Miracle-dz/UniFAR-FTUs huggingface dataset:
Selective Modulation of the Pupil Light Reflex by Microstimulation of Prefrontal Cortex

The prefrontal cortex (PFC) is thought to flexibly regulate sensorimotor responses, perhaps through modulating activity in other circuits. However, the scope of that control remains unknown: it remains unclear whether the PFC can modulate basic reflexes. One canonical example of a central reflex is the pupil light reflex (PLR): the automatic constriction of the pupil in response to luminance increments. Unlike pupil size, which depends on the interaction of multiple physiological and neuromodulatory influences, the PLR reflects the action of a simple brainstem circuit. However, emerging behavioral evidence suggests that the PLR may be modulated by cognitive processes. Although the neural basis of these modulations remains unknown, one possible source is the PFC, particularly the frontal eye field (FEF), an area of the PFC implicated in the control of attention. We show that microstimulation of the rhesus macaque FEF alters the magnitude of the PLR in a spatially specific manner. FEF microstimulation enhanced the PLR to probes presented within the stimulated visual field, but suppressed the PLR to probes at nonoverlapping locations. The spatial specificity of this effect parallels the effect of FEF stimulation on attention and suggests that FEF is capable of modulating visuomotor transformations performed at a lower level than was previously known. These results provide evidence of the selective regulation of a basic brainstem reflex by the PFC. SIGNIFICANCE STATEMENT The pupil light reflex (PLR) is our brain's first and most fundamental mechanism for light adaptation. Although it is often described in textbooks as being an immutable reflex, converging evidence suggests that the magnitude of the PLR is modulated by cognitive factors. The neural bases of these modulations are unknown. Here, we report that microstimulation in the prefrontal cortex (PFC) modulates the gain of the PLR, changing how a simple reflex circuit responds to physically identical stimuli. These results suggest that control structures such as the PFC can add complexity and flexibility to even a basic brainstem circuit.
Sensitivity of Noisy Neurons to Coincident Inputs

How do neurons compute? Two main theories compete: neurons could temporally integrate noisy inputs (rate-based theories) or they could detect coincident input spikes (spike timing-based theories). Correlations at fine timescales have been observed in many areas of the nervous system, but they might have a minor impact. To address this issue, we used a probabilistic approach to quantify the impact of coincidences on neuronal response in the presence of fluctuating synaptic activity. We found that when excitation and inhibition are balanced, as in the sensory cortex in vivo, synchrony in a very small proportion of inputs results in dramatic increases in output firing rate. Our theory was experimentally validated with in vitro recordings of cortical neurons of mice. We conclude that not only are noisy neurons well equipped to detect coincidences, but they are so sensitive to fine correlations that a rate-based description of neural computation is unlikely to be accurate in general.
Alternative methods for estimating common descriptors for QSAR studies of dyes and fluorescent probes using molecular modeling software. 2. Correlations between log P and the hydrophilic/lipophilic index, and new methods for estimating degrees of amphiphilicity

Abstract The log P descriptor, despite its usefulness, can be difficult to use, especially for researchers lacking skills in physical chemistry. Moreover this classic measure has been determined in numerous ways, which can result in inconsistant estimates of log P values, especially for relatively complex molecules such as fluorescent probes. Novel measures of hydrophilicity/lipophilicity (the Hydrophilic/Lipophilic Index, HLI) and amphiphilicity (hydrophilic/lipophilic indices for the head group and tail, HLIT and HLIHG, respectively) therefore have been devised. We compare these descriptors with measures based on log P, the standard method for quantitative structure activity relationships (QSAR) studies. HLI can be determined using widely available molecular modeling software, coupled with simple arithmetic calculations. It is based on partial atomic charges and is intended to be a stand-alone measure of hydrophilicity/lipophilicity. Given the wide application of log P, however, we investigated the correlation between HLI and log P using a test set of 56 fluorescent probes of widely different physicochemical character. Overall correlation was poor; however, correlation of HLI and log P for probes of narrowly specified charge types, i.e., non-ionic compounds, anions, conjugated cations, or zwitterions, was excellent. Values for probes with additional nonconjugated quaternary cations, however, were less well correlated. The newly devised HLI can be divided into domain-specific descriptors, HLIT and HLIHG in amphiphilic probes. Determinations of amphiphilicity, made independently by the authors using their respective methods, showed excellent agreement. Quantifying amphiphilicity from partial log P values of the head group (head group hydrophilicity; HGH) and tail (amphiphilicity index; AI) has proved useful for undertanding fluorescent probe action. The same limitations of log P apply to HGH and AI, however. The novel descriptors, HLIT and HLIHG, offer analogous advantages to those seen with HLI over log P. The high correlation between log P and HLI, and the concordance between the two systems for assessing amphiphilicity, provide a powerful tool for QSAR studies. It is possible now to select a probe with missing fragments, and thus no log P, AI or HGH; and to estimate these important descriptors from parameters derived from HLI.
Effort-Based Reinforcement Processing and Functional Connectivity Underlying Amotivation in Medicated Patients with Depression and Schizophrenia

Amotivation is a common phenotype of major depressive disorder and schizophrenia, which are clinically distinct disorders. Effective treatment targets and strategies can be discovered by examining the dopaminergic reward network function underlying amotivation between these disorders. We conducted an fMRI study in healthy human participants and medicated patients with depression and schizophrenia using an effort-based reinforcement task. We examined regional activations related to reward type (positive and negative reinforcement), effort level, and their composite value, as well as resting-state functional connectivities within the meso–striatal–prefrontal pathway. We found that integrated reward and effort values of low effort-positive reinforcement and high effort-negative reinforcement were behaviorally anticipated and represented in the putamen and medial orbitofrontal cortex activities. Patients with schizophrenia and depression did not show anticipation-related and work-related reaction time reductions, respectively. Greater amotivation severity correlated with smaller work-related putamen activity changes according to reward type in schizophrenia and effort level in depression. Patients with schizophrenia showed feedback-related putamen hyperactivity of low effort compared with healthy controls and depressed patients. The strength of medial orbitofrontal-striatal functional connectivity predicted work-related reaction time reduction of high effort negative reinforcement in healthy controls and amotivation severity in both patients with schizophrenia and those with depression. Patients with depression showed deficient medial orbitofrontal-striatal functional connectivity compared with healthy controls and patients with schizophrenia. These results indicate that amotivation in depression and schizophrenia involves different pathophysiology in the prefrontal-striatal circuitry. SIGNIFICANCE STATEMENT Amotivation is present in both depression and schizophrenia. However, treatment involves the use of drugs that enhance serotonin activity in depression and inhibit serotonin and dopamine activity in schizophrenia. Understanding how motivation processed in the mesocorticolimbic and nigostriatal pathways is affected in depression and schizophrenia is important in discovering treatment targets and strategies for amotivation. To our knowledge, this is the first study to compare patients with depression and schizophrenia in a common functional construct. By using an effort-based reinforcement task and examining resting-state functional connectivity in the dopaminergic network, we propose that difference in striato–orbitofrontal dysfunction in effort-based reinforcement between depression and schizophrenia may be related to differences in the extent of functional dysconnectivity in the dopaminergic pathway.
Modeling Fall Propensity in Parkinson's Disease: Deficits in the Attentional Control of Complex Movements in Rats with Cortical-Cholinergic and Striatal–Dopaminergic Deafferentation

Cognitive symptoms, complex movement deficits, and increased propensity for falls are interrelated and levodopa-unresponsive symptoms in patients with Parkinson's disease (PD). We developed a test system for the assessment of fall propensity in rats and tested the hypothesis that interactions between loss of cortical cholinergic and striatal dopaminergic afferents increase fall propensity. Rats were trained to traverse stationary and rotating rods, placed horizontally or at inclines, and while exposed to distractors. Rats also performed an operant Sustained Attention Task (SAT). Partial cortical cholinergic and/or caudate dopaminergic deafferentation were produced by bilateral infusions of 192 IgG-saporin (SAP) into the basal forebrain and/or 6-hydroxydopamine (6-OHDA) into the caudate nucleus, respectively, modeling the lesions seen in early PD. Rats with dual cholinergic–dopaminergic lesions (DL) fell more frequently than SAP or 6-OHDA rats. Falls in DL rats were associated with incomplete rebalancing after slips and low traversal speed. Ladder rung walking and pasta handling performance did not indicate sensorimotor deficits. SAT performance was impaired in DL and SAP rats; however, SAT performance and falls were correlated only in DL rats. Furthermore, in DL rats, but not in rats with only dopaminergic lesions, the placement and size of dopaminergic lesion correlated significantly with fall rates. The results support the hypothesis that after dual cholinergic–dopaminergic lesions, attentional resources can no longer be recruited to compensate for diminished striatal control of complex movement, thereby “unmasking” impaired striatal control of complex movements and yielding falls.
Nerve-Specific Input Modulation to Spinal Neurons during a Motor Task in the Monkey

If not properly regulated, the large amount of reafferent sensory signals generated by our own movement could destabilize the CNS. We investigated how input from peripheral nerves to spinal cord is modulated during behavior. We chronically stimulated the deep radial nerve (DR; proprioceptive, wrist extensors), the median nerve (M; mixed, wrist flexors and palmar skin) and the superficial radial nerve (SR; cutaneous, hand dorsum) while four monkeys performed a delayed wrist flexion–extension task. Spinal neurons putatively receiving direct sensory input were defined based on their evoked response latency following nerve stimulation. We compared the influence of behavior on the evoked response (responsiveness to a specific peripheral input) and firing rate of 128 neuron-nerve pairs based on their source nerve. Firing rate increased during movement regardless of source nerve, whereas evoked response modulation was strikingly nerve-dependent. In SR (n = 47) and M (n = 27) neurons (cutaneous or mixed input), the evoked response was suppressed during wrist flexion and extension. In contrast, in DR neurons (n = 54, pure proprioceptive input), the evoked response was facilitated exclusively during movements corresponding to the contraction of DR spindle-bearing muscles (i.e., wrist extension). Furthermore, modulations of firing rate and evoked response were uncorrelated in SR and M neurons, whereas they tended to be positively comodulated in DR neurons. Our results suggest that proprioceptive and cutaneous inputs to the spinal cord are modulated differently during voluntary movements, suggesting a refined gating mechanism of sensory signals according to behavior. SIGNIFICANCE STATEMENT Voluntary movements produce copious sensory signals, which may overwhelm the CNS if not properly regulated. This regulation is called “gating” and occurs at several levels of the CNS. To evaluate the specificity of sensory gating, we investigated how different sources of somatosensory inputs to the spinal cord were modulated while monkeys performed wrist movements. We recorded activity from spinal neurons that putatively received direct connections from peripheral nerves while stimulating their source nerves, and measured the evoked responses. Whereas cutaneous inputs were suppressed regardless of the type of movement, muscular inputs were specifically facilitated during relevant movements. We conclude that, even at the spinal level, sensory gating is a refined and input-specific process.
Pathologic diagnosis, immunohistochemistry, multigene assays and breast cancer treatment: progress toward “precision” cancer therapy

Abstract Clinical decisions regarding the suitability of adjuvant systemic therapy for individual patients with breast cancer depends on comprehensive assessment of the underlying biology of each patient's tumor. The previous clinical-pathologic paradigm for treatment, which had been used for decades, now has been augmented by significant advances in molecular analysis of breast tumor tissue samples. Molecular testing has the potential to understand better both tumor biology and clinical behavior, which enables more appropriate therapy choices to be made. We review the rapid evolution in profiling breast cancer tissues, and discuss the current evidence for clinical use of this information and how the emerging molecular paradigm can be integrated into the clinical-pathologic context as we progress toward “precision” therapy for patients with breast cancer and other solid tumors.
Efficacy of granisetron on prevention of shivering, nausea and vomiting during cesarean delivery under spinal anesthesia: A randomized double-blinded clinical trial

Background: Hypothermia, shivering, nausea and vomiting are frequent perioperative events in patients undergoing cesarean delivery under spinal anesthesia. Apart from physical warming for shivering many drugs have also been used for prevention of these events. Objectives: We conducted a randomized double-blinded clinical trial to evaluate the effect of a single drug, granisetron on prevention of shivering, nausea and vomiting during cesarean section performed under spinal anesthesia. Materials and Methods: One hundred American Society of Anesthesiologists I-II patients undergoing elective cesarean section under spinal anesthesia were randomly allocated into two groups, control saline (n = 50) or granisetron groups (n = 50). Warmed (37°C) lactated ringer′s solution was infused over 15 min before anesthesia. Spinal block was performed with the same technique in both groups. In the saline group 3 ml of 0.9% saline and in granisetron 3 mg (3 ml) granisetron was injected intravenously after intrathecal injection at identical times. Shivering, maximum and minimum level of spinal block, core body temperature, nausea and vomiting and need to treat shivering with intravenous pethidine and neonates APGAR scores were all recorded. Results: Demographic data, median of sensory block level and mean core body temperature were not statistically different in groups. Eight percent (4/50) of patients in granisetron and 54% (27/50) of patients in the saline group had shivering during the perioperative period that was treated with pethidine (P = 0.001). Ten patients (20%) in granisetron and 30 patients (60%) in saline group had nausea (P = 0.002). No patients in both groups needed rescue medication. 1 st and 5 th minutes APGAR scores of neonates were not statistically different in the groups. Ten patients (20%) in granisetron and 30 patients (60%) in saline group had nausea (P = 0.002). Conclusions: Granisetron is an effective way to prevent shivering, nausea and vomiting during cesarean delivery under spinal anesthesia with no effect on APGAR score.
1α,25-Dihydroxyvitamin D3 Reduces Cerebral Amyloid-β Accumulation and Improves Cognition in Mouse Models of Alzheimer's Disease

We demonstrate a role of the vitamin D receptor (VDR) in reducing cerebral soluble and insoluble amyloid-β (Aβ) peptides. Short-term treatment of two human amyloid precursor protein-expressing models, Tg2576 and TgCRND8 mice, with 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], the endogenous active ligand of VDR, resulted in higher brain P-glycoprotein (P-gp) and lower soluble Aβ levels, effects negated with coadministration of elacridar, a P-gp inhibitor. Long-term treatment of TgCRND8 mice with 1,25(OH)2D3 during the period of plaque formation reduced soluble and insoluble plaque-associated Aβ, particularly in the hippocampus in which the VDR is abundant and P-gp induction is greatest after 1,25(OH)2D3 treatment, and this led to improved conditioned fear memory. In mice fed a vitamin D-deficient diet, lower cerebral P-gp expression was observed, but levels were restored on replenishment with VDR ligands. The composite data suggest that the VDR is an important therapeutic target in the prevention and treatment of Alzheimer's disease.
Phase–Amplitude Coupling and Interlaminar Synchrony Are Correlated in Human Neocortex

One of the striking manifestations of neuronal population activity is that of rhythmic oscillations in the local field potential. It is thought that such oscillatory patterns, including phase-amplitude coupling (PAC) and inter-regional synchrony, may represent forms of local and long-range cortical computations, respectively. Although it has been speculated that these two oscillatory patterns are functionally related, and bind disparate cortical assemblies to one another at different timescales, there is little direct evidence to support this hypothesis. We have demonstrated recently that theta to high-gamma PAC and interlaminar phase coherence at theta frequencies can be generated in human cortical slices maintained in vitro. Here we show that not only do such oscillatory patterns exist within human temporal neocortex, but that the strength of one is related to the strength of the other. We demonstrate that at theta frequencies, metrics of temporal synchrony between superficial and deep cortical laminae (phase-dependent power correlations, and phase coherence) are correlated to the magnitude of intralaminar PAC between theta and high-gamma. Specifically, our results suggest that interlaminar communication within human temporal neocortex and local laminar excitability are linked to one another through a dependence mediated by theta oscillations. More generally, our results provide evidence for the hypothesis that theta oscillations may coordinate inter-areal excitability in the human brain.
Increased Diagnosis of Primary Aldosteronism, Including Surgically Correctable Forms, in Centers from Five Continents

Primary aldosteronism (PA) is a common form of endocrine hypertension previously believed to account for less than 1% of hypertensive patients. Hypokalemia was considered a prerequisite for pursuing diagnostic tests for PA. Recent studies applying the plasma aldosterone/plasma renin activity ratio (ARR) as a screening test have reported a higher prevalence. This study is a retrospective evaluation of the diagnosis of PA from clinical centers in five continents before and after the widespread use of the ARR as a screening test. The application of this strategy to a greater number of hypertensives led to a 5- to 15-fold increase in the identification of patients affected by PA. Only a small proportion of patients (between 9 and 37%) were hypokalemic. The annual detection rate of aldosterone-producing adenoma (APA) increased in all centers (by 1.3-6.3 times) after the wide application of ARR. Aldosterone-producing adenomas constituted a much higher proportion of patients with PA in the four centers that employed adrenal venous sampling (28-50%) than in the center that did not (9%). In conclusion, the wide use of the ARR as a screening test in hypertensive patients led to a marked increase in the detection rate of PA.
CONSENSUS: Guidelines for Diagnosis and Therapy of MEN Type 1 and Type 2

This is a consensus statement from an international group, mostly of clinical endocrinologists. MEN1 and MEN2 are hereditary cancer syndromes. The commonest tumors secrete PTH or gastrin in MEN1, and calcitonin or catecholamines in MEN2. Management strategies improved after the discoveries of their genes. MEN1 has no clear syndromic variants. Tumor monitoring in MEN1 carriers includes biochemical tests yearly and imaging tests less often. Neck surgery includes subtotal or total parathyroidectomy, parathyroid cryopreservation, and thymectomy. Proton pump inhibitors or somatostatin analogs are the main management for oversecretion of entero-pancreatic hormones, except insulin. The roles for surgery of most entero-pancreatic tumors present several controversies: exclusion of most operations on gastrinomas and indications for surgery on other tumors. Each MEN1 family probably has an inactivating MEN1 germline mutation. Testing for a germline MEN1 mutation gives useful information, but rarely mandates an intervention. The most distinctive MEN2 variants are MEN2A, MEN2B, and familial medullary thyroid cancer (MTC). They vary in aggressiveness of MTC and spectrum of disturbed organs. Mortality in MEN2 is greater from MTC than from pheochromocytoma. Thyroidectomy, during childhood if possible, is the goal in all MEN2 carriers to prevent or cure MTC. Each MEN2 index case probably has an activating germline RET mutation. RET testing has replaced calcitonin testing to diagnose the MEN2 carrier state. The specific RET codon mutation correlates with the MEN2 syndromic variant, the age of onset of MTC, and the aggressiveness of MTC; consequently, that mutation should guide major management decisions, such as whether and when to perform thyroidectomy.