Grid-like entorhinal representation of an abstract value space during prospective decision making.

How valuable a choice option is often changes over time, making the prediction of value changes an important challenge for decision making. Prior studies identified a cognitive map in the hippocampal-entorhinal system that encodes relationships between states and enables prediction of future states, but does not inherently convey value during prospective decision making. In this fMRI study, participants predicted changing values of choice options in a sequence, forming a trajectory through an abstract two-dimensional value space. During this task, the entorhinal cortex exhibited a grid-like representation with an orientation aligned to the axis through the value space most informative for choices. A network of brain regions, including ventromedial prefrontal cortex, tracked the prospective value difference between options. These findings suggest that the entorhinal grid system supports the prediction of future values by representing a cognitive map, which might be used to generate lower-dimensional value signals to guide prospective decision making.

Mnemonic construction and representation of temporal structure in the hippocampal formation.

The hippocampal-entorhinal region supports memory for episodic details, such as temporal relations of sequential events, and mnemonic constructions combining experiences for inferential reasoning. However, it is unclear whether hippocampal event memories reflect temporal relations derived from mnemonic constructions, event order, or elapsing time, and whether these sequence representations generalize temporal relations across similar sequences. Here, participants mnemonically constructed times of events from multiple sequences using infrequent cues and their experience of passing time. After learning, event representations in the anterior hippocampus reflected temporal relations based on constructed times. Temporal relations were generalized across sequences, revealing distinct representational formats for events from the same or different sequences. Structural knowledge about time patterns, abstracted from different sequences, biased the construction of specific event times. These findings demonstrate that mnemonic construction and the generalization of relational knowledge combine in the hippocampus, consistent with the simulation of scenarios from episodic details and structural knowledge.

The dynamics of CO production from the photolysis of acetone across the whole S1 ← S0 absorption spectrum: Roaming and triple fragmentation pathways.

The unimolecular photodissociation dynamics of acetone spanning the entire S1 ← S0 absorption spectrum have been reinvestigated, with a focus on mechanisms that produce CO. At excitation wavelengths of λ > 305.8 nm, all photoproducts are formed on the S0 state after internal conversion. A roaming mechanism forming C2H6 + CO is active in the window λ = 311.2-305.8 nm. From λ = 305.8 to 262 nm, little or no CO is produced with the photochemistry dominated by the Norrish-type I C-C bond cleavage on the lowest excited triplet state, T1. At higher energy (λ < 262 nm), an increasing fraction of CH3CO radicals from the primary reaction have sufficient internal energy to spontaneously decompose to CH3 + CO. A new model is presented to account for the kinetic energy distribution of the secondary CH3 radical, allowing us to determine the height of the energetic barrier to CH3CO decomposition as 68 ± 4 kJ mol-1, which lies midway between previous measurements. The fraction of CO from triple fragmentation rises smoothly from 260 to 248 nm. We see no evidence of the return of roaming, or any other S0 reaction, in this higher energy region of the first electronic absorption band.

An immersive first-person navigation task for abstract knowledge acquisition.

Advances in virtual reality (VR) technology have greatly benefited spatial navigation research. By presenting space in a controlled manner, changing aspects of the environment one at a time or manipulating the gain from different sensory inputs, the mechanisms underlying spatial behaviour can be investigated. In parallel, a growing body of evidence suggests that the processes involved in spatial navigation extend to non-spatial domains. Here, we leverage VR technology advances to test whether participants can navigate abstract knowledge. We designed a two-dimensional quantity space-presented using a head-mounted display-to test if participants can navigate abstract knowledge using a first-person perspective navigation paradigm. To investigate the effect of physical movement, we divided participants into two groups: one walking and rotating on a motion platform, the other group using a gamepad to move through the abstract space. We found that both groups learned to navigate using a first-person perspective and formed accurate representations of the abstract space. Interestingly, navigation in the quantity space resembled behavioural patterns observed in navigation studies using environments with natural visuospatial cues. Notably, both groups demonstrated similar patterns of learning. Taken together, these results imply that both self-movement and remote exploration can be used to learn the relational mapping between abstract stimuli.

Piecing Together Cognitive Maps One Dimension at a Time.

In this issue of Neuron, Park et al. (2020) show that the brain forms unified cognitive maps of relational knowledge. The hippocampal-entorhinal region and medial prefrontal cortices spontaneously combine multiple, distinct rank orders to two-dimensional cognitive maps enabling flexible inference.

Sequence Memory in the Hippocampal-Entorhinal Region.

Episodic memories are constructed from sequences of events. When recalling such a memory, we not only recall individual events, but we also retrieve information about how the sequence of events unfolded. Here, we focus on the role of the hippocampal-entorhinal region in processing and remembering sequences of events, which are thought to be stored in relational networks. We summarize evidence that temporal relations are a central organizational principle for memories in the hippocampus. Importantly, we incorporate novel insights from recent studies about the role of the adjacent entorhinal cortex in sequence memory. In rodents, the lateral entorhinal subregion carries temporal information during ongoing behavior. The human homologue is recruited during memory recall where its representations reflect the temporal relationships between events encountered in a sequence. We further introduce the idea that the hippocampal-entorhinal region might enable temporal scaling of sequence representations. Flexible changes of sequence progression speed could underlie the traversal of episodic memories and mental simulations at different paces. In conclusion, we describe how the entorhinal cortex and hippocampus contribute to remembering event sequences-a core component of episodic memory.

Deforming the metric of cognitive maps distorts memory.

Environmental boundaries anchor cognitive maps that support memory. However, trapezoidal boundary geometry distorts the regular firing patterns of entorhinal grid cells, proposedly providing a metric for cognitive maps. Here we test the impact of trapezoidal boundary geometry on human spatial memory using immersive virtual reality. Consistent with reduced regularity of grid patterns in rodents and a grid-cell model based on the eigenvectors of the successor representation, human positional memory was degraded in a trapezoid environment compared with a square environment-an effect that was particularly pronounced in the narrow part of the trapezoid. Congruent with changes in the spatial frequency of eigenvector grid patterns, distance estimates between remembered positions were persistently biased, revealing distorted memory maps that explained behaviour better than the objective maps. Our findings demonstrate that environmental geometry affects human spatial memory in a similar manner to rodent grid-cell activity and, therefore, strengthen the putative link between grid cells and behaviour along with their cognitive functions beyond navigation.

Navigating cognition: Spatial codes for human thinking.

The hippocampal formation has long been suggested to underlie both memory formation and spatial navigation. We discuss how neural mechanisms identified in spatial navigation research operate across information domains to support a wide spectrum of cognitive functions. In our framework, place and grid cell population codes provide a representational format to map variable dimensions of cognitive spaces. This highly dynamic mapping system enables rapid reorganization of codes through remapping between orthogonal representations across behavioral contexts, yielding a multitude of stable cognitive spaces at different resolutions and hierarchical levels. Action sequences result in trajectories through cognitive space, which can be simulated via sequential coding in the hippocampus. In this way, the spatial representational format of the hippocampal formation has the capacity to support flexible cognition and behavior.

Hexadirectional coding of visual space in human entorhinal cortex.

Entorhinal grid cells map the local environment, but their involvement beyond spatial navigation remains elusive. We examined human functional MRI responses during a highly controlled visual tracking task and show that entorhinal cortex exhibited a sixfold rotationally symmetric signal encoding gaze direction. Our results provide evidence for a grid-like entorhinal code for visual space and suggest a more general role of the entorhinal grid system in coding information along continuous dimensions.

Role of dentinal carious lesions in the pathogenesis of oral candidiasis in HIV infection.

The authors describe a clinicopathologic study that evaluated whether dentinal carious lesions are colonized by candidal organisms--and if so, whether there is a relationship between dentinal carious lesion colonization and clinical oral candidiasis, or OC, in HIV infection. Using light microscopy, the authors examined 30 extracted teeth with dentinal carious lesions from people in each of two groups: 30 consecutively treated HIV-positive patients and 30 consecutively treated HIV-negative patients. OC was diagnosed only in HIV-positive patients (40 percent). The dentinal carious lesion pattern in both groups was similar in occlusal, root and proximal caries. Candidal colonization of carious dentinal tubules was more frequent in HIV-positive subjects than it was in HIV-negative subjects. This research shows that it may be important to restore dentinal caries in HIV-infected patients to remove a protected niche for candidal organisms.

Experimental local therapy of human melanoma with lytic magainin peptides.

Magainin peptides and model amphipathic peptides exhibit antibiotic activity and are also cytolytic for transformed human cells. Here we demonstrate in vitro that MSI-511 (an all-D amino-acid model magainin peptide) and MSI-130 (a margainin analogue) were more lytic for 17 human melanomas than for normal melanocytes. Melanomas established s.c. in athymic nude mice and then injected once with the peptide MSI-511 completely disappeared in 6 out of 9 animals, whereas a control peptide had no effect. Murine skin at the tumor injection site was initially affected, but healed within 2 weeks with minimal scarring. Similarly, accelerated healing was seen in human skin grafted to SCID mice and injected with MSI-511. Our results indicate that lytic magainin peptides can be used for local tumor therapy with minimal long-term damage to normal tissues.

Anticancer efficacy of Magainin2 and analogue peptides.

Linear helical channel-forming peptides structurally similar to the Xenopus-derived antibiotic, Magainin2-amide, were synthesized. Because activity resides in the physicochemical properties of the peptides, an all-D-amino acid as well as an all-L-amino acid sequence were tested for anticancer activity. In vitro activity against carcinoma cells and in vivo efficacy against four murine ascites tumors were determined. The novel peptides proved to have enhanced potency in vitro and in vivo as compared to the parent compound. The 50% inhibitory concentrations against A549 cells for the all-D, the all-L, and Magainin2 were 6, 10, and 110 micrograms/ml, respectively. All three peptides had activity against P388 leukemia, S180 ascites, and a spontaneous ovarian tumor when injected i.p. Increase in life span of over 100% was produced for the analogues in the latter two models. The maximally effective concentrations for the analogues were 20 to 25 mg/kg while Magainin2 required 50-60 mg/kg for in vivo efficacy. The all-D-amino acid peptide, MSI-238, proved as effective as doxorubicin at a more advanced stage of the ovarian tumor and this activity may be attributed to its resistance to proteolytic degradation. Therefore, this class of amphiphilic alpha-helical cationic peptides has potential in the peritoneal treatment of ovarian cancer.

Effects of magainins on ameba and cyst stages of Acanthamoeba polyphaga.

Amebic keratitis produced by Acanthamoeba spp. is an increasingly important ocular infection in extended-use contact lens wearers. Problems associated with the infection are compounded by the lack of effective and well-tolerated chemotherapeutic agents. The magainins, a group of naturally occurring and synthetic membrane-active peptide compounds, have been shown to be active in vitro against a clinical isolate of Acanthamoeba polyphaga. Two magainins tested extensively had minimal inhibitory and minimal amebicidal values of 20 and 25 micrograms/ml for magainin MSI-103 and 25 and 40 micrograms/ml for magainin MSI-94, respectively. Both amebastatic and amebicidal activities are enhanced by combining the magainins with silver nitrate (200 micrograms/ml) and/or other marginally effective antimicrobial agents. These combinations have activity against both trophic and cystic stages in the Acanthamoeba life cycle and have promise as antimicrobial agents in the treatment of amebic keratitis.

Academic-industrial cooperative graduate program in clinical pharmacology.

Because a new level of sophistication among clinical investigators is necessary for the testing of new agents in human subjects, a close integration of basic science, clinical medicine, and pharmaceutical medicine is required. Experts from the Departments of Pharmacology and Medicine at Temple University School of Medicine and Smith Kline and French Laboratories have combined to form a joint training program in clinical pharmacology. This structured graduate program for physicians couples didactic courses with a defined program of independent research, leading to a Master of Science degree in pharmacology. The development of new technologies and the transfer of them from the "bench to the bedside" demands that the clinician have special competence in clinical pharmacology. This unique joint academic-industrial program sets the goals ensuring that this objective is met.

Role of nocturnal acid suppression on the rate of duodenal ulcer healing: clinical dose-range trials with oxmetidine.

These studies represent the first attempt to compare, concurrently, several once or twice daily dosage regimens of an H2-receptor antagonist for ulcer-healing efficacy in the same national population within the same time period, using the same criteria for patient selection, duration of treatment, and end-point. Investigators from 66 centers entered 745 patients, 17-71 years of age, with endoscopically documented uncomplicated duodenal or pyloric channel ulcers, greater than or equal to 0.5 cm in the longest axis. Patients were randomly assigned to six regimens (five oxmetidine, one placebo) and were dosed once (bedtime) or twice (morning and bedtime) daily. Antacid use was restricted. Endoscopy was performed at wk 0 and 2, and at wk 4 in patients not healed at wk 2. Statistical analysis at wk 4 revealed the following healing rates with oxmetidine: 400 mg bid-73.3%; 600 hs-71%; 400 hs-68.6 and 61.6%; 200 mg bid-61.5%; and 200 hs-59.9%. All of the regimens except 200 hs were statistically significantly superior to placebo. The efficacy of the nocturnal 600-mg dose was comparable to that of 400 mg bid and the efficacy of the nocturnal 400-mg dose was comparable to that of 200 mg bid.

Cefonicid: an overview of clinical studies in the United States.

Cefonicid, an investigational cephalosporin with a half-life just under 5 hr, was studied by more than 100 investigators in the United States. Of 1,060 cefonicid-treated patients for whom the clinical efficacy of the compound could be evaluated, 91.7% were cured or improved; 95% received a single daily dose. Rates of bacteriologic cure were equal for infections due to gram-positive cocci (89.9%) and gram-negative bacilli (93.2%). Overall rates of favorable response to cefonicid therapy, by disease, were 88.4%, urinary tract infections; 91.4%, lower respiratory tract infections; 95.1%, skin and skin-structure infections; and 91.3%, bone and joint infections. Prophylaxis with cefonicid administered 1 hr before surgery was as effective as that with control antibiotic in reducing the incidence of perioperative infection. For 795 patients who received cefonicid or control drug who underwent gynecologic surgery, prosthetic arthroplasty, cesarean section, or intraabdominal surgery, the reduction in incidence of perioperative infections were equivalent. Resistance to cefonicid developed infrequently (1.3%). Overall safety of cefonicid was comparable with that of control agents except for the frequency of occurrence of diarrhea, which was lower among patients who received cefonicid than among those who received a control drug.

Treatment of urinary tract infections in hospitalized patients: a double-blind comparison of cefonicid and cefamandole.

In a randomized double-blind comparison of cefonicid (dose, 1.0 g every 24 hr) and cefmandole (dose, 1.0 g iv every 6 hr), 147 hospitalized patients (105 men, 42 women) with urinary tract infections (UTIs) were assessed. Ninety-one of the men had complicated UTIs. For the 62 cefonicid-treated men, 61 of 62 etiologic pathogens were eliminated. For 17 patients, reinfection with the pretherapy pathogen occurred in the five- to nine-day posttherapy follow-up. Overall cure rate for cefonicid in the treatment of complicated UTIs was 71%. For the 29 cefamandole-treated men, 28 of 29 etiologic pathogens were eliminated. Reinfection occurred in nine patients. Overall cure rate for cefamandole in the treatment of complicated UTIs was 66%. All 14 men (nine receiving cefonicid; five, cefamandole) with uncomplicated infection were cured. For 25 cefonicid-treated women, cure rate was 84%; one of the failures was due to persistence of the pathogen; three were reinfections during follow-up. For 17 cefamandole-treated women, the cure rate was 82%; two of the failures were due to persistence of the pathogen, and one was a reinfection. Similar, minimal adverse reactions occurred with both drugs. Cefonicid is as effective as cefamandole in curing complicated UTIs in men and uncomplicated infections in both sexes. Cefonicid, however, offers the advantage of once-daily therapy.

Penetration of cefonicid into human breast milk and various body fluids and tissues.

A new cephalosporin, cefonicid (1 g), was given intramuscularly to 49 patients 1 hr before they were to undergo surgery and to 10 healthy lactating women. The concentration of cefonicid was assayed by disk agar diffusion with the use of Bacillus subtilis as the test organism. Concentrations of cefonicid in tissue and fluid specimens were obtained. The data demonstrate that within 1 hr of intramuscular injection of cefonicid, effective concentrations of cefonicid in serum and tissue for common microbial pathogens were achieved. This finding suggests that cefonicid would be useful for perioperative prophylaxis in surgical patients. Although the concentration of cefonicid in breast milk was low at 1 hr after injection, more information is needed regarding the subsequent secretion of cefonicid before a conclusive statement can be made concerning the danger of sensitization in infants of nursing mothers.