8* and VP5* domains independently contribute to pathogenesis and transmission. IMPORTANCE Human group A rotaviruses (RVs) remain the most important cause of severe acute gastroenteritis among infants and young children worldwide despite the introduction of several safe and effective live attenuated vaccines. The lack of knowledge regarding fundamental aspects of RV biology, such as the genetic basis of host range restriction (HRR), has made it difficult to predictively and efficiently design improved, next-generation live attenuated rotavirus vaccines. Here, we engineered a collection of VP4 monoreassortant RVs to systematically explore the role of VP4 in replication, pathogenicity, and spread, as measures of HRR, in a suckling mouse model. The genetic and mechanistic bases of HRR have substantial clinical relevance given that this restriction forms the basis of attenuation for several replication-competent human RV vaccines. In addition, a better understanding of RV pathogenesis and the determinants of RV spread is likely to enhance our ability to improve antiviral drug and therapy development.

In primates, neurons giving rise to the corticospinal tract (CST) are distributed in several motor-related areas of the frontal lobe, such as the primary motor cortex (M1), the supplementary motor area (SMA), and the dorsal and ventral divisions of the premotor cortex (PMd, PMv). Recently, we have analyzed the morphology of basal dendrites of CST neurons, i.e., large layer V pyramidal neurons in macaque monkeys and shown that the complexity and spine density of the dendrites vary across the motor-related areas. Here, we investigated the alterations in basal dendrite morphology of CST neurons after spinal cord injury (SCI). In our SCI model, both the intersection number and the spine density of basal dendrites were highly decreased throughout the motor-related areas. Notably, these events were less prominent for the PMd than for the M1, SMA, and PMv. When we further compared the density changes post-SCI of the filopodia-, thin-, stubby-, and mushroom-type spines in individual areas, it was found that the density of filopodia-type (immature) spines was increased for all the areas, whereas the other types of spines exhibited their density reductions. Again, such spine density reductions were so limited for the PMd as compared to the M1, SMA, and PMv.

The cytoplasmic accumulation and aggregates of TARDBP/TDP-43 (TAR DNA binding protein) are a pathological hallmark in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. We previously reported that the primate specific cleavage of TARDBP accounts for its cytoplasmic mislocalization in the primate brains, prompting us to further investigate how the cytoplasmic TARDBP mediates neuropathology. Here we reported that cytoplasmic mutant TARDBP reduced SQSTM1 expression selectively in the monkey brain, when compared with the mouse brain, by inducing SQSTM1 mRNA instability via its binding to the unique 3ʹUTR sequence (GU/UG)n of the primate SQSTM1 transcript. Overexpression of SQSTM1 could diminish the cytoplasmic C-terminal TARDBP accumulation in the monkey brain by augmenting macroautophagy/autophagy activity. Our findings provide additional clues for the pathogenesis of cytoplasmic TARDBP and a potential therapy for mutant TARDBP-mediated neuropathology.

Praziquantel is the only available drug to treat schistosomiasis, a parasitic disease that currently infects more than 240 million people globally. Due to increasing concerns about resistance and inadequate efficacy there is a need for new therapeutics. In this study, a series of 17 pyrazolines (15–31) and three pyrazoles (32–34) were synthesized and evaluated for their antiparasitic properties against ex vivo adult Schistosoma mansoni worms. Of the 20 compounds tested, six had a 50% effective concentration (EC50) below 30 μM. Our best hit, pyrazoline 22, showed promising activity against adult schistosomes, with an EC50 22 had low cytotoxicity, with selectivity index of 21.6 and 32.2 for monkey and human cell lines, respectively. All active pyrazolines demonstrated a negative effect on schistosome fecundity, with a marked reduction in the number of eggs. Structure–activity relationship analysis showed that the presence of the non-aromatic heterocycle and N-substitution are fundamental to the antischistosomal properties. Pharmacokinetics, drug-likeness and medicinal chemistry friendliness studies were performed, and predicted values demonstrated an excellent drug-likeness profile for pyrazolines as well as an adherence to major pharmaceutical companies’ filters. Collectively, this study demonstrates that pyrazoline derivatives are promising scaffolds in the discovery of novel antischistosomal agents.

Studies of sensory-evoked neuronal responses often focus on mean spike rates, with fluctuations treated as internally-generated noise. However, fluctuations of spontaneous activity, often organized as traveling waves, shape stimulus-evoked responses and perceptual sensitivity. The mechanisms underlying these waves are unknown. Further, it is unclear whether waves are consistent with the low rate and weakly correlated “asynchronous-irregular” dynamics observed in cortical recordings. Here, we describe a large-scale computational model with topographically-organized connectivity and conduction delays relevant to biological scales. We find that spontaneous traveling waves are a general property of these networks. The traveling waves that occur in the model are sparse, with only a small fraction of neurons participating in any individual wave. Consequently, they do not induce measurable spike correlations and remain consistent with locally asynchronous irregular states. Further, by modulating local network state, they can shape responses to incoming inputs as observed in vivo., Spontaneous traveling cortical waves shape neural responses. Using a large-scale computational model, the authors show that transmission delays shape locally asynchronous spiking dynamics into traveling waves without inducing correlations and boost responses to external input, as observed in vivo.

Type I interferon is promising in treating different kinds of tumors, but has been limited by its toxicity, lack of tumor targeting, and very short half-life. To target tumors, reduce systemic toxicity, and increase half-life, here we engineer a masked type I IFN-Fc (ProIFN) with its natural receptor connected by a cleavable linker that can be targeted by tumor-associated proteases. ProIFN has a prolonged serum half-life and shows an improved tumor-targeting effect. Interestingly, ProIFN-treated mice show enhanced DC cross-priming and significant increased CD8+ infiltration and effector function in the tumor microenvironment. ProIFN is able to improve checkpoint blockade efficacy in established tumors, as well as radiation efficacy for both primary and metastatic tumors. ProIFN exhibits superior long-term pharmacokinetics with minimal toxicity in monkeys. Therefore, this study demonstrates an effective tumor-activating IFN that can increase targeted immunity against primary tumor or metastasis and reduce periphery toxicity to the host., Several studies have demonstrated that IFN-I administration can boost anti-tumor immune response against solid tumors. Here, to overcome the limitations of systemic IFN-I therapy (side effects, short half-life), the authors design a masked IFN-I prodrug activatable by tumor-associated proteases, showing preserved anti-tumor activity but reduced toxicity.

Monoacylglycerol lipase (MAGL) is a 33 kDa serine protease primarily responsible for hydrolyzing 2-arachidonoylglycerol into the proinflammatory eicosanoid precursor arachidonic acid in the central nervous system. Inhibition of MAGL constitutes an attractive therapeutic concept for treating psychiatric disorders and neurodegenerative diseases. Herein, we present the design and synthesis of multiple reversible MAGL inhibitor candidates based on a piperazinyl azetidine scaffold. Compounds 10 and 15 were identified as the best-performing reversible MAGL inhibitors by pharmacological evaluations, thus channeling their radiolabeling with fluorine-18 in high radiochemical yields and favorable molar activity. Furthermore, evaluation of [18F]10 and [18F]15 ([18F]MAGL-2102) by autoradiography and positron emission tomography (PET) imaging in rodents and nonhuman primates demonstrated favorable brain uptakes, heterogeneous radioactivity distribution, good specific binding, and adequate brain kinetics, and [18F]15 demonstrated a better performance. In conclusion, [18F]15 was found to be a suitable PET radioligand for the visualization of MAGL, harboring potential for the successful translation into humans.

Background & Aims HEV is a significant cause of acute hepatitis globally. Some genotypes establish persistent infection when immunity is impaired. Adaptive immune mechanisms that mediate resolution of infection have not been identified. Herein, the requirement for CD8+ T cells to control HEV infection was assessed in rhesus macaques, a model of acute and persistent HEV infection in humans. Methods Rhesus macaques were untreated or treated with depleting anti-CD8α monoclonal antibodies before challenge with an HEV genotype (gt)3 isolate derived from a chronically infected human patient. HEV replication, alanine aminotransferase, anti-capsid antibody and HEV-specific CD4+ and CD8+ T cell responses were assessed after infection. Results HEV control in untreated macaques coincided with the onset of a neutralizing IgG response against the ORF2 capsid and liver infiltration of functional HEV-specific CD4+ and CD8+ T cells. Virus control was delayed by 1 week in CD8+ T cell-depleted macaques. Infection resolved with onset of a neutralizing IgG antibody response and a much more robust expansion of CD4+ T cells with antiviral effector function. Conclusions Liver infiltration of functional CD8+ T cells coincident with HEV clearance in untreated rhesus macaques, and a 1-week delay in HEV clearance in CD8+ T cell-depleted rhesus macaques, support a role for this subset in timely control of virus replication. Resolution of infection in the absence of CD8+ T cells nonetheless indicates that neutralizing antibodies and/or CD4+ T cells may act autonomously to inhibit HEV replication. HEV susceptibility to multiple adaptive effector mechanisms may explain why persistence occurs only with generalized immune suppression. The findings also suggest that neutralizing antibodies and/or CD4+ T cells should be considered as a component of immunotherapy for chronic infection. Lay summary The hepatitis E virus (HEV) is a major cause of liver disease globally. Some genetic types (genotypes) of HEV persist in the body if immunity is impaired. Our objective was to identify immune responses that promote clearance of HEV. Findings indicate that HEV may be susceptible to multiple arms of the immune response that can act independently to terminate infection. They also provide a pathway to assess immune therapies for chronic HEV infection.

Summary Here, we evaluate the efficacy of cryopreserved human embryonic stem cell (hESC)-derived corneal endothelial cells (CECs) to form a functional monolayer of corneal endothelium (CE) in rabbits and monkeys. We injected cryopreserved hESC-derived CECs into the anterior chamber of rabbits and monkeys either immediately after mechanical scraping of the central CE or a few days later when corneal edema developed. All preclinical models developed deturgesced and clear corneas following the injection of cryopreserved hESC-derived CECs and remained comparable to the corneas of the untreated eye. Confocal scanning microscopy confirmed an intact structure of hexagonal/polygonal cells and immunohistochemical analysis illustrated a monolayer expressing barrier and pump function proteins in the regenerated CE. The necropsy examination confirmed no remarkable change in multiple tissues assessed for teratoma formation. In conclusion, our data demonstrate the efficacy of cryopreserved hESC-derived CECs to form a functional CE on the denuded Descemet's membrane., Highlights • RNA-Seq confirmed similar transcriptomes of non-cryopreserved and cryopreserved hESC-derived CECs. • All preclinical models developed clear corneas following the injection of cryopreserved hESC-derived CECs. • The transparency of the regenerated corneas remained comparable to the corneas of the untreated eye. • Necropsy examination confirmed no remarkable change and/or teratoma formation in all preclinical models., In this article, Ali and colleagues show that intracameral injection of cryopreserved hESC-derived CECs can form a functional CE in rabbits and monkeys.

Aims: Preclinical comparative similarity studies of trastuzumab-dkst, a Herceptin® biosimilar, are reported. Materials & methods: Primary sequence and higher order structure and pharmacological mechanisms of action were compared using multiple techniques. Pharmacokinetics and repeat-dose toxicity were assessed in cynomolgus monkeys. Results: Primary structures were identical; secondary and tertiary structures were highly similar. Non-significant differences were observed for charge heterogeneity. Twelve of 13 glycan species were highly similar, with slightly higher total mannose levels in trastuzumab-dkst. FcγR and FcRn binding activity was highly similar. Each drug equally inhibited HER2+ cell proliferation, demonstrating equivalent relative potency in mediating HER2+ cell cytolysis by antibody-dependent cellular cytotoxicity. Pharmacokinetic and toxicological profiles in cynomolgus monkeys were similar. Conclusion: Trastuzumab-dkst, US-licensed trastuzumab and EU-approved trastuzumab demonstrate high structural and functional similarity.

Human Adenovirus 36 (HAdV-36) has been related to diverse effects on metabolism and may attenuate the lipid accumulation in kidneys with increased adiposity. Some of these effects would be related to viral persistence. However, until now, a model of persistent in vitro infection by HAdV-36 is unknown. In this study, we examined the cells of the Vero lineage to explore their permissiveness to long-term HAdV-36 infection. HAdV-36 was productively replicated in Vero cells and maintained long-term infection for up to 35 cell passages. A subculture was obtained from the cells that survived the primary infection at a low MOI (0.5). The production of the extracellular infectious virus with titers ranging from 104 to 106 TCID50/mL and DNA-bearing cells was detected. In long-term infected cells, the intracellular distribution of viral antigen was demonstrated by performing immunolocalization (IFI) and expression of cell-viral antigen in 50% of cells by flow cytometry, using anti-HAdV-36 hyperimmune rabbit serum. Furthermore, E1a and E4orf1 genes in long-term infected passages showed a decreasing trend. Our preliminary results reveal that renal epithelial monkey cells are permissive for the productive infection of HAdV-36. Vero cell culture long-term infection might be a promising model for addressing the fundamental aspects of the HAdV-36 biology that cannot reveal broadly-used cultures, which do not maintain long-term infection in primary or transformed cells.

The simian parasite Plasmodium knowlesi is the predominant species causing human malaria infection, including hospitalisations for severe disease and death, in Malaysian Borneo. By contrast, there have been only a few case reports of knowlesi malaria from Indonesian Borneo. This situation seems paradoxical since both regions share the same natural macaque hosts and Anopheles mosquito vectors, and therefore have a similar epidemiologically estimated risk of infection. To determine whether there is a true cross-border disparity in P. knowlesi prevalence, we conducted a community-based malaria screening study using PCR in Kapuas Hulu District, West Kalimantan. Blood samples were taken between April and September 2019 from 1000 people aged 6 months to 85 years attending health care facilities at 27 study sites within or close to jungle areas. There were 16 Plasmodium positive samples by PCR, five human malarias (two Plasmodium vivax, two Plasmodium ovale and one Plasmodium malariae) and 11 in which no species could be definitively identified. These data suggest that, if present, simian malarias including P. knowlesi are rare in the Kapuas Hulu District of West Kalimantan, Indonesian Borneo compared to geographically adjacent areas of Malaysian Borneo. The reason for this discrepancy, if confirmed in other epidemiologically similar regions of Indonesian Borneo, warrants further studies targeting possible cross-border differences in human activities in forested areas, together with more detailed surveys to complement the limited data relating to monkey hosts and Anopheles mosquito vectors in Indonesian Borneo.

Drug-induced liver injury (DILI) is a leading cause of candidate attrition during drug development in the pharmaceutical industry. This study evaluated liver toxicity signals for 249 approved drugs (114 of "most-DILI concern" and 135 of "no-DILI concern") using PharmaPendium and assessed the association between nonclinical and clinical injuries using contingency table analysis. All animal liver findings were combined into eight toxicity categories based on nature and severity. Together, these analyses revealed that cholestasis [odds ratio (OR): 5.02; 95% confidence interval (CI) 1.04-24.03] or liver aminotransferase increases (OR: 1.86; 95% CI 1.09-3.09) in rats and steatosis (OR-1.9; 95% CI 1.03-3.49) or liver aminotransferase increases (OR-2.57; 95% CI 1.4-4.7) in dogs were significant predictors of human liver injury. The predictive value further improved when the liver injury categories were combined into less severe (steatosis, cholestasis, liver aminotransferase increase, hyperbilirubinemia, or jaundice) and more-severe (liver necrosis, acute liver failure, or hepatotoxicity) injuries. In particular, less-severe liver injuries in the following pairs of species predicted human hepatotoxicity {[dog and mouse] (OR: 2.70; 95% CI 1.25-5.84), [dog and rat] (OR-2.61; 95% CI 1.48-4.59), [monkey and mouse] (OR-4.22; 95% CI 1.33-13.32), and [monkey and rat] (OR-2.45; 95% CI 1.15-5.21)} were predictive of human hepatotoxicity. Meanwhile, severe liver injuries in both [dog and rat] (OR-1.9; 95% CI 1.04-3.49) were significant predictors of human liver toxicity. Therefore, we concluded that the occurrence of DILI in humans is highly likely if liver injuries are observed in one rodent and one nonrodent species and that liver aminotransferase increases in dogs and rats can predict DILI in humans. Together, these findings indicate that the liver safety signals observed in animal toxicity studies indicate potential DILI risk in humans and could therefore be used to prioritize small molecules with less potential to cause DILI in humans.

Funding: This research was supported by the National Research Foundation (NRF) Singapore, under its CRP funding programme (NRF-CRP 20-2017-0001 Award). JOPG was supported by a PhD Scholarship from the Singapore International Graduate Award (SINGA). CH received funding from the European Union’s 8th Framework Programme, Horizon 2020, under Grant Agreement No. 802719. External eye appearance across primate species is diverse in shape and colouration, yet we still lack an explanation for the drivers of such diversity. Here we quantify substantial interspecific variation in eye shape and colouration across 77 primate species representing all extant genera of anthropoid primates. We reassess a series of hypotheses aiming to explain ocular variation in horizontal elongation and in colouration across species. Heavier body weight and terrestrial locomotion are associated with elongated eye outlines. Species living closer to the equator present more pigmented conjunctivae, suggesting photoprotective functions. Irises become bluer in species living further away from the equator, adding to existing literature supporting a circadian clock function for bluer irises. These results shift the current focus from communicative, to ecological factors in driving variation in external eye appearance in anthropoid primates. They also highlight the possibility that similar ecological factors contributed to selection for blue eyes in ancestral human populations living in northern latitudes. Publisher PDF

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Significance. Primates from the Americas and Madagascar are predominantly arboreal but occasionally descend to the ground. This increased ground use was associated with multiple ecological drivers, including increased temperature and a decrease in canopy cover, as well as species-specific traits, including a dietary shift away from fruits and larger group size. As anthropogenic impacts to habitats and climate worsen, our results suggest that diurnal species already inhabiting hot, sparsely canopied sites, and exhibiting more generalized diets, are more likely to shift toward greater ground use., Among mammals, the order Primates is exceptional in having a high taxonomic richness in which the taxa are arboreal, semiterrestrial, or terrestrial. Although habitual terrestriality is pervasive among the apes and African and Asian monkeys (catarrhines), it is largely absent among monkeys of the Americas (platyrrhines), as well as galagos, lemurs, and lorises (strepsirrhines), which are mostly arboreal. Numerous ecological drivers and species-specific factors are suggested to set the conditions for an evolutionary shift from arboreality to terrestriality, and current environmental conditions may provide analogous scenarios to those transitional periods. Therefore, we investigated predominantly arboreal, diurnal primate genera from the Americas and Madagascar that lack fully terrestrial taxa, to determine whether ecological drivers (habitat canopy cover, predation risk, maximum temperature, precipitation, primate species richness, human population density, and distance to roads) or species-specific traits (body mass, group size, and degree of frugivory) associate with increased terrestriality. We collated 150,961 observation hours across 2,227 months from 47 species at 20 sites in Madagascar and 48 sites in the Americas. Multiple factors were associated with ground use in these otherwise arboreal species, including increased temperature, a decrease in canopy cover, a dietary shift away from frugivory, and larger group size. These factors mostly explain intraspecific differences in terrestriality. As humanity modifies habitats and causes climate change, our results suggest that species already inhabiting hot, sparsely canopied sites, and exhibiting more generalized diets, are more likely to shift toward greater ground use.

Previous studies showed that baby monkeys separated from their mothers develop strong and lasting attachments to inanimate surrogate mothers, but only if the surrogate has a soft texture; soft texture is more important for the infant’s attachment than is the provision of milk. Here I report that postpartum female monkeys also form strong and persistent attachments to inanimate surrogate infants, that the template for triggering maternal attachment is also tactile, and that even a brief period of attachment formation can dominate visual and auditory cues indicating a more appropriate target.

There are strong physiological and behavioral differences that allow animals to live in forests versus savannas. For example, terrestrial forest-dwelling mammals tend to be small compared to species living in savannas. Robust capuchin monkeys (genus Sapajus) are widespread in tropical South America, occurring in both forest and savanna environments, with forest species considered basal in an evolutionary context. Whether or not skull shape and size variations are associated with variation in resource use remains unknown, particularly for the two species living in savanna (Sapajus libidinosus and S. cay). Here we show that savanna species present convergent size and skull characteristics that may facilitate living in this new environment. Geometric morphometric methods were used to assess skull size and shape variation for 184 Sapajus specimens distributed across South America. We used phylogenetic generalized least squares to test size against environmental variables and multivariate morphological trajectories/partial least square analyses on the skull shape to detect shape differences in specimens between forest and savanna biomes. Our findings reveal Sapajus size reduction in the evolutionary transition from forest to savanna, a process related to increasing seasonality. Moreover, we found morphological parallelism in the skull (e.g., muzzle shortening) and (large) molars in the two savanna species, features that may facilitate the processing of harder food such as fallback resources. We associate these phenotypic differences to the evolutionary process of colonizing the savannas by primates (including early hominins), leading to morphological adaptations to tolerate stressful, seasonal environments, such as body size reduction and ingestion and mastication of tough foods.

Tiankeng acts as a refugium for biodiversity amid a changing global climate, and a previous study has shown that some ancient (

Traditional methods to access subcortical structures involve the use of anatomical atlases and high precision stereotaxic frames but suffer from significant variations in implantation accuracy. Here, we leveraged the use of the ROSA One(R) Robot Assistance Platform in non-human primates to study electrophysiological interactions of the corticospinal tract with spinal cord circuits. We were able to target and stimulate the corticospinal tract within the internal capsule with high accuracy and efficiency while recording spinal local field potentials and multi-unit spikes. Our method can be extended to any subcortical structure and allows implantation of multiple deep brain stimulation probes at the same time. Clinical Relevance- Our method will allow us to elucidate further roles of the corticospinal tract and its interactions with other processing centers in intact animals and in motor syndromes in the future.

Zoonotic malaria due to Plasmodium knowlesi infection in Southeast Asia is sometimes life-threatening. Post-mortem examination of human knowlesi malaria cases showed sequestration of P. knowlesi-infected red blood cells (iRBCs) in blood vessels, which has been proposed to be linked to disease severity. This sequestration is likely mediated by the cytoadhesion of parasite-iRBCs to vascular endothelial cells; however, the responsible parasite ligands remain undetermined. This study selected P. knowlesi lines with increased iRBC cytoadhesion activity by repeated panning against human umbilical vein endothelial cells (HUVECs). Transcriptome analysis revealed that the transcript level of one gene, encoding a Schizont Infected Cell Agglutination (SICA) protein, herein termed SICA-HUVEC, was more than 100-fold increased after the panning. Transcripts of other P. knowlesi proteins were also significantly increased, such as PIR proteins exported to the iRBC cytosol, suggesting their potential role in increasing cytoadhesion activity. Transgenic P. knowlesi parasites expressing Myc-fused SICA-HUVEC increased cytoadhesion activity following infection of monkey as well as human RBCs, confirming that SICA-HUVEC conveys activity to bind to HUVECs., Scientific Reports, 12 (1), art. no. 14942; 2022

The SARS-CoV-2 Omicron variant has very high levels of transmission, is resistant to neutralization by authorized therapeutic human monoclonal antibodies (mAb) and is less sensitive to vaccine-mediated immunity. To provide additional therapies against Omicron, we isolated a mAb named P2G3 from a previously infected vaccinated donor and showed that it has picomolar-range neutralizing activity against Omicron BA.1, BA.1.1, BA.2 and all other variants tested. We solved the structure of P2G3 Fab in complex with the Omicron spike using cryo-electron microscopy at 3.04 angstrom resolution to identify the P2G3 epitope as a Class 3 mAb that is different from mAb-binding spike epitopes reported previously. Using a SARS-CoV-2 Omicron monkey challenge model, we show that P2G3 alone, or in combination with P5C3 (a broadly active Class 1 mAb previously identified), confers complete prophylactic or therapeutic protection. Although we could select for SARS-CoV-2 mutants escaping neutralization by P2G3 or by P5C3 in vitro, they had low infectivity and 'escape' mutations are extremely rare in public sequence databases. We conclude that this combination of mAbs has potential as an anti-Omicron drug. A potent mAb shows promise in monkeys either alone or in a combination therapy for either prophylaxis or treatment of infection with SARS-CoV-2 Omicron BA.1, BA.1.1 and BA.2.

The study of perceptual decision making in monkeys has provided insights into the process by which sensory evidence is integrated towards a decision. When monkeys make decisions with the knowledge of the motor actions the decisions bear upon, the process of evidence integration is instantiated by neurons involved in the selection of said actions. It is less clear how monkeys make decisions when unaware of the actions required to communicate their choice—what we refer to as ‘abstract’ decisions. We investigated this by training monkeys to associate the direction of motion of a noisy random-dot display with the color of two targets. Crucially, the targets were displayed at unpredictable locations after the motion stimulus was extinguished. We found that monkeys postponed decision formation until the targets were revealed. Neurons in the parietal association area LIP represented the integration of evidence leading to a choice, but as the stimulus was no longer visible, the samples of evidence must have been retrieved from short-term memory. Our results imply that when decisions are temporally unyoked from the motor actions they bear upon, decision formation is protracted until they can be framed in terms of motor actions.

Point mutations in isocitrate dehydrogenase 1 (IDH1) result in conversion of α-ketoglutarate to the oncometabolite, d-2-hydroxyglutarate (2-HG). Ivosidenib is a once daily (QD), orally available, potent, mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor approved for the treatment of patients with relapsed or refractory acute myeloid leukemia (AML) and intensive chemotherapy-ineligible newly diagnosed AML, with a susceptible IDH1 mutation. We characterized the protein binding, metabolism, metabolites, cell permeability, and drug-drug interaction potential of ivosidenib in humans, monkeys, dogs, rats, and/or mice in in vitro experiments. In vivo pharmacokinetic (PK) profiling and assessment of drug distribution and excretion was undertaken in rats, dogs, and monkeys administered single-dose ivosidenib. The PK/pharmacodynamic (PD) relationship between ivosidenib and 2-HG was analyzed in an mIDH1 xenograft mouse model. Ivosidenib was well absorbed, showed low clearance, and moderate to long terminal half-life (5.3–18.5 hours) in rats, dogs, and monkeys. Brain to plasma exposure ratio was low (2.3%), plasma protein binding was high, and oxidative metabolism was the major elimination pathway. Ivosidenib had high cell permeability and was identified as a substrate for P-glycoprotein. There was moderate induction of cytochrome P450 (P450) enzymes CYP3A4 and CYP2B6 but minimal P450 inhibition or autoinduction. Tumor 2-HG reduction appeared to be dose- and drug-exposure–dependent. Ivosidenib showed a favorable PK profile in several animal species, along with a clear PK/PD relationship demonstrating 2-HG inhibition that translated well to patients with AML. SIGNIFICANCE STATEMENT Ivosidenib is a mutant IDH1 (mIDH1) inhibitor approved for the treatment of certain patients with mIDH1 acute myeloid leukemia. In Sprague-Dawley rats, beagle dogs, and cynomolgus monkeys, ivosidenib demonstrated a favorable pharmacokinetic profile, and in female BALB/c mice showed clear dose- and exposure-dependent inhibition of the oncometabolite, d-2-hydroxyglutarate, which is present at abnormal levels in mIDH1 tumors. These findings led to the further development of ivosidenib and are consistent with data from patients with mIDH1 cancers and healthy participants.

Advances in multiplexed imaging technologies have drastically improved our ability to characterize healthy and diseased tissues at the single-cell level. Co-detection by indexing (CODEX) relies on DNA-conjugated antibodies and the cyclic addition and removal of complementary fluorescently labeled DNA probes and has been used so far to simultaneously visualize up to 60 markers in situ. CODEX enables a deep view into the single-cell spatial relationships in tissues and is intended to spur discovery in developmental biology, disease and therapeutic design. Herein, we provide optimized protocols for conjugating purified antibodies to DNA oligonucleotides, validating the conjugation by CODEX staining and executing the CODEX multicycle imaging procedure for both formalin-fixed, paraffin-embedded (FFPE) and fresh-frozen tissues. In addition, we describe basic image processing and data analysis procedures. We apply this approach to an FFPE human tonsil multicycle experiment. The hands-on experimental time for antibody conjugation is ~4.5 h, validation of DNA-conjugated antibodies with CODEX staining takes ~6.5 h and preparation for a CODEX multicycle experiment takes ~8 h. The multicycle imaging and data analysis time depends on the tissue size, number of markers in the panel and computational complexity. This protocol describes co-detection by indexing, a highly multiplexed imaging technology that uses DNA-conjugated antibodies to image up to 60 markers in formalin-fixed, paraffin-embedded and fresh-frozen tissues.

Objectives Due to the remote forest area locations of sporadic cases and outbreaks of Kyasanur forest disease (KFD), rapid diagnosis poses a significant challenge. This study aimed to evaluate the diagnostic performance of Truenat KFD, a simple, rapid and user-friendly point-of-care test for detection of KFD and compare diagnostic accuracy with conventional real-time reverse transcription-polymerase chain reaction (RT-PCR) testing. Truenat KFD can be deployed in a field laboratory setting. Methods The study involved 145 clinical specimens, including human serum, monkey necropsy tissues and tick pool, to validate Truenat KFD (Molbio Diagnostics Pvt.Ltd.) for KFD diagnosis. Results We have optimized and validated the microchip-based Truenat KFD (Molbio Diagnostics Pvt.Ltd.) for KFD diagnosis. Point-of-care testing was highly sensitive and specific, with a detection limit of up to 10 copies of KFD viral RNA. Results were comparable with the gold-standard TaqMan and commercially available Altona RealStar AHFV / KFDV real-time RT-PCR assays. Screening results for human, monkey and tick specimens were 100% concordant across the assays. Conclusion Truenat KFD(Molbio Diagnostics Pvt.Ltd.) was found to be highly sensitive and specific with a significant limit of detection. This point-of-care test would be useful in rapid diagnosis of KFD in remote and/or field settings, quick patient management and control of virus spread.

Blindsight is the residual visuo-motor ability without subjective awareness observed after lesions of the primary visual cortex (V1). Various visual functions are retained, however, instrumental visual associative learning remains to be investigated. Here we examined the secondary reinforcing properties of visual cues presented to the hemianopic field of macaque monkeys with unilateral V1 lesions. Our aim was to test the potential role of visual pathways bypassing V1 in reinforcing visual instrumental learning. When learning the location of a hidden area in an oculomotor search task, conditioned visual cues presented to the lesion-affected hemifield operated as an effective secondary reinforcer. We noted that not only the hidden area location, but also the vector of the saccade entering the target area was reinforced. Importantly, when the visual reinforcement signal was presented in the lesion-affected field, the monkeys continued searching, as opposed to stopping when the cue was presented in the intact field. This suggests the monkeys were less confident that the target location had been discovered when the reinforcement cue was presented in the affected field. These results indicate that the visual signals mediated by the residual visual pathways after V1 lesions can access fundamental reinforcement mechanisms but with impaired visual, 盲視マカクサルは視覚意識が無くても自発的行動を学習できる. 京都大学プレスリリース. 2021-09-14., Using visual information to learn voluntary behavior while blind. 京都大学プレスリリース. 2021-09-14.